ISSN 1866-8836
Клеточная терапия и трансплантация
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Introduction

Advances of gene and cell therapy of last two decades have resulted into FDA approval of tisagenlecleucel (Kymria) in 2017 as the first product for CAR-T therapy in pediatric B-cell acute lymphoblastic leukemia, finally showing impressive clinical results. In particular, the CGT approach has produced long-time cancer remissions in cases refractory to any available treatments, becoming curative for some patients [1, 2]. This single-injection treatment for previously incurable patients has been marketed by Novartis, the leading pharma company, thus finally opening the road to therapies, based on gene or cell engineering approaches, which were "on hold" by regulators and industry for a long time. Since then we have 6 approved items for CAR-T therapies [2], with CD-19 and BCMA as molecular targets for chimeric antigen receptors, thus allowing treatment in patients with refractory B-cell acute lymphoblastic leukemia (B-ALL), large B-cell lymphoma (LBCL), relapsed and/or refractory (R/R) follicular lymphoma (FL), mantle cell lymphoma (MCL) with CD-19 expression, and in multiple myeloma (MM) for BCMA-targeted cells.

The regulatory improvements in the gene and cell therapy and industry guidance by leading regulators have catalyzed other key approvals in the field: we have seen first accepted gene therapies of rare genetic diseases, including Duchenne Muscular Dystrophy (DMD), Spinal Muscular Atrophy (SMA), Hereditary Transthyretin-related Amyloidosis, Hereditary homozygote blindness, beta-thalassemia, as well as recently approved therapies against sickle cell disease, including the CRISPR/Cas9-based Casgevy product [4]. These approvals are quite important, covering almost all modalities of gene and cell therapies for distinct life-threatening and rare disorders. However, there were two drug approvals in the field of RNA therapeutic products for treatment of common human diseases (except of multiple RNA-based COVID vaccines) thus suggesting that we are approaching a tipping point in wide range of common disorders. E.g., a possible shift from daily drug administration to once-a-6 month injection was shown by Leqvio (inclisiran), an RNA antisense therapeutic used in hyperlipidemia, that demonstrating feasibility and cost-effectiveness of such drugs at the larger scale [5].

This is an opportunity, or emerging trend that may dramatically change general healthcare and, in particular, pharma business models. The future looks bright according to the Q3 2023 ASGCT report [3] reviewing present state of gene and cell therapies. Currently, there are 3,866 therapies under development. Of them, 53% concern gene therapies (share of CAR-T cell products); 25% are RNA-based preparations, and 22% represent therapies with non-gene-modified cells.

Samsonov-fig01.jpg

Figure 1. Drug pricing in New Gene and Cell therapy (2012-2023). Abscissa, years of approval. Ordinate, prices for newly approved gene and cell therapy brands (thousands of US dollars).

Every point refers to price of a single GCT injection/infusion for single-shot agents. In case of several injections/infusions per treatment course (i.e., in some chronic conditions), the one-year price estimates are shown. This graph is based on the price data analysis from open sources [7, 8]. The trend line for prices of CGT therapies is based on a standard linear approximation model.

Table 1. Annual sales of selected gene and cell therapies (GCTs) over 2019 to 2022

Samsonov-ftab01.jpg

*Data of annual sales volumes were prepared by authors based on public financial reports of Novartis and Gilead companies.

Current challenges

Hence, the trend for a personalized, highly effective, single-injection CGT is very attractive. This treatment mode is available for as long as 5 years. Do we still have revolutionary changes with respect to the numbers of patients treated, and, especially, acceptance of high price for such therapies by the payers?

The more therapies are coming to market, the higher they are priced, as shown by simple linear analysis (Fig. 1). The 2023 data on drug approvals again hit the roof with 3.2 mln USD per injection of Elevidys (delandistrogene moxeparvovec) for DMD therapy thus continuing the price of 3,5 mln USD (2022) per a single injection achieved by Hemgenix (etranacogene dezaparvovec) for Hemophilia B treatment. Even despite administration of these drugs in orphan diseases, the overall pricing trend raises the issue of treatment accessibility. Indeed, CAR-T therapy, with longest track record on the market and three Big Pharma players (Gilead, Novartis and BMS) could reach therapy for only about 33,000 patients globally from 2017 [6]. Moreover, when looking on sales growth for CAR-T cell products (Table 1), one may see that Kymria sales declined in 2022, indicating that overall CAR-T market possibly is close to reaching its limit. The emerging competition may sufficiently affect sales, even though a small proportion of eligible patients will receive this therapy.

It should be noted that the annual sales for CD19 targeted CAR-T Kymriah declined in 2022, sales of most commercially successful CD19-targeted CAR-T cells (Yescarta) are lower than those for Zolgensma, the first tool for therapy of SMA, a rare genetic disease: it also seems to reach its sales limit in 2022 (Table 1).

Another problem that affects accessibility for GCT treatments is clearly seen by examples of approved CAR-T cell treatments: the general production strategy which employs big production sites is very expensive to build, thus intending to meet the demands from several countries [9].

The manufacturing of CAR-T cells starts with leukapheresis in a certified medical center followed by delivery of frozen patient’s cells to the production site, where an appropriate time slot for the production should be allocated first. Thereafter, the cells are quality-checked, isolated, activated, transfected with CAR vector, expanded, assigned to particular cell number, quality-controlled (QC) in order to ensure efficacy, potency and safety of the cell product. The cell preparations are cryoconserved and delivered back to the medical center where CAR-T cells are finally infused to patient. This process, as assigned for the two leading market products, Axicabtagene ciloleucel and Tisagenlecleucel is reported to have target median turnaround times of 17 and 22 days respectively [10, 11]. However, this timing may be increased up to 2 months [11]. Approval of medical center prior to start providing a CAR-T cell therapy is critical, since the cytokine release syndrome is the most common adverse effect which is a well manageable but life-threatening event. Leading regulators (FDA and EMA) require Risk Evaluation Mitigation Strategy (REMS) or similar procedures to be implemented in medical centers providing CAR-T therapy, being a substantial obligation from medical center [11] thus limiting the number of centers authorized for CAR-T (or other advanced CGT) therapies. However, the overall production process starting with slot allocation may be much longer.

All these factors form a set of barriers on patient journey to receive CAR-T cell (or, in general, any expensive CGT) therapy. Analysis of CAR-T therapy for diffuse large B-cell lymphoma (DLBCL) was performed in Italy where it is covered by state insurance program [12]. The authors revealed that only 17% of patients received this treatment in 2020 among ca. 600 patients eligible for CAR-T cell therapy by EMA label indication. 83% of the patients were lost in this funnel, due to multi-level medical, financial, logistic obstacles, and other steps that is required by CAR-T therapy [10, 11].

Otherwise, we must accept usage of personalized CGT therapy according to the "one-fits-all" paradigm. Research on real-life clinical outcomes of commercial CAR-T therapies Axi-cel or Tisa-cel [26] showed that 7% of patients after apheresis did not receive this treatment due to different factors, like as in other clinical trials in the field [12]. This pharma production paradigm remains quite effective to provide non-personalized drugs. However, direct application of this paradigm seems to be not ideal and self-limiting for GCT therapy which presumes a personalized treatment in most cases. Main reason is expenses. If we look at expenses that are associated with bringing new CGT therapy to market, even taking into account all the supportive measures from leading regulators, for example, FDA-hosted programs as "Accelerated approval", "Breakthrough therapy" and "Orphan" designations, it doesn’t dramatically affect the development costs [13, 14]. Appropriate expenses to bring new CGT therapy into the market are about 1,5-2 bln. USD per a single approved drug therapy, and the overall trend is still rising despite >50% of newly approved drugs are covered by such support measures [15].

Samsonov-fig02.jpg

Figure 2. Vicious circle of personalization in drugs development and production within current centralized production paradigm. The picture shows some interdependencies in development of new drug by pharma companies, and reflects an approach to avoid both patient-based and commercial limitations.

This leads to vicious circle of personalization, which is briefly depicted in Fig. 2. It reflects the current approaches to CGT. A conventional strategy of drug development and usage by pharma companies, if applied to personalized drug therapies, will automatically lead to be extremely high expenditures and very limited patient access. Indeed, drug personalization leads to decrease of patient population that can be treated by particular drug, and distinct batch of produced drug in case of personal medication. This trend, due to unchanged or even growing expenses, when trying to reach the market for a single drug, with high expenses of personalized production by a pharma company, leads to increase of calculated price per patient. Such situation becomes more obvious in case of one-shot curable treatments like some CAR-T therapies. As a result, the expense-driven setting of too high prices for treatment may be justified only for very limited number of clinical cases, which again leading to decrease in potential number of patients to be cured, thus closing this vicious circle.

Currently, there are three ways to resolve this self-limiting circle: (1) development of non- or less personalized CGT, e.g., Leqvio (inclusiran), an RNA-based drug; (2) justify high price using pharmacoeconomic approaches, as it is done by all marketed drugs (with few exceptions, i.e., of Glybera, Zynteglo and Skysona, that was withdrawn in EU by commercial reasons [16]); (3) usage of special regulatory pathways like "hospital exemption", "compassionate use" etc, thus allowing development of drugs by academic labs, in order to produce the medication and provide its clinical approval at dramatically reduced costs.

On the contrary, we may refer to interesting results of modeling analysis being most impactful for both society health benefit and pharma companies. I.e., only 10% increase in patient eligibility and access to CGT therapies in rare blood diseases may lead to an estimated increase of savings for payers over $3 billion by 2029 [17]. For the pharma companies, potential patient number and time to market are crucial for commercial success, aiming for successful delivery of novel CGT therapies to the market and return of investments [18].

Point-of-care options

Point-of-care CGT production seems to be a powerful way to expand the eligible patient cohort, to decrease price of treatment and improve patient access, and to speed up development of the product [19]. Indeed, small-scale GCT production, e.g., CAR-T cells for the personalized cell-based therapy at a single academia center might be adequate for needs of its patients. Due to origin of such product, it is manufactured personally for each patient, either being produced at a big factory or at a small cell lab at a clinical facility, when keeping proper quality control measures. Moreover, in case of such point-of-care (POC) manufacturing, there are no issues with logistics, any delays and treatment failures due to changes in clinical condition of the patients. Hence, it may dramatically reduce the vein-to-vein time down to 8 days [19], and the cell product would act more effectively since its viability is better preserved. However, quality of cell products and regulatory approvals cause biggest concerns with POC manufacturing of CGT preparations.

Quality assurance is required to provide a clinical grade product, including good manufacturing practices (GMP-grade processes) with validated raw materials (i.e., cell culture media, cytokines and other reagents, as well as leukapheresis products), and certified clean rooms. These requirements can be met at a large number of academia centers due to several factors: 1. Research spillover due to infrastructure, skilled personnel and knowledge acquired during previous grant-funded studies in CGT which be used in further production at GMP-grade clean rooms and equipment assigned for preclinical and early clinical trials [20, 21]; 2. Wider approval and utilization of closed automated cell-production systems like Miltenyi Biotec CliniMACS Prodigy® and Lonza Cocoon® [17, 19], as well as new products from China, like Sino-Biocan Wukong [22], that provides modular automated cell production, that are much less sensitive to clean room conditions and operator experience, being already supplied with GMP-grade consumables, thus providing high-success rates of CAR-T cells production. In Russia, there are also promising developments in this filed [23].

Ability for many academia centers to provide high-quality POC production is successfully used to prepare efficient cell products for clinical trials. A number of such academia CGT production centers, at least in Europe, were used to get clinical evidence for adoption of currently marketed CAR-T therapies [9]. A number of clinical trials demonstrate comparable or even better clinical results compared to previously approved CAR-T cell therapies (Table 2).

Table 2. Clinical performance of commercial and academia-developed CAR-T products

Samsonov-tab02.jpg

Abbreviations: ORR, overall response rate; CRR, complete response/remission rate; OS, overall survival; PFS, progression-free survival; AE, adverse events; CRS, cytokine release syndrome; ICAN, immune effector cell-associated neurotoxicity syndrome; LBCL, relapsed or refractory (r/r) large B cell lymphoma; r/r ALL, relapsed/refractory acute lymphoblastic leukemia; DLBCL, diffuse large B-cell lymphoma; ABCL, Relapse of aggressive B cell lymphoma; NHL, B cell non-Hodgkin lymphoma; RWE, Real world evidence.

Clinical experience

Significant amount of real-world evidence (RWE) with commercial CAR-T products (see Table 2) demonstrates a very similar performance of such products in real-live setting and 2nd phase clinical trials. These data were mostly used as the basis for clinical approval. We can see it for tisagenlecleucel (tisa-cel, Kymriah, Novartis) and axicabtagene ciloleucel (axi-cel, Yescarta, Gilead). Comparison of these products, despite significant superiority over conventional therapy, shows some differences in response rates, overall survival, and intensity of typical CAR-T adverse events (e.g., CRS and ICANS). This body of evidence was also supported by direct RWE comparisons in DLBCL patients: ORR of axi-cel of 80% vs 66% with tisa-cel, and CRR of 60% vs 42% for patients treated with axi-cel vs tisa-cel. One-year PFS was 46.6% and 33.2% for axi-cel and for tisa-cel, respectively. One-year OS was also improved after axi-cel infusion compared to tisa-cel. Interestingly, the real-world evidence studies for tisa-cel [25, 26] demonstrate that about 10 to 30% of patients received an out-of-specification product, with reduced cell viability (>20% loss), still showing a comparable clinical benefit.

The results shown in Table 2, demonstrate some differences between the two most mature commercial CAR-T products. Moreover, this evidence promotes current advances in methodology of CAR-T clinical trials or, more generally, CGT trials, by enabling high predictability on safety and efficacy at rather small sizes of patients’ groups. Of note, the data from clinical trials were rather limited but they permitted approval for the both therapies, i.e., Kymriah was approved on the basis of ELIANA clinical trial with 75 patients, and Yescarta has been proven with 108 patients from ZUMA-1 trial and 68 patients of ZUMA-2 trail only [2, 27, 28]. These group sizes would be sufficient to obtain approvals of the POC therapy for academia clinical centers, if such mode of action is acceptable to the regulator.

This is important due to growing number of successful POC clinical trials, which seem to show comparable results and may declare even better results than those observed with commercial products. These results may be promising with superior clinical outcomes over centralized commercial CAR-T production model.

Some examples of POC CAR-T cell therapy are worthy of mention. A work by Maschan et al. [29] has demonstrated an opportunity of decentralized POC CAR-T production with single protocol at two academia clinical sites, i.e., in Moscow (Russia) and Cleveland (USA), based on automated closed-cycle production using CliniMACS Prodigy®) systems with CAR19-T cells manufactured at stable quality under current good manufacturing practices (cGMP). The results of two independent Phase 1 clinical trials in relapsed/refractory pediatric B-cell acute lymphocytic leukemia (ALL; n=31), or adult B-cell lymphoma (NHL; n=23) were as follows: complete remission (CR) rates were 89% (ALL), and 73% (NHL). After a median follow-up of 17 months, one-year survival for ALL complete responders was 79.2% (95%CI 64.5-97.2%). For NHL complete responders, one-year survival was 92.9%. Importantly, the manufacturing success rate exceeded 96% with automated closed-cycle production system used at two different sites in distant countries, at the median apheresis-to-infusion time of 13 days, thus sufficiently outperforming commercial CAR-T cell products.

Sheba Medical Center developed POC CAR-T product to treat aggressive B cell lymphoma (ABCL), with CAR construct designed to lower toxicity [30]. Clinical trial with 73 patients has shown a shortened CAR-T cell production time from apheresis product (a mean of 10 days only), that allowing to avoid bridging chemotherapy. Overall survival rate was 62.5%, with complete response rate (CRR) of 37.5%, median progression-free survival (PFS) of 3.7 months, and median OS of 12.1 months. OS rate at 12 months was 52.1% (CI: 40.8%-66.5%) and PFS, 40% (CI: 30%-53.7%). Grade 3-4 cytokine release syndrome (CRS) was observed in 9.5% of the patients, and ICANS grade 3-4 was documented in 21.9%. In general, these data demonstrate similar efficacy and safety to commercial products. Along with rather short vein-to-vein time, production efficiency was 98.6 %, and all the screened patients were eventually treated with CAR-T cells, that suggesting its superiority over commercial model with around 10% cell losses after apheresis. Based on results of clinical trials, POC CAR-T therapy in this center was approved by Israeli Ministry of Health, and currently priced 30-80% less than commercial CAR-Ts with >200 patients infused [31, 32]. Interesting application for in-house made POC CAR-T cells has been suggested at Sheba Center. The patients underwent salvage therapy and were scheduled for tisa-cel-treatment, being, however, supplied with out-of-specs (OOS) cell products [33]. This study showed that 24% of OOS are observed in real-life setting, and POC products may benefit in the patients who cannot wait for another lot of CAR-T cells. POC approach also allows fast clinical development for other indications, i.e., new molecular targets. This opportunity is supported by promising results on the CAR-T cells targeted against BMCA in relapsed/refractory multiple myeloma [34], developed in Sheba Center, using similar genetic CAR construct backbone and the same production facilities. The pilot study showed an estimated 6-mo OS of 89% (95% CI: 75-100), PFS of 48% (95% CI: 33-72), with no bridging therapy required in most cases. Additional advantage of POC production is ability to fast extension of clinical indications for therapy, as proven by the same clinical team who demonstrated good results of anti-CD19 CAR-T therapy to treat relapsed/refractory follicular lymphoma [35]. At enrollment, the disease stage was III-IV in 85% of the patients (n=26), with 77% having high-risk FLIPI score, and 77% were in progressive disease. ORR at 1 mo was 88%, with one-year OS of 100%, and PFS rate of 63%.

Another important success story of POC CAR-T therapy is ARI-0001, launched at the Hospital Clinic de Barcelona, employing an automated closed CliniMACS Prodigy cell processing system (Miltenyi Biotec). In February 2021, this product received authorization by European regulations as an ATMP (advanced therapy medicinal product) from the Spanish Agency of Medicines and Medical Devices under the ’hospital exemption’ (HE), according to EC Regulation No 1394/2007 (article 28.7), for the treatment of patients >25 years old with relapsed/refractory acute lymphoblastic leukemia (ALL) [2]. Interestingly, this is the first approved CAR-T product, developed in EU. The following results were obtained at Phase 1 clinical trial of ARI-0001 [36], on which the HE approval was based: of 58 patients included, 47 received the therapy, which resulted in 1-year PFS of 47% (95% IC 27%-67%), and OS of 68.6% (95% IC 49.2%-88%). In ALL patients, the grade ≥3 cytokine release syndrome (CRS) was observed in 13.2%; grade ≥3 neurotoxicity was registered in 2.6% of the cases. The last proportion is significantly lower versus commercial products. Cell production time varied between 7 to 10 days. However, the average vein-to-vein time was 42 days, due to complications and requirements of 2nd apheresis procedure in 14% of patients. Of note, this shows flexibility of POC approach, that allows to adapt for lower number of produced CAR-T cells by adding 2nd production cycle for the same patient, which is difficult or not feasible in the centralized production paradigm.

Similar to the mentioned approach used in Sheba clinic, POC production of CAR-T cells allowed fast launch of BMCA-targeted CAR-T therapy of multiple myeloma using the same backbone CAR construct and ARI0002h, a humanized BMCA antibody [37] for phase 1 clinical trial. 35 patients from 5 centers were enrolled in this trial, of which 86% received ARI0002h. With median follow-up of 12.1 months (IQR 9,1-13,5), OR was 100% during the first 100 days from infusion; CR rate of 50%, and partial remission (PR), in 50% of cases. Grade 1-2 CRS was registered in 80% of patients, and, notably, no neurotoxic events were observed. Of note, price for ARI-0001 was around 30% of commercial CAR-T products available in Spain [38].

An interesting collaboration experience extended into volunteering organizations has been reported by Canadian consortia [39], consolidating several clinical and research centers (Vancouver, Victoria and Ottawa) that were able to manufacture CD-19 CAR-T cells by CliniMACS Prodigy system (Miltenyi Biotec). The challenge was successfully resolved by manufacturing CAR-T product without cryopreservation, with 15 days vein-to-vein time and at the distances of up to 4300 km between the production site and clinical centers, by non-commercial academic sites and volunteer couriers. Thirty-five patients with CD19-positive hematologic malignancies were enrolled in CLIC-01 clinical study of non-cryopreserved CLIC-1901 CAR-T cell product, and 30 patients received the cell product infusion. Even despite some limitations in clinical interim results, one should note ORR of 77% at day 28, with median OS of 11 months, median PFS of 6 months. The manufacturing failure rate was only 6% (2 of 35). Grade >3 adverse events, mainly CRS, were registered in 7% (2 pts), and ICANS was observed in 3% of cases (1 pts). This result demonstrate that CAR-T technology in automated closed-cycle systems may provide robust results and fast vein-to-vein time even at long transportation routes. Hence the consortia of academia institutions can also resolve the issues related to CAR-T cell production, even upon delivery of fresh cells without cryopreservation.

These examples demonstrate both the ability for academia- based POC CAR-T cells to produce clinically beneficial results being comparable with commercial products, however, at significantly lower price and increased operational flexibility.

The mentioned factors are increasingly important, since new applications for CAR-T therapy in autoimmune diseases showed very promising results, mostly in academia setting using POC CAR-T cell production. Specific feature of systemic autoimmune diseases is production of autoantibodies and autoreactive T lymphocytes, which damage organs and tissues and cause various symptoms which may limit everyday normal life, and are able to cause life-threatening conditions. These disorders are caused by cytotoxic autoantibodies, and autoreactive cytotoxic T lymphocytes (CTLs) that recognize target cells and damage it. In this respect, very promising results were shown in limited clinical trials on systemic lupus erythematosus (SLE), idiopathic inflammatory myositis (IIM), systemic sclerosis (SSc) rheumatoid arthritis (RA), multiple sclerosis (MS), myasthenia gravis (MG) and other autoimmune disorders [40]. One should note that such diseases affect millions people worldwide, and effective therapeutic options are limited by their choice and efficacy. E.g., systemic lupus erythematosus (SLE) is a life-threatening autoimmune disease characterized by adaptive immune system activation, formation of double-stranded DNA (dsDNA) autoantibodies and organ inflammation, which affects more than 3.4 million people worldwide. Quite promising results were obtained by European research team, when treating SLE patients with CD-19 targeted CAR-T cells [41, 42]. Five patients with SLE, refractory to several immunosuppressive treatments enrolled in a compassionate-use CAR-T program, have shown a deep depletion of B cells, improvement of clinical symptoms, including decrease in anti-dsDNA antibodies. Remission developed within 3 month, and drug-free remission was maintained >8 months after CAR T cell treatment, being not affected by reappearance of B cells. The treatment was accompanied by low-grade CRS.

Another CAR-T cell-based treatment in SLE was successfully applied in Phase 1 clinical trial in China [43], where the researchers aimed to overcome possible drawbacks of single CD19-directed CAR-T cells, e.g., inability to clear CD19-negative, long-lived plasma cells, which also produce numerous antibodies. According to published results of clinical trial, twelve refractory SLE patients were treated with autologous anti-CD19 and anti-BCMA CAR-T cells. After lymphodepleting chemotherapy, the patients received a single infusion of CD19 CAR-T cells and BCMA CAR-T cells. Median follow-up time was 118.5 (45-524) days. All patients developed grade 1 CRS, and no ICANS. The SLEDAI-2K score decreased in all patients, from a mean of 18.3 to 1.5 points. All patients could successfully discontinue all SLE-related medications, and remained in drug-free remission by the date of report. Now there are >14 clinical trials of CAR-T therapies only in SLE patients [44]. However, there are more examples of different autoimmune diseases, that may be brought into remission by POC CD-19 CAR-T treatment.

MB-CART19.1, a product developed by Miltenyi Biotec, being not yet approved, apart from being used in numerous oncology-related clinical trials, was also successfully used in 15 patients with severe autoimmune diseases (8, SLE; 3, IIM, and 4 with SSc), with a single infusion of anti-CD19 CAR-T cells based on compassionate use approach [45]. Median disease duration before CAR-T therapy was 3 years, and all patients failed to respond at previous treatments. As a result of CAR-T therapy, CD19+ cells were eliminated in all patients, however, re-occurred later. Nonetheless, all SLE patients reached complete remission, all IIM patients showed normalization of CK levels; SSC patients demonstrated significant disease improvement, and importantly, all patients stopped immunosuppressive drugs. Safety of CAR-T cell therapy was very good, CRS of Grade 0-2 was observed in all patients, one patient experienced grade 1 ICANS.

The same approach was used, again as a POC protocol with CD19 CAR-T cells, with ClinMaxProdigy automated system from Miltenyi Biotec, in order to successfully treat patient with refractory antisynthetase syndrome, a rare immune disease from group of Idiopathic inflammatory myopathies [46]. In this single patient, a complete and long-lasting resolution of symptoms was observed, i.e., improvements in sit-to-stand test (from 0 to 7 after 6 months) and in maximal walking distance (10 m before therapy to >5km after 6 month).

A recent comprehensive review in Nature has summarized fast development of CAR-T therapies in autoimmune disease, showing very a promising approach, specifically feasible in academia setting. When immunologists meet the needs of oncologists and prepare CAR-T treatment for their patients with common cellular target (B-cells), this collaboration leads to very fast and "mind-blowing" clinical results with already proven safety and potential clinical efficiency [47].

Regulatory agencies and POC manufacturing

Recently, FDA had issued recommendations for distributed manufacturing and Point-Of-Care Manufacturing [48], describing approaches to regulatory approval of such approaches, however not yet being a guidance for industry. Hospital exemption rules are working in EU, with several products approved under it, including CAR-T cells. In Russia, new amendment to regulation on biomedical cell products had been enacted recently, and a complete set of regulations for POC should appear in 2024 [49]. Similarly, Switzerland has created a distributed framework for CAR-T cell production. UK is in the process of establishing legislation for localized cell manufacturing. In China, CAR-T development is booming on basis of ultra-localized clinical centers, thus allowing to support several small start-ups developing CAR-T therapies [2, 9].

China [50] has issued a set of regulations to boost cell and gene therapy, most importantly dual-track approval mechanism for somatic cell therapies, implying that hospitals can legally use somatic-cell therapies through approval by local governments regions, that can be used after a strict inspection, in addition to somatic-cell therapies marketed as a drug from the NMPA. Given that China had set up large number of pilot zones some of which have taken the development of cellular and gene therapies as a high priority, like Hebei, Hainan, Chongqing, and local governments have built industrial parks specialized for cellular therapies including the Zhang-jiang Cell Industrial Park in Shanghai, the China Cell Valley in Nanjing. Several documents of Chinese regulators, like Management of Clinical Research and Transformation Application for Somatic Cell Therapy policy proposed that the somatic cell-based therapies with proven safety and efficacy could be used clinically in selected qualified hospitals under strict supervision. This document declares that the researchers and the project host at these institutions are required to obtain a license from the Chinese regulator, and the somatic-cell therapy Expert Committee will be responsible for evaluation of the licensing process. In this case hospitals even can obtain market authorization for somatic-cell-therapy products, and use the data obtained from clinical research as evidence to support the applications if GCP and GMP practices were followed.

Conclusion

The point-of-care CGT production may be a powerful tool of treating the incurable diseases, providing effective and safe treatment, ensuring broader access and reducing financial burden. Since personalization may interfere with effective commercial models for delivery of such drugs to the market, it opens the non-competitive door for academic institutions to bring such products to the patients. Regulatory pathways for their approval are developing in US, Europe, China, and Russia. POC production of CGT, and, specifically, CAR-T products, has big future not only in cancers, but in other areas, with most promising advances can be seen in treatment of autoimmune diseases. These advancements, if successful, will help crossing the death valley [51] for new CGTs to reach patients all over the world.

Conflict of interests

None declared.

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Introduction

Advances of gene and cell therapy of last two decades have resulted into FDA approval of tisagenlecleucel (Kymria) in 2017 as the first product for CAR-T therapy in pediatric B-cell acute lymphoblastic leukemia, finally showing impressive clinical results. In particular, the CGT approach has produced long-time cancer remissions in cases refractory to any available treatments, becoming curative for some patients [1, 2]. This single-injection treatment for previously incurable patients has been marketed by Novartis, the leading pharma company, thus finally opening the road to therapies, based on gene or cell engineering approaches, which were "on hold" by regulators and industry for a long time. Since then we have 6 approved items for CAR-T therapies [2], with CD-19 and BCMA as molecular targets for chimeric antigen receptors, thus allowing treatment in patients with refractory B-cell acute lymphoblastic leukemia (B-ALL), large B-cell lymphoma (LBCL), relapsed and/or refractory (R/R) follicular lymphoma (FL), mantle cell lymphoma (MCL) with CD-19 expression, and in multiple myeloma (MM) for BCMA-targeted cells.

The regulatory improvements in the gene and cell therapy and industry guidance by leading regulators have catalyzed other key approvals in the field: we have seen first accepted gene therapies of rare genetic diseases, including Duchenne Muscular Dystrophy (DMD), Spinal Muscular Atrophy (SMA), Hereditary Transthyretin-related Amyloidosis, Hereditary homozygote blindness, beta-thalassemia, as well as recently approved therapies against sickle cell disease, including the CRISPR/Cas9-based Casgevy product [4]. These approvals are quite important, covering almost all modalities of gene and cell therapies for distinct life-threatening and rare disorders. However, there were two drug approvals in the field of RNA therapeutic products for treatment of common human diseases (except of multiple RNA-based COVID vaccines) thus suggesting that we are approaching a tipping point in wide range of common disorders. E.g., a possible shift from daily drug administration to once-a-6 month injection was shown by Leqvio (inclisiran), an RNA antisense therapeutic used in hyperlipidemia, that demonstrating feasibility and cost-effectiveness of such drugs at the larger scale [5].

This is an opportunity, or emerging trend that may dramatically change general healthcare and, in particular, pharma business models. The future looks bright according to the Q3 2023 ASGCT report [3] reviewing present state of gene and cell therapies. Currently, there are 3,866 therapies under development. Of them, 53% concern gene therapies (share of CAR-T cell products); 25% are RNA-based preparations, and 22% represent therapies with non-gene-modified cells.

Samsonov-fig01.jpg

Figure 1. Drug pricing in New Gene and Cell therapy (2012-2023). Abscissa, years of approval. Ordinate, prices for newly approved gene and cell therapy brands (thousands of US dollars).

Every point refers to price of a single GCT injection/infusion for single-shot agents. In case of several injections/infusions per treatment course (i.e., in some chronic conditions), the one-year price estimates are shown. This graph is based on the price data analysis from open sources [7, 8]. The trend line for prices of CGT therapies is based on a standard linear approximation model.

Table 1. Annual sales of selected gene and cell therapies (GCTs) over 2019 to 2022

Samsonov-ftab01.jpg

*Data of annual sales volumes were prepared by authors based on public financial reports of Novartis and Gilead companies.

Current challenges

Hence, the trend for a personalized, highly effective, single-injection CGT is very attractive. This treatment mode is available for as long as 5 years. Do we still have revolutionary changes with respect to the numbers of patients treated, and, especially, acceptance of high price for such therapies by the payers?

The more therapies are coming to market, the higher they are priced, as shown by simple linear analysis (Fig. 1). The 2023 data on drug approvals again hit the roof with 3.2 mln USD per injection of Elevidys (delandistrogene moxeparvovec) for DMD therapy thus continuing the price of 3,5 mln USD (2022) per a single injection achieved by Hemgenix (etranacogene dezaparvovec) for Hemophilia B treatment. Even despite administration of these drugs in orphan diseases, the overall pricing trend raises the issue of treatment accessibility. Indeed, CAR-T therapy, with longest track record on the market and three Big Pharma players (Gilead, Novartis and BMS) could reach therapy for only about 33,000 patients globally from 2017 [6]. Moreover, when looking on sales growth for CAR-T cell products (Table 1), one may see that Kymria sales declined in 2022, indicating that overall CAR-T market possibly is close to reaching its limit. The emerging competition may sufficiently affect sales, even though a small proportion of eligible patients will receive this therapy.

It should be noted that the annual sales for CD19 targeted CAR-T Kymriah declined in 2022, sales of most commercially successful CD19-targeted CAR-T cells (Yescarta) are lower than those for Zolgensma, the first tool for therapy of SMA, a rare genetic disease: it also seems to reach its sales limit in 2022 (Table 1).

Another problem that affects accessibility for GCT treatments is clearly seen by examples of approved CAR-T cell treatments: the general production strategy which employs big production sites is very expensive to build, thus intending to meet the demands from several countries [9].

The manufacturing of CAR-T cells starts with leukapheresis in a certified medical center followed by delivery of frozen patient’s cells to the production site, where an appropriate time slot for the production should be allocated first. Thereafter, the cells are quality-checked, isolated, activated, transfected with CAR vector, expanded, assigned to particular cell number, quality-controlled (QC) in order to ensure efficacy, potency and safety of the cell product. The cell preparations are cryoconserved and delivered back to the medical center where CAR-T cells are finally infused to patient. This process, as assigned for the two leading market products, Axicabtagene ciloleucel and Tisagenlecleucel is reported to have target median turnaround times of 17 and 22 days respectively [10, 11]. However, this timing may be increased up to 2 months [11]. Approval of medical center prior to start providing a CAR-T cell therapy is critical, since the cytokine release syndrome is the most common adverse effect which is a well manageable but life-threatening event. Leading regulators (FDA and EMA) require Risk Evaluation Mitigation Strategy (REMS) or similar procedures to be implemented in medical centers providing CAR-T therapy, being a substantial obligation from medical center [11] thus limiting the number of centers authorized for CAR-T (or other advanced CGT) therapies. However, the overall production process starting with slot allocation may be much longer.

All these factors form a set of barriers on patient journey to receive CAR-T cell (or, in general, any expensive CGT) therapy. Analysis of CAR-T therapy for diffuse large B-cell lymphoma (DLBCL) was performed in Italy where it is covered by state insurance program [12]. The authors revealed that only 17% of patients received this treatment in 2020 among ca. 600 patients eligible for CAR-T cell therapy by EMA label indication. 83% of the patients were lost in this funnel, due to multi-level medical, financial, logistic obstacles, and other steps that is required by CAR-T therapy [10, 11].

Otherwise, we must accept usage of personalized CGT therapy according to the "one-fits-all" paradigm. Research on real-life clinical outcomes of commercial CAR-T therapies Axi-cel or Tisa-cel [26] showed that 7% of patients after apheresis did not receive this treatment due to different factors, like as in other clinical trials in the field [12]. This pharma production paradigm remains quite effective to provide non-personalized drugs. However, direct application of this paradigm seems to be not ideal and self-limiting for GCT therapy which presumes a personalized treatment in most cases. Main reason is expenses. If we look at expenses that are associated with bringing new CGT therapy to market, even taking into account all the supportive measures from leading regulators, for example, FDA-hosted programs as "Accelerated approval", "Breakthrough therapy" and "Orphan" designations, it doesn’t dramatically affect the development costs [13, 14]. Appropriate expenses to bring new CGT therapy into the market are about 1,5-2 bln. USD per a single approved drug therapy, and the overall trend is still rising despite >50% of newly approved drugs are covered by such support measures [15].

Samsonov-fig02.jpg

Figure 2. Vicious circle of personalization in drugs development and production within current centralized production paradigm. The picture shows some interdependencies in development of new drug by pharma companies, and reflects an approach to avoid both patient-based and commercial limitations.

This leads to vicious circle of personalization, which is briefly depicted in Fig. 2. It reflects the current approaches to CGT. A conventional strategy of drug development and usage by pharma companies, if applied to personalized drug therapies, will automatically lead to be extremely high expenditures and very limited patient access. Indeed, drug personalization leads to decrease of patient population that can be treated by particular drug, and distinct batch of produced drug in case of personal medication. This trend, due to unchanged or even growing expenses, when trying to reach the market for a single drug, with high expenses of personalized production by a pharma company, leads to increase of calculated price per patient. Such situation becomes more obvious in case of one-shot curable treatments like some CAR-T therapies. As a result, the expense-driven setting of too high prices for treatment may be justified only for very limited number of clinical cases, which again leading to decrease in potential number of patients to be cured, thus closing this vicious circle.

Currently, there are three ways to resolve this self-limiting circle: (1) development of non- or less personalized CGT, e.g., Leqvio (inclusiran), an RNA-based drug; (2) justify high price using pharmacoeconomic approaches, as it is done by all marketed drugs (with few exceptions, i.e., of Glybera, Zynteglo and Skysona, that was withdrawn in EU by commercial reasons [16]); (3) usage of special regulatory pathways like "hospital exemption", "compassionate use" etc, thus allowing development of drugs by academic labs, in order to produce the medication and provide its clinical approval at dramatically reduced costs.

On the contrary, we may refer to interesting results of modeling analysis being most impactful for both society health benefit and pharma companies. I.e., only 10% increase in patient eligibility and access to CGT therapies in rare blood diseases may lead to an estimated increase of savings for payers over $3 billion by 2029 [17]. For the pharma companies, potential patient number and time to market are crucial for commercial success, aiming for successful delivery of novel CGT therapies to the market and return of investments [18].

Point-of-care options

Point-of-care CGT production seems to be a powerful way to expand the eligible patient cohort, to decrease price of treatment and improve patient access, and to speed up development of the product [19]. Indeed, small-scale GCT production, e.g., CAR-T cells for the personalized cell-based therapy at a single academia center might be adequate for needs of its patients. Due to origin of such product, it is manufactured personally for each patient, either being produced at a big factory or at a small cell lab at a clinical facility, when keeping proper quality control measures. Moreover, in case of such point-of-care (POC) manufacturing, there are no issues with logistics, any delays and treatment failures due to changes in clinical condition of the patients. Hence, it may dramatically reduce the vein-to-vein time down to 8 days [19], and the cell product would act more effectively since its viability is better preserved. However, quality of cell products and regulatory approvals cause biggest concerns with POC manufacturing of CGT preparations.

Quality assurance is required to provide a clinical grade product, including good manufacturing practices (GMP-grade processes) with validated raw materials (i.e., cell culture media, cytokines and other reagents, as well as leukapheresis products), and certified clean rooms. These requirements can be met at a large number of academia centers due to several factors: 1. Research spillover due to infrastructure, skilled personnel and knowledge acquired during previous grant-funded studies in CGT which be used in further production at GMP-grade clean rooms and equipment assigned for preclinical and early clinical trials [20, 21]; 2. Wider approval and utilization of closed automated cell-production systems like Miltenyi Biotec CliniMACS Prodigy® and Lonza Cocoon® [17, 19], as well as new products from China, like Sino-Biocan Wukong [22], that provides modular automated cell production, that are much less sensitive to clean room conditions and operator experience, being already supplied with GMP-grade consumables, thus providing high-success rates of CAR-T cells production. In Russia, there are also promising developments in this filed [23].

Ability for many academia centers to provide high-quality POC production is successfully used to prepare efficient cell products for clinical trials. A number of such academia CGT production centers, at least in Europe, were used to get clinical evidence for adoption of currently marketed CAR-T therapies [9]. A number of clinical trials demonstrate comparable or even better clinical results compared to previously approved CAR-T cell therapies (Table 2).

Table 2. Clinical performance of commercial and academia-developed CAR-T products

Samsonov-tab02.jpg

Abbreviations: ORR, overall response rate; CRR, complete response/remission rate; OS, overall survival; PFS, progression-free survival; AE, adverse events; CRS, cytokine release syndrome; ICAN, immune effector cell-associated neurotoxicity syndrome; LBCL, relapsed or refractory (r/r) large B cell lymphoma; r/r ALL, relapsed/refractory acute lymphoblastic leukemia; DLBCL, diffuse large B-cell lymphoma; ABCL, Relapse of aggressive B cell lymphoma; NHL, B cell non-Hodgkin lymphoma; RWE, Real world evidence.

Clinical experience

Significant amount of real-world evidence (RWE) with commercial CAR-T products (see Table 2) demonstrates a very similar performance of such products in real-live setting and 2nd phase clinical trials. These data were mostly used as the basis for clinical approval. We can see it for tisagenlecleucel (tisa-cel, Kymriah, Novartis) and axicabtagene ciloleucel (axi-cel, Yescarta, Gilead). Comparison of these products, despite significant superiority over conventional therapy, shows some differences in response rates, overall survival, and intensity of typical CAR-T adverse events (e.g., CRS and ICANS). This body of evidence was also supported by direct RWE comparisons in DLBCL patients: ORR of axi-cel of 80% vs 66% with tisa-cel, and CRR of 60% vs 42% for patients treated with axi-cel vs tisa-cel. One-year PFS was 46.6% and 33.2% for axi-cel and for tisa-cel, respectively. One-year OS was also improved after axi-cel infusion compared to tisa-cel. Interestingly, the real-world evidence studies for tisa-cel [25, 26] demonstrate that about 10 to 30% of patients received an out-of-specification product, with reduced cell viability (>20% loss), still showing a comparable clinical benefit.

The results shown in Table 2, demonstrate some differences between the two most mature commercial CAR-T products. Moreover, this evidence promotes current advances in methodology of CAR-T clinical trials or, more generally, CGT trials, by enabling high predictability on safety and efficacy at rather small sizes of patients’ groups. Of note, the data from clinical trials were rather limited but they permitted approval for the both therapies, i.e., Kymriah was approved on the basis of ELIANA clinical trial with 75 patients, and Yescarta has been proven with 108 patients from ZUMA-1 trial and 68 patients of ZUMA-2 trail only [2, 27, 28]. These group sizes would be sufficient to obtain approvals of the POC therapy for academia clinical centers, if such mode of action is acceptable to the regulator.

This is important due to growing number of successful POC clinical trials, which seem to show comparable results and may declare even better results than those observed with commercial products. These results may be promising with superior clinical outcomes over centralized commercial CAR-T production model.

Some examples of POC CAR-T cell therapy are worthy of mention. A work by Maschan et al. [29] has demonstrated an opportunity of decentralized POC CAR-T production with single protocol at two academia clinical sites, i.e., in Moscow (Russia) and Cleveland (USA), based on automated closed-cycle production using CliniMACS Prodigy®) systems with CAR19-T cells manufactured at stable quality under current good manufacturing practices (cGMP). The results of two independent Phase 1 clinical trials in relapsed/refractory pediatric B-cell acute lymphocytic leukemia (ALL; n=31), or adult B-cell lymphoma (NHL; n=23) were as follows: complete remission (CR) rates were 89% (ALL), and 73% (NHL). After a median follow-up of 17 months, one-year survival for ALL complete responders was 79.2% (95%CI 64.5-97.2%). For NHL complete responders, one-year survival was 92.9%. Importantly, the manufacturing success rate exceeded 96% with automated closed-cycle production system used at two different sites in distant countries, at the median apheresis-to-infusion time of 13 days, thus sufficiently outperforming commercial CAR-T cell products.

Sheba Medical Center developed POC CAR-T product to treat aggressive B cell lymphoma (ABCL), with CAR construct designed to lower toxicity [30]. Clinical trial with 73 patients has shown a shortened CAR-T cell production time from apheresis product (a mean of 10 days only), that allowing to avoid bridging chemotherapy. Overall survival rate was 62.5%, with complete response rate (CRR) of 37.5%, median progression-free survival (PFS) of 3.7 months, and median OS of 12.1 months. OS rate at 12 months was 52.1% (CI: 40.8%-66.5%) and PFS, 40% (CI: 30%-53.7%). Grade 3-4 cytokine release syndrome (CRS) was observed in 9.5% of the patients, and ICANS grade 3-4 was documented in 21.9%. In general, these data demonstrate similar efficacy and safety to commercial products. Along with rather short vein-to-vein time, production efficiency was 98.6 %, and all the screened patients were eventually treated with CAR-T cells, that suggesting its superiority over commercial model with around 10% cell losses after apheresis. Based on results of clinical trials, POC CAR-T therapy in this center was approved by Israeli Ministry of Health, and currently priced 30-80% less than commercial CAR-Ts with >200 patients infused [31, 32]. Interesting application for in-house made POC CAR-T cells has been suggested at Sheba Center. The patients underwent salvage therapy and were scheduled for tisa-cel-treatment, being, however, supplied with out-of-specs (OOS) cell products [33]. This study showed that 24% of OOS are observed in real-life setting, and POC products may benefit in the patients who cannot wait for another lot of CAR-T cells. POC approach also allows fast clinical development for other indications, i.e., new molecular targets. This opportunity is supported by promising results on the CAR-T cells targeted against BMCA in relapsed/refractory multiple myeloma [34], developed in Sheba Center, using similar genetic CAR construct backbone and the same production facilities. The pilot study showed an estimated 6-mo OS of 89% (95% CI: 75-100), PFS of 48% (95% CI: 33-72), with no bridging therapy required in most cases. Additional advantage of POC production is ability to fast extension of clinical indications for therapy, as proven by the same clinical team who demonstrated good results of anti-CD19 CAR-T therapy to treat relapsed/refractory follicular lymphoma [35]. At enrollment, the disease stage was III-IV in 85% of the patients (n=26), with 77% having high-risk FLIPI score, and 77% were in progressive disease. ORR at 1 mo was 88%, with one-year OS of 100%, and PFS rate of 63%.

Another important success story of POC CAR-T therapy is ARI-0001, launched at the Hospital Clinic de Barcelona, employing an automated closed CliniMACS Prodigy cell processing system (Miltenyi Biotec). In February 2021, this product received authorization by European regulations as an ATMP (advanced therapy medicinal product) from the Spanish Agency of Medicines and Medical Devices under the ’hospital exemption’ (HE), according to EC Regulation No 1394/2007 (article 28.7), for the treatment of patients >25 years old with relapsed/refractory acute lymphoblastic leukemia (ALL) [2]. Interestingly, this is the first approved CAR-T product, developed in EU. The following results were obtained at Phase 1 clinical trial of ARI-0001 [36], on which the HE approval was based: of 58 patients included, 47 received the therapy, which resulted in 1-year PFS of 47% (95% IC 27%-67%), and OS of 68.6% (95% IC 49.2%-88%). In ALL patients, the grade ≥3 cytokine release syndrome (CRS) was observed in 13.2%; grade ≥3 neurotoxicity was registered in 2.6% of the cases. The last proportion is significantly lower versus commercial products. Cell production time varied between 7 to 10 days. However, the average vein-to-vein time was 42 days, due to complications and requirements of 2nd apheresis procedure in 14% of patients. Of note, this shows flexibility of POC approach, that allows to adapt for lower number of produced CAR-T cells by adding 2nd production cycle for the same patient, which is difficult or not feasible in the centralized production paradigm.

Similar to the mentioned approach used in Sheba clinic, POC production of CAR-T cells allowed fast launch of BMCA-targeted CAR-T therapy of multiple myeloma using the same backbone CAR construct and ARI0002h, a humanized BMCA antibody [37] for phase 1 clinical trial. 35 patients from 5 centers were enrolled in this trial, of which 86% received ARI0002h. With median follow-up of 12.1 months (IQR 9,1-13,5), OR was 100% during the first 100 days from infusion; CR rate of 50%, and partial remission (PR), in 50% of cases. Grade 1-2 CRS was registered in 80% of patients, and, notably, no neurotoxic events were observed. Of note, price for ARI-0001 was around 30% of commercial CAR-T products available in Spain [38].

An interesting collaboration experience extended into volunteering organizations has been reported by Canadian consortia [39], consolidating several clinical and research centers (Vancouver, Victoria and Ottawa) that were able to manufacture CD-19 CAR-T cells by CliniMACS Prodigy system (Miltenyi Biotec). The challenge was successfully resolved by manufacturing CAR-T product without cryopreservation, with 15 days vein-to-vein time and at the distances of up to 4300 km between the production site and clinical centers, by non-commercial academic sites and volunteer couriers. Thirty-five patients with CD19-positive hematologic malignancies were enrolled in CLIC-01 clinical study of non-cryopreserved CLIC-1901 CAR-T cell product, and 30 patients received the cell product infusion. Even despite some limitations in clinical interim results, one should note ORR of 77% at day 28, with median OS of 11 months, median PFS of 6 months. The manufacturing failure rate was only 6% (2 of 35). Grade >3 adverse events, mainly CRS, were registered in 7% (2 pts), and ICANS was observed in 3% of cases (1 pts). This result demonstrate that CAR-T technology in automated closed-cycle systems may provide robust results and fast vein-to-vein time even at long transportation routes. Hence the consortia of academia institutions can also resolve the issues related to CAR-T cell production, even upon delivery of fresh cells without cryopreservation.

These examples demonstrate both the ability for academia- based POC CAR-T cells to produce clinically beneficial results being comparable with commercial products, however, at significantly lower price and increased operational flexibility.

The mentioned factors are increasingly important, since new applications for CAR-T therapy in autoimmune diseases showed very promising results, mostly in academia setting using POC CAR-T cell production. Specific feature of systemic autoimmune diseases is production of autoantibodies and autoreactive T lymphocytes, which damage organs and tissues and cause various symptoms which may limit everyday normal life, and are able to cause life-threatening conditions. These disorders are caused by cytotoxic autoantibodies, and autoreactive cytotoxic T lymphocytes (CTLs) that recognize target cells and damage it. In this respect, very promising results were shown in limited clinical trials on systemic lupus erythematosus (SLE), idiopathic inflammatory myositis (IIM), systemic sclerosis (SSc) rheumatoid arthritis (RA), multiple sclerosis (MS), myasthenia gravis (MG) and other autoimmune disorders [40]. One should note that such diseases affect millions people worldwide, and effective therapeutic options are limited by their choice and efficacy. E.g., systemic lupus erythematosus (SLE) is a life-threatening autoimmune disease characterized by adaptive immune system activation, formation of double-stranded DNA (dsDNA) autoantibodies and organ inflammation, which affects more than 3.4 million people worldwide. Quite promising results were obtained by European research team, when treating SLE patients with CD-19 targeted CAR-T cells [41, 42]. Five patients with SLE, refractory to several immunosuppressive treatments enrolled in a compassionate-use CAR-T program, have shown a deep depletion of B cells, improvement of clinical symptoms, including decrease in anti-dsDNA antibodies. Remission developed within 3 month, and drug-free remission was maintained >8 months after CAR T cell treatment, being not affected by reappearance of B cells. The treatment was accompanied by low-grade CRS.

Another CAR-T cell-based treatment in SLE was successfully applied in Phase 1 clinical trial in China [43], where the researchers aimed to overcome possible drawbacks of single CD19-directed CAR-T cells, e.g., inability to clear CD19-negative, long-lived plasma cells, which also produce numerous antibodies. According to published results of clinical trial, twelve refractory SLE patients were treated with autologous anti-CD19 and anti-BCMA CAR-T cells. After lymphodepleting chemotherapy, the patients received a single infusion of CD19 CAR-T cells and BCMA CAR-T cells. Median follow-up time was 118.5 (45-524) days. All patients developed grade 1 CRS, and no ICANS. The SLEDAI-2K score decreased in all patients, from a mean of 18.3 to 1.5 points. All patients could successfully discontinue all SLE-related medications, and remained in drug-free remission by the date of report. Now there are >14 clinical trials of CAR-T therapies only in SLE patients [44]. However, there are more examples of different autoimmune diseases, that may be brought into remission by POC CD-19 CAR-T treatment.

MB-CART19.1, a product developed by Miltenyi Biotec, being not yet approved, apart from being used in numerous oncology-related clinical trials, was also successfully used in 15 patients with severe autoimmune diseases (8, SLE; 3, IIM, and 4 with SSc), with a single infusion of anti-CD19 CAR-T cells based on compassionate use approach [45]. Median disease duration before CAR-T therapy was 3 years, and all patients failed to respond at previous treatments. As a result of CAR-T therapy, CD19+ cells were eliminated in all patients, however, re-occurred later. Nonetheless, all SLE patients reached complete remission, all IIM patients showed normalization of CK levels; SSC patients demonstrated significant disease improvement, and importantly, all patients stopped immunosuppressive drugs. Safety of CAR-T cell therapy was very good, CRS of Grade 0-2 was observed in all patients, one patient experienced grade 1 ICANS.

The same approach was used, again as a POC protocol with CD19 CAR-T cells, with ClinMaxProdigy automated system from Miltenyi Biotec, in order to successfully treat patient with refractory antisynthetase syndrome, a rare immune disease from group of Idiopathic inflammatory myopathies [46]. In this single patient, a complete and long-lasting resolution of symptoms was observed, i.e., improvements in sit-to-stand test (from 0 to 7 after 6 months) and in maximal walking distance (10 m before therapy to >5km after 6 month).

A recent comprehensive review in Nature has summarized fast development of CAR-T therapies in autoimmune disease, showing very a promising approach, specifically feasible in academia setting. When immunologists meet the needs of oncologists and prepare CAR-T treatment for their patients with common cellular target (B-cells), this collaboration leads to very fast and "mind-blowing" clinical results with already proven safety and potential clinical efficiency [47].

Regulatory agencies and POC manufacturing

Recently, FDA had issued recommendations for distributed manufacturing and Point-Of-Care Manufacturing [48], describing approaches to regulatory approval of such approaches, however not yet being a guidance for industry. Hospital exemption rules are working in EU, with several products approved under it, including CAR-T cells. In Russia, new amendment to regulation on biomedical cell products had been enacted recently, and a complete set of regulations for POC should appear in 2024 [49]. Similarly, Switzerland has created a distributed framework for CAR-T cell production. UK is in the process of establishing legislation for localized cell manufacturing. In China, CAR-T development is booming on basis of ultra-localized clinical centers, thus allowing to support several small start-ups developing CAR-T therapies [2, 9].

China [50] has issued a set of regulations to boost cell and gene therapy, most importantly dual-track approval mechanism for somatic cell therapies, implying that hospitals can legally use somatic-cell therapies through approval by local governments regions, that can be used after a strict inspection, in addition to somatic-cell therapies marketed as a drug from the NMPA. Given that China had set up large number of pilot zones some of which have taken the development of cellular and gene therapies as a high priority, like Hebei, Hainan, Chongqing, and local governments have built industrial parks specialized for cellular therapies including the Zhang-jiang Cell Industrial Park in Shanghai, the China Cell Valley in Nanjing. Several documents of Chinese regulators, like Management of Clinical Research and Transformation Application for Somatic Cell Therapy policy proposed that the somatic cell-based therapies with proven safety and efficacy could be used clinically in selected qualified hospitals under strict supervision. This document declares that the researchers and the project host at these institutions are required to obtain a license from the Chinese regulator, and the somatic-cell therapy Expert Committee will be responsible for evaluation of the licensing process. In this case hospitals even can obtain market authorization for somatic-cell-therapy products, and use the data obtained from clinical research as evidence to support the applications if GCP and GMP practices were followed.

Conclusion

The point-of-care CGT production may be a powerful tool of treating the incurable diseases, providing effective and safe treatment, ensuring broader access and reducing financial burden. Since personalization may interfere with effective commercial models for delivery of such drugs to the market, it opens the non-competitive door for academic institutions to bring such products to the patients. Regulatory pathways for their approval are developing in US, Europe, China, and Russia. POC production of CGT, and, specifically, CAR-T products, has big future not only in cancers, but in other areas, with most promising advances can be seen in treatment of autoimmune diseases. These advancements, if successful, will help crossing the death valley [51] for new CGTs to reach patients all over the world.

Conflict of interests

None declared.

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Самсонов<sup>1,2</sup>, Андрей М. Ломоносов<sup>2</sup></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(103) "

Михаил Ю. Самсонов1,2, Андрей М. Ломоносов2

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1 АО Р-Фарм, Москва, Россия
2 Кафедра фармакологии, Первый Московский государственный медицинский университет имени И.М. Сеченова, Москва, Россия

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Современные достижения в области генной и клеточной терапии показали впечатляющие результаты на протяжении последнего десятилетия, которые привели к разрешению на клиническое использование методик CAR-T-клеточной терапии, что позволяет добиться долгосрочных ремиссий и, в ряде случаев, полного излечения у ранее безнадежных пациентов онкологического профиля. Эти разработки создали возможность для успеха генной терапии, в том числе при таких наследственных заболеваниях, как бета-талассемия и миодистрофия Дюшенна. Однако доступность этих жизненно важных методов терапии все еще очень ограничена ввиду исключительно высокой стоимости и ряда узких мест в персонализованной продукции препаратов. Эффективность персонализированной терапии является проблемой для централизованного производства, которое является обычным для фарминдустрии и регулирующих органов, что может самоограничивать ее развитие. Мы обсуждаем современные доводы в пользу новых перспективных путей клеточной и генной терапии (КГТ), т.е. производства препаратов на месте лечения (POC-продукции) в качестве прогрессивной тенденции их клинического применения. Показано, что POC-продукция на базе академических учреждений может быть одобрена для клинического применения, будучи даже более эффективной, нежели коммерческие продукты, благодаря большей скорости производства, доле качественного продукта и более низких расходах на производство в случае принятия новых регулирующих правил. Примеры успешной POC-продукции для CAR-T-клеточной терапии даже более важны в аспекте новых данных о высокоэффективном внедрении однократной CAR-T-клеточной терапии при аутоиммунных заболеваниях, в том числе системной красной волчанке и тяжелой миастении. После данной терапии отмечены долгосрочные ремиссии, не требующие дополнительного лечения.

Ключевые слова

Клеточная терапия, CAR-T-клетки, стоимость, доступность, регулирование, продукция по месту лечения.

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Mikhail Yu. Samsonov1,2, Andrey M. Lomonosov2

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1 R-Pharm JSC, Moscow, Russia
2 Pharmacology Department, Sechenov Medical University, Moscow, Russia


Correspondence:
Dr. Mikhail Yu. Samsonov, Medicinal Department, R-Pharm JSC, 111 Leninsky Ave, Bldg 1, 119421, Moscow, Russia
Phone: +7 (985) 997-39-02
E-mail: mikesamsonov@yahoo.com


Citation: Samsonov MY, Lomonosov AM. Towards personal gene and cell therapy: accelerating factors and roadblocks on point-of-care production approach. Cell Ther Transplant 2024; 13(1): 6-15.

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Recent advances in gene and cell therapy showed impressive results over last decade that culminated into approval of CAR-T therapies, i.e., long-term remissions in hopeless cancer patients that may be considered curative in the number of cases. These developments brought us to the recent gene therapies for such inherited disorders as beta-thalassemia and Duchenne myodystrophy. However, access of the patient to such life-saving therapies is still very limited, due to extremely high pricing and some bottlenecks specific for the personalized production approach. Efficacy of personalized therapies presents a challenge to the centralized manufacturing model which is commonly accepted by pharma and regulators and may self-limit its development. We discuss current evidence in favor of novel promising ways for cell and gene therapy (CGT), i.e., point-of-care (POC) manufacturing as a developing trend in its clinical applications. It is demonstrated that POC production by academic facilities may be approved for clinical use, being even more effective than commercial products, due to higher production speed, percent of successful manufacturing and lower total production costs, if the new regulations are applied. Examples of successful POC CAR-T therapies are even more important in view of new data on the highly efficient implementation of single-shot CAR-T therapies in autoimmune diseases, including systemic lupus erythematosus (SLE) and severe myasthenia, followed by long-term remissions which do not require any additional treatment.

Keywords

Cellular therapy, CAR-T cells, pricing, access, regulations, point-of-care production.

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string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "30944" ["VALUE"]=> array(2) { ["TEXT"]=> string(111) "<p>Mikhail Yu. Samsonov<sup>1,2</sup>, Andrey M. Lomonosov<sup>2</sup> </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(75) "

Mikhail Yu. Samsonov1,2, Andrey M. Lomonosov2

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Mikhail Yu. Samsonov1,2, Andrey M. Lomonosov2

" } ["SUMMARY_EN"]=> array(37) { ["ID"]=> string(2) "39" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:02:59" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(21) "Description / Summary" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_EN" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "39" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "30946" ["VALUE"]=> array(2) { ["TEXT"]=> string(1788) "<p style="text-align: justify;">Recent advances in gene and cell therapy showed impressive results over last decade that culminated into approval of CAR-T therapies, i.e., long-term remissions in hopeless cancer patients that may be considered curative in the number of cases. These developments brought us to the recent gene therapies for such inherited disorders as beta-thalassemia and Duchenne myodystrophy. However, access of the patient to such life-saving therapies is still very limited, due to extremely high pricing and some bottlenecks specific for the personalized production approach. Efficacy of personalized therapies presents a challenge to the centralized manufacturing model which is commonly accepted by pharma and regulators and may self-limit its development. We discuss current evidence in favor of novel promising ways for cell and gene therapy (CGT), i.e., point-of-care (POC) manufacturing as a developing trend in its clinical applications. It is demonstrated that POC production by academic facilities may be approved for clinical use, being even more effective than commercial products, due to higher production speed, percent of successful manufacturing and lower total production costs, if the new regulations are applied. Examples of successful POC CAR-T therapies are even more important in view of new data on the highly efficient implementation of single-shot CAR-T therapies in autoimmune diseases, including systemic lupus erythematosus (SLE) and severe myasthenia, followed by long-term remissions which do not require any additional treatment. </p> <h2>Keywords</h2> <p style="text-align: justify;"> Cellular therapy, CAR-T cells, pricing, access, regulations, point-of-care production. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1732) "

Recent advances in gene and cell therapy showed impressive results over last decade that culminated into approval of CAR-T therapies, i.e., long-term remissions in hopeless cancer patients that may be considered curative in the number of cases. These developments brought us to the recent gene therapies for such inherited disorders as beta-thalassemia and Duchenne myodystrophy. However, access of the patient to such life-saving therapies is still very limited, due to extremely high pricing and some bottlenecks specific for the personalized production approach. Efficacy of personalized therapies presents a challenge to the centralized manufacturing model which is commonly accepted by pharma and regulators and may self-limit its development. We discuss current evidence in favor of novel promising ways for cell and gene therapy (CGT), i.e., point-of-care (POC) manufacturing as a developing trend in its clinical applications. It is demonstrated that POC production by academic facilities may be approved for clinical use, being even more effective than commercial products, due to higher production speed, percent of successful manufacturing and lower total production costs, if the new regulations are applied. Examples of successful POC CAR-T therapies are even more important in view of new data on the highly efficient implementation of single-shot CAR-T therapies in autoimmune diseases, including systemic lupus erythematosus (SLE) and severe myasthenia, followed by long-term remissions which do not require any additional treatment.

Keywords

Cellular therapy, CAR-T cells, pricing, access, regulations, point-of-care production.

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Recent advances in gene and cell therapy showed impressive results over last decade that culminated into approval of CAR-T therapies, i.e., long-term remissions in hopeless cancer patients that may be considered curative in the number of cases. These developments brought us to the recent gene therapies for such inherited disorders as beta-thalassemia and Duchenne myodystrophy. However, access of the patient to such life-saving therapies is still very limited, due to extremely high pricing and some bottlenecks specific for the personalized production approach. Efficacy of personalized therapies presents a challenge to the centralized manufacturing model which is commonly accepted by pharma and regulators and may self-limit its development. We discuss current evidence in favor of novel promising ways for cell and gene therapy (CGT), i.e., point-of-care (POC) manufacturing as a developing trend in its clinical applications. It is demonstrated that POC production by academic facilities may be approved for clinical use, being even more effective than commercial products, due to higher production speed, percent of successful manufacturing and lower total production costs, if the new regulations are applied. Examples of successful POC CAR-T therapies are even more important in view of new data on the highly efficient implementation of single-shot CAR-T therapies in autoimmune diseases, including systemic lupus erythematosus (SLE) and severe myasthenia, followed by long-term remissions which do not require any additional treatment.

Keywords

Cellular therapy, CAR-T cells, pricing, access, regulations, point-of-care production.

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1 R-Pharm JSC, Moscow, Russia
2 Pharmacology Department, Sechenov Medical University, Moscow, Russia


Correspondence:
Dr. Mikhail Yu. Samsonov, Medicinal Department, R-Pharm JSC, 111 Leninsky Ave, Bldg 1, 119421, Moscow, Russia
Phone: +7 (985) 997-39-02
E-mail: mikesamsonov@yahoo.com


Citation: Samsonov MY, Lomonosov AM. Towards personal gene and cell therapy: accelerating factors and roadblocks on point-of-care production approach. Cell Ther Transplant 2024; 13(1): 6-15.

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1 R-Pharm JSC, Moscow, Russia
2 Pharmacology Department, Sechenov Medical University, Moscow, Russia


Correspondence:
Dr. Mikhail Yu. Samsonov, Medicinal Department, R-Pharm JSC, 111 Leninsky Ave, Bldg 1, 119421, Moscow, Russia
Phone: +7 (985) 997-39-02
E-mail: mikesamsonov@yahoo.com


Citation: Samsonov MY, Lomonosov AM. Towards personal gene and cell therapy: accelerating factors and roadblocks on point-of-care production approach. Cell Ther Transplant 2024; 13(1): 6-15.

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Михаил Ю. Самсонов1,2, Андрей М. Ломоносов2

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Михаил Ю. Самсонов1,2, Андрей М. Ломоносов2

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Эти разработки создали возможность для успеха генной терапии, в том числе при таких наследственных заболеваниях, как бета-талассемия и миодистрофия Дюшенна. Однако доступность этих жизненно важных методов терапии все еще очень ограничена ввиду исключительно высокой стоимости и ряда узких мест в персонализованной продукции препаратов. Эффективность персонализированной терапии является проблемой для централизованного производства, которое является обычным для фарминдустрии и регулирующих органов, что может самоограничивать ее развитие. Мы обсуждаем современные доводы в пользу новых перспективных путей клеточной и генной терапии (КГТ), т.е. производства препаратов на месте лечения (POC-продукции) в качестве прогрессивной тенденции их клинического применения. Показано, что POC-продукция на базе академических учреждений может быть одобрена для клинического применения, будучи даже более эффективной, нежели коммерческие продукты, благодаря большей скорости производства, доле качественного продукта и более низких расходах на производство в случае принятия новых регулирующих правил. Примеры успешной POC-продукции для CAR-T-клеточной терапии даже более важны в аспекте новых данных о высокоэффективном внедрении однократной CAR-T-клеточной терапии при аутоиммунных заболеваниях, в том числе системной красной волчанке и тяжелой миастении. После данной терапии отмечены долгосрочные ремиссии, не требующие дополнительного лечения.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Клеточная терапия, CAR-T-клетки, стоимость, доступность, регулирование, продукция по месту лечения. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3612) "

Современные достижения в области генной и клеточной терапии показали впечатляющие результаты на протяжении последнего десятилетия, которые привели к разрешению на клиническое использование методик CAR-T-клеточной терапии, что позволяет добиться долгосрочных ремиссий и, в ряде случаев, полного излечения у ранее безнадежных пациентов онкологического профиля. Эти разработки создали возможность для успеха генной терапии, в том числе при таких наследственных заболеваниях, как бета-талассемия и миодистрофия Дюшенна. Однако доступность этих жизненно важных методов терапии все еще очень ограничена ввиду исключительно высокой стоимости и ряда узких мест в персонализованной продукции препаратов. Эффективность персонализированной терапии является проблемой для централизованного производства, которое является обычным для фарминдустрии и регулирующих органов, что может самоограничивать ее развитие. Мы обсуждаем современные доводы в пользу новых перспективных путей клеточной и генной терапии (КГТ), т.е. производства препаратов на месте лечения (POC-продукции) в качестве прогрессивной тенденции их клинического применения. Показано, что POC-продукция на базе академических учреждений может быть одобрена для клинического применения, будучи даже более эффективной, нежели коммерческие продукты, благодаря большей скорости производства, доле качественного продукта и более низких расходах на производство в случае принятия новых регулирующих правил. Примеры успешной POC-продукции для CAR-T-клеточной терапии даже более важны в аспекте новых данных о высокоэффективном внедрении однократной CAR-T-клеточной терапии при аутоиммунных заболеваниях, в том числе системной красной волчанке и тяжелой миастении. После данной терапии отмечены долгосрочные ремиссии, не требующие дополнительного лечения.

Ключевые слова

Клеточная терапия, CAR-T-клетки, стоимость, доступность, регулирование, продукция по месту лечения.

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Современные достижения в области генной и клеточной терапии показали впечатляющие результаты на протяжении последнего десятилетия, которые привели к разрешению на клиническое использование методик CAR-T-клеточной терапии, что позволяет добиться долгосрочных ремиссий и, в ряде случаев, полного излечения у ранее безнадежных пациентов онкологического профиля. Эти разработки создали возможность для успеха генной терапии, в том числе при таких наследственных заболеваниях, как бета-талассемия и миодистрофия Дюшенна. Однако доступность этих жизненно важных методов терапии все еще очень ограничена ввиду исключительно высокой стоимости и ряда узких мест в персонализованной продукции препаратов. Эффективность персонализированной терапии является проблемой для централизованного производства, которое является обычным для фарминдустрии и регулирующих органов, что может самоограничивать ее развитие. Мы обсуждаем современные доводы в пользу новых перспективных путей клеточной и генной терапии (КГТ), т.е. производства препаратов на месте лечения (POC-продукции) в качестве прогрессивной тенденции их клинического применения. Показано, что POC-продукция на базе академических учреждений может быть одобрена для клинического применения, будучи даже более эффективной, нежели коммерческие продукты, благодаря большей скорости производства, доле качественного продукта и более низких расходах на производство в случае принятия новых регулирующих правил. Примеры успешной POC-продукции для CAR-T-клеточной терапии даже более важны в аспекте новых данных о высокоэффективном внедрении однократной CAR-T-клеточной терапии при аутоиммунных заболеваниях, в том числе системной красной волчанке и тяжелой миастении. После данной терапии отмечены долгосрочные ремиссии, не требующие дополнительного лечения.

Ключевые слова

Клеточная терапия, CAR-T-клетки, стоимость, доступность, регулирование, продукция по месту лечения.

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1 АО Р-Фарм, Москва, Россия
2 Кафедра фармакологии, Первый Московский государственный медицинский университет имени И.М. Сеченова, Москва, Россия

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1 АО Р-Фарм, Москва, Россия
2 Кафедра фармакологии, Первый Московский государственный медицинский университет имени И.М. Сеченова, Москва, Россия

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Introduction

According to the World Health Organization (WHO), cardiovascular disease (CVDs) is the leading cause of death in the world [1]. In 2021, about 20.5 million people died of cardiovascular disease, which accounts for 30% of all global deaths [2]. Of the 17 million premature deaths under the age of 70 caused by non-communicable diseases in 2019, 39% were due to cardiovascular disease [3]. Most cardiovascular diseases can be prevented by avoiding the behavioral risk factors such as smoking[4], unhealthy diet [5] and obesity [6], sedentary lifestyle [7] and harmful alcohol consumption [8]. It is important to diagnose cardiovascular disease as soon as possible so that it could be managed with counseling and medication.

Advanced cardiac support, medical treatment, and early reperfusion strategies have dramatically improved survival rate in patients with heart disease [9]. Despite this success, the risk of heart failure (HF) following myocardial infarction remains high in these patients, and there is no effective treatment to prevent this progression [10, 11]. Cardiac repair is strongly associated with the inflammatory process after injury, suggesting that targeting inflammation may be a promising way to preserving heart tissue and reducing mortality in patients surviving heart disease.

Stem cell therapies have the potential to fundamentally alter the conventional treatment of cardiovascular disease by stimulating damaged myocardial regeneration [12-14]. Over the past two decades, many clinical trials have demonstrated the safety and efficacy of multiple stem cell types. Various stem cell therapy studies have been performed by several groups for heart diseases, which can be divided into: (a) inhibition of remodeling after acute myocardial infarction; (b) stimulation of regeneration in chronically damaged hearts, and (c) induction of angiogenesis in coronary artery disease [15].

stem cell therapy studies have been performed by several groups for heart diseases, which can be divided into: (a) inhibition of remodeling after acute myocardial infarction; (b) stimulation of regeneration in chronically damaged hearts, and (c) induction of angiogenesis in coronary artery disease [15].

The aim of this review article was to investigate the usage of MSCs in regenerative medicine for the treatment of heart diseases. In addition, the potential mechanisms involved in stem cell-based heart repair are highlighted. Since the efficacy of stem cell therapy is quite limited, we will discuss more promising strategies to improve the transplantation outcomes.

Types of Stem Cells and their use in heart diseases treatment

Most of the available treatments can only act as rehabilitative approach to reduce the symptoms associated with the disease. Stem cell treatment can offer tremendous hope to the heart patients, especially in preventing the disease progression. Currently, stem cell therapy is the most preferred noninvasive treatment available. Various strategies have been applied by the medical science to limit the cardiac cells damage and reduce the symptoms with the help of stem cells.

Mesenchymal stem cells are unique primary cells in our body that are able to differentiate into distinct cell lineages [24]. This stem cell feature has been potentially used by many scientists for their clinical applications. Stem cells are inactive throughout a person's life, but may be adapted to specific tissue cells when needed for faster regeneration and repair [25]. Due to advanced technology, stem cells can now be isolated from two rich sources, i.e., bone marrow and adipose tissue [26]. Mesenchymal stem cells, when infused into the cardiac tissue, can differentiate into cardiac progenitor cells to restore lost heart function (Fig. 1).

Nejad-Moghaddam-fig01.jpg

Figure 1. Application of stem cells for treatment of heart diseases

Many clinical trials accrue from the use of MSCs for cardiovascular disease (CVD) treatment in animal model. Efficacy and safety of MSC in animal experiments is proven before starting clinical trials. There are several clinical trials underway which evaluate the safety and efficacy of MSCs in the treatment of heart diseases. In our review, we have considered 29 clinical trials which are terminated and ongoing on MSC types for treatment heart diseases.

In the new paradigm, autologous freshly isolated stromal vascular fraction (SVF) is reinjected into the patient without its expansion and differentiation in ex vivo culture, [27]. Umbilical cord (UC) blood is the most reliable and rich source of hematopoietic stem cells (HSCs). The Wharton’s jelly found in the umbilical cord tissue is a rich source of mesenchymal stem cells (MSCs). Using one’s own mesenchymal stem cells for treatment is a potentially a new treatment for cardiac diseases.

Therapeutic potential of mesenchymal stem cells for heart diseases

Mesenchymal stem cells (MSCs) are self-renewing, multipotent cells that can differentiate into many cell types, including osteocytes, chondrocytes, fat cells, hepatocytes, myocytes, neurons, and cardiomyocytes [28]. MSCs can be isolated from various tissues such as adipose tissue, bone marrow and umbilical cord. MSCs have a significant ability to modulate the immune response mainly by inhibiting T cell proliferation and protecting damaged tissues through paracrine mechanisms [29]. There is an urgent need to evaluate the true efficacy of the MSC transplant and its possible position in the current heart therapeutic.

Most early cell-based clinical trials for heart disease have been performed in cases of acute myocardial infarction (AMI) using autologous MSCs [30]. Extensive use of MSCs can be attributed to immediate cell access by the recipient. Isolation, ex vivo culture and manipulation of mature MSCs are easy to perform [31]. In this regard, MSCs, in part due to their long history in regenerative medicine, with proven safety and potency, are considered a major candidate cell type as confirmed by clinical research using this stem cell population in acute myocardial infarction (AMI) and chronic heart disease.

Myocardial infarction (MI) is the leading cause of death worldwide. The Global Burden of Disease Study reports that deaths from coronary heart disease in developing countries will double by 2030 [32]. Despite significant advances in treatment, ventricular dysfunction remains the leading cause of morbidity and mortality in these patients. Cell therapy is important for myocardial infarction. Intracoronary infusion of various cell populations (circulating progenitor cells, bone marrow-derived progenitor cells, bone marrow cells, peripheral blood stem cells, hematopoietic stem cells, and allogeneic bone marrow mesenchymal stromal cells) in acute MI has been used in some cases with promising results [33, 34]. There are several publications on the role of stem cell therapy in ischemic heart disease [35, 36].

Bone marrow-derived mesenchymal cell population (BM-MSCs) have both myogenic and angiogenic potential and have been studied for their therapeutic potential in regeneration/repair of damaged myocardial tissue. In addition, these cells are non-immunogenic [37] and have anti-inflammatory properties and facilitate vasculogenesis by increasing the level of vascular endothelial growth factor (VEGF) [38]. Clinical trials with MSCs for the treatment of heart diseases taken from clinical trials.gov website are listed in Table 1. The selection criteria of these trials included: distinct type of mesenchymal cell; numbers of injected cells, phase of the trial, and the effectiveness of the stem cell used.

Table 1. Mesenchymal stem cells therapy clinical trials for heart diseases

Nejad-Moghaddam-tab01-part01.jpg Nejad-Moghaddam-tab01-part02.jpg Nejad-Moghaddam-tab01-part03.jpg Nejad-Moghaddam-tab01-part04.jpg Nejad-Moghaddam-tab01-part05.jpg

Abbreviations: MSCs, Mesenchymal stem cells; MPCs, Mesenchymal precursor cells; UC-MSCs, Umbilical cord-derived mesenchymal stem cells; Ad-MSCs, Adipose tissue-derived mesenchymal stem cells; BM-MSCs, Bone marrow-derived mesenchymal stem cells, mBMC, mononuclear bone marrow cells; WJ-MSCs, Wharton's jelly-derived mesenchymal stem cells; MI, Myocardial Infarction; MI, Acute myocardial infarction; IHD, ischemic heart disease, CAD, coronary artery disease, ICM, Ischemic cardiomyopathy; DCM, dilated cardiomyopathy; HF, Heart failure; ILVD, Ischemic left ventricular dysfunction; LV, left heart ventricle.

Clinical trials for acute myocardial infarction, and ischemic coronary heart disease

Preliminary experimental and clinical studies suggest that transplantation of circulating blood-cells (CBC) or bone marrow-derived mesenchymal progenitor cell (BMPC) may beneficially affect post-infarction regeneration processes after acute MI. Yao and et al. observed 47 patients with ischemic heart disease which occurred after previous MI [73]. Of them, 24 were randomized to intracoronary infusion of BMPC (BMPC group), and 23 received an intracoronary saline infusion (control group). Left ventricle (LV) systolic and diastolic function, infarction size and myocardial perfusion deficiency were assessed by means of echocardiography, MRI or single-photon-emission computed tomography (SPECT) at baseline (before MI) and repeated at the 9 month of follow-up examination. BMPC treatment did not result in a significant increase in LV ejection fraction in either group by any of the diagnostic methods used, and the apparent tendency for improvement was not statistically different between the two groups. No inter-group changes were seen in diastolic and systolic end volume of LV, infarction size or myocardial perfusion rates. Autologous BMC transfusion in the patients with improved MI was associated with improved diastolic function [73].

Also, Britten et al. investigated functional effects of infused BMCs to quantitative outcomes at 4-month follow-up, performing serial contrast-enhanced MRI and assessing migratory capacity of the transplanted progenitor cells immediately after intracoronary infusion [74]. Analysis suggests that intracoronary infusion of BMCs in patients with AMI beneficially affects postinfarction remodeling processes.

Schaefer et al. showed that autologous BMCs transplantation improves LV ejection fraction in AMI patients. However, the effect of BMC therapy on diastolic LV function in patients after AMI remained unclear [75]. In this regard, autologous BMC intra-coronary transfusion has a limited therapeutic effect on echocardiographic parameters of diastolic function in patients after AMI. However, this effect is mainly related to the initial improvement of diastolic function parameters without a lasting effect at long-term follow-up [76]. Meyer et al. showed that intracoronary transfusion of autologous BM-MSCs may improve LV function in patients after AMI. However, clinical studies dealing with the effects of BM-MSCs after AMI have covered only limited time periods of 3 to 6 months [77].

Dill et al. reported that intracoronary administration of BM-MSCs improved LV function in patients with LV dysfunction after MI, despite reperfusion and optimal drug therapy at 1-year follow-up and beneficially with adverse LV remodeling [78]. Doppler subclinical study by Erbs et al, evaluate the effects of intra-coronary infusion of BM-MSCs on coronary blood flow regulation in patients with AMI[79]. The results showed that BM-MSCs treatment after AMI restored the microvascular function of infarcted arteries being associated with a significant improvement in maximal vascular flow capacity. These data provide clinical evidence for the concept that progenitor mesenchymal cell transplantation may contribute to repair of blood vessels [79].

Wöhrle et al. investigated the results of intracoronary mesenchymal stem cell therapy after AMI in 42 patients enrolled [80]. The patients received intracoronary infusion 380×106 mononuclear BMCs. The initial clinical parameters and cardiac magnetic resonance imaging (MRI) did not differ. No differences in secondary endpoints were observed between the two groups, including changes in infarction size or end-diastolic and end-systolic LV volume indexes. As a result, not found any evidence of a positive effect of intracoronary BMC on LV ejection fraction, LV volume indexes, or infarction size.

Tendera et al. studied the intracoronary infusion of BM-derived selected CD34+CXCR4+ cells and non-selected mononuclear cells in patients with acute ST-elevation myocardial infarction (STEMI) and reduced left ventricular ejection fraction (LVEF) [81]. 200 patients were randomized to intracoronary infusion of BM cells or to the control group without BM cell treatment. Treatment with BM cells in patients with impaired AMI and LVEF did not cause significant improvement LVEF or volume. However, there was a trend toward better outcomes after cell therapy in patients with the most severe LVEF disorder and the longer delay between symptoms and revascularization.

Prognosis of progenitor cell transplantation and enhanced regeneration in AMI demonstrates both safety, feasibility, and potential effects on circulatory performance parameters of intracoronary myocardial infusion of circulating progenitor cells (CPCs) or bone marrow-derived progenitor cells (BMCs) in patients with AMI [82]. Intracoronary infusion of progenitor cells (either BMCs or CPC) is safe and feasible in patients after successful vascular reconstruction in AMI with stent implantation. Both excellent safety profile and the observed positive effects on LV regeneration make sense for larger double-blind randomized trials [82].

Intramyocardial cell injection

Intramyocardial BM cells injection is associated with improvements in myocardial blood flow and angina symptoms in patients with refractory angina. The effect of repeated injections of BM-MSCs into the heart muscle in patients with recurrent ischemia or myocardial ischemia has been studied previously [83]. In the study by Mann et al., 23 patients have shown an improved myocardial perfusion after the first injection but had residual or recurrent angina and ischemia on myocardial perfusion imaging by SPECT visualization. The patients again received intramyocardial injection of 1×108 autologous BM-MSCs, 2 years after the first injection[83]. Repeated BM cells injections in previously responding patients with refractory angina were associated with improvements in myocardial perfusion, anginal complaints, and quality of life score after 12 months of follow-up.

Rodrigo et al. reported that intramyocardial injection of BM-MSCs in chronic myocardial ischemia patients after previous placebo injection improves myocardial perfusion and anginal symptoms[84]. Sixteen patients, who previously received intramyocardial placebo injections within a randomized trial, 1×108 BMC were injected using the NOGA-system. Cardiovascular angina score and quality of life were evaluated at baseline, 3 and 6 months. LV end-systolic volume significantly decreased after BMC injection but not after placebo injection. LV end-diastolic volume and LV ejection fraction did not change. Intramyocardial BMC injection in patients with chronic myocardial ischemia significantly improved angina symptoms and myocardial perfusion. These results confirm the outcome of our previously reported randomized trial [84].

Mathiasen et al. assessed 4-year outcomes of intramyocardial injections of autologous BM-MSCs in 60 patients with ischemic heart failure [85]. Hospitalization for angina attacks was significantly lower in the MSC group, otherwise there was no difference in hospitalization or survival. No side effects were revealed. Intra-myocardial injection of autologous BM-MSCs improved heart function and myocardial mass in patients with ischemic heart failure. Randomized, double-blind, placebo-controlled trial at a Netherlands University hospital (trialregister.nl Identifier: NTR400 and isrctn.org Identifier: ISRCTN58194927), with 6-month follow-up was performed for intramyocardial 1×108 autologous BM-MSCs injection for chronic myocardial ischemia of 50 patients with chronic myocardial ischemia [86]. Injection of intramyocardial BM cells resulted in a statistically significant but moderate improvement in myocardial perfusion compared with placebo.

Beeres et al. investigated usefulness of intramyocardial injection of 1×108 autologous BM-MSCs in 20 patients with severe angina pectoris and stress-induced myocardial ischemia [87]. The results showed that injection of autologous BM-MSCs was safe in patients with ischemia, reduced angina symptoms, improved myocardial perfusion, and increased LV function.

In a study by Sørensen et al. patients with stable CAD and refractory angina were treated by direct injection of autologous MSCs into the myocardium, and the safety and efficacy of the treatment were monitored for 12 months [88]. A total of 31 patients were included with stable CAD, with moderate to severe angina, normal LV ejection fraction, and no further revascularization options. Seattle Angina Questionnaire (SAQ) evaluations demonstrated highly significant improvements in physical limitation, angina stability, angina frequency, and quality of life. autologous culture expanded MSCs is safe in the intermediate/long term to treat patients with stable CAD.

Conclusion

Stem cell therapy is a promising treatment strategy for patients with heart failure, accounting for more than 10% of deaths worldwide each year [12]. Despite more than a decade of research, further investigation is needed to determine whether stem cell regeneration therapy is an effective treatment strategy and can be routinely performed in clinical practice.

MSCs have many benefits, including available resources, easy separation, cell expansion and low immunogenicity. In addition, transplanted MSCs can migrate to myocardial infarcted tissue, reduce the inflammatory response, alleviate fibrosis, enhance the formation of new blood vessels, differentiate into cardiomyocyte-like cells and finally help repair myocardial infarction. Despite their benefits in treating heart disease, the use of MSCs still faces challenges such as poor targeted migration and low MSCs survival rates in the ischemic myocardium. The feasibility and safety of MSC treatment have been tested in many clinical trials, but the optimal dose of MSC and delivery route for treatment should be studied. However, some problems remain with using MSCs to treat heart disorders, MSCs are still a promising form of cell therapy.

Conflict of interest

The author confirms that there are no conflicts of interest.

Acknowledgements

This review article was supported by Marine Medicine Research Center, Baqiyatallah University of Medical Sciences.

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    doi: 10.3727/096368912X636830

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Introduction

According to the World Health Organization (WHO), cardiovascular disease (CVDs) is the leading cause of death in the world [1]. In 2021, about 20.5 million people died of cardiovascular disease, which accounts for 30% of all global deaths [2]. Of the 17 million premature deaths under the age of 70 caused by non-communicable diseases in 2019, 39% were due to cardiovascular disease [3]. Most cardiovascular diseases can be prevented by avoiding the behavioral risk factors such as smoking[4], unhealthy diet [5] and obesity [6], sedentary lifestyle [7] and harmful alcohol consumption [8]. It is important to diagnose cardiovascular disease as soon as possible so that it could be managed with counseling and medication.

Advanced cardiac support, medical treatment, and early reperfusion strategies have dramatically improved survival rate in patients with heart disease [9]. Despite this success, the risk of heart failure (HF) following myocardial infarction remains high in these patients, and there is no effective treatment to prevent this progression [10, 11]. Cardiac repair is strongly associated with the inflammatory process after injury, suggesting that targeting inflammation may be a promising way to preserving heart tissue and reducing mortality in patients surviving heart disease.

Stem cell therapies have the potential to fundamentally alter the conventional treatment of cardiovascular disease by stimulating damaged myocardial regeneration [12-14]. Over the past two decades, many clinical trials have demonstrated the safety and efficacy of multiple stem cell types. Various stem cell therapy studies have been performed by several groups for heart diseases, which can be divided into: (a) inhibition of remodeling after acute myocardial infarction; (b) stimulation of regeneration in chronically damaged hearts, and (c) induction of angiogenesis in coronary artery disease [15].

stem cell therapy studies have been performed by several groups for heart diseases, which can be divided into: (a) inhibition of remodeling after acute myocardial infarction; (b) stimulation of regeneration in chronically damaged hearts, and (c) induction of angiogenesis in coronary artery disease [15].

The aim of this review article was to investigate the usage of MSCs in regenerative medicine for the treatment of heart diseases. In addition, the potential mechanisms involved in stem cell-based heart repair are highlighted. Since the efficacy of stem cell therapy is quite limited, we will discuss more promising strategies to improve the transplantation outcomes.

Types of Stem Cells and their use in heart diseases treatment

Most of the available treatments can only act as rehabilitative approach to reduce the symptoms associated with the disease. Stem cell treatment can offer tremendous hope to the heart patients, especially in preventing the disease progression. Currently, stem cell therapy is the most preferred noninvasive treatment available. Various strategies have been applied by the medical science to limit the cardiac cells damage and reduce the symptoms with the help of stem cells.

Mesenchymal stem cells are unique primary cells in our body that are able to differentiate into distinct cell lineages [24]. This stem cell feature has been potentially used by many scientists for their clinical applications. Stem cells are inactive throughout a person's life, but may be adapted to specific tissue cells when needed for faster regeneration and repair [25]. Due to advanced technology, stem cells can now be isolated from two rich sources, i.e., bone marrow and adipose tissue [26]. Mesenchymal stem cells, when infused into the cardiac tissue, can differentiate into cardiac progenitor cells to restore lost heart function (Fig. 1).

Nejad-Moghaddam-fig01.jpg

Figure 1. Application of stem cells for treatment of heart diseases

Many clinical trials accrue from the use of MSCs for cardiovascular disease (CVD) treatment in animal model. Efficacy and safety of MSC in animal experiments is proven before starting clinical trials. There are several clinical trials underway which evaluate the safety and efficacy of MSCs in the treatment of heart diseases. In our review, we have considered 29 clinical trials which are terminated and ongoing on MSC types for treatment heart diseases.

In the new paradigm, autologous freshly isolated stromal vascular fraction (SVF) is reinjected into the patient without its expansion and differentiation in ex vivo culture, [27]. Umbilical cord (UC) blood is the most reliable and rich source of hematopoietic stem cells (HSCs). The Wharton’s jelly found in the umbilical cord tissue is a rich source of mesenchymal stem cells (MSCs). Using one’s own mesenchymal stem cells for treatment is a potentially a new treatment for cardiac diseases.

Therapeutic potential of mesenchymal stem cells for heart diseases

Mesenchymal stem cells (MSCs) are self-renewing, multipotent cells that can differentiate into many cell types, including osteocytes, chondrocytes, fat cells, hepatocytes, myocytes, neurons, and cardiomyocytes [28]. MSCs can be isolated from various tissues such as adipose tissue, bone marrow and umbilical cord. MSCs have a significant ability to modulate the immune response mainly by inhibiting T cell proliferation and protecting damaged tissues through paracrine mechanisms [29]. There is an urgent need to evaluate the true efficacy of the MSC transplant and its possible position in the current heart therapeutic.

Most early cell-based clinical trials for heart disease have been performed in cases of acute myocardial infarction (AMI) using autologous MSCs [30]. Extensive use of MSCs can be attributed to immediate cell access by the recipient. Isolation, ex vivo culture and manipulation of mature MSCs are easy to perform [31]. In this regard, MSCs, in part due to their long history in regenerative medicine, with proven safety and potency, are considered a major candidate cell type as confirmed by clinical research using this stem cell population in acute myocardial infarction (AMI) and chronic heart disease.

Myocardial infarction (MI) is the leading cause of death worldwide. The Global Burden of Disease Study reports that deaths from coronary heart disease in developing countries will double by 2030 [32]. Despite significant advances in treatment, ventricular dysfunction remains the leading cause of morbidity and mortality in these patients. Cell therapy is important for myocardial infarction. Intracoronary infusion of various cell populations (circulating progenitor cells, bone marrow-derived progenitor cells, bone marrow cells, peripheral blood stem cells, hematopoietic stem cells, and allogeneic bone marrow mesenchymal stromal cells) in acute MI has been used in some cases with promising results [33, 34]. There are several publications on the role of stem cell therapy in ischemic heart disease [35, 36].

Bone marrow-derived mesenchymal cell population (BM-MSCs) have both myogenic and angiogenic potential and have been studied for their therapeutic potential in regeneration/repair of damaged myocardial tissue. In addition, these cells are non-immunogenic [37] and have anti-inflammatory properties and facilitate vasculogenesis by increasing the level of vascular endothelial growth factor (VEGF) [38]. Clinical trials with MSCs for the treatment of heart diseases taken from clinical trials.gov website are listed in Table 1. The selection criteria of these trials included: distinct type of mesenchymal cell; numbers of injected cells, phase of the trial, and the effectiveness of the stem cell used.

Table 1. Mesenchymal stem cells therapy clinical trials for heart diseases

Nejad-Moghaddam-tab01-part01.jpg Nejad-Moghaddam-tab01-part02.jpg Nejad-Moghaddam-tab01-part03.jpg Nejad-Moghaddam-tab01-part04.jpg Nejad-Moghaddam-tab01-part05.jpg

Abbreviations: MSCs, Mesenchymal stem cells; MPCs, Mesenchymal precursor cells; UC-MSCs, Umbilical cord-derived mesenchymal stem cells; Ad-MSCs, Adipose tissue-derived mesenchymal stem cells; BM-MSCs, Bone marrow-derived mesenchymal stem cells, mBMC, mononuclear bone marrow cells; WJ-MSCs, Wharton's jelly-derived mesenchymal stem cells; MI, Myocardial Infarction; MI, Acute myocardial infarction; IHD, ischemic heart disease, CAD, coronary artery disease, ICM, Ischemic cardiomyopathy; DCM, dilated cardiomyopathy; HF, Heart failure; ILVD, Ischemic left ventricular dysfunction; LV, left heart ventricle.

Clinical trials for acute myocardial infarction, and ischemic coronary heart disease

Preliminary experimental and clinical studies suggest that transplantation of circulating blood-cells (CBC) or bone marrow-derived mesenchymal progenitor cell (BMPC) may beneficially affect post-infarction regeneration processes after acute MI. Yao and et al. observed 47 patients with ischemic heart disease which occurred after previous MI [73]. Of them, 24 were randomized to intracoronary infusion of BMPC (BMPC group), and 23 received an intracoronary saline infusion (control group). Left ventricle (LV) systolic and diastolic function, infarction size and myocardial perfusion deficiency were assessed by means of echocardiography, MRI or single-photon-emission computed tomography (SPECT) at baseline (before MI) and repeated at the 9 month of follow-up examination. BMPC treatment did not result in a significant increase in LV ejection fraction in either group by any of the diagnostic methods used, and the apparent tendency for improvement was not statistically different between the two groups. No inter-group changes were seen in diastolic and systolic end volume of LV, infarction size or myocardial perfusion rates. Autologous BMC transfusion in the patients with improved MI was associated with improved diastolic function [73].

Also, Britten et al. investigated functional effects of infused BMCs to quantitative outcomes at 4-month follow-up, performing serial contrast-enhanced MRI and assessing migratory capacity of the transplanted progenitor cells immediately after intracoronary infusion [74]. Analysis suggests that intracoronary infusion of BMCs in patients with AMI beneficially affects postinfarction remodeling processes.

Schaefer et al. showed that autologous BMCs transplantation improves LV ejection fraction in AMI patients. However, the effect of BMC therapy on diastolic LV function in patients after AMI remained unclear [75]. In this regard, autologous BMC intra-coronary transfusion has a limited therapeutic effect on echocardiographic parameters of diastolic function in patients after AMI. However, this effect is mainly related to the initial improvement of diastolic function parameters without a lasting effect at long-term follow-up [76]. Meyer et al. showed that intracoronary transfusion of autologous BM-MSCs may improve LV function in patients after AMI. However, clinical studies dealing with the effects of BM-MSCs after AMI have covered only limited time periods of 3 to 6 months [77].

Dill et al. reported that intracoronary administration of BM-MSCs improved LV function in patients with LV dysfunction after MI, despite reperfusion and optimal drug therapy at 1-year follow-up and beneficially with adverse LV remodeling [78]. Doppler subclinical study by Erbs et al, evaluate the effects of intra-coronary infusion of BM-MSCs on coronary blood flow regulation in patients with AMI[79]. The results showed that BM-MSCs treatment after AMI restored the microvascular function of infarcted arteries being associated with a significant improvement in maximal vascular flow capacity. These data provide clinical evidence for the concept that progenitor mesenchymal cell transplantation may contribute to repair of blood vessels [79].

Wöhrle et al. investigated the results of intracoronary mesenchymal stem cell therapy after AMI in 42 patients enrolled [80]. The patients received intracoronary infusion 380×106 mononuclear BMCs. The initial clinical parameters and cardiac magnetic resonance imaging (MRI) did not differ. No differences in secondary endpoints were observed between the two groups, including changes in infarction size or end-diastolic and end-systolic LV volume indexes. As a result, not found any evidence of a positive effect of intracoronary BMC on LV ejection fraction, LV volume indexes, or infarction size.

Tendera et al. studied the intracoronary infusion of BM-derived selected CD34+CXCR4+ cells and non-selected mononuclear cells in patients with acute ST-elevation myocardial infarction (STEMI) and reduced left ventricular ejection fraction (LVEF) [81]. 200 patients were randomized to intracoronary infusion of BM cells or to the control group without BM cell treatment. Treatment with BM cells in patients with impaired AMI and LVEF did not cause significant improvement LVEF or volume. However, there was a trend toward better outcomes after cell therapy in patients with the most severe LVEF disorder and the longer delay between symptoms and revascularization.

Prognosis of progenitor cell transplantation and enhanced regeneration in AMI demonstrates both safety, feasibility, and potential effects on circulatory performance parameters of intracoronary myocardial infusion of circulating progenitor cells (CPCs) or bone marrow-derived progenitor cells (BMCs) in patients with AMI [82]. Intracoronary infusion of progenitor cells (either BMCs or CPC) is safe and feasible in patients after successful vascular reconstruction in AMI with stent implantation. Both excellent safety profile and the observed positive effects on LV regeneration make sense for larger double-blind randomized trials [82].

Intramyocardial cell injection

Intramyocardial BM cells injection is associated with improvements in myocardial blood flow and angina symptoms in patients with refractory angina. The effect of repeated injections of BM-MSCs into the heart muscle in patients with recurrent ischemia or myocardial ischemia has been studied previously [83]. In the study by Mann et al., 23 patients have shown an improved myocardial perfusion after the first injection but had residual or recurrent angina and ischemia on myocardial perfusion imaging by SPECT visualization. The patients again received intramyocardial injection of 1×108 autologous BM-MSCs, 2 years after the first injection[83]. Repeated BM cells injections in previously responding patients with refractory angina were associated with improvements in myocardial perfusion, anginal complaints, and quality of life score after 12 months of follow-up.

Rodrigo et al. reported that intramyocardial injection of BM-MSCs in chronic myocardial ischemia patients after previous placebo injection improves myocardial perfusion and anginal symptoms[84]. Sixteen patients, who previously received intramyocardial placebo injections within a randomized trial, 1×108 BMC were injected using the NOGA-system. Cardiovascular angina score and quality of life were evaluated at baseline, 3 and 6 months. LV end-systolic volume significantly decreased after BMC injection but not after placebo injection. LV end-diastolic volume and LV ejection fraction did not change. Intramyocardial BMC injection in patients with chronic myocardial ischemia significantly improved angina symptoms and myocardial perfusion. These results confirm the outcome of our previously reported randomized trial [84].

Mathiasen et al. assessed 4-year outcomes of intramyocardial injections of autologous BM-MSCs in 60 patients with ischemic heart failure [85]. Hospitalization for angina attacks was significantly lower in the MSC group, otherwise there was no difference in hospitalization or survival. No side effects were revealed. Intra-myocardial injection of autologous BM-MSCs improved heart function and myocardial mass in patients with ischemic heart failure. Randomized, double-blind, placebo-controlled trial at a Netherlands University hospital (trialregister.nl Identifier: NTR400 and isrctn.org Identifier: ISRCTN58194927), with 6-month follow-up was performed for intramyocardial 1×108 autologous BM-MSCs injection for chronic myocardial ischemia of 50 patients with chronic myocardial ischemia [86]. Injection of intramyocardial BM cells resulted in a statistically significant but moderate improvement in myocardial perfusion compared with placebo.

Beeres et al. investigated usefulness of intramyocardial injection of 1×108 autologous BM-MSCs in 20 patients with severe angina pectoris and stress-induced myocardial ischemia [87]. The results showed that injection of autologous BM-MSCs was safe in patients with ischemia, reduced angina symptoms, improved myocardial perfusion, and increased LV function.

In a study by Sørensen et al. patients with stable CAD and refractory angina were treated by direct injection of autologous MSCs into the myocardium, and the safety and efficacy of the treatment were monitored for 12 months [88]. A total of 31 patients were included with stable CAD, with moderate to severe angina, normal LV ejection fraction, and no further revascularization options. Seattle Angina Questionnaire (SAQ) evaluations demonstrated highly significant improvements in physical limitation, angina stability, angina frequency, and quality of life. autologous culture expanded MSCs is safe in the intermediate/long term to treat patients with stable CAD.

Conclusion

Stem cell therapy is a promising treatment strategy for patients with heart failure, accounting for more than 10% of deaths worldwide each year [12]. Despite more than a decade of research, further investigation is needed to determine whether stem cell regeneration therapy is an effective treatment strategy and can be routinely performed in clinical practice.

MSCs have many benefits, including available resources, easy separation, cell expansion and low immunogenicity. In addition, transplanted MSCs can migrate to myocardial infarcted tissue, reduce the inflammatory response, alleviate fibrosis, enhance the formation of new blood vessels, differentiate into cardiomyocyte-like cells and finally help repair myocardial infarction. Despite their benefits in treating heart disease, the use of MSCs still faces challenges such as poor targeted migration and low MSCs survival rates in the ischemic myocardium. The feasibility and safety of MSC treatment have been tested in many clinical trials, but the optimal dose of MSC and delivery route for treatment should be studied. However, some problems remain with using MSCs to treat heart disorders, MSCs are still a promising form of cell therapy.

Conflict of interest

The author confirms that there are no conflicts of interest.

Acknowledgements

This review article was supported by Marine Medicine Research Center, Baqiyatallah University of Medical Sciences.

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Одной из главных проблем является уточнение и выбор наилучшего типа стволовых клеток, пригодных для регенеративного лечения. Мононуклеары костного мозга, мезенхимные клетки из костного мозга или жировой ткани, эндогенные стволовые клетки сердца, предшественники эндотелия и индуцированные плюрипотентные стволовые клетки находятся в ряду клеточных разновидностей, которые проверяли в плане усиления регенерации миокарда. В то же время многие из этих типов клеток оценивали в клинических испытаниях с точки зрения безопасности и эффективности. Однако тестирование их эффективности в клинике показало различные результаты в плане. Поэтому основной проблемой является получение четких экспериментальных доказательств улучшения сердечной функции после трансплантации стволовых клеток. В числе различных типов трансплантатов, мезенхимные стволовые клетки (МСК) получают из различных источников, их легко выделять и культивировать. 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string(10) "20.12.2023" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Дата подачи" ["~DEFAULT_VALUE"]=> NULL } ["ACCEPTED"]=> array(36) { ["ID"]=> string(2) "21" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(25) "Дата принятия" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(8) "ACCEPTED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "21" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(8) "DateTime" ["USER_TYPE_SETTINGS"]=> NULL ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "30951" ["VALUE"]=> string(10) "01.03.2024" ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> string(10) "01.03.2024" ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(25) "Дата принятия" ["~DEFAULT_VALUE"]=> NULL } ["PUBLISHED"]=> array(36) { ["ID"]=> string(2) "22" ["TIMESTAMP_X"]=> string(19) "2015-09-02 17:21:42" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Дата публикации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "PUBLISHED" ["DEFAULT_VALUE"]=> NULL ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "22" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> 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array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "30956" ["VALUE"]=> array(2) { ["TEXT"]=> string(83) "<p>Амир Неджад Мохаддам<sup>1,2</sup></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(59) "

Амир Неджад Мохаддам1,2

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "30957" ["VALUE"]=> array(2) { ["TEXT"]=> string(349) "<p><sup>1</sup> Научный центр морской медицины, Медицинский университет Бахияталла, Тегеран, Иран<br> <sup>2</sup> Факультет наук, Университет имама Хаменеи, Зибакенар, Решт, Иран</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(307) "

1 Научный центр морской медицины, Медицинский университет Бахияталла, Тегеран, Иран
2 Факультет наук, Университет имама Хаменеи, Зибакенар, Решт, Иран

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "30958" ["VALUE"]=> array(2) { ["TEXT"]=> string(3125) "<p style="text-align: justify;"> Лечение стволовыми клетками является перспективным подходом к терапии сердечных заболеваний. Одной из главных проблем является уточнение и выбор наилучшего типа стволовых клеток, пригодных для регенеративного лечения. Мононуклеары костного мозга, мезенхимные клетки из костного мозга или жировой ткани, эндогенные стволовые клетки сердца, предшественники эндотелия и индуцированные плюрипотентные стволовые клетки находятся в ряду клеточных разновидностей, которые проверяли в плане усиления регенерации миокарда. В то же время многие из этих типов клеток оценивали в клинических испытаниях с точки зрения безопасности и эффективности. Однако тестирование их эффективности в клинике показало различные результаты в плане. Поэтому основной проблемой является получение четких экспериментальных доказательств улучшения сердечной функции после трансплантации стволовых клеток. В числе различных типов трансплантатов, мезенхимные стволовые клетки (МСК) получают из различных источников, их легко выделять и культивировать. МСК способны к пролиферации и самообновлению <i>in vitro</i>, обладают низкой иммуногенностью и имеют иммуномодулирующие свойства и, при определенных условиях, могут дифференцироваться в конкретные типы клеток. В этой обзорной статье мы рассматриваем применение МСК для регенерации сердца и обсуждаем, почему другие факторы, в том числе – процедуры и сложности сбора клеток также должны учитываться при выборе стволовых клеток для трансплантации.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Клеточная терапия, регенерация, мезенхимные стволовые клетки, сердечно-сосудистые заболевания, сердечная недостаточность. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3057) "

Лечение стволовыми клетками является перспективным подходом к терапии сердечных заболеваний. Одной из главных проблем является уточнение и выбор наилучшего типа стволовых клеток, пригодных для регенеративного лечения. Мононуклеары костного мозга, мезенхимные клетки из костного мозга или жировой ткани, эндогенные стволовые клетки сердца, предшественники эндотелия и индуцированные плюрипотентные стволовые клетки находятся в ряду клеточных разновидностей, которые проверяли в плане усиления регенерации миокарда. В то же время многие из этих типов клеток оценивали в клинических испытаниях с точки зрения безопасности и эффективности. Однако тестирование их эффективности в клинике показало различные результаты в плане. Поэтому основной проблемой является получение четких экспериментальных доказательств улучшения сердечной функции после трансплантации стволовых клеток. В числе различных типов трансплантатов, мезенхимные стволовые клетки (МСК) получают из различных источников, их легко выделять и культивировать. МСК способны к пролиферации и самообновлению in vitro, обладают низкой иммуногенностью и имеют иммуномодулирующие свойства и, при определенных условиях, могут дифференцироваться в конкретные типы клеток. В этой обзорной статье мы рассматриваем применение МСК для регенерации сердца и обсуждаем, почему другие факторы, в том числе – процедуры и сложности сбора клеток также должны учитываться при выборе стволовых клеток для трансплантации.

Ключевые слова

Клеточная терапия, регенерация, мезенхимные стволовые клетки, сердечно-сосудистые заболевания, сердечная недостаточность.

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Amir Nejad-Moghaddam1,2

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1 Marine Medicine Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
2 Faculty of Science, Imam Khamenei University, Zibakenar, Rasht, Iran


Correspondence:
Dr. Amir Nejad-Moghaddam, Marine Medicine Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
Phone: +98 (911) 227-65-63
E-mail: mab.biology@gmail.com


Citation: Nejad-Moghaddam A. Clinical safety and efficacy of mesenchymal stem cell transplantation for the treatment of heart diseases: A narrative review. Cell Ther Transplant 2024; 13(1): 16-27.

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Stem cell therapy is a promising therapeutic approach for the treatment of heart diseases. One of the major challenges is identifying and selecting the best type of stem cell suitable for regenerative treatment. Bone marrow mononuclear cells, bone marrow, and adipose tissue-derived mesenchymal stem cells, endogenous cardiac stem cells, endothelial progenitor cells, and induced pluripotent stem cells are some of the types of stem cells that have been tested in order to promote the missed myocardial regeneration. Meanwhile, most of these cell types are evaluated for safety and efficacy in clinical trials. However, their clinical testing showed significant heterogeneity in terms of efficacy. Therefore, the main challenge is to provide clear experimental evidence of heart function improvement after stem cell administration. Among different transplant types, mesenchymal stem cells (MSCs) are derived from a wide range of sources and are easily isolated and cultured. MSCs have the capacity for proliferation and self-renewal in vitro, low immunogenicity and immunomodulatory properties, and, under certain conditions, may be differentiated into distinct cell types. In this review article, we take a comprehensive look at the use of MSCs for heart regeneration and discuss why related factors such as practicality and difficulty in cell collection should also be considered when selecting stem cells for transplantation.

Keywords

Cell therapy, regeneration, heart diseases, mesenchymal stem cell, cardiovascular disease, heart failure.

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Amir Nejad-Moghaddam1,2

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Amir Nejad-Moghaddam1,2

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Stem cell therapy is a promising therapeutic approach for the treatment of heart diseases. One of the major challenges is identifying and selecting the best type of stem cell suitable for regenerative treatment. Bone marrow mononuclear cells, bone marrow, and adipose tissue-derived mesenchymal stem cells, endogenous cardiac stem cells, endothelial progenitor cells, and induced pluripotent stem cells are some of the types of stem cells that have been tested in order to promote the missed myocardial regeneration. Meanwhile, most of these cell types are evaluated for safety and efficacy in clinical trials. However, their clinical testing showed significant heterogeneity in terms of efficacy. Therefore, the main challenge is to provide clear experimental evidence of heart function improvement after stem cell administration. Among different transplant types, mesenchymal stem cells (MSCs) are derived from a wide range of sources and are easily isolated and cultured. MSCs have the capacity for proliferation and self-renewal in vitro, low immunogenicity and immunomodulatory properties, and, under certain conditions, may be differentiated into distinct cell types. In this review article, we take a comprehensive look at the use of MSCs for heart regeneration and discuss why related factors such as practicality and difficulty in cell collection should also be considered when selecting stem cells for transplantation.

Keywords

Cell therapy, regeneration, heart diseases, mesenchymal stem cell, cardiovascular disease, heart failure.

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Stem cell therapy is a promising therapeutic approach for the treatment of heart diseases. One of the major challenges is identifying and selecting the best type of stem cell suitable for regenerative treatment. Bone marrow mononuclear cells, bone marrow, and adipose tissue-derived mesenchymal stem cells, endogenous cardiac stem cells, endothelial progenitor cells, and induced pluripotent stem cells are some of the types of stem cells that have been tested in order to promote the missed myocardial regeneration. Meanwhile, most of these cell types are evaluated for safety and efficacy in clinical trials. However, their clinical testing showed significant heterogeneity in terms of efficacy. Therefore, the main challenge is to provide clear experimental evidence of heart function improvement after stem cell administration. Among different transplant types, mesenchymal stem cells (MSCs) are derived from a wide range of sources and are easily isolated and cultured. MSCs have the capacity for proliferation and self-renewal in vitro, low immunogenicity and immunomodulatory properties, and, under certain conditions, may be differentiated into distinct cell types. In this review article, we take a comprehensive look at the use of MSCs for heart regeneration and discuss why related factors such as practicality and difficulty in cell collection should also be considered when selecting stem cells for transplantation.

Keywords

Cell therapy, regeneration, heart diseases, mesenchymal stem cell, cardiovascular disease, heart failure.

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1 Marine Medicine Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
2 Faculty of Science, Imam Khamenei University, Zibakenar, Rasht, Iran


Correspondence:
Dr. Amir Nejad-Moghaddam, Marine Medicine Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
Phone: +98 (911) 227-65-63
E-mail: mab.biology@gmail.com


Citation: Nejad-Moghaddam A. Clinical safety and efficacy of mesenchymal stem cell transplantation for the treatment of heart diseases: A narrative review. Cell Ther Transplant 2024; 13(1): 16-27.

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1 Marine Medicine Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
2 Faculty of Science, Imam Khamenei University, Zibakenar, Rasht, Iran


Correspondence:
Dr. Amir Nejad-Moghaddam, Marine Medicine Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
Phone: +98 (911) 227-65-63
E-mail: mab.biology@gmail.com


Citation: Nejad-Moghaddam A. Clinical safety and efficacy of mesenchymal stem cell transplantation for the treatment of heart diseases: A narrative review. Cell Ther Transplant 2024; 13(1): 16-27.

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Амир Неджад Мохаддам1,2

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Амир Неджад Мохаддам1,2

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Одной из главных проблем является уточнение и выбор наилучшего типа стволовых клеток, пригодных для регенеративного лечения. Мононуклеары костного мозга, мезенхимные клетки из костного мозга или жировой ткани, эндогенные стволовые клетки сердца, предшественники эндотелия и индуцированные плюрипотентные стволовые клетки находятся в ряду клеточных разновидностей, которые проверяли в плане усиления регенерации миокарда. В то же время многие из этих типов клеток оценивали в клинических испытаниях с точки зрения безопасности и эффективности. Однако тестирование их эффективности в клинике показало различные результаты в плане. Поэтому основной проблемой является получение четких экспериментальных доказательств улучшения сердечной функции после трансплантации стволовых клеток. В числе различных типов трансплантатов, мезенхимные стволовые клетки (МСК) получают из различных источников, их легко выделять и культивировать. МСК способны к пролиферации и самообновлению <i>in vitro</i>, обладают низкой иммуногенностью и имеют иммуномодулирующие свойства и, при определенных условиях, могут дифференцироваться в конкретные типы клеток. В этой обзорной статье мы рассматриваем применение МСК для регенерации сердца и обсуждаем, почему другие факторы, в том числе – процедуры и сложности сбора клеток также должны учитываться при выборе стволовых клеток для трансплантации.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Клеточная терапия, регенерация, мезенхимные стволовые клетки, сердечно-сосудистые заболевания, сердечная недостаточность. </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3057) "

Лечение стволовыми клетками является перспективным подходом к терапии сердечных заболеваний. Одной из главных проблем является уточнение и выбор наилучшего типа стволовых клеток, пригодных для регенеративного лечения. Мононуклеары костного мозга, мезенхимные клетки из костного мозга или жировой ткани, эндогенные стволовые клетки сердца, предшественники эндотелия и индуцированные плюрипотентные стволовые клетки находятся в ряду клеточных разновидностей, которые проверяли в плане усиления регенерации миокарда. В то же время многие из этих типов клеток оценивали в клинических испытаниях с точки зрения безопасности и эффективности. Однако тестирование их эффективности в клинике показало различные результаты в плане. Поэтому основной проблемой является получение четких экспериментальных доказательств улучшения сердечной функции после трансплантации стволовых клеток. В числе различных типов трансплантатов, мезенхимные стволовые клетки (МСК) получают из различных источников, их легко выделять и культивировать. МСК способны к пролиферации и самообновлению in vitro, обладают низкой иммуногенностью и имеют иммуномодулирующие свойства и, при определенных условиях, могут дифференцироваться в конкретные типы клеток. В этой обзорной статье мы рассматриваем применение МСК для регенерации сердца и обсуждаем, почему другие факторы, в том числе – процедуры и сложности сбора клеток также должны учитываться при выборе стволовых клеток для трансплантации.

Ключевые слова

Клеточная терапия, регенерация, мезенхимные стволовые клетки, сердечно-сосудистые заболевания, сердечная недостаточность.

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Лечение стволовыми клетками является перспективным подходом к терапии сердечных заболеваний. Одной из главных проблем является уточнение и выбор наилучшего типа стволовых клеток, пригодных для регенеративного лечения. Мононуклеары костного мозга, мезенхимные клетки из костного мозга или жировой ткани, эндогенные стволовые клетки сердца, предшественники эндотелия и индуцированные плюрипотентные стволовые клетки находятся в ряду клеточных разновидностей, которые проверяли в плане усиления регенерации миокарда. В то же время многие из этих типов клеток оценивали в клинических испытаниях с точки зрения безопасности и эффективности. Однако тестирование их эффективности в клинике показало различные результаты в плане. Поэтому основной проблемой является получение четких экспериментальных доказательств улучшения сердечной функции после трансплантации стволовых клеток. В числе различных типов трансплантатов, мезенхимные стволовые клетки (МСК) получают из различных источников, их легко выделять и культивировать. МСК способны к пролиферации и самообновлению in vitro, обладают низкой иммуногенностью и имеют иммуномодулирующие свойства и, при определенных условиях, могут дифференцироваться в конкретные типы клеток. В этой обзорной статье мы рассматриваем применение МСК для регенерации сердца и обсуждаем, почему другие факторы, в том числе – процедуры и сложности сбора клеток также должны учитываться при выборе стволовых клеток для трансплантации.

Ключевые слова

Клеточная терапия, регенерация, мезенхимные стволовые клетки, сердечно-сосудистые заболевания, сердечная недостаточность.

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1 Научный центр морской медицины, Медицинский университет Бахияталла, Тегеран, Иран
2 Факультет наук, Университет имама Хаменеи, Зибакенар, Решт, Иран

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1 Научный центр морской медицины, Медицинский университет Бахияталла, Тегеран, Иран
2 Факультет наук, Университет имама Хаменеи, Зибакенар, Решт, Иран

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Introduction

Hematopoietic stem cell transplantation (HSCT) is an effective method of treating malignant diseases of the blood system (leukemia, lymphoma, chronic myeloproliferative diseases, multiple myeloma), congenital and acquired aplasia of hematopoiesis, primary immunodeficiency, autoimmune disorders.

More than 50,000 HSCTs are performed annually worldwide [1, 2]. The life-threatening diseases comprise major indication for HSCT which is routinely applied and consists of several stages: 1) myelo- and immunoablation with the use of chemotherapy of varying intensity (conditioning regimen); 2) prevention of the graft-versus-host disease (GvHD), 3) graft transfusion; 4) prevention and treatment of complications during postcytostatic aplasia of hematopoiesis and graft engraftment period [3].

The following factors are most important for the successful HSCT: 1) clinical status of the underlying disease (remission, progression, etc.); 2) the type of HSCT associated with donor selection [4]; 3) conditioning regimen and GvHD prevention; 4) comorbidity (obesity, significant dysfunction of the heart, kidneys, liver, lungs, diabetes mellitus, other tumors, autoimmune diseases, significant gastrointestinal diseases, infections, etc).

The comorbidity index of HSCT patient [5, 6] as recommended by the European Society for Blood and Marrow Transplantation (EBMT), involves 17 parameters, each of which is assessed in 1 to 3 points. The total zero score determines a low risk of death (4%) up to 100 days after HSCT. The values of 1 to 3 points represent intermediate risk (16%); >3 points are associated with high risk of death (29%). Hence, the recipient is assessed at 3 points in case of severe liver, or lung dysfunction. A history of acute cerebrovascular accident (CVA) may add only 1 point, thus implying a possible negative contribution of previous acute CVA of <3%.

Thus, we discuss a clinical category that may impact the survival of HSCT recipient, however, considered in the context of other, more affecting factors. Precise role of the past acute stroke as a risk factor for HSCT outcomes is difficult within a single-center study. However, evaluation of this factor seems to be important for the problem statement.

Brain stroke is known to be a common complication in the cancer patients [7-9]. Some oncological diseases, especially with primary damage to the nervous system, as well as leukemias (due to high risk of blast cell-induced damage), may be strongly associated with development of ischemic and hemorrhagic strokes [10-12]. Some data indicate a higher risk of hemorrhagic and ischemic stroke in the first 6 months after the oncological diagnosis, while the development of a cerebrovascular event worsens the patient's prognosis in the future [13-15]. The stroke is known to occur in 3% of patients over the post-transplant period (potentially 1,500 per year). Of them, 70% are at risk of unfavorable outcome in the next 1.5 years [9]. The data on effects of preceding stroke on the outcome of subsequent HSCT are not presented in the literature. Our aim was to evaluate the effects of pre-transplant cerebrovascular accidents (CVA) on the outcomes of HSCT in patients with oncohematological diseases.

Materials and methods

Within single-center retrospective cohort study, medical documents of 899 HSCT patients were analyzed at the RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology (Pavlov University, St. Petersburg) from January 2016 to January 2018. Different HSCT parameters, characteristics of the donor and recipient, as well as performance status and clinical data at the last visit to neurologist were registered for all patients (Table 1). The protocol of the recipient examination before HSCT included a survey by a neurologist and results of imaging studies (depending on the age and type of HSCT). The endpoint of the study was the recording of lethal outcomes.

Two groups of patients were under study: 1) subjects with a history of stroke (till 2 years) before HSCT (n=16), 2) patients without a history of stroke before HSCT (n=883). The intergroup characteristics were compared using Fisher test (for categorical features) and Mann-Whitney-Wilcoxon test (for quantitative parameters). The obtained p values were compared at a threshold level of 0.05. To ensure the balance of clinically significant signs between the compared groups, pseudo-randomization was performed using the Propensity Score Matching method (group ratio 1:15). Such parameters as allogeneic HSCT, underlying disease (leukemia), complete HLA compatibility of the donor-recipient pairs were coded as "1". Autologous type of HSCT, primary disease other than leukemia, partial matching of donor and recipient were coded as "0". Survival analysis was performed using the Kaplan-Meier method and log-rank test. Statistical data processing was carried out using the R application package (version 4.1.2).

Table 1. Clinical characteristics of HSCT recipients over the period of 2016 to 2018 depending on the presence/absence of stroke in anamnesis

Polushin-tab01.jpg

Note: F, females, M, males; MPD, myeloproliferative disease; MDS, myelodysplastic syndrome; CR – conditioning regimen; CVD, cardiovascular disease.

Results

Among the recipients of HSCT for the period 2016-2018, cerebrovascular events (within a period of no more than 2 years before the procedure) were noted in 1.8% of cases (n=16) including 4 patients (0.4%) with a history of ischemic stroke, and 12 patients (1.4%), with hemorrhagic stroke or intracranial hemorrhage. Among the patients with a history of CVA, when compared with CVA-free cases, the leukemia patients were more common (68.8% vs 64.0%; p=0.01). Partial HLA-compatibility in recipient-donor pairs was more often (60.0% versus 35.7%; p=0.06). The patients with cerebrovascular events also had a lower body mass index (1.23±0.5 vs 1.55±0.5; p=0.02) and lower Karnofsky/Lansky index among patients <14 years of age (73.75±20.9 vs 85.14±15.0, р=0.01), as shown in Table 1.

Due to the revealed heterogeneity of groups for a number of clinically significant parameters and small number of patients with CVA, pseudo-randomization was carried out, and a sample of patients without CVA was established according to a ratio of 1:15 (Fig. 1).

Polushin-fig01.jpg

Figure 1. Balance of covariates during pseudorandomization of patients with a stroke observed before HSCT

Following the pseudorandomization, occurence of CVA proved to be significantly associated with decrease in overall survival post-transplant (mean observation period was 24 months) (Fig. 2).

Polushin-fig02.jpg

Figure 2. Survival after HSCT in patients with a history of stroke

In the group of patients with a history of CVA before HSCT, the proportion of acute leukemias was higher (68.8% vs 40.4%, p=0.02) compared to the non-leukemic cases. Of 11 patients with acute leukemia and stroke, 3 had acute lymphoblastic leukemia (ALL). These ALL patients were under 13 years, with long clinical history (from 1 to 9 years) and recurrent disease with extramedullary lesions (2 cases, CNS; 1, testicular affection), severe pretreatment (repeated chemotherapy, 3; immunotherapy, 2; history of 1st HSCT, 1). The disease status at the start of conditioning therapy was as follows: 3rd remission in 2 patients, and first relapse in one case.

In the CVA group, 8 recipients of HSCT (children, 2; adults, 6 cases) had the primary diagnosis of acute myeloid leukemia. At the time of HSCT, 3 patients were in remission, whereas 5 cases showed the disease progression. There were no previous episodes of specific CNS damage. In three cases, repeated HSCT was performed. In 7 patients, HSCT was carried out within first 6 months from the diagnosis; in one case, within 1 year, and in 1 patient – after 6 years.

One patient at the age of 7 years had mature cell T-lymphoma, being rare in childhood, with brain damage and development of subacute subdural hematoma (6,5 months prior to HSCT). This patient underwent autologous HSCT and 2 allogeneic HSCTs from a haploidentical donor (now it is remission).

In one patient aged 22 years with acquired aplastic anemia, a spontaneous subarachnoid hemorrhage occurred 5 months prior to unrelated HSCT. Currently, the patient is in remission with stable donor hematopoiesis.

Two patients with congenital diseases (Fanconi anemia and osteopetrosis, 2 and 6 years, respectively) had a history of subdural hematomas 3 and 6 months before allogeneic HSCT. A patient with Fanconi anemia died from infectious complications due to insufficient graft function. The patient with osteopetrosis is alive, the graft is functioning properly.

Discussion

A significantly increased choice of pharmacological drugs over recent years has an impact on therapeutic strategies for this category of patients, and, consequently, on the range of complications connected with their use. Damage to the central nervous system, not associated with the underlying disease and infectious complications, may develop both due to direct toxic effects of certain drugs, and by indirect pathways. Complications of HSCT result from a large number of factors, e.g., high intensity of conditioning regimen, comorbidity and transplant-associated mechanisms. In most CNS events, the etiology of the process is not obvious, with similar clinical manifestations or significantly erased symptoms. The diagnostic options are limited to neuroimaging, functional, cytological, microbiological studies. Any in vivo morphological and immunological diagnostics are extremely difficult.

Among other approaches, targeted therapy may be performed as a "bridge-therapy" prior to HSCT. The target treatment may be accompanied by the development of neurological complications. Their occurrence has not been studied enough in oncohematological patients. The frequency of complications of allogeneic HSCT according to the literature data varies at a large scale: 3 to 70% [16-20]. Long-term (sequel) neurological complications make a negative contribution to survival after allogeneic HSCT, doubling mortality rates (p=0.007) [21]. CVA as a complication of HSCT, could be simply diagnosed, being a risk factor for poor outcome in patients undergoing HSCT (p=0.001) [22, 23]. To our knowledge, there are no data on the effect of stroke before HSCT on its outcome in the group of oncohematological patients.

The data analysis of the clinical register of HSCT recipients at the RM Gorbacheva Research Institute (EBMT CIC 725) for the period 2016-2018 has shown that, among 899 patients, the incidence of stroke before HSCT is 1.8% (n=16; 1.4%, hemorrhagic stroke; 0.4%, ischemic).

The relationship between stroke and leukemia revealed in our study does not contradict the data of Del Prete C. et al. [24] who reported that the risk of stroke increases 50-fold in the AML group, and their mortality is 5.5% times higher than among stroke patients without oncohematological disease [24]. Other factors logically fit into the previously proposed "red flags" for pre-transplant evaluation of oncohematological patients [4-6] including some risk factors, e.g., allogeneic HSCT, low Karnofsky/Lansky index (ECOG).

It should be noted that among the studied patients with stroke, there were no cases with definite risk factors for CVA, such as diabetes mellitus, venous disorders, radiation therapy before HSCT, and reduced cardiac output. One should also note that there were no signs of cardiovascular pathology before HSCT in 13 out of 16 patients with stroke, thus, probably, indicating a discrepancy between the risk factors of patients in the study group versus patients without oncohematological diagnosis. Therefore, it may be incorrect to apply current recommendations for secondary prevention of stroke at the stage of treatment of the main oncological diseases to the patients from our study group [25, 26]. Moreover, stroke in the oncohematological group of patients may result from other causes.

CVA of the hemorrhagic type in patients with osteopetrosis can develop with the slightest injury, which is most likely associated with damage to the developing brain caused by abnormally changed size of the skull (hyperostosis). As a result, the structures of the brain lose their "compensatory" spaces, in addition, "tension" of the choroid plexuses can form. Also, in oncological patients, the development of stroke of the hemorrhagic type can be facilitated by emetic syndrome during therapy with chemotherapy drugs, antibiotics, etc. and high infusion load. In some types of AML, bleeding is especially common, being, associated with the properties of the tumor clone and thrombocytopenia. In AML treatment, aplasia and thrombocytopenia develop at each stage of chemotherapy. Toxic effects of chemotherapy drugs include damage of vascular walls.

Hemorrhagic stroke in patients with oncohematological profile is usually associated with thrombocytopenia, acute renal failure, high fibrinogen levels, and cytokine reactions in response to a bacterial infection [27]. Cytokine responses may also result from an immune donor/recipient aberrant response. Pathological significance of these factors is enhanced after HSCT.

Moreover, ischemic stroke in this cohort of patients may be associated with hyperleukocytosis, hypernatremia, and disseminated intravascular coagulation [28]. So, for example, stroke in acute myeloid leukemia at the onset of the disease is associated with severely altered hematopoiesis and its replacement with a non-functional malignant cells. Our experience indicates that oncohematological patients do not have atherosclerotic manifestations at the intra- and extracerebral vascular level, so the probability of an athero-thrombotic subtype of stroke is minimal.

Infiltration of the ischemic brain with immune cells marks an essential step in post-ischemic inflammation. It has been demonstrated that CD38+ cell deficiency impairs lymphocyte activation, modulates the production of cytokines by lymphocytes [29], affects migration and activation of immune cells necessary for the development of a postischemic inflammatory response that contributes to secondary brain damage and an increase in the area of focal ischemia [30]. However, to date, there is no complete understanding of the behavior of cells (monocytes, macrophages) of both the recipient and the donor in the area of the brain ischemic/hemorrhagic zone before HSCT, especially under conditions of pancytopenia.

Conclusion

A history of stroke before HSCT can probably negatively affect the course of the post-transplant period. However, the high risk of death in such a complex category of patients cannot be explained by the only history of stroke, since CVA (stroke) is not an independent and absolutely fatal factor. It is associated with the most important criteria that have proven their influence on the outcome of HSCT, i.e., the status of malignant disease at the time of HSCT, comorbidity and constitutional features of the patient, degree of the donor-recipient HLA-compatibility, and the choice of conditioning regimen based on clinical characteristics and stage of the malignancy [4-6].

To date, a pre-transplant stroke in the history of HSCT recipient is not a contraindication for this treatment option. However, in view of their condition, assessed by ECOG, Karnofsky, Lansky scales, not every patient is eligible for this treatment method. All indices assess the patient's ability to self-service, respectively, potential recipients who, after stroke, did not reach the required level, may be not fit for HSCT. Thus, the selection of HSCT recipients is a very important point of the preparatory stage when planning such a complex procedure.

Possible reasons affecting outcomes in the study group of patients may be as follows: inability to comply with recommendations for secondary prevention of stroke at the stage of conditioning and during post-transplant period, as well as limitation of motor activity (low Karnofsky index), which hypothetically may be associated with an increased risk of venous thrombosis, hypodynamic muscle atrophy, thus delaying restoration of hematopoiesis.

Despite the fact that patients with a history of stroke had a lower survival rate after HSCT, a quarter of patients were able to tolerate the treatment. This finding indicates that a history of stroke cannot be an exclusion criterion for the potentially life-saving procedure in case of oncohematological disorder. Therefore, an interdisciplinary search for a balance between indications and contraindications for allogeneic HSCT is needed.

The limitations of our study are due to its design (single-center, retrospective), a relatively small sample of patients with a documented acute cerebrovascular accident before HSCT (limitation of certain types of statistical analysis, including assessment of the impact of the timing from the onset of stroke to the start of the procedure HSCT) and factors associated with the use of pseudorandomization [31]. Further studies are needed to identify and classify the factors associated with poor outcomes in patients with oncohematological diseases and a history of stroke.

Conflict of interest

The study had no sponsorship. Authors declare no conflict of interest. The authors are fully responsible for submitting the final version of the manuscript. All the authors took part in the development of the concept of the article and the writing of the manuscript. The final version of the manuscript was approved by all authors.

Compliance with ethical principles

The authors confirm that they respect the rights of the people participated in the study, including obtaining the required informed consent.

References

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  27. Zöller B, Ji J, Sundquist J, Sundquist K. Risk of haemorrhagic and ischaemic stroke in patients with cancer: a nationwide follow-up study from Sweden. Eur J Cancer. 2012; 48(12): 1875-1883. doi: 10.1016/j.ejca.2012.01.005
  28. Bova I, Bornstein N, Korczyn A. Acute infection as a risk factor for ischemic stroke. Stroke 1996; 27:2204-6. doi: 10.1161/01.str.27.12.2204
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  30. Choe CU, Lardong K, Gelderblom M, Ludewig P, Leypoldt F, Koch-Nolte F, et al. CD38 exacerbates focal cytokine production, postischemic inflammation and brain injury after focal cerebral ischemia. PLoS One. 2011; 6(5):e19046.
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" ["~DETAIL_TEXT"]=> string(29723) "

Introduction

Hematopoietic stem cell transplantation (HSCT) is an effective method of treating malignant diseases of the blood system (leukemia, lymphoma, chronic myeloproliferative diseases, multiple myeloma), congenital and acquired aplasia of hematopoiesis, primary immunodeficiency, autoimmune disorders.

More than 50,000 HSCTs are performed annually worldwide [1, 2]. The life-threatening diseases comprise major indication for HSCT which is routinely applied and consists of several stages: 1) myelo- and immunoablation with the use of chemotherapy of varying intensity (conditioning regimen); 2) prevention of the graft-versus-host disease (GvHD), 3) graft transfusion; 4) prevention and treatment of complications during postcytostatic aplasia of hematopoiesis and graft engraftment period [3].

The following factors are most important for the successful HSCT: 1) clinical status of the underlying disease (remission, progression, etc.); 2) the type of HSCT associated with donor selection [4]; 3) conditioning regimen and GvHD prevention; 4) comorbidity (obesity, significant dysfunction of the heart, kidneys, liver, lungs, diabetes mellitus, other tumors, autoimmune diseases, significant gastrointestinal diseases, infections, etc).

The comorbidity index of HSCT patient [5, 6] as recommended by the European Society for Blood and Marrow Transplantation (EBMT), involves 17 parameters, each of which is assessed in 1 to 3 points. The total zero score determines a low risk of death (4%) up to 100 days after HSCT. The values of 1 to 3 points represent intermediate risk (16%); >3 points are associated with high risk of death (29%). Hence, the recipient is assessed at 3 points in case of severe liver, or lung dysfunction. A history of acute cerebrovascular accident (CVA) may add only 1 point, thus implying a possible negative contribution of previous acute CVA of <3%.

Thus, we discuss a clinical category that may impact the survival of HSCT recipient, however, considered in the context of other, more affecting factors. Precise role of the past acute stroke as a risk factor for HSCT outcomes is difficult within a single-center study. However, evaluation of this factor seems to be important for the problem statement.

Brain stroke is known to be a common complication in the cancer patients [7-9]. Some oncological diseases, especially with primary damage to the nervous system, as well as leukemias (due to high risk of blast cell-induced damage), may be strongly associated with development of ischemic and hemorrhagic strokes [10-12]. Some data indicate a higher risk of hemorrhagic and ischemic stroke in the first 6 months after the oncological diagnosis, while the development of a cerebrovascular event worsens the patient's prognosis in the future [13-15]. The stroke is known to occur in 3% of patients over the post-transplant period (potentially 1,500 per year). Of them, 70% are at risk of unfavorable outcome in the next 1.5 years [9]. The data on effects of preceding stroke on the outcome of subsequent HSCT are not presented in the literature. Our aim was to evaluate the effects of pre-transplant cerebrovascular accidents (CVA) on the outcomes of HSCT in patients with oncohematological diseases.

Materials and methods

Within single-center retrospective cohort study, medical documents of 899 HSCT patients were analyzed at the RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology (Pavlov University, St. Petersburg) from January 2016 to January 2018. Different HSCT parameters, characteristics of the donor and recipient, as well as performance status and clinical data at the last visit to neurologist were registered for all patients (Table 1). The protocol of the recipient examination before HSCT included a survey by a neurologist and results of imaging studies (depending on the age and type of HSCT). The endpoint of the study was the recording of lethal outcomes.

Two groups of patients were under study: 1) subjects with a history of stroke (till 2 years) before HSCT (n=16), 2) patients without a history of stroke before HSCT (n=883). The intergroup characteristics were compared using Fisher test (for categorical features) and Mann-Whitney-Wilcoxon test (for quantitative parameters). The obtained p values were compared at a threshold level of 0.05. To ensure the balance of clinically significant signs between the compared groups, pseudo-randomization was performed using the Propensity Score Matching method (group ratio 1:15). Such parameters as allogeneic HSCT, underlying disease (leukemia), complete HLA compatibility of the donor-recipient pairs were coded as "1". Autologous type of HSCT, primary disease other than leukemia, partial matching of donor and recipient were coded as "0". Survival analysis was performed using the Kaplan-Meier method and log-rank test. Statistical data processing was carried out using the R application package (version 4.1.2).

Table 1. Clinical characteristics of HSCT recipients over the period of 2016 to 2018 depending on the presence/absence of stroke in anamnesis

Polushin-tab01.jpg

Note: F, females, M, males; MPD, myeloproliferative disease; MDS, myelodysplastic syndrome; CR – conditioning regimen; CVD, cardiovascular disease.

Results

Among the recipients of HSCT for the period 2016-2018, cerebrovascular events (within a period of no more than 2 years before the procedure) were noted in 1.8% of cases (n=16) including 4 patients (0.4%) with a history of ischemic stroke, and 12 patients (1.4%), with hemorrhagic stroke or intracranial hemorrhage. Among the patients with a history of CVA, when compared with CVA-free cases, the leukemia patients were more common (68.8% vs 64.0%; p=0.01). Partial HLA-compatibility in recipient-donor pairs was more often (60.0% versus 35.7%; p=0.06). The patients with cerebrovascular events also had a lower body mass index (1.23±0.5 vs 1.55±0.5; p=0.02) and lower Karnofsky/Lansky index among patients <14 years of age (73.75±20.9 vs 85.14±15.0, р=0.01), as shown in Table 1.

Due to the revealed heterogeneity of groups for a number of clinically significant parameters and small number of patients with CVA, pseudo-randomization was carried out, and a sample of patients without CVA was established according to a ratio of 1:15 (Fig. 1).

Polushin-fig01.jpg

Figure 1. Balance of covariates during pseudorandomization of patients with a stroke observed before HSCT

Following the pseudorandomization, occurence of CVA proved to be significantly associated with decrease in overall survival post-transplant (mean observation period was 24 months) (Fig. 2).

Polushin-fig02.jpg

Figure 2. Survival after HSCT in patients with a history of stroke

In the group of patients with a history of CVA before HSCT, the proportion of acute leukemias was higher (68.8% vs 40.4%, p=0.02) compared to the non-leukemic cases. Of 11 patients with acute leukemia and stroke, 3 had acute lymphoblastic leukemia (ALL). These ALL patients were under 13 years, with long clinical history (from 1 to 9 years) and recurrent disease with extramedullary lesions (2 cases, CNS; 1, testicular affection), severe pretreatment (repeated chemotherapy, 3; immunotherapy, 2; history of 1st HSCT, 1). The disease status at the start of conditioning therapy was as follows: 3rd remission in 2 patients, and first relapse in one case.

In the CVA group, 8 recipients of HSCT (children, 2; adults, 6 cases) had the primary diagnosis of acute myeloid leukemia. At the time of HSCT, 3 patients were in remission, whereas 5 cases showed the disease progression. There were no previous episodes of specific CNS damage. In three cases, repeated HSCT was performed. In 7 patients, HSCT was carried out within first 6 months from the diagnosis; in one case, within 1 year, and in 1 patient – after 6 years.

One patient at the age of 7 years had mature cell T-lymphoma, being rare in childhood, with brain damage and development of subacute subdural hematoma (6,5 months prior to HSCT). This patient underwent autologous HSCT and 2 allogeneic HSCTs from a haploidentical donor (now it is remission).

In one patient aged 22 years with acquired aplastic anemia, a spontaneous subarachnoid hemorrhage occurred 5 months prior to unrelated HSCT. Currently, the patient is in remission with stable donor hematopoiesis.

Two patients with congenital diseases (Fanconi anemia and osteopetrosis, 2 and 6 years, respectively) had a history of subdural hematomas 3 and 6 months before allogeneic HSCT. A patient with Fanconi anemia died from infectious complications due to insufficient graft function. The patient with osteopetrosis is alive, the graft is functioning properly.

Discussion

A significantly increased choice of pharmacological drugs over recent years has an impact on therapeutic strategies for this category of patients, and, consequently, on the range of complications connected with their use. Damage to the central nervous system, not associated with the underlying disease and infectious complications, may develop both due to direct toxic effects of certain drugs, and by indirect pathways. Complications of HSCT result from a large number of factors, e.g., high intensity of conditioning regimen, comorbidity and transplant-associated mechanisms. In most CNS events, the etiology of the process is not obvious, with similar clinical manifestations or significantly erased symptoms. The diagnostic options are limited to neuroimaging, functional, cytological, microbiological studies. Any in vivo morphological and immunological diagnostics are extremely difficult.

Among other approaches, targeted therapy may be performed as a "bridge-therapy" prior to HSCT. The target treatment may be accompanied by the development of neurological complications. Their occurrence has not been studied enough in oncohematological patients. The frequency of complications of allogeneic HSCT according to the literature data varies at a large scale: 3 to 70% [16-20]. Long-term (sequel) neurological complications make a negative contribution to survival after allogeneic HSCT, doubling mortality rates (p=0.007) [21]. CVA as a complication of HSCT, could be simply diagnosed, being a risk factor for poor outcome in patients undergoing HSCT (p=0.001) [22, 23]. To our knowledge, there are no data on the effect of stroke before HSCT on its outcome in the group of oncohematological patients.

The data analysis of the clinical register of HSCT recipients at the RM Gorbacheva Research Institute (EBMT CIC 725) for the period 2016-2018 has shown that, among 899 patients, the incidence of stroke before HSCT is 1.8% (n=16; 1.4%, hemorrhagic stroke; 0.4%, ischemic).

The relationship between stroke and leukemia revealed in our study does not contradict the data of Del Prete C. et al. [24] who reported that the risk of stroke increases 50-fold in the AML group, and their mortality is 5.5% times higher than among stroke patients without oncohematological disease [24]. Other factors logically fit into the previously proposed "red flags" for pre-transplant evaluation of oncohematological patients [4-6] including some risk factors, e.g., allogeneic HSCT, low Karnofsky/Lansky index (ECOG).

It should be noted that among the studied patients with stroke, there were no cases with definite risk factors for CVA, such as diabetes mellitus, venous disorders, radiation therapy before HSCT, and reduced cardiac output. One should also note that there were no signs of cardiovascular pathology before HSCT in 13 out of 16 patients with stroke, thus, probably, indicating a discrepancy between the risk factors of patients in the study group versus patients without oncohematological diagnosis. Therefore, it may be incorrect to apply current recommendations for secondary prevention of stroke at the stage of treatment of the main oncological diseases to the patients from our study group [25, 26]. Moreover, stroke in the oncohematological group of patients may result from other causes.

CVA of the hemorrhagic type in patients with osteopetrosis can develop with the slightest injury, which is most likely associated with damage to the developing brain caused by abnormally changed size of the skull (hyperostosis). As a result, the structures of the brain lose their "compensatory" spaces, in addition, "tension" of the choroid plexuses can form. Also, in oncological patients, the development of stroke of the hemorrhagic type can be facilitated by emetic syndrome during therapy with chemotherapy drugs, antibiotics, etc. and high infusion load. In some types of AML, bleeding is especially common, being, associated with the properties of the tumor clone and thrombocytopenia. In AML treatment, aplasia and thrombocytopenia develop at each stage of chemotherapy. Toxic effects of chemotherapy drugs include damage of vascular walls.

Hemorrhagic stroke in patients with oncohematological profile is usually associated with thrombocytopenia, acute renal failure, high fibrinogen levels, and cytokine reactions in response to a bacterial infection [27]. Cytokine responses may also result from an immune donor/recipient aberrant response. Pathological significance of these factors is enhanced after HSCT.

Moreover, ischemic stroke in this cohort of patients may be associated with hyperleukocytosis, hypernatremia, and disseminated intravascular coagulation [28]. So, for example, stroke in acute myeloid leukemia at the onset of the disease is associated with severely altered hematopoiesis and its replacement with a non-functional malignant cells. Our experience indicates that oncohematological patients do not have atherosclerotic manifestations at the intra- and extracerebral vascular level, so the probability of an athero-thrombotic subtype of stroke is minimal.

Infiltration of the ischemic brain with immune cells marks an essential step in post-ischemic inflammation. It has been demonstrated that CD38+ cell deficiency impairs lymphocyte activation, modulates the production of cytokines by lymphocytes [29], affects migration and activation of immune cells necessary for the development of a postischemic inflammatory response that contributes to secondary brain damage and an increase in the area of focal ischemia [30]. However, to date, there is no complete understanding of the behavior of cells (monocytes, macrophages) of both the recipient and the donor in the area of the brain ischemic/hemorrhagic zone before HSCT, especially under conditions of pancytopenia.

Conclusion

A history of stroke before HSCT can probably negatively affect the course of the post-transplant period. However, the high risk of death in such a complex category of patients cannot be explained by the only history of stroke, since CVA (stroke) is not an independent and absolutely fatal factor. It is associated with the most important criteria that have proven their influence on the outcome of HSCT, i.e., the status of malignant disease at the time of HSCT, comorbidity and constitutional features of the patient, degree of the donor-recipient HLA-compatibility, and the choice of conditioning regimen based on clinical characteristics and stage of the malignancy [4-6].

To date, a pre-transplant stroke in the history of HSCT recipient is not a contraindication for this treatment option. However, in view of their condition, assessed by ECOG, Karnofsky, Lansky scales, not every patient is eligible for this treatment method. All indices assess the patient's ability to self-service, respectively, potential recipients who, after stroke, did not reach the required level, may be not fit for HSCT. Thus, the selection of HSCT recipients is a very important point of the preparatory stage when planning such a complex procedure.

Possible reasons affecting outcomes in the study group of patients may be as follows: inability to comply with recommendations for secondary prevention of stroke at the stage of conditioning and during post-transplant period, as well as limitation of motor activity (low Karnofsky index), which hypothetically may be associated with an increased risk of venous thrombosis, hypodynamic muscle atrophy, thus delaying restoration of hematopoiesis.

Despite the fact that patients with a history of stroke had a lower survival rate after HSCT, a quarter of patients were able to tolerate the treatment. This finding indicates that a history of stroke cannot be an exclusion criterion for the potentially life-saving procedure in case of oncohematological disorder. Therefore, an interdisciplinary search for a balance between indications and contraindications for allogeneic HSCT is needed.

The limitations of our study are due to its design (single-center, retrospective), a relatively small sample of patients with a documented acute cerebrovascular accident before HSCT (limitation of certain types of statistical analysis, including assessment of the impact of the timing from the onset of stroke to the start of the procedure HSCT) and factors associated with the use of pseudorandomization [31]. Further studies are needed to identify and classify the factors associated with poor outcomes in patients with oncohematological diseases and a history of stroke.

Conflict of interest

The study had no sponsorship. Authors declare no conflict of interest. The authors are fully responsible for submitting the final version of the manuscript. All the authors took part in the development of the concept of the article and the writing of the manuscript. The final version of the manuscript was approved by all authors.

Compliance with ethical principles

The authors confirm that they respect the rights of the people participated in the study, including obtaining the required informed consent.

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В посттрансплантационном периоде инсульт возникает у 3% (около 1500 ежегодно) пациентов, при этом в 70% из них в последующие 1,5 года существует вероятность неблагоприятного исхода. Данных же о влиянии ОНМК в анамнезе на исход последующей ТГСК в литературе не представлено. Целью нашего исследования была оценка влияния перенесенного острого нарушения мозгового кровообращения (ОНМК) до ТГСК на исход трансплантации у пациентов с онкогематологическими заболеваниями.</p> <h3>Пациенты и методы</h3> <p style="text-align: justify;"> Проанализировано 899 трансплантаций в НИИ ДОГиТ им. Р.М. Горбачевой (ПСПбГМУ им. И.П. Павлова) с 2016 по 2018 гг. Анализу подлежали параметры трансплантации, характеристики донора и реципиента. Помимо сравнения признаков между группами, проводилась псевдорандомизация с помощью метода Propensity Score Matching. Анализ выживаемости осуществлялся с помощью метода Каплан-Майера и логрангового теста.</p> <h3>Результаты</h3> <p style="text-align: justify;"> Из 899 трансплантаций костного мозга у 16 пациентов (1,8%) выявлены цереброваскулярные события в анамнезе до трансплантации (0,4% – ишемический, 1,4% – геморрагический инсульт или внутричерепное кровоизлияние). В группе пациентов с цереброваскулярными событиями в анамнезе в сравнении с группой пациентов без таковых было больше пациентов с лейкозами (р=0,02), чаще выполнялась аллогенная трансплантация (р=0,01), доноры чаще имели частичную, а не полную совместимость с реципиентом по HLA-системе (р=0,06). Эти пациенты имели более низкие индекс массы тела (р=0,02) и индекс Карновского/Ланского (р=0,01). Наличие цереброваскулярного события было значимо ассоциировано со снижением общей выживаемости реципиентов ТГСК (р=0,0012).</p> <h3>Заключение</h3> <p style="text-align: justify;"> Для онкогематологических пациентов с инсультом перед трансплантацией не характерны «классические» факторы риска (сахарный диабет, заболевания венозной системы, сниженный сердечный выброс, выраженный атеросклероз прецеребральных артерий), что не в полной мере позволяет рассчитывать на потенциальную эффективность рекомендаций по вторичной профилактике ОНМК на этапе лечения основного заболевания. В статье обсуждаются более актуальные вероятные причины ОНМК у онкогематологических пациентов. Инсульт в анамнезе перед ТГСК (в совокупности с другими факторами, связанными с характеристиками донора, реципиента и методом лечения) может оказывать значимое влияние на исход трансплантации. На сегодняшний день ОНМК в анамнезе реципиента ТГСК не является противопоказанием для данного метода лечения. Однако селекция реципиентов является очень важным этапом при планировании столь сложного лечения и требует междисциплинарного поиска баланса между показаниями и противопоказаниями к проведению неродственной ТГСК.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;"> Инсульт, ишемический инсульт, геморрагический инсульт, гематологические заболевания, лейкозы, трансплантация гемопоэтических клеток, аллогенная трансплантация, неврологические осложнения.</p>" ["ELEMENT_PREVIEW_PICTURE_FILE_TITLE"]=> string(287) "Инсульт перед трансплантацией гемопоэтических стволовых клеток – возможный фактор риска неблагоприятного исхода терапии онкогематологических пациентов" ["ELEMENT_DETAIL_PICTURE_FILE_ALT"]=> string(287) "Инсульт перед трансплантацией гемопоэтических стволовых клеток – возможный фактор риска неблагоприятного исхода терапии онкогематологических пациентов" ["ELEMENT_DETAIL_PICTURE_FILE_TITLE"]=> string(287) "Инсульт перед трансплантацией гемопоэтических стволовых клеток – возможный фактор риска неблагоприятного исхода терапии онкогематологических пациентов" ["SECTION_META_TITLE"]=> string(287) "Инсульт перед трансплантацией гемопоэтических стволовых клеток – возможный фактор риска неблагоприятного исхода терапии онкогематологических пациентов" ["SECTION_META_KEYWORDS"]=> string(287) "Инсульт перед трансплантацией гемопоэтических стволовых клеток – возможный фактор риска неблагоприятного исхода терапии онкогематологических пациентов" ["SECTION_META_DESCRIPTION"]=> string(287) "Инсульт перед трансплантацией гемопоэтических стволовых клеток – возможный фактор риска неблагоприятного исхода терапии онкогематологических пациентов" ["SECTION_PICTURE_FILE_ALT"]=> string(287) "Инсульт перед трансплантацией гемопоэтических стволовых клеток – возможный фактор риска неблагоприятного исхода терапии онкогематологических пациентов" ["SECTION_PICTURE_FILE_TITLE"]=> string(287) "Инсульт перед трансплантацией гемопоэтических стволовых клеток – возможный фактор риска неблагоприятного исхода терапии онкогематологических пациентов" ["SECTION_PICTURE_FILE_NAME"]=> string(4) "-img" ["SECTION_DETAIL_PICTURE_FILE_ALT"]=> string(287) "Инсульт перед трансплантацией гемопоэтических стволовых клеток – возможный фактор риска неблагоприятного исхода терапии онкогематологических пациентов" ["SECTION_DETAIL_PICTURE_FILE_TITLE"]=> string(287) "Инсульт перед трансплантацией гемопоэтических стволовых клеток – возможный фактор риска неблагоприятного исхода терапии онкогематологических пациентов" ["SECTION_DETAIL_PICTURE_FILE_NAME"]=> string(4) "-img" ["ELEMENT_PREVIEW_PICTURE_FILE_NAME"]=> string(4) "-img" ["ELEMENT_DETAIL_PICTURE_FILE_NAME"]=> string(4) "-img" } ["FIELDS"]=> array(1) { ["IBLOCK_SECTION_ID"]=> string(3) "278" } ["PROPERTIES"]=> array(18) { ["KEYWORDS"]=> array(36) { ["ID"]=> string(2) "19" ["TIMESTAMP_X"]=> string(19) "2015-09-03 10:46:01" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(27) "Ключевые слова" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> 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["IBLOCK_MESS"]=> string(1) "N" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> bool(false) ["VALUE"]=> bool(false) ["DESCRIPTION"]=> bool(false) ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> bool(false) ["~DESCRIPTION"]=> bool(false) ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHOR_RU"]=> array(36) { ["ID"]=> string(2) "25" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "25" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "30978" ["VALUE"]=> array(2) { ["TEXT"]=> string(190) "<p>Алексей Ю. Полушин, Ярослав Б. Скиба, Мария Д. Владовская, Иван С. Моисеев, Александр Д. Кулагин </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(178) "

Алексей Ю. Полушин, Ярослав Б. Скиба, Мария Д. Владовская, Иван С. Моисеев, Александр Д. Кулагин

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "30979" ["VALUE"]=> array(2) { ["TEXT"]=> string(222) "<p>Первый Санкт-Петербургский государственный медицинский университет им. И. П. Павлова, Санкт-Петербург, Россия</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(210) "

Первый Санкт-Петербургский государственный медицинский университет им. И. П. Павлова, Санкт-Петербург, Россия

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "30980" ["VALUE"]=> array(2) { ["TEXT"]=> string(6066) "<p style="text-align: justify;">Ежегодно в мире выполняется более 50 тысяч трансплантаций гемопоэтических стволовых клеток (ТГСК) при злокачественных заболеваниях системы крови, солидных опухолях, аплазиях кроветворения, первичных иммунодефицитах, аутоиммунных заболеваниях и болезнях накопления. В посттрансплантационном периоде инсульт возникает у 3% (около 1500 ежегодно) пациентов, при этом в 70% из них в последующие 1,5 года существует вероятность неблагоприятного исхода. Данных же о влиянии ОНМК в анамнезе на исход последующей ТГСК в литературе не представлено. Целью нашего исследования была оценка влияния перенесенного острого нарушения мозгового кровообращения (ОНМК) до ТГСК на исход трансплантации у пациентов с онкогематологическими заболеваниями.</p> <h3>Пациенты и методы</h3> <p style="text-align: justify;"> Проанализировано 899 трансплантаций в НИИ ДОГиТ им. Р.М. Горбачевой (ПСПбГМУ им. И.П. Павлова) с 2016 по 2018 гг. Анализу подлежали параметры трансплантации, характеристики донора и реципиента. Помимо сравнения признаков между группами, проводилась псевдорандомизация с помощью метода Propensity Score Matching. Анализ выживаемости осуществлялся с помощью метода Каплан-Майера и логрангового теста.</p> <h3>Результаты</h3> <p style="text-align: justify;"> Из 899 трансплантаций костного мозга у 16 пациентов (1,8%) выявлены цереброваскулярные события в анамнезе до трансплантации (0,4% – ишемический, 1,4% – геморрагический инсульт или внутричерепное кровоизлияние). В группе пациентов с цереброваскулярными событиями в анамнезе в сравнении с группой пациентов без таковых было больше пациентов с лейкозами (р=0,02), чаще выполнялась аллогенная трансплантация (р=0,01), доноры чаще имели частичную, а не полную совместимость с реципиентом по HLA-системе (р=0,06). Эти пациенты имели более низкие индекс массы тела (р=0,02) и индекс Карновского/Ланского (р=0,01). Наличие цереброваскулярного события было значимо ассоциировано со снижением общей выживаемости реципиентов ТГСК (р=0,0012).</p> <h3>Заключение</h3> <p style="text-align: justify;"> Для онкогематологических пациентов с инсультом перед трансплантацией не характерны «классические» факторы риска (сахарный диабет, заболевания венозной системы, сниженный сердечный выброс, выраженный атеросклероз прецеребральных артерий), что не в полной мере позволяет рассчитывать на потенциальную эффективность рекомендаций по вторичной профилактике ОНМК на этапе лечения основного заболевания. В статье обсуждаются более актуальные вероятные причины ОНМК у онкогематологических пациентов. Инсульт в анамнезе перед ТГСК (в совокупности с другими факторами, связанными с характеристиками донора, реципиента и методом лечения) может оказывать значимое влияние на исход трансплантации. На сегодняшний день ОНМК в анамнезе реципиента ТГСК не является противопоказанием для данного метода лечения. Однако селекция реципиентов является очень важным этапом при планировании столь сложного лечения и требует междисциплинарного поиска баланса между показаниями и противопоказаниями к проведению неродственной ТГСК.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;"> Инсульт, ишемический инсульт, геморрагический инсульт, гематологические заболевания, лейкозы, трансплантация гемопоэтических клеток, аллогенная трансплантация, неврологические осложнения.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(5908) "

Ежегодно в мире выполняется более 50 тысяч трансплантаций гемопоэтических стволовых клеток (ТГСК) при злокачественных заболеваниях системы крови, солидных опухолях, аплазиях кроветворения, первичных иммунодефицитах, аутоиммунных заболеваниях и болезнях накопления. В посттрансплантационном периоде инсульт возникает у 3% (около 1500 ежегодно) пациентов, при этом в 70% из них в последующие 1,5 года существует вероятность неблагоприятного исхода. Данных же о влиянии ОНМК в анамнезе на исход последующей ТГСК в литературе не представлено. Целью нашего исследования была оценка влияния перенесенного острого нарушения мозгового кровообращения (ОНМК) до ТГСК на исход трансплантации у пациентов с онкогематологическими заболеваниями.

Пациенты и методы

Проанализировано 899 трансплантаций в НИИ ДОГиТ им. Р.М. Горбачевой (ПСПбГМУ им. И.П. Павлова) с 2016 по 2018 гг. Анализу подлежали параметры трансплантации, характеристики донора и реципиента. Помимо сравнения признаков между группами, проводилась псевдорандомизация с помощью метода Propensity Score Matching. Анализ выживаемости осуществлялся с помощью метода Каплан-Майера и логрангового теста.

Результаты

Из 899 трансплантаций костного мозга у 16 пациентов (1,8%) выявлены цереброваскулярные события в анамнезе до трансплантации (0,4% – ишемический, 1,4% – геморрагический инсульт или внутричерепное кровоизлияние). В группе пациентов с цереброваскулярными событиями в анамнезе в сравнении с группой пациентов без таковых было больше пациентов с лейкозами (р=0,02), чаще выполнялась аллогенная трансплантация (р=0,01), доноры чаще имели частичную, а не полную совместимость с реципиентом по HLA-системе (р=0,06). Эти пациенты имели более низкие индекс массы тела (р=0,02) и индекс Карновского/Ланского (р=0,01). Наличие цереброваскулярного события было значимо ассоциировано со снижением общей выживаемости реципиентов ТГСК (р=0,0012).

Заключение

Для онкогематологических пациентов с инсультом перед трансплантацией не характерны «классические» факторы риска (сахарный диабет, заболевания венозной системы, сниженный сердечный выброс, выраженный атеросклероз прецеребральных артерий), что не в полной мере позволяет рассчитывать на потенциальную эффективность рекомендаций по вторичной профилактике ОНМК на этапе лечения основного заболевания. В статье обсуждаются более актуальные вероятные причины ОНМК у онкогематологических пациентов. Инсульт в анамнезе перед ТГСК (в совокупности с другими факторами, связанными с характеристиками донора, реципиента и методом лечения) может оказывать значимое влияние на исход трансплантации. На сегодняшний день ОНМК в анамнезе реципиента ТГСК не является противопоказанием для данного метода лечения. Однако селекция реципиентов является очень важным этапом при планировании столь сложного лечения и требует междисциплинарного поиска баланса между показаниями и противопоказаниями к проведению неродственной ТГСК.

Ключевые слова

Инсульт, ишемический инсульт, геморрагический инсульт, гематологические заболевания, лейкозы, трансплантация гемопоэтических клеток, аллогенная трансплантация, неврологические осложнения.

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Alexey Yu. Polushin, Iaroslav B. Skiba, Maria D. Vladovskaya, Ivan S. Moiseev, Alexander D. Kulagin

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Pavlov University, St. Petersburg, Russia


Correspondence:
Dr. Alexey Yu. Polushin, Pavlov University, 6-8, L. Tolstoy St, 197022, St. Petersburg, Russia
Phone: +7 (911) 816-75-59
E-mail: alexpolushin@yandex.ru


Citation: Polushin AY, Skiba IB, Vladovskaya MD, et al. Stroke before hematopoietic stem cell transplantation is a possible risk factor for post-transplant adverse outcomes. Cell Ther Transplant 2024; 13(1): 34-41.

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More than 50,000 hematopoietic stem cell transplants (HSCT) are performed annually in the world for blood malignancies, solid tumors, aplastic anemia, primary immunodeficiency, autoimmune and metabolic diseases. Stroke occurs in 3% of patients over post-transplant period (about 1,500 cases annually), whereas 70% of them are at risk for unfavorable outcome in the next 1.5 years. The data on effects of preceding acute cerebrovascular accident (CVA) on the outcomes of subsequent HSCT are not presented in the literature. Our aim was to evaluate the effects of stroke occurring before HSCT on the transplant outcomes in patients with hematological diseases.

Patients and methods

The stories of 899 HSCTs were reviewed at the RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation (Pavlov University) from january 2016 to january 2018. The HSCT parameters, characteristics of the donor and recipient were taken for analysis. In addition to comparing features between groups, pseudorandomization was performed using the Propensity Score Matching method. The survival analysis was carried out using the Kaplan-Meier method and the log-rank test.

Results

Of 899 HSCTs, 16 patients (1.8%) had a history of cerebrovascular events before transplantation (0.4%, ischemic stroke; 1.4%, hemorrhagic stroke or intracranial hemorrhage). In the group of patients with a history of stroke, compared with the group of patients without them, there were more patients with leukemia (p=0.02); allogeneic transplantation (vs autologous, p=0.01), donors were more likely to have partial rather than full HLA compatibility with recipients (p=0.06). These patients had lower body mass index (p=0.02) and Karnofsky/ECOG score (p=0.01). Presence of a cerebrovascular event was significantly associated with decreased overall survival among HSCT recipients (p=0.0012).

Conclusion

Oncohematological patients with stroke before HSCT are not characterized by "classical" risk factors (diabetes mellitus, venous system diseases, decreased cardiac output, massive atherosclerosis of the extracranial arteries), thus limiting ability of assessing potential efficiency of guidelines for secondary stroke prevention when treating the underlying disease. The article discusses more relevant causes of stroke in oncohematological patients. A history of stroke before HSCT, along with other factors related to the treatment method, donor and recipient characteristics may have a significant impact on the HSCT outcome. To date, stroke in the history of HSCT recipient is not a contraindication for this treatment mode. However, the selection of recipients is a very important stage when planning such an intensive (difficult) treatment, and requires an interdisciplinary balance between indications and contraindications for unrelated HSCT.

Keywords

Stroke, ischemic stroke, hemorrhage stroke, hematological diseases, leukemia, hematopoietic cells transplantation, allogeneic transplantation, neurological complications.

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Polushin, Iaroslav B. Skiba, Maria D. Vladovskaya, Ivan S. Moiseev, Alexander D. Kulagin</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(106) "

Alexey Yu. Polushin, Iaroslav B. Skiba, Maria D. Vladovskaya, Ivan S. Moiseev, Alexander D. Kulagin

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Alexey Yu. Polushin, Iaroslav B. Skiba, Maria D. Vladovskaya, Ivan S. Moiseev, Alexander D. Kulagin

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More than 50,000 hematopoietic stem cell transplants (HSCT) are performed annually in the world for blood malignancies, solid tumors, aplastic anemia, primary immunodeficiency, autoimmune and metabolic diseases. Stroke occurs in 3% of patients over post-transplant period (about 1,500 cases annually), whereas 70% of them are at risk for unfavorable outcome in the next 1.5 years. The data on effects of preceding acute cerebrovascular accident (CVA) on the outcomes of subsequent HSCT are not presented in the literature. Our aim was to evaluate the effects of stroke occurring before HSCT on the transplant outcomes in patients with hematological diseases.

Patients and methods

The stories of 899 HSCTs were reviewed at the RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation (Pavlov University) from january 2016 to january 2018. The HSCT parameters, characteristics of the donor and recipient were taken for analysis. In addition to comparing features between groups, pseudorandomization was performed using the Propensity Score Matching method. The survival analysis was carried out using the Kaplan-Meier method and the log-rank test.

Results

Of 899 HSCTs, 16 patients (1.8%) had a history of cerebrovascular events before transplantation (0.4%, ischemic stroke; 1.4%, hemorrhagic stroke or intracranial hemorrhage). In the group of patients with a history of stroke, compared with the group of patients without them, there were more patients with leukemia (p=0.02); allogeneic transplantation (vs autologous, p=0.01), donors were more likely to have partial rather than full HLA compatibility with recipients (p=0.06). These patients had lower body mass index (p=0.02) and Karnofsky/ECOG score (p=0.01). Presence of a cerebrovascular event was significantly associated with decreased overall survival among HSCT recipients (p=0.0012).

Conclusion

Oncohematological patients with stroke before HSCT are not characterized by "classical" risk factors (diabetes mellitus, venous system diseases, decreased cardiac output, massive atherosclerosis of the extracranial arteries), thus limiting ability of assessing potential efficiency of guidelines for secondary stroke prevention when treating the underlying disease. The article discusses more relevant causes of stroke in oncohematological patients. A history of stroke before HSCT, along with other factors related to the treatment method, donor and recipient characteristics may have a significant impact on the HSCT outcome. To date, stroke in the history of HSCT recipient is not a contraindication for this treatment mode. However, the selection of recipients is a very important stage when planning such an intensive (difficult) treatment, and requires an interdisciplinary balance between indications and contraindications for unrelated HSCT.

Keywords

Stroke, ischemic stroke, hemorrhage stroke, hematological diseases, leukemia, hematopoietic cells transplantation, allogeneic transplantation, neurological complications.

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More than 50,000 hematopoietic stem cell transplants (HSCT) are performed annually in the world for blood malignancies, solid tumors, aplastic anemia, primary immunodeficiency, autoimmune and metabolic diseases. Stroke occurs in 3% of patients over post-transplant period (about 1,500 cases annually), whereas 70% of them are at risk for unfavorable outcome in the next 1.5 years. The data on effects of preceding acute cerebrovascular accident (CVA) on the outcomes of subsequent HSCT are not presented in the literature. Our aim was to evaluate the effects of stroke occurring before HSCT on the transplant outcomes in patients with hematological diseases.

Patients and methods

The stories of 899 HSCTs were reviewed at the RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation (Pavlov University) from january 2016 to january 2018. The HSCT parameters, characteristics of the donor and recipient were taken for analysis. In addition to comparing features between groups, pseudorandomization was performed using the Propensity Score Matching method. The survival analysis was carried out using the Kaplan-Meier method and the log-rank test.

Results

Of 899 HSCTs, 16 patients (1.8%) had a history of cerebrovascular events before transplantation (0.4%, ischemic stroke; 1.4%, hemorrhagic stroke or intracranial hemorrhage). In the group of patients with a history of stroke, compared with the group of patients without them, there were more patients with leukemia (p=0.02); allogeneic transplantation (vs autologous, p=0.01), donors were more likely to have partial rather than full HLA compatibility with recipients (p=0.06). These patients had lower body mass index (p=0.02) and Karnofsky/ECOG score (p=0.01). Presence of a cerebrovascular event was significantly associated with decreased overall survival among HSCT recipients (p=0.0012).

Conclusion

Oncohematological patients with stroke before HSCT are not characterized by "classical" risk factors (diabetes mellitus, venous system diseases, decreased cardiac output, massive atherosclerosis of the extracranial arteries), thus limiting ability of assessing potential efficiency of guidelines for secondary stroke prevention when treating the underlying disease. The article discusses more relevant causes of stroke in oncohematological patients. A history of stroke before HSCT, along with other factors related to the treatment method, donor and recipient characteristics may have a significant impact on the HSCT outcome. To date, stroke in the history of HSCT recipient is not a contraindication for this treatment mode. However, the selection of recipients is a very important stage when planning such an intensive (difficult) treatment, and requires an interdisciplinary balance between indications and contraindications for unrelated HSCT.

Keywords

Stroke, ischemic stroke, hemorrhage stroke, hematological diseases, leukemia, hematopoietic cells transplantation, allogeneic transplantation, neurological complications.

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Pavlov University, St. Petersburg, Russia


Correspondence:
Dr. Alexey Yu. Polushin, Pavlov University, 6-8, L. Tolstoy St, 197022, St. Petersburg, Russia
Phone: +7 (911) 816-75-59
E-mail: alexpolushin@yandex.ru


Citation: Polushin AY, Skiba IB, Vladovskaya MD, et al. Stroke before hematopoietic stem cell transplantation is a possible risk factor for post-transplant adverse outcomes. Cell Ther Transplant 2024; 13(1): 34-41.

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Pavlov University, St. Petersburg, Russia


Correspondence:
Dr. Alexey Yu. Polushin, Pavlov University, 6-8, L. Tolstoy St, 197022, St. Petersburg, Russia
Phone: +7 (911) 816-75-59
E-mail: alexpolushin@yandex.ru


Citation: Polushin AY, Skiba IB, Vladovskaya MD, et al. Stroke before hematopoietic stem cell transplantation is a possible risk factor for post-transplant adverse outcomes. Cell Ther Transplant 2024; 13(1): 34-41.

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Алексей Ю. Полушин, Ярослав Б. Скиба, Мария Д. Владовская, Иван С. Моисеев, Александр Д. Кулагин

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Алексей Ю. Полушин, Ярослав Б. Скиба, Мария Д. Владовская, Иван С. Моисеев, Александр Д. Кулагин

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В посттрансплантационном периоде инсульт возникает у 3% (около 1500 ежегодно) пациентов, при этом в 70% из них в последующие 1,5 года существует вероятность неблагоприятного исхода. Данных же о влиянии ОНМК в анамнезе на исход последующей ТГСК в литературе не представлено. Целью нашего исследования была оценка влияния перенесенного острого нарушения мозгового кровообращения (ОНМК) до ТГСК на исход трансплантации у пациентов с онкогематологическими заболеваниями.</p> <h3>Пациенты и методы</h3> <p style="text-align: justify;"> Проанализировано 899 трансплантаций в НИИ ДОГиТ им. Р.М. Горбачевой (ПСПбГМУ им. И.П. Павлова) с 2016 по 2018 гг. Анализу подлежали параметры трансплантации, характеристики донора и реципиента. Помимо сравнения признаков между группами, проводилась псевдорандомизация с помощью метода Propensity Score Matching. Анализ выживаемости осуществлялся с помощью метода Каплан-Майера и логрангового теста.</p> <h3>Результаты</h3> <p style="text-align: justify;"> Из 899 трансплантаций костного мозга у 16 пациентов (1,8%) выявлены цереброваскулярные события в анамнезе до трансплантации (0,4% – ишемический, 1,4% – геморрагический инсульт или внутричерепное кровоизлияние). В группе пациентов с цереброваскулярными событиями в анамнезе в сравнении с группой пациентов без таковых было больше пациентов с лейкозами (р=0,02), чаще выполнялась аллогенная трансплантация (р=0,01), доноры чаще имели частичную, а не полную совместимость с реципиентом по HLA-системе (р=0,06). Эти пациенты имели более низкие индекс массы тела (р=0,02) и индекс Карновского/Ланского (р=0,01). Наличие цереброваскулярного события было значимо ассоциировано со снижением общей выживаемости реципиентов ТГСК (р=0,0012).</p> <h3>Заключение</h3> <p style="text-align: justify;"> Для онкогематологических пациентов с инсультом перед трансплантацией не характерны «классические» факторы риска (сахарный диабет, заболевания венозной системы, сниженный сердечный выброс, выраженный атеросклероз прецеребральных артерий), что не в полной мере позволяет рассчитывать на потенциальную эффективность рекомендаций по вторичной профилактике ОНМК на этапе лечения основного заболевания. В статье обсуждаются более актуальные вероятные причины ОНМК у онкогематологических пациентов. Инсульт в анамнезе перед ТГСК (в совокупности с другими факторами, связанными с характеристиками донора, реципиента и методом лечения) может оказывать значимое влияние на исход трансплантации. На сегодняшний день ОНМК в анамнезе реципиента ТГСК не является противопоказанием для данного метода лечения. Однако селекция реципиентов является очень важным этапом при планировании столь сложного лечения и требует междисциплинарного поиска баланса между показаниями и противопоказаниями к проведению неродственной ТГСК.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;"> Инсульт, ишемический инсульт, геморрагический инсульт, гематологические заболевания, лейкозы, трансплантация гемопоэтических клеток, аллогенная трансплантация, неврологические осложнения.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(5908) "

Ежегодно в мире выполняется более 50 тысяч трансплантаций гемопоэтических стволовых клеток (ТГСК) при злокачественных заболеваниях системы крови, солидных опухолях, аплазиях кроветворения, первичных иммунодефицитах, аутоиммунных заболеваниях и болезнях накопления. В посттрансплантационном периоде инсульт возникает у 3% (около 1500 ежегодно) пациентов, при этом в 70% из них в последующие 1,5 года существует вероятность неблагоприятного исхода. Данных же о влиянии ОНМК в анамнезе на исход последующей ТГСК в литературе не представлено. Целью нашего исследования была оценка влияния перенесенного острого нарушения мозгового кровообращения (ОНМК) до ТГСК на исход трансплантации у пациентов с онкогематологическими заболеваниями.

Пациенты и методы

Проанализировано 899 трансплантаций в НИИ ДОГиТ им. Р.М. Горбачевой (ПСПбГМУ им. И.П. Павлова) с 2016 по 2018 гг. Анализу подлежали параметры трансплантации, характеристики донора и реципиента. Помимо сравнения признаков между группами, проводилась псевдорандомизация с помощью метода Propensity Score Matching. Анализ выживаемости осуществлялся с помощью метода Каплан-Майера и логрангового теста.

Результаты

Из 899 трансплантаций костного мозга у 16 пациентов (1,8%) выявлены цереброваскулярные события в анамнезе до трансплантации (0,4% – ишемический, 1,4% – геморрагический инсульт или внутричерепное кровоизлияние). В группе пациентов с цереброваскулярными событиями в анамнезе в сравнении с группой пациентов без таковых было больше пациентов с лейкозами (р=0,02), чаще выполнялась аллогенная трансплантация (р=0,01), доноры чаще имели частичную, а не полную совместимость с реципиентом по HLA-системе (р=0,06). Эти пациенты имели более низкие индекс массы тела (р=0,02) и индекс Карновского/Ланского (р=0,01). Наличие цереброваскулярного события было значимо ассоциировано со снижением общей выживаемости реципиентов ТГСК (р=0,0012).

Заключение

Для онкогематологических пациентов с инсультом перед трансплантацией не характерны «классические» факторы риска (сахарный диабет, заболевания венозной системы, сниженный сердечный выброс, выраженный атеросклероз прецеребральных артерий), что не в полной мере позволяет рассчитывать на потенциальную эффективность рекомендаций по вторичной профилактике ОНМК на этапе лечения основного заболевания. В статье обсуждаются более актуальные вероятные причины ОНМК у онкогематологических пациентов. Инсульт в анамнезе перед ТГСК (в совокупности с другими факторами, связанными с характеристиками донора, реципиента и методом лечения) может оказывать значимое влияние на исход трансплантации. На сегодняшний день ОНМК в анамнезе реципиента ТГСК не является противопоказанием для данного метода лечения. Однако селекция реципиентов является очень важным этапом при планировании столь сложного лечения и требует междисциплинарного поиска баланса между показаниями и противопоказаниями к проведению неродственной ТГСК.

Ключевые слова

Инсульт, ишемический инсульт, геморрагический инсульт, гематологические заболевания, лейкозы, трансплантация гемопоэтических клеток, аллогенная трансплантация, неврологические осложнения.

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Ежегодно в мире выполняется более 50 тысяч трансплантаций гемопоэтических стволовых клеток (ТГСК) при злокачественных заболеваниях системы крови, солидных опухолях, аплазиях кроветворения, первичных иммунодефицитах, аутоиммунных заболеваниях и болезнях накопления. В посттрансплантационном периоде инсульт возникает у 3% (около 1500 ежегодно) пациентов, при этом в 70% из них в последующие 1,5 года существует вероятность неблагоприятного исхода. Данных же о влиянии ОНМК в анамнезе на исход последующей ТГСК в литературе не представлено. Целью нашего исследования была оценка влияния перенесенного острого нарушения мозгового кровообращения (ОНМК) до ТГСК на исход трансплантации у пациентов с онкогематологическими заболеваниями.

Пациенты и методы

Проанализировано 899 трансплантаций в НИИ ДОГиТ им. Р.М. Горбачевой (ПСПбГМУ им. И.П. Павлова) с 2016 по 2018 гг. Анализу подлежали параметры трансплантации, характеристики донора и реципиента. Помимо сравнения признаков между группами, проводилась псевдорандомизация с помощью метода Propensity Score Matching. Анализ выживаемости осуществлялся с помощью метода Каплан-Майера и логрангового теста.

Результаты

Из 899 трансплантаций костного мозга у 16 пациентов (1,8%) выявлены цереброваскулярные события в анамнезе до трансплантации (0,4% – ишемический, 1,4% – геморрагический инсульт или внутричерепное кровоизлияние). В группе пациентов с цереброваскулярными событиями в анамнезе в сравнении с группой пациентов без таковых было больше пациентов с лейкозами (р=0,02), чаще выполнялась аллогенная трансплантация (р=0,01), доноры чаще имели частичную, а не полную совместимость с реципиентом по HLA-системе (р=0,06). Эти пациенты имели более низкие индекс массы тела (р=0,02) и индекс Карновского/Ланского (р=0,01). Наличие цереброваскулярного события было значимо ассоциировано со снижением общей выживаемости реципиентов ТГСК (р=0,0012).

Заключение

Для онкогематологических пациентов с инсультом перед трансплантацией не характерны «классические» факторы риска (сахарный диабет, заболевания венозной системы, сниженный сердечный выброс, выраженный атеросклероз прецеребральных артерий), что не в полной мере позволяет рассчитывать на потенциальную эффективность рекомендаций по вторичной профилактике ОНМК на этапе лечения основного заболевания. В статье обсуждаются более актуальные вероятные причины ОНМК у онкогематологических пациентов. Инсульт в анамнезе перед ТГСК (в совокупности с другими факторами, связанными с характеристиками донора, реципиента и методом лечения) может оказывать значимое влияние на исход трансплантации. На сегодняшний день ОНМК в анамнезе реципиента ТГСК не является противопоказанием для данного метода лечения. Однако селекция реципиентов является очень важным этапом при планировании столь сложного лечения и требует междисциплинарного поиска баланса между показаниями и противопоказаниями к проведению неродственной ТГСК.

Ключевые слова

Инсульт, ишемический инсульт, геморрагический инсульт, гематологические заболевания, лейкозы, трансплантация гемопоэтических клеток, аллогенная трансплантация, неврологические осложнения.

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Первый Санкт-Петербургский государственный медицинский университет им. И. П. Павлова, Санкт-Петербург, Россия

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Первый Санкт-Петербургский государственный медицинский университет им. И. П. Павлова, Санкт-Петербург, Россия

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Introduction

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment for a wide range of malignant and non-malignant diseases [1]. The selection of a donor of hematopoietic stem cells is based on compatibility of the major histocompatibility complex (HLA) class I and II genes [2], ABO compatibility is usually a minor factor when selecting a donor. As shown in a number of studies, ABO incompatibility does not significantly affect overall and disease-free survival in allo-HSCT [3-7]. However, it can cause a number of serious complications, such as post-transplant pure red cell aplasia (PRCA), leading to a significant deterioration in the patient’s somatic status and quality of life [3].

Three types of ABO incompatibility are discerned, i.e., minor, when the recipient is transfused with graft containing anti-A and anti-B antibodies; major, when the recipient’s plasma contains anti-A and anti-B antibodies, and combined incompatibility, with presence of anti-A and anti-B antibodies both in donor graft and recipient’s plasma [6]. According to the literature, ABO – incompatible allo-HSCT accounts for 25-50% of all transplantations [6-8], with 7-30% of these patients developing PRCA [7, 9-11].

PRCA is characterized by persistent normochromic anemia, severe reticulocytopenia and deep suppression of erythroid lineage in the bone marrow [9, 12]. The pathophysiology of PRCA involves inhibition of donor erythroid progenitors by persistent recipient-derived antibodies that may be produced by residual long-lived plasma cells. [9, 13]. The average duration of this condition without specific treatment is 60-90 days, however, in some cases PRCA may continue for a longer time period [14]. It should be noted that the patients are transfusion-dependent over the entire period of PRCA thus increasing the duration of hospitalization and leading to iron overload with development of organ hemochromatosis. Currently, there is no consensus for the PRCA treatment, mainly, due to variability of proposed therapeutic options (glucocorticoids, plasmapheresis, monoclonal antibodies (anti-CD20) rituximab, infusion of donor lymphocytes, bortezomib) and their limitations for use in the post-transplant period [15-18]. The time frame for initiating specific treatment has been not yet determined. A number of studies recommend to decide on the initiation of therapy on the basis of changes in the levels of anti-A and anti-B antibodies [13, 14]. Taking into account the source of antibody production, the most reasonable principle for PRCA treatment is the depletion of long-lived plasma cells in the recipient. This hypothesis is confirmed by published clinical cases of successful use of the anti-CD38 monoclonal antibody daratumumab in PRCA [19-24].

The aim of the present article was to describe our clinical experience with usage of daratumumab in the patients with long-term persistence of PRCA.

Patients and methods

The study was performed at RM Gorbacheva Research Institute, Pavlov University, St. Petersburg, Russia over 2021 to 2022. A retrospective single-center study included 5 patients. The inclusion criteria were as follows: past allo-HSCT, major ABO incompatibility, documented clinical PRCA pattern, therapy with daratumumab.

The male to female ratio was 3:2, the median age was 35 (range, 25-48) years, the median follow-up period since the PRCA development was 921 (range, 381-1515) days. Detailed characteristics of the patients are presented in Table 1. PRCA was established when myeloid, lymphoid and megakaryocyte lineages were determined in absence of erythropoietic precursors (erythroblasts) in the bone marrow aspirate combined with reticulocytopenia (<10 000/ μL) in peripheral blood, upon the exclusion of other causes, e.g., infections, hemolysis, disease relapse and drug toxicity. The complete hematological response was defined by normal hemoglobin levels without transfusions and the reticulocyte level of >30 000/μL, and erythroid lineage cells of >14.5% at bone marrow cytology examination. Partial hematological response was registered at hemoglobin level of ≥100 g/L, or its increase by, at least, 20 g/L compared to the pre-treatment level in the absence of blood transfusions, at reticulocyte levels of 10 000 to 30 000/μL, erythroid lineage cells of more than 1%, but <14.5% at the cytology examination. Non-responders are those who do not meet the criteria for complete or partial response. Early reticulocyte response was determined at reticulocyte level of more than 30 000/μL during the first week after starting therapy; delayed response was defined as reaching the reticulocyte levels of >30 000/μL after 21 days of treatment.

Table 1. Clinical characteristics of patients

Tsvirko-tab01.jpg

Abbreviations: PRCA, post-transplant pure red cell aplasia; AML, acute myeloid leukemia; NHL, Non-Hodgkin Lymphoma; AA, aplastic anemia; R, recipient; D, donor; F, female; M, male; TPE, therapeutic plasma exchange; IVIG, intravenous immunoglobulin; RTX, rituximab; MSD, matched sibling donor; MUD, matched unrelated donor; CML, chronic myeloid leukemia; MAC, myeloablative conditioning; RIC, reduced intensity conditioning; Cy, cyclophosphamide; MMF, mycophenolate mofetil; Tac, tacrolimus; CsA, cyclosporine A; MTX, methotrexate; ATG anti-thymocyte globulin; CS, corticosteroids; BORT, Bortezomib; Dara, Daratumumab; CR, complete remission

Clinical case 1

A 31-year-old woman with aplastic anemia and paroxysmal nocturnal hemoglobinuria (AA/PNH) received allo-HSCT from an HLA-identical related donor. Due to active hemolytic PNH eculizumab was used (D-8, D-1 before allo-HSCT).

Recovery of granulocyte counts was recorded on D+18 and the megakaryocytic lineage has restored on D+19 after allo-HSCT. In the early period, reactivation of herpes virus type 6 was detected, for which therapy with valganciclovir was carried out. In the control bone marrow aspirate at D+47, there were no detectable erythroid lineage cells, along with single megakaryocytes, and mixed donor chimerism (80-89%). Over time, a progression in neutropenia and thrombocytopenia was noted, thus requiring administration of granulocyte colony-stimulating factor (G-CSF) and a thrombopoietin receptor agonist. Clinical effect showed up in partial restoration of the two lineages, but deep hyporegenerative anemia with high transfusion dependence still remained. Based on clinical and laboratory data, PRCA was diagnosed. Intravenous immunoglobulins were used as first-line therapy with no response. Usage of other therapeutic options was limited by the persistence of herpesvirus infection. The patient’s status did not change following resolution of viral infection: the blood counts at D+180 from allo-HSCT presented with severe anemia, grade 2-3 thrombocytopenia, grade 2-3 neutropenia, scarce erythroid lineage cells in bone marrow aspirate (<1%), mixed donor chimerism. With respect to persistent cytopenia, a course of therapy with rituximab was carried out, but without clinical effect. Subsequent lines of therapy (pulse therapy with dexamethasone, bortezomib) were also not effective. Due to the refractory course of PRCA, a decision was made to use daratumumab, an anti-CD38 monoclonal antibody. In order to achieve faster response in PRCA, 2 plasma exchange sessions were performed at weekly intervals (D+490, 498), followed by 2 injections of daratumumab at a dose of 16 mg/kg (D+501, 508).

During the first administration, the development of an infusion reaction in the form of skin itching and accommodative dysfunction was noted which resolved after adjustment of drug infusion rate, with full dose administered. At the 2nd administration, no adverse reactions were registered. Increased reticulocyte counts were recorded 3 days after the start of daratumumab therapy with achievement of blood transfusion independence since D+502. Erythroid lineage was restored in the control marrow aspirate 2 months later, and full donor chimerism was achieved. A complete response was recorded at D+670 from allo-HSCT. Remarkably, the granulocyte and platelet counts also restored to normal values after the treatment. At the time of the last contact with the patient (D+1500), the response was maintained; no significant infectious complications were noted.

Clinical case 2

A 48-year-old patient with acute myeloid leukemia underwent peripheral blood stem cell transplantation from an HLA-matched unrelated donor with major ABO incompatibility. The leukocyte engraftment was recorded at D+18; platelet recovery was observed at D+20, and complete donor chimerism was achieved at D+30 after allo-HSCT. The early post-transplant period was complicated by reactivation of cytomegalovirus (CMV) infection with a complete response to valganciclovir therapy. According to the bone marrow cytology at D+22, D+60, D+100, erythroid lineage was reduced to 1%, and the blood counts showed severe anemia. PRCA was diagnosed since other possible causes of anemia were excluded. Therapy with rituximab was initiated (D+464) without effect. By D+570, the erythroid lineage was restricted to <1%, with persistence of deep hyporegenerative anemia requiring RBC transfusions (one dose every 2-3 weeks). A resistant course of PRCA was established, and therapy with daratumumab was decided. As in case 1, two plasma exchange sessions were performed immediately before the drug administration (D+575, 581), followed by two infusions of daratumamab 16 mg/kg (D+586, +593) without any adverse events. A reticulocyte response was recorded a 1 week after the first administration of the drug, complete hematological response developed at D+634. During the follow-up examination at D+1515 after allo-HSCT, the blood counts were within normal ranges, and no significant infectious complications were observed.

Clinical case 3

A 35-year-old man diagnosed with acute myeloid leukemia underwent an allogeneic transplant from an HLA-identical unrelated donor. The early post-transplant period (D+15 after allo-HSCT) was complicated by the reactivation of CMV infection, and therapy with ganciclovir was initiated. On D+19 after allo-HSCT, recovery of leukocytes was recorded; on D+21 there was a significant reduction of erythroid lineage to 0.6%, along with complete donor chimerism in the control bone marrow aspirates, and no manifestations of the underlying disease. On D+41, a complete response to CMV was obtained, but severe anemia with high dependence on transfusions, reticulocytopenia, and grade 3-4 thrombocytopenia still persisted at D+100 after allo-HSCT. Thus, PRCA was diagnosed on the basis of clinical and laboratory data. In view of expected spontaneous resolution of this condition and potential undesirable complications of specific therapy, it was decided to continue monitoring the patient. However, dependence on RBC transfusions (once every 2 weeks) and thrombocytopenia remained by D+200 after allo-HSCT. As part of first-line therapy, 2 injections of daratumumab were performed at a dose of 16 mg/kg on D+205, 212 after allo-HSCT. At the first administration, an infusion reaction with transient accommodative dysfunction developed, which resolved after adjustment of the infusion rate. The reticulocyte response was recorded at D+21. According to the results of a bone marrow cytology, the erythroid lineage was 50.2% on D+226. A complete response was achieved at D+234 and remained to the last follow-up (D+921). Restoration of platelet levels to normal values was also achieved.

Clinical case 4

A 39-year-old man diagnosed with chronic myeloid leukemia (CML) underwent an allogeneic transplant from an HLA-identical unrelated donor. The patient had refractory CML in accelerated phase before allo-HSCT. On D+20 after allo-HSCT, recovery of leukocytes was recorded, bone marrow examination on D+21 after allo-HSCT showed complete donor chimerism with negative minimal residual disease (Bcr-abl transcript) status and no erythroid lineage cells.

At D+54 severe anemia remained with dependence on RBC transfusions (1-2 doses per week), grade 3-4 thrombocytopenia, reticulocytopenia, erythroid lineage of 0.4%, Upon exclusion of other possible causes of anemia, PRCA was diagnosed. Due to persistent anemia, reticulocytopenia, blood transfusion dependence (1-2 times a week), 2 injections of daratumumab were performed as a part of first-line therapy, at a dose of 13 mg/kg on D+113 and D+120 after allo-HSCT; both injections were tolerated well.

On D+163 blood transfusion independence was achieved. The reticulocyte response was recorded at D+167 after allo-HSCT. According to results of the bone marrow cytology, the erythroid lineage comprised 21.8%. However, a complete response of PRCA was not achieved; the maximum value of hemoglobin level of 109 g/L was recorded on D+201.

At D+131 after allo-HSCT, the patient developed severe chronic skin GvHD, which required modification of immunosuppressive therapy. On D+190 severe chronic lung GvHD was diagnosed, which required further 2nd line immunosuppression. Since D+223 the patient had multiple infectious episodes (reactivation of CMV, herpes virus type 6, pneumonia, development of probable pulmonary aspergillosis) and died on D+381 after allo-HSCT.

Clinical case 5

A 25-year-old man with non-Hodgkin lymphoma underwent an allogeneic transplant from an HLA-identical unrelated donor. On D+26 recovery of leukocytes was recorded, a control bone marrow aspiration showed no erythroid lineage cells; complete donor chimerism was established. Therefore, based on clinical and laboratory data, PRCA was diagnosed. On D+31 acute skin GvHD developed with complete resolution on topical steroids. On D+68, a relapse of the underlying disease without bone marrow involvement was detected; therapy with ceritinib and crizotinib induced a complete metabolic response on D+120. Due to persisting PRCA, the patient received first-line therapy with 2 injections of daratumumab at a dose of 12 mg/kg (D+110 and D+117) which were well tolerated without immediate adverse reactions. The reticulocyte response was recorded at D+135; bone marrow cytology showed 16% of erythroid lineage. RBC transfusion independence was registered at D+148 after allo-HSCT. A complete response according to PRCA was achieved at D+271 and persisted at the last follow-up (D+549).

Discussion

Fig. 1 summarizes the clinical course and outcomes in all 5 patients with post-transplant PRCA treated with daratumumab. An early reticulocyte response after the first dose was observed in three cases. Two patients experienced a delayed reticulocyte response and achieved transfusion independence 1-1.5 months after the second administration of daratumumab. The rapid achievement of response supports the hypothesis that removal of residual long-lived host plasma cells results in curation of PRCA. Selective elimination of plasma cells with a monoclonal anti-CD38 antibody proved to be superior to previously used therapeutic options. One should also note a low toxicity profile of daratumumab known from clinical experience with multiple myeloma patients. However, there is a high risk of developing infectious complications [25-27]. Currently, there is insufficient data on the use of daratumumab after allo-HSCT and assessing its effect on GvHD [28, 29]. Among our patients, severe GvHD and significant infectious complications developed in one case, thus requiring further study of the effectiveness and safety, possible immunomodulatory effects of daratumumab. Also, two out of five patients developed a complication in the form of transient accommodative dysfunction. Meanwhile, PRCA may resolve spontaneously and no rapid response was observed in two cases, with therapeutic options administered between D+100 and D+200 after allo-HSCT. Therefore, it is difficult to assess whether the resolution of PRCA is related to the therapy or a spontaneous remission occurred.

Tsvirko-fig01.jpg

Figure 1. Clinical course and outcomes in the patients with post-transplant PRCA treated with daratumumab

Abbreviations: PRCA, posttransplantation pure red cell aplasia; RetResp, Reticulocyte response; CR, complete response; PR, partial response; TPE, therapeutic plasma exchange; IVIG, intravenous immunoglobulin; RTX, rituximab; CS, corticosteroids; BORT, Bortezomib; Dara, Daratumumab.

Conclusion

To assess the efficiency and safety of daratumumab in PRCA therapy and to determine the minimally effective dose, one should further accumulate clinical data with inclusion of a large number of transplant centers, due to low incidence of this post-transplant complication.

One should note that the concept of depletion of long-lived plasma cells is also promising in treatment of other hematological diseases associated with allo- and autoantibody mechanisms, such as autoimmune hemolytic anemia and immune thrombocytopenic purpura, as demonstrated by a number of clinical cases [22, 30], and a positive effect in systemic autoimmune conditions cannot be ruled out [31].

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Introduction

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment for a wide range of malignant and non-malignant diseases [1]. The selection of a donor of hematopoietic stem cells is based on compatibility of the major histocompatibility complex (HLA) class I and II genes [2], ABO compatibility is usually a minor factor when selecting a donor. As shown in a number of studies, ABO incompatibility does not significantly affect overall and disease-free survival in allo-HSCT [3-7]. However, it can cause a number of serious complications, such as post-transplant pure red cell aplasia (PRCA), leading to a significant deterioration in the patient’s somatic status and quality of life [3].

Three types of ABO incompatibility are discerned, i.e., minor, when the recipient is transfused with graft containing anti-A and anti-B antibodies; major, when the recipient’s plasma contains anti-A and anti-B antibodies, and combined incompatibility, with presence of anti-A and anti-B antibodies both in donor graft and recipient’s plasma [6]. According to the literature, ABO – incompatible allo-HSCT accounts for 25-50% of all transplantations [6-8], with 7-30% of these patients developing PRCA [7, 9-11].

PRCA is characterized by persistent normochromic anemia, severe reticulocytopenia and deep suppression of erythroid lineage in the bone marrow [9, 12]. The pathophysiology of PRCA involves inhibition of donor erythroid progenitors by persistent recipient-derived antibodies that may be produced by residual long-lived plasma cells. [9, 13]. The average duration of this condition without specific treatment is 60-90 days, however, in some cases PRCA may continue for a longer time period [14]. It should be noted that the patients are transfusion-dependent over the entire period of PRCA thus increasing the duration of hospitalization and leading to iron overload with development of organ hemochromatosis. Currently, there is no consensus for the PRCA treatment, mainly, due to variability of proposed therapeutic options (glucocorticoids, plasmapheresis, monoclonal antibodies (anti-CD20) rituximab, infusion of donor lymphocytes, bortezomib) and their limitations for use in the post-transplant period [15-18]. The time frame for initiating specific treatment has been not yet determined. A number of studies recommend to decide on the initiation of therapy on the basis of changes in the levels of anti-A and anti-B antibodies [13, 14]. Taking into account the source of antibody production, the most reasonable principle for PRCA treatment is the depletion of long-lived plasma cells in the recipient. This hypothesis is confirmed by published clinical cases of successful use of the anti-CD38 monoclonal antibody daratumumab in PRCA [19-24].

The aim of the present article was to describe our clinical experience with usage of daratumumab in the patients with long-term persistence of PRCA.

Patients and methods

The study was performed at RM Gorbacheva Research Institute, Pavlov University, St. Petersburg, Russia over 2021 to 2022. A retrospective single-center study included 5 patients. The inclusion criteria were as follows: past allo-HSCT, major ABO incompatibility, documented clinical PRCA pattern, therapy with daratumumab.

The male to female ratio was 3:2, the median age was 35 (range, 25-48) years, the median follow-up period since the PRCA development was 921 (range, 381-1515) days. Detailed characteristics of the patients are presented in Table 1. PRCA was established when myeloid, lymphoid and megakaryocyte lineages were determined in absence of erythropoietic precursors (erythroblasts) in the bone marrow aspirate combined with reticulocytopenia (<10 000/ μL) in peripheral blood, upon the exclusion of other causes, e.g., infections, hemolysis, disease relapse and drug toxicity. The complete hematological response was defined by normal hemoglobin levels without transfusions and the reticulocyte level of >30 000/μL, and erythroid lineage cells of >14.5% at bone marrow cytology examination. Partial hematological response was registered at hemoglobin level of ≥100 g/L, or its increase by, at least, 20 g/L compared to the pre-treatment level in the absence of blood transfusions, at reticulocyte levels of 10 000 to 30 000/μL, erythroid lineage cells of more than 1%, but <14.5% at the cytology examination. Non-responders are those who do not meet the criteria for complete or partial response. Early reticulocyte response was determined at reticulocyte level of more than 30 000/μL during the first week after starting therapy; delayed response was defined as reaching the reticulocyte levels of >30 000/μL after 21 days of treatment.

Table 1. Clinical characteristics of patients

Tsvirko-tab01.jpg

Abbreviations: PRCA, post-transplant pure red cell aplasia; AML, acute myeloid leukemia; NHL, Non-Hodgkin Lymphoma; AA, aplastic anemia; R, recipient; D, donor; F, female; M, male; TPE, therapeutic plasma exchange; IVIG, intravenous immunoglobulin; RTX, rituximab; MSD, matched sibling donor; MUD, matched unrelated donor; CML, chronic myeloid leukemia; MAC, myeloablative conditioning; RIC, reduced intensity conditioning; Cy, cyclophosphamide; MMF, mycophenolate mofetil; Tac, tacrolimus; CsA, cyclosporine A; MTX, methotrexate; ATG anti-thymocyte globulin; CS, corticosteroids; BORT, Bortezomib; Dara, Daratumumab; CR, complete remission

Clinical case 1

A 31-year-old woman with aplastic anemia and paroxysmal nocturnal hemoglobinuria (AA/PNH) received allo-HSCT from an HLA-identical related donor. Due to active hemolytic PNH eculizumab was used (D-8, D-1 before allo-HSCT).

Recovery of granulocyte counts was recorded on D+18 and the megakaryocytic lineage has restored on D+19 after allo-HSCT. In the early period, reactivation of herpes virus type 6 was detected, for which therapy with valganciclovir was carried out. In the control bone marrow aspirate at D+47, there were no detectable erythroid lineage cells, along with single megakaryocytes, and mixed donor chimerism (80-89%). Over time, a progression in neutropenia and thrombocytopenia was noted, thus requiring administration of granulocyte colony-stimulating factor (G-CSF) and a thrombopoietin receptor agonist. Clinical effect showed up in partial restoration of the two lineages, but deep hyporegenerative anemia with high transfusion dependence still remained. Based on clinical and laboratory data, PRCA was diagnosed. Intravenous immunoglobulins were used as first-line therapy with no response. Usage of other therapeutic options was limited by the persistence of herpesvirus infection. The patient’s status did not change following resolution of viral infection: the blood counts at D+180 from allo-HSCT presented with severe anemia, grade 2-3 thrombocytopenia, grade 2-3 neutropenia, scarce erythroid lineage cells in bone marrow aspirate (<1%), mixed donor chimerism. With respect to persistent cytopenia, a course of therapy with rituximab was carried out, but without clinical effect. Subsequent lines of therapy (pulse therapy with dexamethasone, bortezomib) were also not effective. Due to the refractory course of PRCA, a decision was made to use daratumumab, an anti-CD38 monoclonal antibody. In order to achieve faster response in PRCA, 2 plasma exchange sessions were performed at weekly intervals (D+490, 498), followed by 2 injections of daratumumab at a dose of 16 mg/kg (D+501, 508).

During the first administration, the development of an infusion reaction in the form of skin itching and accommodative dysfunction was noted which resolved after adjustment of drug infusion rate, with full dose administered. At the 2nd administration, no adverse reactions were registered. Increased reticulocyte counts were recorded 3 days after the start of daratumumab therapy with achievement of blood transfusion independence since D+502. Erythroid lineage was restored in the control marrow aspirate 2 months later, and full donor chimerism was achieved. A complete response was recorded at D+670 from allo-HSCT. Remarkably, the granulocyte and platelet counts also restored to normal values after the treatment. At the time of the last contact with the patient (D+1500), the response was maintained; no significant infectious complications were noted.

Clinical case 2

A 48-year-old patient with acute myeloid leukemia underwent peripheral blood stem cell transplantation from an HLA-matched unrelated donor with major ABO incompatibility. The leukocyte engraftment was recorded at D+18; platelet recovery was observed at D+20, and complete donor chimerism was achieved at D+30 after allo-HSCT. The early post-transplant period was complicated by reactivation of cytomegalovirus (CMV) infection with a complete response to valganciclovir therapy. According to the bone marrow cytology at D+22, D+60, D+100, erythroid lineage was reduced to 1%, and the blood counts showed severe anemia. PRCA was diagnosed since other possible causes of anemia were excluded. Therapy with rituximab was initiated (D+464) without effect. By D+570, the erythroid lineage was restricted to <1%, with persistence of deep hyporegenerative anemia requiring RBC transfusions (one dose every 2-3 weeks). A resistant course of PRCA was established, and therapy with daratumumab was decided. As in case 1, two plasma exchange sessions were performed immediately before the drug administration (D+575, 581), followed by two infusions of daratumamab 16 mg/kg (D+586, +593) without any adverse events. A reticulocyte response was recorded a 1 week after the first administration of the drug, complete hematological response developed at D+634. During the follow-up examination at D+1515 after allo-HSCT, the blood counts were within normal ranges, and no significant infectious complications were observed.

Clinical case 3

A 35-year-old man diagnosed with acute myeloid leukemia underwent an allogeneic transplant from an HLA-identical unrelated donor. The early post-transplant period (D+15 after allo-HSCT) was complicated by the reactivation of CMV infection, and therapy with ganciclovir was initiated. On D+19 after allo-HSCT, recovery of leukocytes was recorded; on D+21 there was a significant reduction of erythroid lineage to 0.6%, along with complete donor chimerism in the control bone marrow aspirates, and no manifestations of the underlying disease. On D+41, a complete response to CMV was obtained, but severe anemia with high dependence on transfusions, reticulocytopenia, and grade 3-4 thrombocytopenia still persisted at D+100 after allo-HSCT. Thus, PRCA was diagnosed on the basis of clinical and laboratory data. In view of expected spontaneous resolution of this condition and potential undesirable complications of specific therapy, it was decided to continue monitoring the patient. However, dependence on RBC transfusions (once every 2 weeks) and thrombocytopenia remained by D+200 after allo-HSCT. As part of first-line therapy, 2 injections of daratumumab were performed at a dose of 16 mg/kg on D+205, 212 after allo-HSCT. At the first administration, an infusion reaction with transient accommodative dysfunction developed, which resolved after adjustment of the infusion rate. The reticulocyte response was recorded at D+21. According to the results of a bone marrow cytology, the erythroid lineage was 50.2% on D+226. A complete response was achieved at D+234 and remained to the last follow-up (D+921). Restoration of platelet levels to normal values was also achieved.

Clinical case 4

A 39-year-old man diagnosed with chronic myeloid leukemia (CML) underwent an allogeneic transplant from an HLA-identical unrelated donor. The patient had refractory CML in accelerated phase before allo-HSCT. On D+20 after allo-HSCT, recovery of leukocytes was recorded, bone marrow examination on D+21 after allo-HSCT showed complete donor chimerism with negative minimal residual disease (Bcr-abl transcript) status and no erythroid lineage cells.

At D+54 severe anemia remained with dependence on RBC transfusions (1-2 doses per week), grade 3-4 thrombocytopenia, reticulocytopenia, erythroid lineage of 0.4%, Upon exclusion of other possible causes of anemia, PRCA was diagnosed. Due to persistent anemia, reticulocytopenia, blood transfusion dependence (1-2 times a week), 2 injections of daratumumab were performed as a part of first-line therapy, at a dose of 13 mg/kg on D+113 and D+120 after allo-HSCT; both injections were tolerated well.

On D+163 blood transfusion independence was achieved. The reticulocyte response was recorded at D+167 after allo-HSCT. According to results of the bone marrow cytology, the erythroid lineage comprised 21.8%. However, a complete response of PRCA was not achieved; the maximum value of hemoglobin level of 109 g/L was recorded on D+201.

At D+131 after allo-HSCT, the patient developed severe chronic skin GvHD, which required modification of immunosuppressive therapy. On D+190 severe chronic lung GvHD was diagnosed, which required further 2nd line immunosuppression. Since D+223 the patient had multiple infectious episodes (reactivation of CMV, herpes virus type 6, pneumonia, development of probable pulmonary aspergillosis) and died on D+381 after allo-HSCT.

Clinical case 5

A 25-year-old man with non-Hodgkin lymphoma underwent an allogeneic transplant from an HLA-identical unrelated donor. On D+26 recovery of leukocytes was recorded, a control bone marrow aspiration showed no erythroid lineage cells; complete donor chimerism was established. Therefore, based on clinical and laboratory data, PRCA was diagnosed. On D+31 acute skin GvHD developed with complete resolution on topical steroids. On D+68, a relapse of the underlying disease without bone marrow involvement was detected; therapy with ceritinib and crizotinib induced a complete metabolic response on D+120. Due to persisting PRCA, the patient received first-line therapy with 2 injections of daratumumab at a dose of 12 mg/kg (D+110 and D+117) which were well tolerated without immediate adverse reactions. The reticulocyte response was recorded at D+135; bone marrow cytology showed 16% of erythroid lineage. RBC transfusion independence was registered at D+148 after allo-HSCT. A complete response according to PRCA was achieved at D+271 and persisted at the last follow-up (D+549).

Discussion

Fig. 1 summarizes the clinical course and outcomes in all 5 patients with post-transplant PRCA treated with daratumumab. An early reticulocyte response after the first dose was observed in three cases. Two patients experienced a delayed reticulocyte response and achieved transfusion independence 1-1.5 months after the second administration of daratumumab. The rapid achievement of response supports the hypothesis that removal of residual long-lived host plasma cells results in curation of PRCA. Selective elimination of plasma cells with a monoclonal anti-CD38 antibody proved to be superior to previously used therapeutic options. One should also note a low toxicity profile of daratumumab known from clinical experience with multiple myeloma patients. However, there is a high risk of developing infectious complications [25-27]. Currently, there is insufficient data on the use of daratumumab after allo-HSCT and assessing its effect on GvHD [28, 29]. Among our patients, severe GvHD and significant infectious complications developed in one case, thus requiring further study of the effectiveness and safety, possible immunomodulatory effects of daratumumab. Also, two out of five patients developed a complication in the form of transient accommodative dysfunction. Meanwhile, PRCA may resolve spontaneously and no rapid response was observed in two cases, with therapeutic options administered between D+100 and D+200 after allo-HSCT. Therefore, it is difficult to assess whether the resolution of PRCA is related to the therapy or a spontaneous remission occurred.

Tsvirko-fig01.jpg

Figure 1. Clinical course and outcomes in the patients with post-transplant PRCA treated with daratumumab

Abbreviations: PRCA, posttransplantation pure red cell aplasia; RetResp, Reticulocyte response; CR, complete response; PR, partial response; TPE, therapeutic plasma exchange; IVIG, intravenous immunoglobulin; RTX, rituximab; CS, corticosteroids; BORT, Bortezomib; Dara, Daratumumab.

Conclusion

To assess the efficiency and safety of daratumumab in PRCA therapy and to determine the minimally effective dose, one should further accumulate clinical data with inclusion of a large number of transplant centers, due to low incidence of this post-transplant complication.

One should note that the concept of depletion of long-lived plasma cells is also promising in treatment of other hematological diseases associated with allo- and autoantibody mechanisms, such as autoimmune hemolytic anemia and immune thrombocytopenic purpura, as demonstrated by a number of clinical cases [22, 30], and a positive effect in systemic autoimmune conditions cannot be ruled out [31].

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"AUTHOR_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "25" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "30966" ["VALUE"]=> array(2) { ["TEXT"]=> string(358) "<p>Ксения С. Цвирко, Юрий Н. Кузнецов, Ирина К. Голубовская, Анна Г. Смирнова, Елена Е. Лепик, Зарема К. Абдулхаликова, Николай Ю. Цветков, Ольга В. Пирогова, Иван С. Моисеев, Александр Д. Кулагин</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(346) "

Ксения С. Цвирко, Юрий Н. Кузнецов, Ирина К. Голубовская, Анна Г. Смирнова, Елена Е. Лепик, Зарема К. Абдулхаликова, Николай Ю. Цветков, Ольга В. Пирогова, Иван С. Моисеев, Александр Д. Кулагин

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "30967" ["VALUE"]=> array(2) { ["TEXT"]=> string(374) "<p>НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(362) "

НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "30968" ["VALUE"]=> array(2) { ["TEXT"]=> string(1731) "<p style="text-align: justify;">Посттрансплантационная чистая красноклеточная аплазия (ЧККА) – редкое осложнение, возникающее после проведения аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК) с AB0-несовместимостью. В большинстве случаев данное состояние разрешается самостоятельно, однако у части пациентов ЧККА может сохраняться в течении долгого времени, ухудшая качество жизни и соматический статус. Консенсуса в лечении посттрансплантационной ЧККА в настоящее время нет, ранее применяемые терапевтические опции имеют низкую патогенетическую обоснованность и ограниченную эффективность. В настоящей статье мы представляем серию клинических случаев лечения ЧККА моноклональным антителом IgG1канти-CD38 даратумумабом.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;"> Трансплантация гемопоэтических стволовых клеток, аллогенная, чистая красноклеточная аплазия, посттрансплантационная, даратумумаб.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1675) "

Посттрансплантационная чистая красноклеточная аплазия (ЧККА) – редкое осложнение, возникающее после проведения аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК) с AB0-несовместимостью. В большинстве случаев данное состояние разрешается самостоятельно, однако у части пациентов ЧККА может сохраняться в течении долгого времени, ухудшая качество жизни и соматический статус. Консенсуса в лечении посттрансплантационной ЧККА в настоящее время нет, ранее применяемые терапевтические опции имеют низкую патогенетическую обоснованность и ограниченную эффективность. В настоящей статье мы представляем серию клинических случаев лечения ЧККА моноклональным антителом IgG1канти-CD38 даратумумабом.

Ключевые слова

Трансплантация гемопоэтических стволовых клеток, аллогенная, чистая красноклеточная аплазия, посттрансплантационная, даратумумаб.

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Ksenia S. Tsvirko, Yuriy N. Kuznetsov, Irina K. Golubovskaya, Anna G. Smirnova, Elena E. Lepik, Zarema K. Abdulkhalikova, Nikolay Y. Tsvetkov, Olga V. Pirogova, Ivan S. Moiseev, Alexander D. Kulagin

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RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia


Correspondence:
Dr. Ksenia S. Tsvirko, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, L. Tolstoy St. 6-8, 197022, St. Petersburg, Russia
Phone: +7 (923) 575-70-56
E-mail: Ksenia_Kud_@mail.ru


Citation: Tsvirko KS, Kuznetsov YN, Golubovskaya IK, et al. Daratumumab in post-transplantation pure red cell aplasia in adults. Cell Ther Transplant 2024; 13(1): 28-33.

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Post-transplant pure red cell aplasia (PRCA) is a rare complication that occurs after allogeneic hematopoietic stem cell transplantation (allo-HSCT) with ABO incompatibility. In most cases, this condition resolves without any treatment. However, in some patients, PRCA can persist for a long time, worsening the quality of life and somatic status. There is currently no consensus on the treatment of PRCA: previously used therapeutic options have limited application in the post-transplant period and low pathogenetic validity. In this article, we present a series of clinical cases of PRCA treatment with daratumumab, a monoclonal IgG1k anti-CD38 antibody.

Keywords

Hematopoietic stem cell transplantation, allogeneic, pure red cell aplasia, post-transplant, daratumumab.

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Tsvirko, Yuriy N. Kuznetsov, Irina K. Golubovskaya, Anna G. Smirnova, Elena E. Lepik, Zarema K. Abdulkhalikova, Nikolay Y. Tsvetkov, Olga V. Pirogova, Ivan S. Moiseev, Alexander D. Kulagin</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(205) "

Ksenia S. Tsvirko, Yuriy N. Kuznetsov, Irina K. Golubovskaya, Anna G. Smirnova, Elena E. Lepik, Zarema K. Abdulkhalikova, Nikolay Y. Tsvetkov, Olga V. Pirogova, Ivan S. Moiseev, Alexander D. Kulagin

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Ksenia S. Tsvirko, Yuriy N. Kuznetsov, Irina K. Golubovskaya, Anna G. Smirnova, Elena E. Lepik, Zarema K. Abdulkhalikova, Nikolay Y. Tsvetkov, Olga V. Pirogova, Ivan S. Moiseev, Alexander D. Kulagin

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Post-transplant pure red cell aplasia (PRCA) is a rare complication that occurs after allogeneic hematopoietic stem cell transplantation (allo-HSCT) with ABO incompatibility. In most cases, this condition resolves without any treatment. However, in some patients, PRCA can persist for a long time, worsening the quality of life and somatic status. There is currently no consensus on the treatment of PRCA: previously used therapeutic options have limited application in the post-transplant period and low pathogenetic validity. In this article, we present a series of clinical cases of PRCA treatment with daratumumab, a monoclonal IgG1k anti-CD38 antibody.

Keywords

Hematopoietic stem cell transplantation, allogeneic, pure red cell aplasia, post-transplant, daratumumab.

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Post-transplant pure red cell aplasia (PRCA) is a rare complication that occurs after allogeneic hematopoietic stem cell transplantation (allo-HSCT) with ABO incompatibility. In most cases, this condition resolves without any treatment. However, in some patients, PRCA can persist for a long time, worsening the quality of life and somatic status. There is currently no consensus on the treatment of PRCA: previously used therapeutic options have limited application in the post-transplant period and low pathogenetic validity. In this article, we present a series of clinical cases of PRCA treatment with daratumumab, a monoclonal IgG1k anti-CD38 antibody.

Keywords

Hematopoietic stem cell transplantation, allogeneic, pure red cell aplasia, post-transplant, daratumumab.

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RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia


Correspondence:
Dr. Ksenia S. Tsvirko, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, L. Tolstoy St. 6-8, 197022, St. Petersburg, Russia
Phone: +7 (923) 575-70-56
E-mail: Ksenia_Kud_@mail.ru


Citation: Tsvirko KS, Kuznetsov YN, Golubovskaya IK, et al. Daratumumab in post-transplantation pure red cell aplasia in adults. Cell Ther Transplant 2024; 13(1): 28-33.

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RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia


Correspondence:
Dr. Ksenia S. Tsvirko, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, L. Tolstoy St. 6-8, 197022, St. Petersburg, Russia
Phone: +7 (923) 575-70-56
E-mail: Ksenia_Kud_@mail.ru


Citation: Tsvirko KS, Kuznetsov YN, Golubovskaya IK, et al. Daratumumab in post-transplantation pure red cell aplasia in adults. Cell Ther Transplant 2024; 13(1): 28-33.

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Ксения С. Цвирко, Юрий Н. Кузнецов, Ирина К. Голубовская, Анна Г. Смирнова, Елена Е. Лепик, Зарема К. Абдулхаликова, Николай Ю. Цветков, Ольга В. Пирогова, Иван С. Моисеев, Александр Д. Кулагин

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Ксения С. Цвирко, Юрий Н. Кузнецов, Ирина К. Голубовская, Анна Г. Смирнова, Елена Е. Лепик, Зарема К. Абдулхаликова, Николай Ю. Цветков, Ольга В. Пирогова, Иван С. Моисеев, Александр Д. Кулагин

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Посттрансплантационная чистая красноклеточная аплазия (ЧККА) – редкое осложнение, возникающее после проведения аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК) с AB0-несовместимостью. В большинстве случаев данное состояние разрешается самостоятельно, однако у части пациентов ЧККА может сохраняться в течении долгого времени, ухудшая качество жизни и соматический статус. Консенсуса в лечении посттрансплантационной ЧККА в настоящее время нет, ранее применяемые терапевтические опции имеют низкую патогенетическую обоснованность и ограниченную эффективность. В настоящей статье мы представляем серию клинических случаев лечения ЧККА моноклональным антителом IgG1канти-CD38 даратумумабом.

Ключевые слова

Трансплантация гемопоэтических стволовых клеток, аллогенная, чистая красноклеточная аплазия, посттрансплантационная, даратумумаб.

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Посттрансплантационная чистая красноклеточная аплазия (ЧККА) – редкое осложнение, возникающее после проведения аллогенной трансплантации гемопоэтических стволовых клеток (алло-ТГСК) с AB0-несовместимостью. В большинстве случаев данное состояние разрешается самостоятельно, однако у части пациентов ЧККА может сохраняться в течении долгого времени, ухудшая качество жизни и соматический статус. Консенсуса в лечении посттрансплантационной ЧККА в настоящее время нет, ранее применяемые терапевтические опции имеют низкую патогенетическую обоснованность и ограниченную эффективность. В настоящей статье мы представляем серию клинических случаев лечения ЧККА моноклональным антителом IgG1канти-CD38 даратумумабом.

Ключевые слова

Трансплантация гемопоэтических стволовых клеток, аллогенная, чистая красноклеточная аплазия, посттрансплантационная, даратумумаб.

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НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия

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НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия

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Introduction

Currently, polymeric particles are of great interest as drug delivery systems [1-3], as well as for developing vaccines [4, 5] and trapping systems for viruses [6-8] and pathogens [9]. Polymeric particles can vary in size and properties. In particular, polymer particles <500 nm in size are classified as nanoparticles (NPs), while particles >1000 nm are considered microparticles (MPs) [10, 11]. Biodegradable (co)polymers are preferable for preparation of micro- and nanoparticles, since they can be totally eliminated from the body after degradation. Among these, aliphatic polyesters, e.g. poly(lactic acid) (PLA), or its copolymer with glycolic acid (PLGA), poly-ε-caprolactone, poly-3-hydroxybutirate, etc. are biodegradable and non-toxic polymers, which are promising for biomedical applications [12]. Moreover, they are approved by Food and Drug Administration (FDA) Agency [13]. Sometimes, the mentioned polymers are copolymerized with poly(ethylene glycol) (PEG; also FDA approved polymer) to prepare amphiphilic block- and graft-copolymers [14, 15].

The biological effect of particles is regulated by immobilization of the specific ligands such as peptides, antibodies, carbohydrates, and aptamers, etc., on the surface of polymer particles. To date, there are a number of studies on the evaluation of humoral immune response towards protein immobilized on the surface of micro- and nanoparticles [16-19]. For example, it was shown that the use of particles based on PLGA, carrying ovalbumin and oligonucleotide, and having a diameter of 300 nm led to a higher antigen-specific immune response in mice compared to particles of the same origin, but of different size (1, 7 and 17 μm) [18]. A similar trend for ovalbumin immobilized on the surface of polystyrene particles with diameters ranging from 40 nm to 2 μm has been shown by Fifis et al. [17]. In this case, the highest antibody induction was detected for the complex antigen immobilized on 40- nm NPs, and the lowest level was found for complex antigen based on MPs of 2-µm diameter.

Along with humoral immune response, the complex antigens consisting of polymer particle bearing protein antigen may also affect T-cellular immune response, based on activation of antigen- specific CD4+ and CD8+ T-lymphocytes. Induction of both humoral and also cytotoxic immune system is required, for example, for effective elimination of some viruses (HIV, hepatitis C virus, SARS-Cov2, etc.) from the host organism mediated by specially designed trapping systems. For effective activation of the immune response, the antigen uptake by macrophages or dendritic cells is required, followed by its presentation in a complex with molecules of the major histocompatibility complex. Recently, Uto et al. reported that immunization of mice with nanoparticles (NPs, 210 nm in diameter) based on poly(γ-glutamic acid) bearing immobilized ovalbumin induced significant activation of CD8+ T cells [20]. Similarly, Zhang et al. reported the suitability of ovalbumin-loaded NPs (about 250 nm in diameter) based on poly(glutamic acid) modified with phenylalanine ethyl ester for enhancing cellular immunity [21].

Recently, we studied the humoral immune response on the immunization of mice with PLA-based MPs and NPs bearing β2M-sfGFP as a model protein [16]. When administered intraperitoneally, the PLA-based MPs as carriers for protein were less effective in the production of specific antibodies against the immobilized protein than NPs. Finally, the particles covalently modified with model proteins cause a less pronounced humoral immune response compared to a mixture of particles with protein.

The aim of this study was to investigate the size effect of polymeric particles with covalently bound model protein (complex antigen) on the counts of antigen-specific T-helper cells and cytotoxic T-cells. As another type of polymer particles, the PLA microparticles and nanoparticles based on block-copolymer of PLA with PEG (PEG-b-PLA) were used as carriers for comparative studies. A fusion protein containing human beta2-microglobulin (bMG) with green fluorescent protein (β2M-sfGFP) was selected as a model antigen. The obtained complex antigen (β2M-sfGFP), loaded on micro- and nanoparticles (MPs or NPs), were physically characterized and used for immunization of mice. Finally, the antigen-specific interferon-producing T-lymphocyte populations were analyzed by intracellular cytokine staining and flow cytometry.

Materials and methods

Production and Characterization of Polymer MPs and NPs

MPs were obtained by the single emulsion method using PLA (Мw = 23200, Ð = 1.13). The details on PLA synthesis and microparticle preparation can be found elsewhere [16]. NPs were prepared by nanoprecipitation of PEG-b-PLA (Мw = 30300, Ð = 1.20) from a solution in acetonitrile into water under vigorous stirring as previously described [22]. The mean hydrodynamic diameter (DH) and polydispersity index (PDI) of MPs and NPs, as well as the surface ζ-potential were determined by dynamic and electrophoretic light scattering using the Zetasizer Nano ZS (Malvern, UK). The properties of MPs and NPs are summarized in Table 1.

Table 1. Physico-chemical characteristics of initial and modified with PEG-b-PLA protein particles

Sakhabeev-tab01.jpg

Protein Production and Its Covalent Immobilization on Surface of the Particles

Model protein β2M-sfGFP was produced in Escherichia coli (strain BL21(DE3)) transformed with plasmids containing corresponding genes as elsewhere described [23, 24]. E. coli cells were disrupted by ultrasound treatment, the soluble cell fraction was separated by centrifugation, and the target recombinant proteins were purified by column liquid chromatography using Ni-agarose (Ni-NTA Agarose, QIAgen, USA) according to the manufacturer's protocol.

The process of protein immobilization on the particle surface consisted of several steps. (1) Free carboxyl groups were generated on the surface of polymer particles by partial PLA hydrolysis with 0.1 M NaOH solution for 30 min at room temperature (25°С). The particles were separated and rinsed with distilled water followed by centrifugation; (2) At the second stage, free carboxyl groups were activated. Carboxyl groups formed on the surface of the particles were activated by a mixture of N-hydroxysuccinimide and water-soluble carbodiimide-N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride in order to obtain activated ester [16]. The amount of immobilized β2M-sfGFP was determined as a difference of protein contents in soluble phase before and after the reaction. The protein concentration was determined spectrophotometrically at 490 nm using a ThermoScientific NanoDrop 2000 (USA) spectrophotometer. The calculation was performed by a calibration curve previously plotted for the β2M-sfGFP.

Mice Immunization

Female F1 hybrids (CBA x C57BL) weighing 20-25 g (age 4-6 months) were used for immunization. The mice were kept in the vivarium at ambient temperature and 12/12 h light regime, with food and water ad libitum. To assess immune response to antigens, the mice were injected with test preparations. Both experimental and control groups (naive animals) included 15 mice. The amount of complex antigen was calculated in order to reach 1 μg of β2M-sfGFP per mouse. The preparations diluted in sterile saline solution (0.9% NaCl) were administered intraperitoneally at a volume of 0.4 mL/animal. All animal experiments were performed in accordance with International Recommendations for biomedical research using animals. Mice were immunized 4 times at an interval of 2 weeks.

Isolation and Cryopreservation of Mouse Splenocytes

Splenocytes were isolated from the spleens of mice 2 weeks after the last quadruple immunization. The spleens were placed in 1 mL of sterile DMEM nutrient medium (Gibco, 41965-039) with antibiotic/antimycotic (Gibсo, 15240-062), being gently homogenized. The cell suspension was washed with 10 mL of sterile PBS for 10 min (centrifugation at 200g, 10°C). The cell sediment was resuspended in 3 mL of buffer and, after lysis of erythrocytes, the nucleated cells were washed with excess sterile PBS (10 min at 200g, 10°C). The resulting cell precipitate was resuspended in 1 mL of fetal calf serum (HyClone, SH30071.02), then supplied with 1 mL of double cryopreserving solution (fetal calf serum with 20% DMSO) was added in cold bath (0°C) with constant stirring. 1 mL of the suspension was poured into cryotubes (Biolab, 028049) and stored at -70 °C followed by transfer to liquid nitrogen for the next day.

Intracellular Cytokine Staining

Splenocytes were characterized using antibodies to CD3 labeled with allophycocyanin (BioLegend, 100236), antibodies to CD4 labeled with PE (BioLegend, 100408), antibodies to CD8a labeled with PC7 (BioLegend, 100722), antibodies to IFNγ labeled with FITC (BioLegend, 505806). To identify antigen-specific T cells, the generally accepted method of intracellular cytokine staining (IFNγ) was used [25]. The cells (106/well) were cultured in round-bottomed 96-well plates in 200 µL of complete culture medium prepared on the basis of RPMI-1640 (Sigma-Aldrich, R8758-100ML) supplied with10% embryonic calf serum, HEPES aqueous solution (Biolot, 1.2.6.), antibiotics/antimycotics (Gibсo, 15240-062), 2-mercaptoethanol (Amresco 0482-0.1), ronkoleikin (106 U/mL, NPK Biotech, St. Petersburg). The cells were incubated in a CO2 incubator at 37°C for 12 h with an antigen. Five hours before the end of incubation, a 1x solution of GolgiPlug (BD Bioscience, 555028) was added, blocking the excretion of cytokines from the cell. To determine spontaneous production of IFNγ, an appropriate volume of RPMI-1640 nutrient medium was added, instead of stimulating agent. In the analysis, these data (negative control) were subtracted from the indices obtained for antigen-stimulated cells. Flow cytometry studies were performed with Beckman Coulter Navios device (Beckman, USA).

Statistical Data Processing

Newman-Keuls test was used for pairwise comparison of the groups. Normality was checked using the Shapiro-Wilk criterion. All statistical calculations and plotting were performed in the Rstudio 1.1.453 software. All "box plot" plots were presented as medians with confidence intervals. Each group of animals consisted of 15 mice. The immunoassays were done in 3 replicates for each sample.

Results and discussion

The chosen approach to β2M-sfGFP immobilization presumed formation of hydrolytically stable amide bonds between the protein and the surface of the polymer particle. The protein loading conditions were optimized in order to provide immobilization capacity of 10 μg of protein/mg particles. The protein binding to the surface of polymer particles led to a slight increase in their hydrodynamic diameter (DH) and a decrease in the surface ζ-potential (Table 1).

Two groups of mice were immunized in order to compare the immune effects of model protein loaded on the polymer particles. The first group was immunized with a complex antigen representing polymer nanoparticles bearing model protein (NPs-β2M-sfGFP), and the second group was treated with a complex antigen with polymer microparticles bearing the same protein. A third group represented the non-immunized intact (naive) mice. A four-time immunization of mice at 2-week intervals was performed, and spleen samples were collected 13 days after the last immunization. Mouse spleen cells were phenotyped using antibodies to CD3, CD4, CD8 and interferon γ (IFNγ). A common intracellular cytokine staining method was used to identify antigen-specific interferon-producing T cells followed by flow cytometry analysis of T cell populations.

The relative content of IFNγ+-lymphocytes specific to sfGFP protein was determined for the following T-cell subpopulations: CD4+ T cells (IFNγ+CD3+CD4+), i.e., type 1 T-helper cells, and CD8+ T cells (IFNγ+CD3+CD8+) as shown in Fig. 1.

Sakhabeev-fig01.jpg

Figure 1. Detection of antigen-specific T helper and cytotoxic T lymphocytes by multicolor flow cytometry

A, exclusion of adherent cells from the analysis area based on peak (x-axis) and integral (y-axis) signals of direct light scattering (single cells are located in the "Singlets FSAxFSH" area); B, exclusion of adherent cells from the analysis area based on peak width (x-axis) and integral (y-axis) signals of direct light scattering (single cells are located in the "Singlets FSAxFSW" area); C, identification of splenocytes on the basis of lateral (y-axis) and direct (x-axis) light scattering parameters (single splenocytes are located in the "Splenocytes" area and analyzed in the subsequent histogram); D, removal of dead cells from the analysis area based on the inclusion of Zombie Aqua dye (the "Live" area contains live single splenocytes); E, detection of T-lymphocytes based on CD3 expression (the "T cells" area contains T-lymphocytes); F, separation of T-lymphocytes into T-helper (phenotype CD3+CD4+, area "CD4+ T cells") and cytotoxic T-lymphocytes (phenotype CD3+CD8+, area "CD8+ T cells"); histograms G and H – IFNγ production by T-helper and cytotoxic T-lymphocytes in response to in vitro stimulation, respectively (area "IFNγ+ CD4+ T cells" in histogram G and area "IFNγ+ CD8+ T cells" in histogram H, respectively).

The flow cytometry method was used to assess relative contents of CD4+ and CD8+ T cells. Using the Shapiro-Wilk criterion, it was found that the distribution was not normal in each group (p<0.001). Therefore, the nonparametric Newman-Keuls statistical test was used for pairwise comparison of the three groups. The results of this comparison are summarized in Table 2.

Table 2. Results of statistical analysis of CD4+ and CD8+ T-lymphocytes in the groups of immunized and naïve mice (see text)

Sakhabeev-tab02.jpg

* MPs, microparticles; NPs, nanoparticles; MPs-β2M-sfGFP, mice immunized with complex protein antigen loaded on MPs (DH of 1427 nm); NPs-β2M-sfGFP, mice immunized with complex protein antigen immobilized on NPs (DH of hydrodynamic diameter 115 nm); naïve (intact) mice.

Fig. 2 shows that the number of antigen-specific IFNγ-producing memory T cells of CD4+ phenotype (T-helper cells), was not significantly different between the animals immunized with a complex β2M-sfGFP antigen bound to polymer microparticles and the group immunized with similar antigen loaded on nanoparticles. However, the number of IFNγ-producing antigen-specific CD8+ T cells was significantly (p=0.031) higher in the case of immunization with a complex MPs-β2M-sfGFP conjugate than in the group, immunized with a complex NPs-β2M-sfGFP antigen. It is also worth of note that the group of naïve (non-immunized) mice showed a significantly lower response compared with both immunized groups.

Sakhabeev-fig02.jpg

Figure 2. Relative contents of antigen-specific CD4+ T cells (A) and CD8+ T cells (B) responding to the model protein sfGFP in mice

***, P level of significance <0.005. ** P level of significance >0.005 but less than 0.05. NS, differences are insignificant (p>0.05). For the group designations, see footnote to Table 2.

The obtained results may be explained by different mechanisms of their interaction and entrance to the cells. In particular, it is known that the particles of <200 nm have been found to penetrate cells in an actin-independent manner (e.g., by clathrin-dependent endocytosis) [26]. The particles of larger size are usually engulfed by actin-dependent manner by phagocytosis. These features of particle uptake appear to play a role in the immune response to the particle-associated antigens. The same features distinguish the immune response to particulate antigens from the response to conventional classical vaccines [27].

Conclusion

Hence, one may conclude that polymer microparticles are more suitable, e.g., for preparation of trapping systems for viruses, since they promote a more pronounced activation of cellular immune response, being quite important for development of antiviral immunity. In turn, the PLA-based nanoparticles around 100 nm in diameter cannot be recommended for this purpose due to the fact that they cause mainly a strong humoral immune response, i.e., production of antigen-specific immunoglobulins [16]. Therefore, the latter type of particles is more preferable as adjuvants in vaccine development.

Compliance with ethical standards

All procedures involving animals complied with the ethical standards approved by the legal acts of the Russian Federation, the principles of the Basel Declaration and recommendations of the Local Ethical Committee of the Institute of Experimental Medicine.

Funding

The work was performed within the frame of State assignments of IMC RAS (124013000730-3) and IEM (FGWG-2022-0009, 122020300191-9).

Conflict of interest

The authors declare no evident and potential conflicts of interest related to the publication of this article.

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Introduction

Currently, polymeric particles are of great interest as drug delivery systems [1-3], as well as for developing vaccines [4, 5] and trapping systems for viruses [6-8] and pathogens [9]. Polymeric particles can vary in size and properties. In particular, polymer particles <500 nm in size are classified as nanoparticles (NPs), while particles >1000 nm are considered microparticles (MPs) [10, 11]. Biodegradable (co)polymers are preferable for preparation of micro- and nanoparticles, since they can be totally eliminated from the body after degradation. Among these, aliphatic polyesters, e.g. poly(lactic acid) (PLA), or its copolymer with glycolic acid (PLGA), poly-ε-caprolactone, poly-3-hydroxybutirate, etc. are biodegradable and non-toxic polymers, which are promising for biomedical applications [12]. Moreover, they are approved by Food and Drug Administration (FDA) Agency [13]. Sometimes, the mentioned polymers are copolymerized with poly(ethylene glycol) (PEG; also FDA approved polymer) to prepare amphiphilic block- and graft-copolymers [14, 15].

The biological effect of particles is regulated by immobilization of the specific ligands such as peptides, antibodies, carbohydrates, and aptamers, etc., on the surface of polymer particles. To date, there are a number of studies on the evaluation of humoral immune response towards protein immobilized on the surface of micro- and nanoparticles [16-19]. For example, it was shown that the use of particles based on PLGA, carrying ovalbumin and oligonucleotide, and having a diameter of 300 nm led to a higher antigen-specific immune response in mice compared to particles of the same origin, but of different size (1, 7 and 17 μm) [18]. A similar trend for ovalbumin immobilized on the surface of polystyrene particles with diameters ranging from 40 nm to 2 μm has been shown by Fifis et al. [17]. In this case, the highest antibody induction was detected for the complex antigen immobilized on 40- nm NPs, and the lowest level was found for complex antigen based on MPs of 2-µm diameter.

Along with humoral immune response, the complex antigens consisting of polymer particle bearing protein antigen may also affect T-cellular immune response, based on activation of antigen- specific CD4+ and CD8+ T-lymphocytes. Induction of both humoral and also cytotoxic immune system is required, for example, for effective elimination of some viruses (HIV, hepatitis C virus, SARS-Cov2, etc.) from the host organism mediated by specially designed trapping systems. For effective activation of the immune response, the antigen uptake by macrophages or dendritic cells is required, followed by its presentation in a complex with molecules of the major histocompatibility complex. Recently, Uto et al. reported that immunization of mice with nanoparticles (NPs, 210 nm in diameter) based on poly(γ-glutamic acid) bearing immobilized ovalbumin induced significant activation of CD8+ T cells [20]. Similarly, Zhang et al. reported the suitability of ovalbumin-loaded NPs (about 250 nm in diameter) based on poly(glutamic acid) modified with phenylalanine ethyl ester for enhancing cellular immunity [21].

Recently, we studied the humoral immune response on the immunization of mice with PLA-based MPs and NPs bearing β2M-sfGFP as a model protein [16]. When administered intraperitoneally, the PLA-based MPs as carriers for protein were less effective in the production of specific antibodies against the immobilized protein than NPs. Finally, the particles covalently modified with model proteins cause a less pronounced humoral immune response compared to a mixture of particles with protein.

The aim of this study was to investigate the size effect of polymeric particles with covalently bound model protein (complex antigen) on the counts of antigen-specific T-helper cells and cytotoxic T-cells. As another type of polymer particles, the PLA microparticles and nanoparticles based on block-copolymer of PLA with PEG (PEG-b-PLA) were used as carriers for comparative studies. A fusion protein containing human beta2-microglobulin (bMG) with green fluorescent protein (β2M-sfGFP) was selected as a model antigen. The obtained complex antigen (β2M-sfGFP), loaded on micro- and nanoparticles (MPs or NPs), were physically characterized and used for immunization of mice. Finally, the antigen-specific interferon-producing T-lymphocyte populations were analyzed by intracellular cytokine staining and flow cytometry.

Materials and methods

Production and Characterization of Polymer MPs and NPs

MPs were obtained by the single emulsion method using PLA (Мw = 23200, Ð = 1.13). The details on PLA synthesis and microparticle preparation can be found elsewhere [16]. NPs were prepared by nanoprecipitation of PEG-b-PLA (Мw = 30300, Ð = 1.20) from a solution in acetonitrile into water under vigorous stirring as previously described [22]. The mean hydrodynamic diameter (DH) and polydispersity index (PDI) of MPs and NPs, as well as the surface ζ-potential were determined by dynamic and electrophoretic light scattering using the Zetasizer Nano ZS (Malvern, UK). The properties of MPs and NPs are summarized in Table 1.

Table 1. Physico-chemical characteristics of initial and modified with PEG-b-PLA protein particles

Sakhabeev-tab01.jpg

Protein Production and Its Covalent Immobilization on Surface of the Particles

Model protein β2M-sfGFP was produced in Escherichia coli (strain BL21(DE3)) transformed with plasmids containing corresponding genes as elsewhere described [23, 24]. E. coli cells were disrupted by ultrasound treatment, the soluble cell fraction was separated by centrifugation, and the target recombinant proteins were purified by column liquid chromatography using Ni-agarose (Ni-NTA Agarose, QIAgen, USA) according to the manufacturer's protocol.

The process of protein immobilization on the particle surface consisted of several steps. (1) Free carboxyl groups were generated on the surface of polymer particles by partial PLA hydrolysis with 0.1 M NaOH solution for 30 min at room temperature (25°С). The particles were separated and rinsed with distilled water followed by centrifugation; (2) At the second stage, free carboxyl groups were activated. Carboxyl groups formed on the surface of the particles were activated by a mixture of N-hydroxysuccinimide and water-soluble carbodiimide-N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride in order to obtain activated ester [16]. The amount of immobilized β2M-sfGFP was determined as a difference of protein contents in soluble phase before and after the reaction. The protein concentration was determined spectrophotometrically at 490 nm using a ThermoScientific NanoDrop 2000 (USA) spectrophotometer. The calculation was performed by a calibration curve previously plotted for the β2M-sfGFP.

Mice Immunization

Female F1 hybrids (CBA x C57BL) weighing 20-25 g (age 4-6 months) were used for immunization. The mice were kept in the vivarium at ambient temperature and 12/12 h light regime, with food and water ad libitum. To assess immune response to antigens, the mice were injected with test preparations. Both experimental and control groups (naive animals) included 15 mice. The amount of complex antigen was calculated in order to reach 1 μg of β2M-sfGFP per mouse. The preparations diluted in sterile saline solution (0.9% NaCl) were administered intraperitoneally at a volume of 0.4 mL/animal. All animal experiments were performed in accordance with International Recommendations for biomedical research using animals. Mice were immunized 4 times at an interval of 2 weeks.

Isolation and Cryopreservation of Mouse Splenocytes

Splenocytes were isolated from the spleens of mice 2 weeks after the last quadruple immunization. The spleens were placed in 1 mL of sterile DMEM nutrient medium (Gibco, 41965-039) with antibiotic/antimycotic (Gibсo, 15240-062), being gently homogenized. The cell suspension was washed with 10 mL of sterile PBS for 10 min (centrifugation at 200g, 10°C). The cell sediment was resuspended in 3 mL of buffer and, after lysis of erythrocytes, the nucleated cells were washed with excess sterile PBS (10 min at 200g, 10°C). The resulting cell precipitate was resuspended in 1 mL of fetal calf serum (HyClone, SH30071.02), then supplied with 1 mL of double cryopreserving solution (fetal calf serum with 20% DMSO) was added in cold bath (0°C) with constant stirring. 1 mL of the suspension was poured into cryotubes (Biolab, 028049) and stored at -70 °C followed by transfer to liquid nitrogen for the next day.

Intracellular Cytokine Staining

Splenocytes were characterized using antibodies to CD3 labeled with allophycocyanin (BioLegend, 100236), antibodies to CD4 labeled with PE (BioLegend, 100408), antibodies to CD8a labeled with PC7 (BioLegend, 100722), antibodies to IFNγ labeled with FITC (BioLegend, 505806). To identify antigen-specific T cells, the generally accepted method of intracellular cytokine staining (IFNγ) was used [25]. The cells (106/well) were cultured in round-bottomed 96-well plates in 200 µL of complete culture medium prepared on the basis of RPMI-1640 (Sigma-Aldrich, R8758-100ML) supplied with10% embryonic calf serum, HEPES aqueous solution (Biolot, 1.2.6.), antibiotics/antimycotics (Gibсo, 15240-062), 2-mercaptoethanol (Amresco 0482-0.1), ronkoleikin (106 U/mL, NPK Biotech, St. Petersburg). The cells were incubated in a CO2 incubator at 37°C for 12 h with an antigen. Five hours before the end of incubation, a 1x solution of GolgiPlug (BD Bioscience, 555028) was added, blocking the excretion of cytokines from the cell. To determine spontaneous production of IFNγ, an appropriate volume of RPMI-1640 nutrient medium was added, instead of stimulating agent. In the analysis, these data (negative control) were subtracted from the indices obtained for antigen-stimulated cells. Flow cytometry studies were performed with Beckman Coulter Navios device (Beckman, USA).

Statistical Data Processing

Newman-Keuls test was used for pairwise comparison of the groups. Normality was checked using the Shapiro-Wilk criterion. All statistical calculations and plotting were performed in the Rstudio 1.1.453 software. All "box plot" plots were presented as medians with confidence intervals. Each group of animals consisted of 15 mice. The immunoassays were done in 3 replicates for each sample.

Results and discussion

The chosen approach to β2M-sfGFP immobilization presumed formation of hydrolytically stable amide bonds between the protein and the surface of the polymer particle. The protein loading conditions were optimized in order to provide immobilization capacity of 10 μg of protein/mg particles. The protein binding to the surface of polymer particles led to a slight increase in their hydrodynamic diameter (DH) and a decrease in the surface ζ-potential (Table 1).

Two groups of mice were immunized in order to compare the immune effects of model protein loaded on the polymer particles. The first group was immunized with a complex antigen representing polymer nanoparticles bearing model protein (NPs-β2M-sfGFP), and the second group was treated with a complex antigen with polymer microparticles bearing the same protein. A third group represented the non-immunized intact (naive) mice. A four-time immunization of mice at 2-week intervals was performed, and spleen samples were collected 13 days after the last immunization. Mouse spleen cells were phenotyped using antibodies to CD3, CD4, CD8 and interferon γ (IFNγ). A common intracellular cytokine staining method was used to identify antigen-specific interferon-producing T cells followed by flow cytometry analysis of T cell populations.

The relative content of IFNγ+-lymphocytes specific to sfGFP protein was determined for the following T-cell subpopulations: CD4+ T cells (IFNγ+CD3+CD4+), i.e., type 1 T-helper cells, and CD8+ T cells (IFNγ+CD3+CD8+) as shown in Fig. 1.

Sakhabeev-fig01.jpg

Figure 1. Detection of antigen-specific T helper and cytotoxic T lymphocytes by multicolor flow cytometry

A, exclusion of adherent cells from the analysis area based on peak (x-axis) and integral (y-axis) signals of direct light scattering (single cells are located in the "Singlets FSAxFSH" area); B, exclusion of adherent cells from the analysis area based on peak width (x-axis) and integral (y-axis) signals of direct light scattering (single cells are located in the "Singlets FSAxFSW" area); C, identification of splenocytes on the basis of lateral (y-axis) and direct (x-axis) light scattering parameters (single splenocytes are located in the "Splenocytes" area and analyzed in the subsequent histogram); D, removal of dead cells from the analysis area based on the inclusion of Zombie Aqua dye (the "Live" area contains live single splenocytes); E, detection of T-lymphocytes based on CD3 expression (the "T cells" area contains T-lymphocytes); F, separation of T-lymphocytes into T-helper (phenotype CD3+CD4+, area "CD4+ T cells") and cytotoxic T-lymphocytes (phenotype CD3+CD8+, area "CD8+ T cells"); histograms G and H – IFNγ production by T-helper and cytotoxic T-lymphocytes in response to in vitro stimulation, respectively (area "IFNγ+ CD4+ T cells" in histogram G and area "IFNγ+ CD8+ T cells" in histogram H, respectively).

The flow cytometry method was used to assess relative contents of CD4+ and CD8+ T cells. Using the Shapiro-Wilk criterion, it was found that the distribution was not normal in each group (p<0.001). Therefore, the nonparametric Newman-Keuls statistical test was used for pairwise comparison of the three groups. The results of this comparison are summarized in Table 2.

Table 2. Results of statistical analysis of CD4+ and CD8+ T-lymphocytes in the groups of immunized and naïve mice (see text)

Sakhabeev-tab02.jpg

* MPs, microparticles; NPs, nanoparticles; MPs-β2M-sfGFP, mice immunized with complex protein antigen loaded on MPs (DH of 1427 nm); NPs-β2M-sfGFP, mice immunized with complex protein antigen immobilized on NPs (DH of hydrodynamic diameter 115 nm); naïve (intact) mice.

Fig. 2 shows that the number of antigen-specific IFNγ-producing memory T cells of CD4+ phenotype (T-helper cells), was not significantly different between the animals immunized with a complex β2M-sfGFP antigen bound to polymer microparticles and the group immunized with similar antigen loaded on nanoparticles. However, the number of IFNγ-producing antigen-specific CD8+ T cells was significantly (p=0.031) higher in the case of immunization with a complex MPs-β2M-sfGFP conjugate than in the group, immunized with a complex NPs-β2M-sfGFP antigen. It is also worth of note that the group of naïve (non-immunized) mice showed a significantly lower response compared with both immunized groups.

Sakhabeev-fig02.jpg

Figure 2. Relative contents of antigen-specific CD4+ T cells (A) and CD8+ T cells (B) responding to the model protein sfGFP in mice

***, P level of significance <0.005. ** P level of significance >0.005 but less than 0.05. NS, differences are insignificant (p>0.05). For the group designations, see footnote to Table 2.

The obtained results may be explained by different mechanisms of their interaction and entrance to the cells. In particular, it is known that the particles of <200 nm have been found to penetrate cells in an actin-independent manner (e.g., by clathrin-dependent endocytosis) [26]. The particles of larger size are usually engulfed by actin-dependent manner by phagocytosis. These features of particle uptake appear to play a role in the immune response to the particle-associated antigens. The same features distinguish the immune response to particulate antigens from the response to conventional classical vaccines [27].

Conclusion

Hence, one may conclude that polymer microparticles are more suitable, e.g., for preparation of trapping systems for viruses, since they promote a more pronounced activation of cellular immune response, being quite important for development of antiviral immunity. In turn, the PLA-based nanoparticles around 100 nm in diameter cannot be recommended for this purpose due to the fact that they cause mainly a strong humoral immune response, i.e., production of antigen-specific immunoglobulins [16]. Therefore, the latter type of particles is more preferable as adjuvants in vaccine development.

Compliance with ethical standards

All procedures involving animals complied with the ethical standards approved by the legal acts of the Russian Federation, the principles of the Basel Declaration and recommendations of the Local Ethical Committee of the Institute of Experimental Medicine.

Funding

The work was performed within the frame of State assignments of IMC RAS (124013000730-3) and IEM (FGWG-2022-0009, 122020300191-9).

Conflict of interest

The authors declare no evident and potential conflicts of interest related to the publication of this article.

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string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "3" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "Y" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(13) "EAutocomplete" ["USER_TYPE_SETTINGS"]=> array(9) { ["VIEW"]=> string(1) "E" ["SHOW_ADD"]=> string(1) "Y" ["MAX_WIDTH"]=> int(0) ["MIN_HEIGHT"]=> int(24) ["MAX_HEIGHT"]=> int(1000) ["BAN_SYM"]=> string(2) ",;" ["REP_SYM"]=> string(1) " " ["OTHER_REP_SYM"]=> string(0) "" ["IBLOCK_MESS"]=> string(1) "N" } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> bool(false) ["VALUE"]=> bool(false) ["DESCRIPTION"]=> bool(false) ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> bool(false) ["~DESCRIPTION"]=> bool(false) ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> string(0) "" } ["AUTHOR_RU"]=> array(36) { ["ID"]=> string(2) "25" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(12) "Авторы" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(9) "AUTHOR_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "25" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "30990" ["VALUE"]=> array(2) { ["TEXT"]=> string(469) "<p>Родион Г. Сахабеев<sup>1</sup>, Дмитрий С. Поляков<sup>2</sup>, Виктор А. Коржиков-Влах<sup>3</sup>, Екатерина С. Синицына<sup>3,4</sup>, Галина А. Платонова<sup>4</sup>, Евгения Г. Коржикова-Влах<sup>3,4</sup>, Михаил М. Шавловский<sup>2</sup></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(373) "

Родион Г. Сахабеев1, Дмитрий С. Поляков2, Виктор А. Коржиков-Влах3, Екатерина С. Синицына3,4, Галина А. Платонова4, Евгения Г. Коржикова-Влах3,4, Михаил М. Шавловский2

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(12) "Авторы" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["ORGANIZATION_RU"]=> array(36) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "30991" ["VALUE"]=> array(2) { ["TEXT"]=> string(809) "<p><sup>1</sup> Санкт-Петербургский государственный технологический институт (Технический университет), Санкт-Петербург, Россия<br> <sup>2</sup> Институт экспериментальной медицины, Санкт-Петербург, Россия<br> <sup>3</sup> Институт химии, Санкт-Петербургский государственный университет, Санкт-Петербург, Россия<br> <sup>4</sup> Институт высокомолекулярных соединений Российской академии наук, Санкт-Петербург, Россия </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(731) "

1 Санкт-Петербургский государственный технологический институт (Технический университет), Санкт-Петербург, Россия
2 Институт экспериментальной медицины, Санкт-Петербург, Россия
3 Институт химии, Санкт-Петербургский государственный университет, Санкт-Петербург, Россия
4 Институт высокомолекулярных соединений Российской академии наук, Санкт-Петербург, Россия

" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "30992" ["VALUE"]=> array(2) { ["TEXT"]=> string(2829) "<p style="text-align: justify;">В работе изучали влияние размера полимерных частиц на основе поли(D,L-молочной кислоты), несущих на поверхности белок слияния бета2-микроглобулина человека с зеленым флуоресцентным белком (β2M-sfGFP), на уровень антиген-специфических Т-хелперов и цитотоксических Т-лимфоцитов. В качестве носителей использовали микрочастицы диаметром около 1400 нм (МЧ) и наночастицы диаметром около 100 нм (НЧ). Для изучения влияния частиц разного размера на иммуногенность модельного белка были проиммунизированы две группы мышей так, чтобы количество β2М-sfGFP было идентичным. Для выявления специфичных к антигену Т-клеток, продуцирующих интерферон, использовали общепринятый метод внутриклеточного окрашивания цитокинов. Для последующего анализа популяций Т-лимфоцитов был использован метод проточной цитофлуориметрии. Количество антигенспецифических Т-клеток иммунологической памяти фенотипа CD4+ (Т-хелперы), продуцирующих IFNγ, значимо не отличалось в случае иммунизации комплексным антигеном МЧ-β2М-sfGFP по сравнению с группой, которая была иммунизирована комплексным антигеном НЧ-β2М-sfGFP. Однако количество антигенспецифических CD8+ Т-клеток, продуцирующих IFNγ, статистически значимо (p=0,031) выше в случае иммунизации комплексным антигеном МЧ-β2М-sfGFP по сравнению с группой, которая была иммунизирована комплексным антигеном НЧ-β2М-sfGFP.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;"> Клеточный иммунный ответ, Т-хелперы, Т-цитотоксические лимфоциты, белковый антиген, микрочастицы, наночастицы, поли(молочная кислота).</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2773) "

В работе изучали влияние размера полимерных частиц на основе поли(D,L-молочной кислоты), несущих на поверхности белок слияния бета2-микроглобулина человека с зеленым флуоресцентным белком (β2M-sfGFP), на уровень антиген-специфических Т-хелперов и цитотоксических Т-лимфоцитов. В качестве носителей использовали микрочастицы диаметром около 1400 нм (МЧ) и наночастицы диаметром около 100 нм (НЧ). Для изучения влияния частиц разного размера на иммуногенность модельного белка были проиммунизированы две группы мышей так, чтобы количество β2М-sfGFP было идентичным. Для выявления специфичных к антигену Т-клеток, продуцирующих интерферон, использовали общепринятый метод внутриклеточного окрашивания цитокинов. Для последующего анализа популяций Т-лимфоцитов был использован метод проточной цитофлуориметрии. Количество антигенспецифических Т-клеток иммунологической памяти фенотипа CD4+ (Т-хелперы), продуцирующих IFNγ, значимо не отличалось в случае иммунизации комплексным антигеном МЧ-β2М-sfGFP по сравнению с группой, которая была иммунизирована комплексным антигеном НЧ-β2М-sfGFP. Однако количество антигенспецифических CD8+ Т-клеток, продуцирующих IFNγ, статистически значимо (p=0,031) выше в случае иммунизации комплексным антигеном МЧ-β2М-sfGFP по сравнению с группой, которая была иммунизирована комплексным антигеном НЧ-β2М-sfGFP.

Ключевые слова

Клеточный иммунный ответ, Т-хелперы, Т-цитотоксические лимфоциты, белковый антиген, микрочастицы, наночастицы, поли(молочная кислота).

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Rodion G. Sakhabeev1, Dmitry S. Polyakov2, Viktor A. Korzhikov-Vlakh3, Ekaterina S. Sinitsyna3,4, Galina A. Platonova4, Evgenia G. Korzhikova-Vlakh3,4, Mikhail M. Shavlovsky2

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1 St. Petersburg Institute of Technology (Technical University), St. Petersburg, Russia
2 Institute of Experimental Medicine, St. Petersburg, Russia
3 Institute of Chemistry, St. Petersburg State University, St. Petersburg, Russia
4 Institute of Macromolecular Compounds of Russian Academy of Sciences, St. Petersburg, Russia


Correspondence:
Rodion G. Sakhabeev, St. Petersburg Institute of Technology (Technical University), St. Petersburg, Russia
E-mail: helm505@mail.ru


Citation: Sakhabeev RG, Polyakov DS, Korzhikov-Vlakh VA et al. Effect of the size of polymer particles bearing protein antigen on the in vivo T-cellular immune response. Cell Ther Transplant 2024; 13(1): 42-48.

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In this work, we studied the effect of size of polymeric particles based on poly(D,L-lactic acid) bearing on the surface the fusion protein of human beta2-microglobulin with green fluorescent protein (β2M-sfGFP) on the levels of antigen-specific T-helper and cytotoxic T-lymphocytes. Microparticles with a diameter of about 1400 nm (MPs) and nanoparticles with a diameter of about 100 nm (NPs) were used as carriers for model protein. To evaluate the effect of different particle sizes on the immunogenicity of the model protein, two groups of mice were immunized so that the amount of β2M-sfGFP was equal. The identification of the antigen-specific interferon-producing T cells was carried out by the method of intracellular cytokine staining. For further analysis of T-lymphocyte populations, the method of flow cytofluorimetry was used. The number of antigen-specific CD4+ IFNγ-producing memory T cells (T-helpers) was not significantly different in the case of immunization with complex antigen MPs-β2M-sfGFP compared with the group immunized with antigen immobilized on the nanoparticles (NPs-β2M-sfGFP). However, the number of antigen-specific CD8+ T cells producing IFNγ was significantly higher (p = 0.031) in the case of immunization with complex antigen based on MPs compared to the group treated with the complex antigen based on NPs.

Keywords

Cellular immune response, T helper cells, T cytotoxic lymphocytes, protein antigen, microparticles, nanoparticles, poly(lactic acid).

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Sakhabeev<sup>1</sup>, Dmitry S. Polyakov<sup>2</sup>, Viktor A. Korzhikov-Vlakh<sup>3</sup>, Ekaterina S. Sinitsyna<sup>3,4</sup>, Galina A. Platonova<sup>4</sup>, Evgenia G. Korzhikova-Vlakh<sup>3,4</sup>, Mikhail M. Shavlovsky<sup>2</sup></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(258) "

Rodion G. Sakhabeev1, Dmitry S. Polyakov2, Viktor A. Korzhikov-Vlakh3, Ekaterina S. Sinitsyna3,4, Galina A. Platonova4, Evgenia G. Korzhikova-Vlakh3,4, Mikhail M. Shavlovsky2

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Rodion G. Sakhabeev1, Dmitry S. Polyakov2, Viktor A. Korzhikov-Vlakh3, Ekaterina S. Sinitsyna3,4, Galina A. Platonova4, Evgenia G. Korzhikova-Vlakh3,4, Mikhail M. Shavlovsky2

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In this work, we studied the effect of size of polymeric particles based on poly(D,L-lactic acid) bearing on the surface the fusion protein of human beta2-microglobulin with green fluorescent protein (β2M-sfGFP) on the levels of antigen-specific T-helper and cytotoxic T-lymphocytes. Microparticles with a diameter of about 1400 nm (MPs) and nanoparticles with a diameter of about 100 nm (NPs) were used as carriers for model protein. To evaluate the effect of different particle sizes on the immunogenicity of the model protein, two groups of mice were immunized so that the amount of β2M-sfGFP was equal. The identification of the antigen-specific interferon-producing T cells was carried out by the method of intracellular cytokine staining. For further analysis of T-lymphocyte populations, the method of flow cytofluorimetry was used. The number of antigen-specific CD4+ IFNγ-producing memory T cells (T-helpers) was not significantly different in the case of immunization with complex antigen MPs-β2M-sfGFP compared with the group immunized with antigen immobilized on the nanoparticles (NPs-β2M-sfGFP). However, the number of antigen-specific CD8+ T cells producing IFNγ was significantly higher (p = 0.031) in the case of immunization with complex antigen based on MPs compared to the group treated with the complex antigen based on NPs.

Keywords

Cellular immune response, T helper cells, T cytotoxic lymphocytes, protein antigen, microparticles, nanoparticles, poly(lactic acid).

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In this work, we studied the effect of size of polymeric particles based on poly(D,L-lactic acid) bearing on the surface the fusion protein of human beta2-microglobulin with green fluorescent protein (β2M-sfGFP) on the levels of antigen-specific T-helper and cytotoxic T-lymphocytes. Microparticles with a diameter of about 1400 nm (MPs) and nanoparticles with a diameter of about 100 nm (NPs) were used as carriers for model protein. To evaluate the effect of different particle sizes on the immunogenicity of the model protein, two groups of mice were immunized so that the amount of β2M-sfGFP was equal. The identification of the antigen-specific interferon-producing T cells was carried out by the method of intracellular cytokine staining. For further analysis of T-lymphocyte populations, the method of flow cytofluorimetry was used. The number of antigen-specific CD4+ IFNγ-producing memory T cells (T-helpers) was not significantly different in the case of immunization with complex antigen MPs-β2M-sfGFP compared with the group immunized with antigen immobilized on the nanoparticles (NPs-β2M-sfGFP). However, the number of antigen-specific CD8+ T cells producing IFNγ was significantly higher (p = 0.031) in the case of immunization with complex antigen based on MPs compared to the group treated with the complex antigen based on NPs.

Keywords

Cellular immune response, T helper cells, T cytotoxic lymphocytes, protein antigen, microparticles, nanoparticles, poly(lactic acid).

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1 St. Petersburg Institute of Technology (Technical University), St. Petersburg, Russia
2 Institute of Experimental Medicine, St. Petersburg, Russia
3 Institute of Chemistry, St. Petersburg State University, St. Petersburg, Russia
4 Institute of Macromolecular Compounds of Russian Academy of Sciences, St. Petersburg, Russia


Correspondence:
Rodion G. Sakhabeev, St. Petersburg Institute of Technology (Technical University), St. Petersburg, Russia
E-mail: helm505@mail.ru


Citation: Sakhabeev RG, Polyakov DS, Korzhikov-Vlakh VA et al. Effect of the size of polymer particles bearing protein antigen on the in vivo T-cellular immune response. Cell Ther Transplant 2024; 13(1): 42-48.

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1 St. Petersburg Institute of Technology (Technical University), St. Petersburg, Russia
2 Institute of Experimental Medicine, St. Petersburg, Russia
3 Institute of Chemistry, St. Petersburg State University, St. Petersburg, Russia
4 Institute of Macromolecular Compounds of Russian Academy of Sciences, St. Petersburg, Russia


Correspondence:
Rodion G. Sakhabeev, St. Petersburg Institute of Technology (Technical University), St. Petersburg, Russia
E-mail: helm505@mail.ru


Citation: Sakhabeev RG, Polyakov DS, Korzhikov-Vlakh VA et al. Effect of the size of polymer particles bearing protein antigen on the in vivo T-cellular immune response. Cell Ther Transplant 2024; 13(1): 42-48.

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Родион Г. Сахабеев1, Дмитрий С. Поляков2, Виктор А. Коржиков-Влах3, Екатерина С. Синицына3,4, Галина А. Платонова4, Евгения Г. Коржикова-Влах3,4, Михаил М. Шавловский2

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Родион Г. Сахабеев1, Дмитрий С. Поляков2, Виктор А. Коржиков-Влах3, Екатерина С. Синицына3,4, Галина А. Платонова4, Евгения Г. Коржикова-Влах3,4, Михаил М. Шавловский2

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В качестве носителей использовали микрочастицы диаметром около 1400 нм (МЧ) и наночастицы диаметром около 100 нм (НЧ). Для изучения влияния частиц разного размера на иммуногенность модельного белка были проиммунизированы две группы мышей так, чтобы количество β2М-sfGFP было идентичным. Для выявления специфичных к антигену Т-клеток, продуцирующих интерферон, использовали общепринятый метод внутриклеточного окрашивания цитокинов. Для последующего анализа популяций Т-лимфоцитов был использован метод проточной цитофлуориметрии. Количество антигенспецифических Т-клеток иммунологической памяти фенотипа CD4+ (Т-хелперы), продуцирующих IFNγ, значимо не отличалось в случае иммунизации комплексным антигеном МЧ-β2М-sfGFP по сравнению с группой, которая была иммунизирована комплексным антигеном НЧ-β2М-sfGFP. Однако количество антигенспецифических CD8+ Т-клеток, продуцирующих IFNγ, статистически значимо (p=0,031) выше в случае иммунизации комплексным антигеном МЧ-β2М-sfGFP по сравнению с группой, которая была иммунизирована комплексным антигеном НЧ-β2М-sfGFP.</p> <h2>Ключевые слова</h2> <p style="text-align: justify;"> Клеточный иммунный ответ, Т-хелперы, Т-цитотоксические лимфоциты, белковый антиген, микрочастицы, наночастицы, поли(молочная кислота).</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(2773) "

В работе изучали влияние размера полимерных частиц на основе поли(D,L-молочной кислоты), несущих на поверхности белок слияния бета2-микроглобулина человека с зеленым флуоресцентным белком (β2M-sfGFP), на уровень антиген-специфических Т-хелперов и цитотоксических Т-лимфоцитов. В качестве носителей использовали микрочастицы диаметром около 1400 нм (МЧ) и наночастицы диаметром около 100 нм (НЧ). Для изучения влияния частиц разного размера на иммуногенность модельного белка были проиммунизированы две группы мышей так, чтобы количество β2М-sfGFP было идентичным. Для выявления специфичных к антигену Т-клеток, продуцирующих интерферон, использовали общепринятый метод внутриклеточного окрашивания цитокинов. Для последующего анализа популяций Т-лимфоцитов был использован метод проточной цитофлуориметрии. Количество антигенспецифических Т-клеток иммунологической памяти фенотипа CD4+ (Т-хелперы), продуцирующих IFNγ, значимо не отличалось в случае иммунизации комплексным антигеном МЧ-β2М-sfGFP по сравнению с группой, которая была иммунизирована комплексным антигеном НЧ-β2М-sfGFP. Однако количество антигенспецифических CD8+ Т-клеток, продуцирующих IFNγ, статистически значимо (p=0,031) выше в случае иммунизации комплексным антигеном МЧ-β2М-sfGFP по сравнению с группой, которая была иммунизирована комплексным антигеном НЧ-β2М-sfGFP.

Ключевые слова

Клеточный иммунный ответ, Т-хелперы, Т-цитотоксические лимфоциты, белковый антиген, микрочастицы, наночастицы, поли(молочная кислота).

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В работе изучали влияние размера полимерных частиц на основе поли(D,L-молочной кислоты), несущих на поверхности белок слияния бета2-микроглобулина человека с зеленым флуоресцентным белком (β2M-sfGFP), на уровень антиген-специфических Т-хелперов и цитотоксических Т-лимфоцитов. В качестве носителей использовали микрочастицы диаметром около 1400 нм (МЧ) и наночастицы диаметром около 100 нм (НЧ). Для изучения влияния частиц разного размера на иммуногенность модельного белка были проиммунизированы две группы мышей так, чтобы количество β2М-sfGFP было идентичным. Для выявления специфичных к антигену Т-клеток, продуцирующих интерферон, использовали общепринятый метод внутриклеточного окрашивания цитокинов. Для последующего анализа популяций Т-лимфоцитов был использован метод проточной цитофлуориметрии. Количество антигенспецифических Т-клеток иммунологической памяти фенотипа CD4+ (Т-хелперы), продуцирующих IFNγ, значимо не отличалось в случае иммунизации комплексным антигеном МЧ-β2М-sfGFP по сравнению с группой, которая была иммунизирована комплексным антигеном НЧ-β2М-sfGFP. Однако количество антигенспецифических CD8+ Т-клеток, продуцирующих IFNγ, статистически значимо (p=0,031) выше в случае иммунизации комплексным антигеном МЧ-β2М-sfGFP по сравнению с группой, которая была иммунизирована комплексным антигеном НЧ-β2М-sfGFP.

Ключевые слова

Клеточный иммунный ответ, Т-хелперы, Т-цитотоксические лимфоциты, белковый антиген, микрочастицы, наночастицы, поли(молочная кислота).

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1 Санкт-Петербургский государственный технологический институт (Технический университет), Санкт-Петербург, Россия
2 Институт экспериментальной медицины, Санкт-Петербург, Россия
3 Институт химии, Санкт-Петербургский государственный университет, Санкт-Петербург, Россия
4 Институт высокомолекулярных соединений Российской академии наук, Санкт-Петербург, Россия

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1 Санкт-Петербургский государственный технологический институт (Технический университет), Санкт-Петербург, Россия
2 Институт экспериментальной медицины, Санкт-Петербург, Россия
3 Институт химии, Санкт-Петербургский государственный университет, Санкт-Петербург, Россия
4 Институт высокомолекулярных соединений Российской академии наук, Санкт-Петербург, Россия

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Introduction

Allogeneic hematopoietic cell transplantation (allo-HSCT) is the treatment of choice for many blood disorders. Currently, it is the only potential curative option for this subset of patients. The allo-HSCT procedure can be divided into separate phases: pre-transplant conditioning, transfusion of allogeneic hematopoietic stem cells and post-transplant period. At each phase of allo-HSCT a set of various measures is implemented, including the usage of drugs, medical devices, biological products, blood components, etc. [1]. However, the information about the effectiveness and safety of each phase of allo-HSCT for each specific disease is far from complete.

Currently in the Russian Federation clinical practice guidelines are an essential part of the healthcare system. Their implementation is regulated by several legal acts i.e. Article 37 of the Federal Law No. 323-FZ of November 21, 2011 (as amended on July 24, 2023) On the fundamentals of public health protection in the Russian Federation (as amended and supplemented, effective as of September 1, 2023). We also have Order of the Ministry of Health of the Russian Federation No. 103n dated 02.28.2019 (as amended on 06.23.2020) On the approval of the procedure and terms for development of clinical practice guidelines, their revision, development of the standard form of clinical practice guidelines and requirements for their structure, composition and scientific validity of the information included therein, and the Order states that the "off-label" prescription of medical products for human use that is not in accordance with the indications and contraindications, route of administration and dosage as per instruction leaflet of the medical product, without the abovementioned evidence and reference to clinical studies on the effectiveness and safety of the specific protocol for a specific disease, or reference to the relevant literature sources is prohibited. In other words, without the information about the effectiveness and safety of a particular drug applicable to a specific transplantation methodology, the drug cannot be included in clinical practice guidelines [2].

As a result there is a situation, when despite of wide usage and effectiveness of drugs in the field of HSCT, approved standards for specialized post-HSCT medical care (examination and treatment correction) under Order of the MoH RF No. 1279n dated 20.12.12, effective Order of the MoH RF No. 875n dated 12.12. 2018 On the approval of the procedure for providing medical care to patients with diseases (conditions) requiring bone marrow and hematopoietic stem cell transplantation and amendments to the procedure for providing medical care in the field of surgery (transplantation of organs and/or human tissues), approved by Order of the MoH RF No. 567n dated 31.12. 2012, there is no data on the effectiveness and safety of individual drugs, their dosage, route of administration and the effectiveness and safety of potential drug combinations.

In Russian and foreign publications there is little information of this kind about conditioning regimens, GvHD prevention and supportive care, in particular for the diseases for which allo-HSCT is performed only in a small percentage of cases. In addition, the sample size is too small and thus too challenging for the analysis. The same applies to GvHD prophylaxis regimens; even less information is available for supportive care, from basic antiemetic therapy to infusion solutions.

Finally, there is no standardized procedure for performing allo-HSCT, but rather generally accepted indications for its implementation [3-6]. A standardized and disease-specific procedure for performing allo-HSCT including conditioning regimens (dosage, frequency, route of administration, etc.), GvHD prophylaxis, supportive care, will allow us to evaluate the effectiveness and safety of each stage of this procedure, and also conduct a pharmacoeconomic analysis of the technology in question.

To assess the current situation in the Russian Federation, and to lay the ground for subsequent standardization, we conducted a survey of expert opinion in a selection of transplantation centers.

The expert assessment method used in this publication belongs to a wide area of the decision-making theory, where the expert assessment is a procedure for obtaining an assessment of a problem based on the opinion of individual specialists (experts). This approach has found its application in cases of extreme complexity of the problem, its novelty and, most importantly, when there is insufficient information in a particular subject area [7].

Our study thereby aims to obtain cumulative information, based on the expert assessment, about the effectiveness and safety of the approaches to perform allo-HSCT in adult patients with different blood disorders.

Limitations of the Study

Given the specifics of expert assessment method, the key limitation for our study is that it does not allow us to compare the impact of different drugs on transplantation outcome. The findings of the study do not allow us drawing any conclusion about advantages or disadvantages of any given approach. Also, considering that for supportive care it is very difficult to select those complications that can be used as safety criteria in the context of allo-HSCT, we decided to not assess them.

Materials and methods

The study was conducted during the period from 07/01/2022 to 02/02/2023. Experts (employees of the institution at the time of the survey) from 10 centers performing allo-HSCT in the Russian Federation were interviewed. The list of centers with their serial numbers in this survey is given in Appendix 1. All the invited responders were asked to fill out an online questionnaire with 150 questions on the approaches to allo-HSCT in their respective institution. Scale questions with answers in the form of a range of values were used. The answers were then collected for further analysis. The highest values were mapped on heat maps which we used for data visualization. The effectiveness and safety criteria used in the study are presented in Table 1 below.

Table 1. Evaluated parameters and effectiveness and safety criteria

Drokov-tab01_eng.jpg

Statistical analysis was performed with R 4.3.2 (USA) statistical software package. Data visualization was done on heat map charts, based on the evaluated parameters for each participating transplantation center. In our research we used descriptive statistics methods.

Results

General information about the transplant centers

Ten transplantation centers of the Russian Federation participated in the study. Over the past decade these centers have performed together more than 5000 allo-HSCT procedures. Three (3) centers do more than 100 allo-HSCTs per year, another three (3) – from 50 to 100, one (1) – from 20 to 50, one (1) –from 10 to 20, one (1) – from 5 to 10, and one (1) – under 5. Among the diagnoses that are indicative for allo-HSCT and for which it was proposed to evaluate the effectiveness and safety of the allo-HSCT approaches were: acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), acute promyelocytic leukemia (APL), myelodysplastic syndrome (MDS), multiple myeloma (MM), Waldenström's macroglobulinemia (WM), primary amyloidosis (AL), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL), chronic myeloid leukemia (CML), mantle cell lymphoma (MCL), Hodgkin lymphoma (HL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMBCL), primary diffuse large B-cell lymphoma of the central nervous system (CNS DLBCL), T-cell lymphoma, myeloproliferative diseases, aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria. Cumulative data on conditioning regimens, type of donor and source of hematopoietic stem cells in the participating centers are presented in Figure 1 below.

Drokov-fig01-eng.jpg

Figure 1. Characteristics of the general approaches in the participating transplantation centers

MAC – myeloablative conditioning regimen; RIC – reduced intensity conditioning mode; NMA – non-myeloablative conditioning regimen; MRD – matched related donor; MUD – matched unrelated donor; MMUD – mismatched unrelated donor; MMRD – mismatched related donor; Haplo – haploidentical donor; PBSC – peripheral blood stem cells; BM – bone marrow; CG – combined graft; PrimeBM – primed bone marrow; green color – the center uses this approach; red color – the center does not use this approach.

Effectiveness and safety of pre-transplant conditioning regimens

The detailed description of pre-transplantation conditioning regimens (conditioning regimens), drugs used and routes of administration is presented in Appendix 2. The findings of the survey on the effectiveness and safety are presented in Figures 2 and 3 respectively. Missing data (crossed out white rectangle) suggests that the center does not use the respective conditioning modality.

Drokov-fig02-eng.jpg

Figure 2. Prevalence and estimated effectiveness of pre-transplant conditioning regimens

Drokov-fig03-eng.jpg

Figure 3. Prevalence and estimated safety of pre-transplant conditioning regimens

As it can be seen in the chart above, fludarabine-containing regimens accounted for 87.5% (n=28) of all conditioning regimens used. Quantitative evaluation of conditioning regimens was not our objective in this study, however even from the list of regimens it is obvious that fludarabine is the most frequently used agent in conditioning regimens for allo-HSCT. This prevalence can be well explained by the fact that the drug is widely available, has multiple generics, affordable price, is characterized by simplicity of use and acceptable toxicity profile.

Other most frequently used drugs were busulfan – it accounted for 37.5% (n=12), and melphalan – 12.5% (n=4) cases.

Noteworthy, for none of the abovementioned pre-transplant conditioning drugs allo-HSCT is stated in the official indications for use.

Only 2 centers (20%) used total body irradiation (TBI) as part of pre-transplant conditioning. It can be explained – the use of TBI is largely limited by its availability in the country.

Effectiveness and safety of graft-versus-host disease prophylaxis regimens

The next block of the questionnaire was devoted to assessing the effectiveness and safety of graft-versus-host disease (GvHD) prophylaxis. To perform this therapy, calcineurin inhibitors (CNIs) were most commonly reported: cyclosporine and tacrolimus are used in almost 85.7% (n=24) of all prophylactic regimens. The use of a particular drug most often depends on the established clinical practice and the availability of equipment and consumables for monitoring its concentration in the body. The second most commonly used drug was post-transplant cyclophosphamide, accounting for 42.9% (n=12) of cases. It is followed by mycophenolate mofetil – 57.1% (n=16).

Leaflet instructions for the abovementioned drugs, just like in the case of pre-transplant conditioning, do not contain, however, direct indications for use during allo-HSCT and for GvHD prevention.

More information on prevalence of other drugs is provided in Figure 4. Missing data (crossed-out white box) suggests that the center does not use the respective conditioning regimens.

Drokov-fig04-eng.jpg

Figure 4. Prevalence and estimated effectiveness of GvHD prophylaxis regimens

With regard to the safety criterion, the objective was to evaluate the day +100 transplant mortality for each of the GvHD prophylaxis regimens used, and calculate mean value for all types of allo-HSCT. It must be pointed out that this parameter is characterized by high degree of variability and strongly depends on the number of transplantations, comorbidities and type of allo-HSCT performed. The results of this evaluation are provided in Figure 5.

Drokov-fig05-eng.jpg

Figure 5. Prevalence and estimated safety of GvHD prophylaxis regimens

A particular aspect that deserves attention is whether graft manipulation methods (to prevent GvHD), for example CD34+ selection, are available in the respective transplantation centers. 60% (n=6) of the centers reported using this technique. This fact is very important, because this technological solution can be used as a platform for selection of other cell populations, e.g. for producing chimeric antigen receptor T-cells (CAR-T).

Effectiveness of supportive care

As for effectiveness of supportive care, there are currently no separate international reviews available. In our study we tried to provide a summary of all the drugs used, in one way or another, for allogeneic hematopoietic stem cell transplantation in adults. Our evaluation has demonstrated extreme heterogeneity of the drugs used, which is apparently determined by availability of the drugs in transplantation centers and the existing institutional practice. As it has been mentioned, in our study responders could not see the feedback from other centers, which suggests that indeed there was no truly significant difference in effectiveness. And yet again, just like it was previously indicated for all the drugs used in conditioning and GvHD prevention regimens, not a single supportive care drug has in its leaflet clear indication for allo-HSCT.

The findings are presented in Figure 6. Missing data (crossed out white box) suggests that the center does not routinely use this supportive therapy.

Drokov-fig06-eng.jpg

Figure 6. Prevalence and estimated effectiveness of individual elements of supportive care.

Discussion and conclusion

The reason for this study was absence of a standardized procedure for performing allo-HSCT in the Russian Federation, which however, is also the case for most countries with high transplantation activity [8]. Methodological limitations of the study do not allow us to compare the effect of the drugs on transplantation outcome and speak about advantages of a certain conditioning or GvHD prevention regimen. Our findings primarily demonstrate great heterogeneity of approaches to therapeutic strategies used for allo-HSCT in the Russian Federation – pre-transplant conditioning regimens, immunosuppressive therapy and supportive care. It should be noted however, that the principles of this procedure remain universal, which makes it possible to move towards standardization.

It seems important to create a Unified Register of allo-HSCT recipients and standardize clinical practice guidelines for performing allo-HSCT in the Russian Federation. For example, after a Unified Transplant Registry Program was created in Japan, allo-HSCT outcomes have improved [9]. In China similar measures made it possible to abandon the practice of using different indications for allo-HSCT depending on the type of donor for some groups of patients, which differs from approaches used in the Western world [10]. The system of monitoring outcomes of unrelated donor transplantation has already been implemented within the framework of the Federal Bone Marrow Donor Registry.

This analysis may serve a springboard for setting tariffs for allo-HSCT based on the diagnosis and technology used. In addition, the identified patterns make it possible to plan prospective randomized clinical studies to evaluate effectiveness of certain drugs in allo-HSCT. In the absence of large-scale studies in the field of allo-HSCT (with the exception of phase III trials), wider application of the expert assessment method will be helpful for reaching consensus in various fields (prevention and treatment of GvHD, treatment of complications, etc.), as we observe it in other transplantation societies [11-14].

Of course in future it would be interesting to do a robust analysis of therapeutic strategies depending on various factors; review the mortality structure, review the frequency of specific adverse drugs effects, standardize definitions and approaches for allo-HSCT and post-transplantation complications.

Conflicts of interest

None declared.

Acknowledgments

We express our gratitude to the management, doctors and nurses in the participating centers who on a daily basis provide medical care to their patients. Special appreciation goes to O.S. Karavaeva and N.N. Popova for their assistance in preparing and formatting the article.

References

  1. Parovichnikova EN, Vasilieva VA, Dovydenko MV, Drokov MYu, Kuzmina LA, Mikhaltsova ED et al. Protocols of allogeneic hematopoietic stem cell transplantation. 2020. https://npngo.ru/uploads/media_document/499/5173454c-5d8c-460d-a1d4-28f3fd0221ac.pdf. ISBN 978-5-89816-178-1
  2. Omelyanovskiy VV, Sura MV, Derkach EV, Avxentyeva MV. Clinical guidelines: from development to implementation. Medical Technologies. Assessment and Choice. 2020;42(4):45 51. (In Russian). doi: 10.17116/medtech20204204145
  3. Duarte RF, Labopin M, Bader P, Basak GW, Bonini C, Chabannon C, et al. Indications for hematopoietic stem cell transplantation for hematological diseases, solid tumors and immune disorders: current practice in Europe, 2019. Bone Marrow Transplant. 2019;54:1525-52 doi: 10.1038/s41409-019-0516-2
  4. Sureda A, Bader P, Cesaro S, Dreger P, Duarte RF, Dufour C, et al. Indications for allo- and auto-SCT for hematological diseases, solid tumors and immune disorders: current practice in Europe, 2015. Bone Marrow Transplant. 2015;50:1037-56. doi: 10.1038/bmt.2015.6
  5. Majhail NS, Farnia SH, Carpenter PA, Champlin RE, Crawford S, Marks DI, et al. Indications for Autologous and Allogeneic Hematopoietic Cell Transplantation: Guidelines from the American Society for Blood and Marrow Transplantation. Biology of Blood and Marrow Transplantation. 2015;21:1863-9. doi: 10.1016/j.bbmt.2015.07.032
  6. Snowden JA, Sánchez-Ortega I, Corbacioglu S, Basak GW, Chabannon C, de la Camara R, et al. Indications for hematopoietic cell transplantation for hematological diseases, solid tumors and immune disorders: current practice in Europe, 2022. Bone Marrow Transplant. 2022;57:1217-39. doi: 10.1038/s41409-022-01691-w
  7. Finkelstein EA, Bhadelia A, Goh C, Baid D, Singh R, Bhatnagar S, et al. Cross Country Comparison of Expert Assessments of the Quality of Death and Dying 2021. J Pain Symptom Manage. 2022;63:e419-29. doi: 10.1016/j.jpainsymman.2021.12.015
  8. Yanada M, Harada K, Shimomura Y, Arai Y, Konuma T. Conditioning regimens for allogeneic hematopoietic cell transplantation in acute myeloid leukemia: Real-world data from the Japanese registry studies. Front Oncol. 2022;12. doi: 10.3389/fonc.2022.1050633
  9. Atsuta Y. [The Japanese Transplant Registry Unified Management Program (TRUMP®): current issues and the future]. Rinsho Ketsueki. 2020;61:387-91. doi: 10.11406/rinketsu.61.387
  10. Xu L, Chen H, Chen J, Han M, Huang H, Lai Y, et al. The consensus on indications, conditioning regimen, and donor selection of allogeneic hematopoietic cell transplantation for hematological diseases in China – recommendations from the Chinese Society of Hematology. J Hematol Oncol. 2018;11:33. doi: 10.1186/s13045-018-0564-x
  11. Ciurea SO, Al Malki MM, Kongtim P, Fuchs EJ, Luznik L, Huang X-J, et al. The European Society for Blood and Marrow Transplantation (EBMT) consensus recommendations for donor selection in haploidentical hematopoietic cell transplantation. Bone Marrow Transplant. 2020;55:12-24. doi: 10.1038/s41409-019-0499-z
  12. Penack O, Marchetti M, Ruutu T, Aljurf M, Bacigalupo A, Bonifazi F, et al. Prophylaxis and management of graft versus host disease after stem-cell transplantation for haematological malignancies: updated consensus recommendations of the European Society for Blood and Marrow Transplantation. Lancet Haematol. 2020;7:e157-67. doi: 10.1016/S2352-3026(19)30256-X
  13. Ciurea SO, Cao K, Fernandez-Vina M, Kongtim P, Malki M Al, Fuchs E, et al. The European Society for Blood and Marrow Transplantation (EBMT) Consensus Guidelines for the Detection and Treatment of Donor-specific Anti-HLA Antibodies (DSA) in Haploidentical Hematopoietic Cell Transplantation. Bone Marrow Transplant. 2018;53:521-34. doi: 10.1038/s41409-017-0062-8
  14. Rejeski K, Subklewe M, Aljurf M, Bachy E, Balduzzi A, Barba P, et al. Immune effector cell-associated hematotoxicity: EHA/EBMT consensus grading and best practice recommendations. Blood. 2023;142:865-77. doi: 10.1182/blood.2023020578

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Introduction

Allogeneic hematopoietic cell transplantation (allo-HSCT) is the treatment of choice for many blood disorders. Currently, it is the only potential curative option for this subset of patients. The allo-HSCT procedure can be divided into separate phases: pre-transplant conditioning, transfusion of allogeneic hematopoietic stem cells and post-transplant period. At each phase of allo-HSCT a set of various measures is implemented, including the usage of drugs, medical devices, biological products, blood components, etc. [1]. However, the information about the effectiveness and safety of each phase of allo-HSCT for each specific disease is far from complete.

Currently in the Russian Federation clinical practice guidelines are an essential part of the healthcare system. Their implementation is regulated by several legal acts i.e. Article 37 of the Federal Law No. 323-FZ of November 21, 2011 (as amended on July 24, 2023) On the fundamentals of public health protection in the Russian Federation (as amended and supplemented, effective as of September 1, 2023). We also have Order of the Ministry of Health of the Russian Federation No. 103n dated 02.28.2019 (as amended on 06.23.2020) On the approval of the procedure and terms for development of clinical practice guidelines, their revision, development of the standard form of clinical practice guidelines and requirements for their structure, composition and scientific validity of the information included therein, and the Order states that the "off-label" prescription of medical products for human use that is not in accordance with the indications and contraindications, route of administration and dosage as per instruction leaflet of the medical product, without the abovementioned evidence and reference to clinical studies on the effectiveness and safety of the specific protocol for a specific disease, or reference to the relevant literature sources is prohibited. In other words, without the information about the effectiveness and safety of a particular drug applicable to a specific transplantation methodology, the drug cannot be included in clinical practice guidelines [2].

As a result there is a situation, when despite of wide usage and effectiveness of drugs in the field of HSCT, approved standards for specialized post-HSCT medical care (examination and treatment correction) under Order of the MoH RF No. 1279n dated 20.12.12, effective Order of the MoH RF No. 875n dated 12.12. 2018 On the approval of the procedure for providing medical care to patients with diseases (conditions) requiring bone marrow and hematopoietic stem cell transplantation and amendments to the procedure for providing medical care in the field of surgery (transplantation of organs and/or human tissues), approved by Order of the MoH RF No. 567n dated 31.12. 2012, there is no data on the effectiveness and safety of individual drugs, their dosage, route of administration and the effectiveness and safety of potential drug combinations.

In Russian and foreign publications there is little information of this kind about conditioning regimens, GvHD prevention and supportive care, in particular for the diseases for which allo-HSCT is performed only in a small percentage of cases. In addition, the sample size is too small and thus too challenging for the analysis. The same applies to GvHD prophylaxis regimens; even less information is available for supportive care, from basic antiemetic therapy to infusion solutions.

Finally, there is no standardized procedure for performing allo-HSCT, but rather generally accepted indications for its implementation [3-6]. A standardized and disease-specific procedure for performing allo-HSCT including conditioning regimens (dosage, frequency, route of administration, etc.), GvHD prophylaxis, supportive care, will allow us to evaluate the effectiveness and safety of each stage of this procedure, and also conduct a pharmacoeconomic analysis of the technology in question.

To assess the current situation in the Russian Federation, and to lay the ground for subsequent standardization, we conducted a survey of expert opinion in a selection of transplantation centers.

The expert assessment method used in this publication belongs to a wide area of the decision-making theory, where the expert assessment is a procedure for obtaining an assessment of a problem based on the opinion of individual specialists (experts). This approach has found its application in cases of extreme complexity of the problem, its novelty and, most importantly, when there is insufficient information in a particular subject area [7].

Our study thereby aims to obtain cumulative information, based on the expert assessment, about the effectiveness and safety of the approaches to perform allo-HSCT in adult patients with different blood disorders.

Limitations of the Study

Given the specifics of expert assessment method, the key limitation for our study is that it does not allow us to compare the impact of different drugs on transplantation outcome. The findings of the study do not allow us drawing any conclusion about advantages or disadvantages of any given approach. Also, considering that for supportive care it is very difficult to select those complications that can be used as safety criteria in the context of allo-HSCT, we decided to not assess them.

Materials and methods

The study was conducted during the period from 07/01/2022 to 02/02/2023. Experts (employees of the institution at the time of the survey) from 10 centers performing allo-HSCT in the Russian Federation were interviewed. The list of centers with their serial numbers in this survey is given in Appendix 1. All the invited responders were asked to fill out an online questionnaire with 150 questions on the approaches to allo-HSCT in their respective institution. Scale questions with answers in the form of a range of values were used. The answers were then collected for further analysis. The highest values were mapped on heat maps which we used for data visualization. The effectiveness and safety criteria used in the study are presented in Table 1 below.

Table 1. Evaluated parameters and effectiveness and safety criteria

Drokov-tab01_eng.jpg

Statistical analysis was performed with R 4.3.2 (USA) statistical software package. Data visualization was done on heat map charts, based on the evaluated parameters for each participating transplantation center. In our research we used descriptive statistics methods.

Results

General information about the transplant centers

Ten transplantation centers of the Russian Federation participated in the study. Over the past decade these centers have performed together more than 5000 allo-HSCT procedures. Three (3) centers do more than 100 allo-HSCTs per year, another three (3) – from 50 to 100, one (1) – from 20 to 50, one (1) –from 10 to 20, one (1) – from 5 to 10, and one (1) – under 5. Among the diagnoses that are indicative for allo-HSCT and for which it was proposed to evaluate the effectiveness and safety of the allo-HSCT approaches were: acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), acute promyelocytic leukemia (APL), myelodysplastic syndrome (MDS), multiple myeloma (MM), Waldenström's macroglobulinemia (WM), primary amyloidosis (AL), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL), chronic myeloid leukemia (CML), mantle cell lymphoma (MCL), Hodgkin lymphoma (HL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMBCL), primary diffuse large B-cell lymphoma of the central nervous system (CNS DLBCL), T-cell lymphoma, myeloproliferative diseases, aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria. Cumulative data on conditioning regimens, type of donor and source of hematopoietic stem cells in the participating centers are presented in Figure 1 below.

Drokov-fig01-eng.jpg

Figure 1. Characteristics of the general approaches in the participating transplantation centers

MAC – myeloablative conditioning regimen; RIC – reduced intensity conditioning mode; NMA – non-myeloablative conditioning regimen; MRD – matched related donor; MUD – matched unrelated donor; MMUD – mismatched unrelated donor; MMRD – mismatched related donor; Haplo – haploidentical donor; PBSC – peripheral blood stem cells; BM – bone marrow; CG – combined graft; PrimeBM – primed bone marrow; green color – the center uses this approach; red color – the center does not use this approach.

Effectiveness and safety of pre-transplant conditioning regimens

The detailed description of pre-transplantation conditioning regimens (conditioning regimens), drugs used and routes of administration is presented in Appendix 2. The findings of the survey on the effectiveness and safety are presented in Figures 2 and 3 respectively. Missing data (crossed out white rectangle) suggests that the center does not use the respective conditioning modality.

Drokov-fig02-eng.jpg

Figure 2. Prevalence and estimated effectiveness of pre-transplant conditioning regimens

Drokov-fig03-eng.jpg

Figure 3. Prevalence and estimated safety of pre-transplant conditioning regimens

As it can be seen in the chart above, fludarabine-containing regimens accounted for 87.5% (n=28) of all conditioning regimens used. Quantitative evaluation of conditioning regimens was not our objective in this study, however even from the list of regimens it is obvious that fludarabine is the most frequently used agent in conditioning regimens for allo-HSCT. This prevalence can be well explained by the fact that the drug is widely available, has multiple generics, affordable price, is characterized by simplicity of use and acceptable toxicity profile.

Other most frequently used drugs were busulfan – it accounted for 37.5% (n=12), and melphalan – 12.5% (n=4) cases.

Noteworthy, for none of the abovementioned pre-transplant conditioning drugs allo-HSCT is stated in the official indications for use.

Only 2 centers (20%) used total body irradiation (TBI) as part of pre-transplant conditioning. It can be explained – the use of TBI is largely limited by its availability in the country.

Effectiveness and safety of graft-versus-host disease prophylaxis regimens

The next block of the questionnaire was devoted to assessing the effectiveness and safety of graft-versus-host disease (GvHD) prophylaxis. To perform this therapy, calcineurin inhibitors (CNIs) were most commonly reported: cyclosporine and tacrolimus are used in almost 85.7% (n=24) of all prophylactic regimens. The use of a particular drug most often depends on the established clinical practice and the availability of equipment and consumables for monitoring its concentration in the body. The second most commonly used drug was post-transplant cyclophosphamide, accounting for 42.9% (n=12) of cases. It is followed by mycophenolate mofetil – 57.1% (n=16).

Leaflet instructions for the abovementioned drugs, just like in the case of pre-transplant conditioning, do not contain, however, direct indications for use during allo-HSCT and for GvHD prevention.

More information on prevalence of other drugs is provided in Figure 4. Missing data (crossed-out white box) suggests that the center does not use the respective conditioning regimens.

Drokov-fig04-eng.jpg

Figure 4. Prevalence and estimated effectiveness of GvHD prophylaxis regimens

With regard to the safety criterion, the objective was to evaluate the day +100 transplant mortality for each of the GvHD prophylaxis regimens used, and calculate mean value for all types of allo-HSCT. It must be pointed out that this parameter is characterized by high degree of variability and strongly depends on the number of transplantations, comorbidities and type of allo-HSCT performed. The results of this evaluation are provided in Figure 5.

Drokov-fig05-eng.jpg

Figure 5. Prevalence and estimated safety of GvHD prophylaxis regimens

A particular aspect that deserves attention is whether graft manipulation methods (to prevent GvHD), for example CD34+ selection, are available in the respective transplantation centers. 60% (n=6) of the centers reported using this technique. This fact is very important, because this technological solution can be used as a platform for selection of other cell populations, e.g. for producing chimeric antigen receptor T-cells (CAR-T).

Effectiveness of supportive care

As for effectiveness of supportive care, there are currently no separate international reviews available. In our study we tried to provide a summary of all the drugs used, in one way or another, for allogeneic hematopoietic stem cell transplantation in adults. Our evaluation has demonstrated extreme heterogeneity of the drugs used, which is apparently determined by availability of the drugs in transplantation centers and the existing institutional practice. As it has been mentioned, in our study responders could not see the feedback from other centers, which suggests that indeed there was no truly significant difference in effectiveness. And yet again, just like it was previously indicated for all the drugs used in conditioning and GvHD prevention regimens, not a single supportive care drug has in its leaflet clear indication for allo-HSCT.

The findings are presented in Figure 6. Missing data (crossed out white box) suggests that the center does not routinely use this supportive therapy.

Drokov-fig06-eng.jpg

Figure 6. Prevalence and estimated effectiveness of individual elements of supportive care.

Discussion and conclusion

The reason for this study was absence of a standardized procedure for performing allo-HSCT in the Russian Federation, which however, is also the case for most countries with high transplantation activity [8]. Methodological limitations of the study do not allow us to compare the effect of the drugs on transplantation outcome and speak about advantages of a certain conditioning or GvHD prevention regimen. Our findings primarily demonstrate great heterogeneity of approaches to therapeutic strategies used for allo-HSCT in the Russian Federation – pre-transplant conditioning regimens, immunosuppressive therapy and supportive care. It should be noted however, that the principles of this procedure remain universal, which makes it possible to move towards standardization.

It seems important to create a Unified Register of allo-HSCT recipients and standardize clinical practice guidelines for performing allo-HSCT in the Russian Federation. For example, after a Unified Transplant Registry Program was created in Japan, allo-HSCT outcomes have improved [9]. In China similar measures made it possible to abandon the practice of using different indications for allo-HSCT depending on the type of donor for some groups of patients, which differs from approaches used in the Western world [10]. The system of monitoring outcomes of unrelated donor transplantation has already been implemented within the framework of the Federal Bone Marrow Donor Registry.

This analysis may serve a springboard for setting tariffs for allo-HSCT based on the diagnosis and technology used. In addition, the identified patterns make it possible to plan prospective randomized clinical studies to evaluate effectiveness of certain drugs in allo-HSCT. In the absence of large-scale studies in the field of allo-HSCT (with the exception of phase III trials), wider application of the expert assessment method will be helpful for reaching consensus in various fields (prevention and treatment of GvHD, treatment of complications, etc.), as we observe it in other transplantation societies [11-14].

Of course in future it would be interesting to do a robust analysis of therapeutic strategies depending on various factors; review the mortality structure, review the frequency of specific adverse drugs effects, standardize definitions and approaches for allo-HSCT and post-transplantation complications.

Conflicts of interest

None declared.

Acknowledgments

We express our gratitude to the management, doctors and nurses in the participating centers who on a daily basis provide medical care to their patients. Special appreciation goes to O.S. Karavaeva and N.N. Popova for their assistance in preparing and formatting the article.

References

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  5. Majhail NS, Farnia SH, Carpenter PA, Champlin RE, Crawford S, Marks DI, et al. Indications for Autologous and Allogeneic Hematopoietic Cell Transplantation: Guidelines from the American Society for Blood and Marrow Transplantation. Biology of Blood and Marrow Transplantation. 2015;21:1863-9. doi: 10.1016/j.bbmt.2015.07.032
  6. Snowden JA, Sánchez-Ortega I, Corbacioglu S, Basak GW, Chabannon C, de la Camara R, et al. Indications for hematopoietic cell transplantation for hematological diseases, solid tumors and immune disorders: current practice in Europe, 2022. Bone Marrow Transplant. 2022;57:1217-39. doi: 10.1038/s41409-022-01691-w
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  8. Yanada M, Harada K, Shimomura Y, Arai Y, Konuma T. Conditioning regimens for allogeneic hematopoietic cell transplantation in acute myeloid leukemia: Real-world data from the Japanese registry studies. Front Oncol. 2022;12. doi: 10.3389/fonc.2022.1050633
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array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "31002" ["VALUE"]=> array(2) { ["TEXT"]=> string(1141) "<p>Михаил Ю. Дроков<sup>1</sup>, Иван С. Моисеев<sup>2,3</sup>, Юлия А. Олейник<sup>4</sup>, Ирина В. Ишматова<sup>5</sup>, Дмитрий В. Моторин<sup>6</sup>, Юлия С. Китаева<sup>7,8</sup>, Наталья А. Зорина<sup>9</sup>, Сергей В. Грицаев<sup>10</sup>, Наталия М. Никифорова<sup>11</sup>, Любовь М. Петрова<sup>12</sup>, Татьяна С. Капорская<sup>12</sup>, Галина Д. Петрова<sup>11</sup>, Сергей В. Волошин<sup>10</sup>, Наталья В. Минаева<sup>9</sup>, Татьяна С. Константинова<sup>7,8</sup>, Илья С. Зюзгин<sup>5</sup>, Вадим В. Птушкин<sup>4</sup>, Александр Д. Кулагин<sup>2,3</sup>, Елена Н. Паровичникова<sup>1</sup></p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(901) "

Михаил Ю. Дроков1, Иван С. Моисеев2,3, Юлия А. Олейник4, Ирина В. Ишматова5, Дмитрий В. Моторин6, Юлия С. Китаева7,8, Наталья А. Зорина9, Сергей В. Грицаев10, Наталия М. Никифорова11, Любовь М. Петрова12, Татьяна С. Капорская12, Галина Д. Петрова11, Сергей В. Волошин10, Наталья В. Минаева9, Татьяна С. Константинова7,8, Илья С. Зюзгин5, Вадим В. Птушкин4, Александр Д. Кулагин2,3, Елена Н. Паровичникова1

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1 ФГБУ «НМИЦ гематологии» МЗ РФ, Москва, Россия
2 НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Санкт-Петербург, Россия
3 ФГБОУ ВО ПСПбГМУ им. И. П. Павлова МЗ РФ, Санкт-Петербург, Россия
4 ГБУЗ «Городская клиническая больница им. С.П. Боткина», Москва, Россия
5 ФГБУ «НМИЦ онкологии им. Н. Н. Петрова» МЗ РФ, Санкт-Петербург, Россия
6 ФГБУ «НМИЦ им. В. А. Алмазова» МЗ РФ, Санкт-Петербург, Россия
7 ГАУЗ «Свердловская областная клиническая больница № 1», Екатеринбург, Россия
8 ФГБОУ ВО Уральский государственный медицинский университет МЗ РФ, Екатеринбург, Россия
9 ФГБУН Кировский НИИ гематологии и переливания крови ФМБА РФ, Киров, Россия
10 ФГБУ «Российский НИИ гематологии и трансфузиологии ФМБА РФ, Санкт-Петербург, Россия
11 ФГБУ «НМИЦ онкологии им. Н. Н. Блохина» МЗ РФ, Москва, Россия
12 ГБУЗ «Иркутская областная клиническая больница, Иркутск, Россия


Для корреспонденции:
Дроков Михаил Юрьевич, руководитель сектора научных исследований химиотерапии гемобластозов, депрессий кроветворения и трансплантации костного мозга, НМИЦ гематологии Минздрава России, Новозыковский пер. 4, 125167, Москва, Россия
E-mail: mdrokov@gmail.com

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Трансплантация аллогенных гемопоэтических стволовых клеток (алло-ТГСК) является методом выбора при многих заболеваниях системы крови. В настоящее время недостаточно информации об эффективности и безопасности каждого этапа при конкретных заболеваниях. В Российской Федерации клинические рекомендации являются неотъемлемой частью системы здравоохранения, однако в настоящее время нет данных об эффективности и безопасности отдельных лекарственных средств, дозировках, методах введения и потенциальных комбинациях при алло-ТГСК. Опрос экспертов из центров трансплантации в Российской Федерации был направлен на оценку текущей ситуации и формирование платформы для последующей стандартизации.

Целью исследования было получение обобщенной информации об эффективности и безопасности подходов к выполнению алло-ТГСК у взрослых пациентов с различными заболеваниями системы крови на основе экспертных оценок. В исследовании приняли участие эксперты из 10 центров Российской Федерации, которые проводили алло-ТГСК. Опрос включал 150 вопросов о методологии проведения алло-ТГСК. Целью исследования была оценка эффективности и безопасности метода алло-ТГСК при лечении различных заболеваний крови. В исследовании был сделан вывод о том, что в Российской Федерации в настоящее время отсутствует стандартизация процедуры проведения алло-ТГСК, а также тот факт, что необходимо создание Единого реестра реципиентов алло-ТГСК и согласование клинических рекомендаций. Этот анализ мог бы помочь в планировании тарифов на проведение алло-ТГСК, планировании проспективных рандомизированных клинических исследований и формирования консенсуса по многим вопросам в данной предметной области.

Ключевые слова

Трансплантация аллогенных гемопоэтических стволовых клеток, трансплантация костного мозга, клинические рекомендации, метод экспертных оценок, алло-ТГСК.

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Mikhail Yu. Drokov1, Ivan S. Moiseev2,3, Julia A. Oleinik4, Irina V. Ishmatova5, Dmitry V. Motorin6, Julia S. Kitaeva7,8, Natalia A. Zorina9, Sergey V. Gritsaev10, Natalia M. Nikiforova11, Lyubov M. Petrova12, Tatyana S. Kaporskaya12, Galina D. Petrova11, Sergey V. Voloshin10, Natalia V. Minaeva9, Tatiana S. Konstantinova7,8, Ilya S. Zyuzgin5, Vadim V. Ptushkin4, Alexander D. Kulagin2,3, Elena N. Parovichnikova1

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1 National Medical Research Centre for Hematology, Federal State Budgetary Institution of the Ministry of Health of the Russian Federation, Moscow, Russia
2 RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, St. Petersburg, Russia
3 Pavlov University, St. Petersburg, Russia
4 S.P. Botkin Hospital, State Budgetary Healthcare Institution of the Moscow City Clinical Hospital, Department of Healthcare of the Moscow City, Moscow, Russia
5 N.N. Petrov National Medicine Research Center of Oncology, Federal State Budgetary Institution of the Ministry of Health of the Russian Federation, St. Petersburg, Russia
6 V.A. Almazov National Medical Research Centre, Federal State Budgetary Institution of the Ministry of Health of the Russian Federation, St. Petersburg, Russia
7 Clinical Hospital No. 1 of the Sverdlovsk region, State Autonomous Institution of Health Protection of the Sverdlovsk Region, Ekaterinburg, Russia
8 The Ural State Medical University, Federal State Budget Educational Institution of Higher Education of the Ministry of Health of the Russian Federation, Ekaterinburg, Russia
9 Kirov Research Institute of Hematology and Blood Transfusion, Federal Medical and Biological Agency, the Federal State Budgetary Institute of Science of the Russian Federation, Kirov, Russia
10 Russian Research Institute of Hematology and Transfusiology, Federal State Budgetary Institution, Federal Medical and Biological Agency of the Russian Federation, St.Petersburg, Russia
11 N.N. Blokhin National Research Center of Oncology, Federal State Budgetary Institution of the Ministry of Health of the Russian Federation, Moscow, Russia
12 Irkutsk Clinical Regional Hospital, State Budgetary Healthcare Institution, Irkutsk, Russia


Correspondence:
Dr. Drokov Mikhail Yu, PhD (Medicine), National Medical Research Center for Hematology, 4 Novozykovsky Lane, 125167, Moscow, Russia
E-mail: mdrokov@gmail.com


Citation: Drokov MY, Moiseev IS, Oleinik JA et al. Effectiveness and safety of allogeneic hematopoietic stem cells transplantation in adult patients with blood disorders: a survey of expert opinion from the Russian transplantation centers. Cell Ther Transplant 2024; 13(1): 49-91.

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Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the treatment of choice for many blood disorders. However insufficient data is available on the effectiveness and safety of each stage of the allo-HSCT procedure for specific diseases. In the Russian Federation clinical practice guidelines are the essential part of the healthcare system, but when it comes to allo-HSCT there is no data on the effectiveness and safety of specific drugs – their dosage, route of administration and potential combinations. This survey of expert opinion from the Russian transplantation centers aimed to assess the current situation in this area and lay the ground for subsequent standardization. The objective of the study was to obtain, based on expert assessment, cumulative information about the effectiveness and safety of the treatment paradigm of allo-HSCT in adult patients with different blood disorders.

Experts from 10 centers of the Russian Federation with experience in allo-HSCT took part in the study. The participants received a questionnaire with 150 questions on allo-HSCT methodology. The study aimed to evaluate the effectiveness and safety of allo-HSCT in treating different blood disorders. The study concluded that in the Russian Federation there is currently no standardized procedure for performing allo-HSCT, and that it is necessary to set up a Unified Register of allo-HSCT recipients and to harmonize clinical practice guidelines in this field. The findings of the study may further be used to inform allo-HSCT pricing policy, plan prospective randomized clinical trials, and reach consensus on many aspects in this field.

Keywords

Allogeneic hematopoietic stem cells transplantation, bone marrow transplantation, clinical practice guidelines, expert evaluation method, allo-HSCT.

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В настоящее время это единственный метод лечения, который позволяет достичь биологического излечения. Алло-ТГСК представляет собой процедуру, состоящую из нескольких этапов: предтрансплантационное кондиционирование, трансфузия аллогенных гемопоэтических стволовых клеток и посттрансплантационный период. Каждый этап алло-ТГСК включает в себя комплекс различных мероприятий, а именно применение лекарственных препаратов, медицинских изделий, биологических препаратов, компонентов крови и другое [1]. Однако до сих пор нет систематизированной информации об эффективности и безопасности каждого этапа выполняемой алло-ТГСК при конкретном заболевании. </p> <p style="text-align: justify;"> В настоящее время в Российской Федерации клинические рекомендации являются неотъемлемой частью системы здравоохранения что регламентировано нормативно-правовыми актами, в частности ст. 37 Федерального закона от 21.11.2011 N 323-ФЗ (ред. от 24.07.2023) «Об основах охраны здоровья граждан в Российской Федерации» (с изм. и доп., вступ. в силу с 01.09.2023). Между тем, согласно Приказу Минздрава России от 28.02.2019 N 103н (ред. от 23.06.2020) «Об утверждении порядка и сроков разработки клинических рекомендаций, их пересмотра, типовой формы клинических рекомендаций и требований к их структуре, составу и научной обоснованности включаемой в клинические рекомендации информации»: «указание лекарственных препаратов для медицинского применения, используемых не в соответствии с показаниями к применению и противопоказаниями, способами применения и дозами, содержащимися в инструкции по применению лекарственного препарата, без указанных выше сведений и ссылок на клинические исследования эффективности и безопасности данного режима при данном заболевании либо ссылок на соответствующие источники литературы не допускается», т.е. без информации об эффективности и безопасности того или иного препарата в составе трансплантационной методики, включение его в клинические рекомендации невозможно [2]. </p> <p style="text-align: justify;"> Таким образом, возникает ситуация, когда несмотря на широту применения препаратов и их эффективность в области алло-ТГСК, наличия утвержденного приказом МЗ РФ № 1279н 20.12.12 стандарта специализированной медицинской помощи после трансплантации аллогенного костного мозга (обследование и коррекция лечения), Приказа Министерства здравоохранения РФ от 12 декабря 2018 г. N 875н «Об утверждении Порядка оказания медицинской помощи при заболеваниях (состояниях), для лечения которых применяется трансплантация (пересадка) костного мозга и гемопоэтических стволовых клеток и внесении изменения в Порядок оказания медицинской помощи по профилю "хирургия (трансплантация органов и (или) тканей человека)", утвержденный приказом Министерства здравоохранения Российской Федерации от 31 октября 2012 г. N 567н», отсутствуют данные об эффективности и безопасности отдельных препаратов, их дозировок, способов введения, а также потенциальных комбинаций. </p> <p style="text-align: justify;"> Как в зарубежной, так и отечественной литературе в настоящее время недостаточно информации об отдельных режимах кондиционирования, профилактики реакции «трансплантат против хозяина» (РТПХ), сопроводительной терапии, особенно для тех нозологий, при которых алло-ТГСК выполняется лишь в небольшом проценте случаев. Вследствие малой выборки проведение анализа представляется затруднительным. То же касается и режимов профилактики РТПХ, еще меньше информации доступно для сопроводительной терапии, начиная с элементарной антиэметической терапии и заканчивая инфузионными растворами. </p> <p style="text-align: justify;"> Процедура выполнения алло-ТГСК не стандартизована, а общепринятыми являются только лишь показания к ее выполнению [3-6]. А между тем, унификация процедуры выполнения алло-ТГСК при конкретной нозологии, включая режимы кондиционирования (дозы, кратность, способ введения лекарственного препарата и т.п.), профилактику РТПХ, сопроводительную терапию, позволит оценить эффективность и безопасность каждого этапа алло-ТГСК, а также провести фармакоэкономический анализ технологии. </p> <p style="text-align: justify;"> Для оценки текущей ситуации в Российской Федерации, а также с целью формирования платформы для последующей стандартизации мы провели опрос среди экспертов трансплантационных центров РФ. </p> <p style="text-align: justify;"> Метод экспертных оценок, используемый в публикации, является частью огромной области, а именно теории принятия решений, а экспертное оценивание – процедура получения оценки проблемы на основе мнения отдельных специалистов (экспертов). Этот подход нашел свое применение в случаях чрезвычайной сложности проблемы, ее новизны и, самое важное, при недостаточности информации в той или иной предметной области [7]. </p> <p style="text-align: justify;"> Таким образом, наше исследование направлено на формирование обобщенной информации об эффективности и безопасности подходов к выполнению алло-ТГСК взрослым пациентам с различными заболеваниями системы крови на основе экспертных оценок. </p> <h3>Ограничения исследования</h3> <p style="text-align: justify;"> Учитывая особенности метода экспертных оценок ключевым ограничением этого метода исследования, является невозможность сравнить влияние используемых препаратов на результаты трансплантации и между собой. Таким образов выводы о преимуществах или недостатках того или иного подхода на основании проведенного исследования сделать нельзя. Также, учитывая, что для сопроводительной терапии очень сложно выбрать те осложнения, которые можно использовать как критерий безопасности в плане алло-ТГСК, от их оценки было решено воздержаться. </p> <h2>Материалы и методы</h2> <p style="text-align: justify;"> Исследование проводилось в период с 01.07.2022 по 02.02.2023 года. Были опрошены эксперты (работавшие в учреждении на момент опроса) из 10 центров, выполняющих алло-ТГСК в Российской Федерации. Список центров и их порядковые номера в опросах приведены в <b><a target="_blank" href="/upload/medialibrary/CTT-2024_13-1_pg49-91_Drokov-MY-App01-rus.pdf"><u>Приложении 1</u></a></b>. Опрос заключался в заполнении онлайн-анкеты, которая включала 150 вопросов по методике выполнения алло-ТГСК. Варианты ответа представляли собой интервалы значений, которые в дальнейшем были использованы для анализа. Далее, при нанесении на «тепловую карту», указывалось верхнее значение данного интервала. Критерии эффективности и безопасности, используемые в исследовании, представлены в Табл. 1. </p> <p class="Table_sign"> Таблица 1. Оцениваемые параметры, критерии их эффективности и безопасности </p> <img alt="Drokov-tab01_rus.jpg" src="/upload/medialibrary/99a/drokov_tab01_rus.jpg" title="Drokov-tab01_rus.jpg"> <p style="text-align: justify;"> Статистический анализ данных проводился с использованием статистического пакета R 4.3.2 (США). Графические данные представлены в виде «тепловых карт», на которых обозначены показатели того или иного параметра для каждого из трансплантационных центров. В работе использовались методы описательной статистики. </p> <h2>Результаты</h2> <h3>Общие сведения о центрах</h3> <p style="text-align: justify;"> В исследовании принимали участие 10 центров, расположенных на всей территории РФ. За последние 10 лет общий объем проведенных этими центрами алло-ТГСК превысил 5000 процедур. Среди центров, участвующих в опросе, 3 выполняют более 100 алло-ТГСК в год, 3 – от 50 до 100, 1 – от 20 до 50, 1 – от 10 до 20, 1 – от 5 до 10 и 1 – до 5. Среди диагнозов, которые являются показанием к выполнению алло-ТГСК и для которых предлагалось оценить эффективность и безопасность метода алло-ТГСК: острый миелоидный лейкоз (ОМЛ), острый лимфобластный лейкоз (ОЛЛ), острый промиелоцитарный лейкоз (ОПЛ), миелодиспластический синдром (МДС), множественная миелома (ММ), макроглобулинемия Вальденстрема, первичный амилоидоз, хронический лимфоцитарный лейкоз/лимфома из малых лимфоцитов (ХЛЛ), хронический миелолейкоз (ХМЛ), лимфома из клеток мантии (ЛКМ), лимфома Ходжкина (ЛХ), фолликулярная лимфома (ФЛ), диффузная В-крупноклеточная лимфома (ДВККЛ), первичная медиастинальная В-крупноклеточная лимфома, первичная диффузная В-крупноклеточная лимфома (ДВККЛ ЦНС), Т-клеточная лимфома, миелопролиферативные заболевания, апластическая анемия (АА) и пароксизмальная ночная гемоглобинурия. Сводные данные по используемым режимам кондиционирования, виду донора, источнику получения гемопоэтических стволовых клеток в центрах участниках опроса представлены на Рис. 1. </p> <img alt="Drokov-fig01-rus.jpg" src="/upload/medialibrary/d4c/drokov_fig01_rus.jpg" title="Drokov-fig01-rus.jpg"> <p class="Table_sign"> Рисунок 1. Характеристика общих подходов трансплантационных центров участвующих в опросе </p> <p style="text-align: justify;"> <small>MAC – миелоаблативный режим кондиционирования; RIC –режим кондиционирования пониженной интенсивности; NMA – немиелоаблативный режим кондиционирования; РСД – родственный совместимый донор; НСД – неродственный совместимый донор; НЧСД – неродственный частично совместимый донор; РЧСД – родственный частично совместимый донор; Гапло – гаплоидентичный донор; СКК – стволовые клетки крови; КМ – костный мозг; КТ – комбинированный трансплантат; ПраймКМ – праймированный костный мозг; Выделение зеленым цветом – центр применяет данный подход. Выделение красным цветом – центр не использует данный подход.</small> </p> <h3>Эффективность и безопасность режимов предтрансплантационного кондиционирования</h3> <p style="text-align: justify;"> Различные режимы предтрансплантационного кондиционирования (РК) с используемыми препаратами и способами их введения детально представлены в <b><u><a target="_blank" href="/upload/medialibrary/CTT-2024_13-1_pg49-91_Drokov-MY-App02-rus.pdf">Приложении 2</a></u></b>. Результаты опроса по эффективности и безопасности РК представлены на Рисунке 2 и 3 соответственно. Отсутствие данных (зачеркнутый белый прямоугольник) предполагает, что центр не использует данные режимы кондиционирования. </p> <p style="text-align: justify;"> На рис. 2 видно, что флюдарабин-содержащие режимы составляют 87,5% (n=28) от всех использованных режимов кондиционирования. Стоит отметить, что нашей задачей не было давать количественные характеристики применения режимов кондиционирования, однако даже сам список приведенных режимов говорит о том, что флюдарабин является самым часто используемым при проведении предтрансплантационного кондиционирования. Такая частота применения объясняется доступностью препарата, наличием большого числа дженериков, ценой, простотой его использования и приемлемым профилем токсичности. Следующими по частоте применения препаратами являлись бусульфан – на него приходилось 37,5% (n=12), и мелфалан – 12,5% (n=4). </p> <p style="text-align: justify;"> Стоит отметить, что алло-ТГСК не является официальным показанием к применению ни у одного из вышеуказанных препаратов, которые были использованы в режимах предтрансплантационного кондиционирования. </p> <p style="text-align: justify;"> Тотальное облучение тела (ТОТ) в качестве предтрансплантационного кондиционирования применялось лишь в 2 центрах (20%). Это обусловлено организационными аспектами: использование ТОТ существенно лимитировано его доступностью в стране. </p> <img alt="Drokov-fig02-rus.jpg" src="/upload/medialibrary/407/drokov_fig02_rus.jpg" title="Drokov-fig02-rus.jpg"> <p class="Table_sign"> Рисунок 2. Распространенность и оценочная эффективность режимов предтрансплантационного кондиционирования </p> <img alt="Drokov-fig03-rus.jpg" src="/upload/medialibrary/ca8/drokov_fig03_rus.jpg" title="Drokov-fig03-rus.jpg"> <p class="Table_sign"> Рисунок 3. Распространенность и оценочная безопасность режимов предтрансплантационного кондиционирования </p> <h3>Эффективность и безопасность режимов профилактики реакции «трансплантат против хозяина»</h3> <p style="text-align: justify;"> Следующий блок анкеты был посвящен оценке эффективности и безопасности режимов профилактики РТПХ. </p> <p style="text-align: justify;"> Ингибиторы кальциневрина (циклоспорин и такролимус) используются почти в 85,7% (n=24) режимов профилактики. Применение того или иного препарата чаще всего зависит от практики и доступности оборудования и расходных материалов для мониторинга его концентрации того или иного препарата. Вторым по частоте использования препаратом стал посттрансплантационный циклофосфамид на него приходилось 42,9% (n=12). Третьим препаратом по частоте применения явился микофенолата мофетил 57,1% (n=16). </p> <p style="text-align: justify;"> Инструкции к вышеперечисленным препаратам также, как и в случаях препаратов предтрансплантационного кондиционирования не содержат прямых показаний к использованию при проведении алло-ТГСК и для профилактики РТПХ. </p> <p style="text-align: justify;"> Другие данные по частоте использования препаратов детально представлены на Рисунке 4. Отсутствие данных (зачеркнутый белый прямоугольник) предполагает, что центр не использует данные режимы кондиционирования. </p> <img alt="Drokov-fig04-rus.jpg" src="/upload/medialibrary/300/drokov_fig04_rus.jpg" title="Drokov-fig04-rus.jpg"> <p class="Table_sign"> Рисунок 4. Распространенность и оценочная эффективность режимов профилактики РТПХ </p> <p style="text-align: justify;"> В качестве критерия безопасности необходимо было оценить 100-дневную трансплантационную летальность для каждой из применяемых схем профилактики РТПХ, указывая среднее значение для всех видов алло-ТГСК. Стоит отметить, что этот параметр очень вариабелен и существенно зависит как от числа трансплантаций, коморбидности пациентов, которым проводится процедура, так и от вида выполняемых алло-ТГСК. Результаты детально представлены на Рис. 5. </p> <img alt="Drokov-fig05-rus.jpg" src="/upload/medialibrary/32c/drokov_fig05_rus.jpg" title="Drokov-fig05-rus.jpg"> <p class="Table_sign"> Рисунок 5. Распространенность и оценочная безопасность режимов профилактики РТПХ </p> <p style="text-align: justify;"> Отдельным аспектом, заслуживающим внимания, является доступность для центров методов манипуляции с трансплантатом (как способов профилактики РТПХ), таких как, например, CD34+ селекция. Об использовании этой методики заявили 60% (n=6) центров. Этот факт является чрезвычайно важным, так как данное технологическое решение является платформой для селекции других популяций клеток, в том числе и для производства Т-клеток с химерным антигенным рецептором (CAR-T). </p> <h3>Эффективность сопроводительной терапии</h3> <p style="text-align: justify;"> Приступая к оценке сопроводительной терапии, следует подчеркнуть, что в доступной литературе отсутствуют специальные обзоры по эффективности препаратов для сопроводительного лечения. В нашем исследовании мы постарались обобщить все лекарственные средства, так или иначе применяемые при трансплантации аллогенных гемопоэтических стволовых клеток у взрослых. Стоит отметить, что при оценке мы увидели крайне высокую гетерогенность применяемых препаратов, что по всей видимости связано с доступностью того или иного препарата для центра и его институциональных практик. В нашем исследовании, как уже было указано выше, эксперты не видели ответов других центров, поэтому мы можем говорить о том, что действительно существенных различий в эффективности зафиксировано не было. И также, что было и ранее указано для всех препаратов в режимах кондиционирования и профилактики РТПХ, ни один препарат из сопроводительной терапии не имеет показания «трансплантация аллогенных гемопоэтических стволовых клеток». </p> <p style="text-align: justify;"> Результаты представлены на Рис. 6. Отсутствие данных (зачеркнутый белый прямоугольник) предполагает, что центр не использует данный препарат в рутинной практике для сопроводительной терапии. </p> <img alt="Drokov-fig06-rus.jpg" src="/upload/medialibrary/b24/drokov_fig06_rus.jpg" title="Drokov-fig06-rus.jpg"> <p class="Table_sign"> Рисунок 6. Распространенность и оценочная эффективность отдельных элементов сопроводительной терапии </p> <h2>Обсуждение и заключение</h2> <p style="text-align: justify;"> Предпосылкой для проведения данного исследования является отсутствие детальной стандартизации процедуры выполнения алло-ТГСК в РФ, что, впрочем, характерно и для большинства стран с высокой трансплантационной активностью [8]. Методические ограничения данного исследования не позволяют нам сравнить влияние используемых препаратов на результаты трансплантации и говорить о преимуществе того или иного режима кондиционирования или профилактики РТПХ. Проведенный анализ прежде всего демонстрирует большую неоднородность терапевтических стратегий, применяемым при алло-ТГСК в РФ: как подходов к схемам предтрансплантационного кондиционирования и иммуносупрессивной терапии, так и к сопроводительной терапии. Между тем следует отметить, что принципы проведения самой процедуры остаются универсальными, что также позволит двигаться в сторону унификации. </p> <p style="text-align: justify;"> Представляется важным создание Единого реестра реципиентов алло-ГСК, а также консенсусных клинических рекомендаций по выполнению алло-ТГСК в РФ. Так, например, создание Программы единого реестра трансплантатов в Японии позволило улучшить результаты алло-ТГСК [9], а подобная практика в Китае позволила отказаться от дифференцирования показаний к трансплантации в зависимости от вида донора для выполнения алло-ТГСК для некоторых групп пациентов, что отличается от западных подходов[10]. Отслеживание результатов неродственной трансплантации уже частично реализовано в рамках Федерального Регистра доноров костного мозга. </p> <p style="text-align: justify;"> Настоящий анализ может стать базовым плацдармом для планирования тарифов на проведение алло-ТГСК в зависимости от диагноза и технологии. Также выявленные закономерности позволяют планировать проспективные рандомизированные клинические исследования применения тех или иных препаратов при алло-ТГСК. Более того, более широкое применение метода экспертных оценок в отсутствие крупных исследований в области алло-ТГСК за исключением III фаз испытаний лекарственных препаратов позволит формировать консенсусы в различных областях (профилактика и лечение РТПХ, лечение осложнений и т.п.), как это происходит в других трансплантационных сообществах [11-14]. </p> <p style="text-align: justify;"> Разумеется, в дальнейшем интересным представляется более глубокий анализ терапевтических стратегий в зависимости от различных факторов; разбор структуры летальности, разбор частоты конкретных побочных эффектов используемых лекарственных препаратов, унификация понятийного аппарата и подходов в области алло-ТГСК и осложнений после нее. </p> <h2>Благодарность</