ISSN 1866-8836
Клеточная терапия и трансплантация

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

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

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.

doi 10.18620/ctt-1866-8836-2024-13-1-49-91
Submitted 21 December 2023
Accepted 01 March 2024

Summary

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.


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.

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Volume 13, Number 1
03/31/2024

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doi 10.18620/ctt-1866-8836-2024-13-1-49-91
Submitted 21 December 2023
Accepted 01 March 2024

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