Volume 10, number 3-4

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Introduction

There are many new therapies approved to treat acute myeloid leukaemia (AML) including new conventional and targeted drugs and immune therapy. A summary of new AML drugs is displayed in Figure 1 increasing from one approval every 6 years to one approval every 150 days, a 12-fold increase.

The question I consider is whether these new therapies will cure AML. My discussion is divided into 3 categories: (1) conventional drugs; (2) targeted therapies; and (3) immune therapy.

Figure 1. Drug approvals in AML 1973-2020

New drugs

I consider 4 new drugs: (a) venetoclax [1]; (b) CPX-351 [2]; (c) CC-486 [3]; and (d) glasdegib (± low-dose cytarabine) [1-4]. Results of these, quite recent trials demonstrate that, although each new drug, alone or combined with previously-approved drugs improved outcomes, there remains a high rate of failures by 2 years.

Targeted drugs

Four targeted drugs are approved in AML including: (1) midostaurin; (2) gilteritinib; (3) enasidenib, and (4) ivosidenib. Results of recent trials of these 3 drugs are published, and the survival curves can be compared [5-8]. Except for enasidenib, these drugs improve outcomes but 2-year failure rates are high. A US trial Beat AML in persons with newly-diagnosed AML assigned subjects with druggable mutations to targeted or conventional drugs. There was no important difference in outcomes [9]. Therefore, according to recent estimates, current targeted drugs are likely to help only a limited subgroup (ca. 10 percent) of patients with acute myeloid leukemia [10].

Immune therapy

Gemtuzumab, an anti-CD33 monoclonal toxin-linked antibody, is the only approved immune therapy of AML [11]. It modestly improves outcomes and is rarely used.

Table 1. Differential effects of azacitidine and venetoclax in sub-cohorts

Table 2. Impact of azacitidine and venetoclax on reversing loss in life-expectancy

Table 3. Relative per year costs of some new drugs

Issues in new drug approvals

Several important issues confound analyses of the appropriate use of new drugs in AML including: (1) who is unfit for intensive therapy? (2) no randomized trial proves less-intensive therapy is better than conventional intensive therapy amongst persons who could receive either; (3) what is the best endpoint for new drug approvals; (4) what is the appropriate comparator for a new drug approval; (5) several recent approvals are for unstudied populations; (6) recent approvals will decrease enrollment in clinical trials; and (7) most new drugs improve survival only slightly and long-term results remain unsatisfactory [12]. Table 1 displays data indicating not everyone benefits from a new drug such as venetoclax [1].

Table 2 shows although azacitidine and venetoclax improve survival of older persons with AML there remains a major loss of potential life-expectancy. Finally, Table 3 displays the cost of several new AML drugs compared with conventional drugs.

Conclusions

Based on the data I review above I conclude: (1) many new AML therapies target specific AML sub-types; (2) none are proved better than intensive radiochemotherapy in persons who could receive either therapy; (3) there is disagreement defining who can or cannot receive intensive therapy; (4) there are important problems with several new drug approvals; (5) azacitidine and venetoclax may be the new standard-of-care in elderly persons with AML judged unable to receive intensive therapy; and (6) new drugs are welcome but have not had a big impact on long-term survival of most people with AML.

Acknowledgement

Presented in part at the Raisa Gorbacheva Symposium in St. Petersburg on 17 September 2021. RPG acknowledges support from the National Institute of Health Research (NIHR) Biomedical Research Centre funding scheme.

Conflict of interest

RPG is a consultant to: BeiGene Ltd., Fusion Pharma LLC, LaJolla NanoMedical Inc., Mingsight Pharmaceuticals Inc. and CStone Pharmaceuticals. Medical Director of FFF Enterprises Inc, on the Board of Directors: RakFond Foundation for Cancer Research Support. Scientific Advisory Board: Antegene Biotech LLC , StemRad Ltd. Author Contribution: I conceived, wrote and submitted the typescript for publication. Ethics Approval: None required.

References

DiNardo CD, Jonas BA, Pullarkat V, Thirman MJ, Garcia JS, Wei AH, et al. Azacitidine and Venetoclax in previously untreated acute myeloid leukemia. N Engl J Med. 2020;383(7):617-629. doi: 10.1056/NEJMoa2012971
Lancet JE, Uy GL, Newell LF, Lin TL, Ritchie EK, Stuart RK, et al. CPX-351 versus 7+3 cytarabine and daunorubicin chemotherapy in older adults with newly diagnosed high-risk or secondary acute myeloid leukaemia: 5-year results of a randomised, open-label, multicentre, phase 3 trial. Lancet Haematol. 2021;8(7):e481-e491. doi: 10.1016/S2352-3026(21)00134-4. PMID: 34171279
Wei AH, Döhner H, Pocock C, Montesinos P, Afanasyev B, Dombret H, et al.; QUAZAR AML-001 Trial Investigators. Oral Azacitidine maintenance therapy for acute myeloid leukemia in first remission. N Engl J Med. 2020; 383(26):2526-2537.
doi: 10.1056/NEJMoa2004444
Cortes JE, Heidel FH, Hellmann A, Fiedler W, Smith BD, Robak T, et al. Randomized comparison of low dose cytarabine with or without glasdegib in patients with newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome. Leukemia. 2019; 33(2):379-389. doi: 10.1038/s41375-018-0312-9
Stone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017; 377(5):454-464. doi: 10.1056/NEJMoa1614359
Perl AE, Martinelli G, Cortes JE, Neubauer A, Berman E, Paolini S, et al. Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML. N Engl J Med. 2019; 381(18):1728-1740. doi: 10.1056/NEJMoa1902688
DiNardo CD, Schuh AC, Stein EM, Montesinos P, Wei AH, de Botton S. Enasidenib plus azacitidine versus azacitidine alone in patients with newly diagnosed, mutant-IDH2 acute myeloid leukaemia (AG221-AML-005): a single-arm, phase 1b and randomised, phase 2 trial. Lancet Oncol. 2021; 22(11):1597-1608. doi: 10.1016/S1470-2045(21)00494-0
Roboz GJ, DiNardo CD, Stein EM, de Botton S, Mims AS, Prince GT, et al. Ivosidenib induces deep durable remissions in patients with newly diagnosed IDH1-mutant acute myeloid leukemia. Blood. 2020 Feb 13;135(7):463-471. doi: 10.1182/blood.2019002140
Burd A, Levine RL, Ruppert AS, Mims AS, Borate U, Stein EM, et al. Precision medicine treatment in acute myeloid leukemia using prospective genomic profiling: feasibility and preliminary efficacy of the Beat AML Master Trial. Nat Med. 2020; 26(12):1852-1858. doi: 10.1038/s41591-020-1089-8
Prasad V, Gale RP. Precision medicine in acute myeloid leukemia: Hope, hype or both? Leuk Res. 2016; 48:73-77.
doi: 10.1016/j.leukres.2016.07.011
Lambert J, Pautas C, Terré C, Raffoux E, Turlure P, Caillot D, et al. Gemtuzumab ozogamicin for de novo acute myeloid leukemia: final efficacy and safety updates from the open-label, phase III ALFA-0701 trial. Haematologica. 2019; 104(1):113-119.
doi: 10.3324/haematol.2018.188888
Estey E, Karp JE, Emadi A, Othus M, Gale RP. Recent drug approvals for newly diagnosed acute myeloid leukemia: gifts or a Trojan horse? Leukemia. 2020;34(3):671-681. doi: 10.1038/s41375-019-0704-5

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Introduction

The question I consider is whether these new therapies will cure AML. My discussion is divided into 3 categories: (1) conventional drugs; (2) targeted therapies; and (3) immune therapy.

Figure 1. Drug approvals in AML 1973-2020

New drugs

Targeted drugs

Immune therapy

Gemtuzumab, an anti-CD33 monoclonal toxin-linked antibody, is the only approved immune therapy of AML [11]. It modestly improves outcomes and is rarely used.

Table 1. Differential effects of azacitidine and venetoclax in sub-cohorts

Table 2. Impact of azacitidine and venetoclax on reversing loss in life-expectancy

Table 3. Relative per year costs of some new drugs

Issues in new drug approvals

Conclusions

Acknowledgement

Conflict of interest

References

DiNardo CD, Jonas BA, Pullarkat V, Thirman MJ, Garcia JS, Wei AH, et al. Azacitidine and Venetoclax in previously untreated acute myeloid leukemia. N Engl J Med. 2020;383(7):617-629. doi: 10.1056/NEJMoa2012971
Lancet JE, Uy GL, Newell LF, Lin TL, Ritchie EK, Stuart RK, et al. CPX-351 versus 7+3 cytarabine and daunorubicin chemotherapy in older adults with newly diagnosed high-risk or secondary acute myeloid leukaemia: 5-year results of a randomised, open-label, multicentre, phase 3 trial. Lancet Haematol. 2021;8(7):e481-e491. doi: 10.1016/S2352-3026(21)00134-4. PMID: 34171279
Wei AH, Döhner H, Pocock C, Montesinos P, Afanasyev B, Dombret H, et al.; QUAZAR AML-001 Trial Investigators. Oral Azacitidine maintenance therapy for acute myeloid leukemia in first remission. N Engl J Med. 2020; 383(26):2526-2537.
doi: 10.1056/NEJMoa2004444
Cortes JE, Heidel FH, Hellmann A, Fiedler W, Smith BD, Robak T, et al. Randomized comparison of low dose cytarabine with or without glasdegib in patients with newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome. Leukemia. 2019; 33(2):379-389. doi: 10.1038/s41375-018-0312-9
Stone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017; 377(5):454-464. doi: 10.1056/NEJMoa1614359
Perl AE, Martinelli G, Cortes JE, Neubauer A, Berman E, Paolini S, et al. Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML. N Engl J Med. 2019; 381(18):1728-1740. doi: 10.1056/NEJMoa1902688
DiNardo CD, Schuh AC, Stein EM, Montesinos P, Wei AH, de Botton S. Enasidenib plus azacitidine versus azacitidine alone in patients with newly diagnosed, mutant-IDH2 acute myeloid leukaemia (AG221-AML-005): a single-arm, phase 1b and randomised, phase 2 trial. Lancet Oncol. 2021; 22(11):1597-1608. doi: 10.1016/S1470-2045(21)00494-0
Roboz GJ, DiNardo CD, Stein EM, de Botton S, Mims AS, Prince GT, et al. Ivosidenib induces deep durable remissions in patients with newly diagnosed IDH1-mutant acute myeloid leukemia. Blood. 2020 Feb 13;135(7):463-471. doi: 10.1182/blood.2019002140
Burd A, Levine RL, Ruppert AS, Mims AS, Borate U, Stein EM, et al. Precision medicine treatment in acute myeloid leukemia using prospective genomic profiling: feasibility and preliminary efficacy of the Beat AML Master Trial. Nat Med. 2020; 26(12):1852-1858. doi: 10.1038/s41591-020-1089-8
Prasad V, Gale RP. Precision medicine in acute myeloid leukemia: Hope, hype or both? Leuk Res. 2016; 48:73-77.
doi: 10.1016/j.leukres.2016.07.011
Lambert J, Pautas C, Terré C, Raffoux E, Turlure P, Caillot D, et al. Gemtuzumab ozogamicin for de novo acute myeloid leukemia: final efficacy and safety updates from the open-label, phase III ALFA-0701 trial. Haematologica. 2019; 104(1):113-119.
doi: 10.3324/haematol.2018.188888
Estey E, Karp JE, Emadi A, Othus M, Gale RP. Recent drug approvals for newly diagnosed acute myeloid leukemia: gifts or a Trojan horse? Leukemia. 2020;34(3):671-681. doi: 10.1038/s41375-019-0704-5

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Гэйл " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(37) "

Роберт П. Гэйл

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Центр гематологии, Департамент иммунологии и воспаления, Лондонский Имперский Колледж, Лондон, Великобритания

Существует много новых методов лечения, одобренных для лечения острого миелоидного лейкоза (ОМЛ), включая традиционные и таргетные препараты, а также иммунотерапию. Большинство из них улучшают различные исходы, включая бессобытийную и безрецидивную выживаемость. Однако в большинстве случаев выраженность эффекта невелика, и высока частота неуспешной терапии при 2-летнем наблюдении. Основываясь на данных, рассмотренных выше, сделаны выводы о том, что: (1) многие новые методы лечения ОМЛ направлены на терапию определенных подтипов ОМЛ; (2) ни один из них не оказался лучше, чем интенсивная химиолучевая терапия пациентов, которые могли бы получать любой из этих видов лечения; (3) существуют разногласия по поводу того, кто может или не может получать интенсивную терапию; (4) существуют серьезные проблемы с одобрением нескольких новых лекарственных препаратов; (5) азацитидин и венетоклакс могут быть новым стандартом лечения пожилых людей с ОМЛ, признанных неспособными получать интенсивную терапию; и (6) новые препараты должны рассматриваться, но пока не оказали большого влияния на долгосрочное выживание большинства пациентов с ОМЛ.

Ключевые слова

Острый миелоидный лейкоз, таргетная терапия, эффективность.

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Robert Peter Gale MD

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Centre for Haematology, Department of Immunology and Inflammation, Imperial College London, London, UK

Correspondence:
Robert Peter Gale MD, PhD, DSc (hc), FACP, FRCPI (hon), FRSM, Centre for Haematology Research, Department of Immunology and Inflammation, Imperial College London, London, UK SW7 2AZ
Phone: +1 908 656 0484
Fax: +1 310 388 1320
E-Mail: robertpetergale@alumni.ucla.edu

Citation: Gale RP. Will new drugs cure acute myeloid leukaemia? Cell Ther Transplant 2021; 10(3-4): 4-7.

There are many new therapies approved to treat acute myeloid leukaemia (AML) including conventional and targeted drugs, and immune therapy. Most improve diverse outcomes including event- and relapse-free survivals and survival. However, most effect sizes are small and failure rates by 2 years are high. Based on the data reviewed above I conclude: (1) many new AML therapies target specific AML sub-types; (2) none are proved better than intensive radiochemotherapy in persons who could receive either therapy; (3) there is disagreement defining who can or cannot receive intensive therapy; (4) there are important problems with several new drug approvals; (5) azacitidine and venetoclax may be the new standard-of-care in elderly persons with AML judged unable to receive intensive therapy; and (6) new drugs are welcome but have not had a big impact on long-term survival of most people with AML.

Keywords

Acute myeloid leukemia, targeted therapy, efficiency.

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Robert Peter Gale MD

Keywords

Acute myeloid leukemia, targeted therapy, efficiency.

Keywords

Acute myeloid leukemia, targeted therapy, efficiency.

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Centre for Haematology, Department of Immunology and Inflammation, Imperial College London, London, UK

Citation: Gale RP. Will new drugs cure acute myeloid leukaemia? Cell Ther Transplant 2021; 10(3-4): 4-7.

Centre for Haematology, Department of Immunology and Inflammation, Imperial College London, London, UK

Citation: Gale RP. Will new drugs cure acute myeloid leukaemia? Cell Ther Transplant 2021; 10(3-4): 4-7.

Роберт П. Гэйл

Ключевые слова

Острый миелоидный лейкоз, таргетная терапия, эффективность.

Ключевые слова

Острый миелоидный лейкоз, таргетная терапия, эффективность.

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Introduction

Ornithine transcarbamylase deficiency (OTCD) is an X-linked genetic urea cycle disorder (UCD) caused by the mutation of the ornithine transcarbamylase (OTC, Xp2.1) gene. OTC is a mitochondrial enzyme synthesized in the cytoplasm. Following OTC transfer to the mitochondria, carbamoyl phosphate and ornithine are catalytically converted to citrulline. Then citrulline is transported to the cytoplasm to participate in the urea cycle reactions. The OTC gene mutations block normal urea metabolism. Therefore, increased blood ammonia, decreased blood citrulline and increased urine orotic acid are typical biochemical phenotypes of OTCD. High blood ammonia could cause the nervous system damage, epilepsy-like symptoms, disturbed consciousness, and cognitive impairment appear.

Early-onset OTCD mainly occurs in male heterozygous infants, usually with a rapid onset and a high mortality in the neonatal period [1]. The patient can be normal at birth. Then irritability, deteriorating feeding, drowsiness and tachypnea appear soon. It often develops into metabolic encephalopathy rapidly and leads to death if treatment is not applied. Severe intellectual impairment will be left in survivors due to the extensive damage to the brain caused by elevated blood ammonia [2]. Late-onset OTCD can occur in hemizygous males and heterozygous females. The clinical symptoms are variable and mild compared with early-onset OTCD.

The main principle of treatment is to control diet, reduce protein intake, avoid hyperammonemia, and use drugs to promote blood ammonia metabolism. However, excessive restriction of protein intake can lead to hypertrophy of endogenous protein catabolism, increase blood ammonia, and affect the patient's intelligence and physical development [3]. If the drug treatment is not effective, dialysis treatment should be considered as soon as possible.

Liver transplantation (LTx) is the most effective treatment of this disease, since OTC activity is mainly expressed in liver tissue. In these cases, the patients can stop anti-hyperammonemia drugs and return to normal diet after LTx. Hyperammonemia will not occur again, and the quality of life is significantly improved [4, 5]. Though LTx can correct the patient's urea cycle disorder and reduce blood ammonia substantially, it cannot reverse the nervous system damage that has occurred before LTx [5].

Indications for surgery

For the neonatal-onset patients, LTx should be performed as soon as possible if the patient’s condition is stable, independently on the blood ammonia levels. Considering the patient's tolerance for surgery and the risk of post-transplant hyperammonemia, the age of 3 months to 1 year, or body mass of >5 kg are appropriate pre-requisites for surgery [3]. It is usually done at six months of age. Early transplantation in the neonatal-onset patients may be associated with normal neurodevelopment compared with those without LTx.

For late-onset patients, it is now generally believed that, even with mild current manifestations, there is a risk of sudden, potentially life-threatening hyperammonemia at any age. Therefore, surgery should be considered for any OTCD patient. Final decision of LTx depends on the individual circumstances.

The peak of death with OTCD is noted at the age of 12-15 years in female patients, thus considering LTx before that time [6]. LTx in adolescents may also promote normal neurodevelopment. The patients should undergo LTx at peak blood ammonia levels of >300 μmol/L [7]. In cases of severe progressive liver disease, repeated metabolic abnormalities after standard treatment or poor compliance with current treatment, LTx can be also performed [3].

Analysis of data on the patients under 18 year subjected to LTx between February 2002 and September 2020, the waiting list time and male sex were associated with long-term risk for a cognitive delay. Minimizing the waiting time is quite important, in order to maintain the patient's cognition capacities at later terms and improve the quality of life [8].

All the patients with OTCD should be considered for LTx to prevent progressive neurological injury. But the decision is usually taken in cases of unstable condition and frequent episodes of hyperammonemia.

Donor selection

Liver transplants from either living or deceased donors are acceptable for the children of 1.5 to 3.0 years old. Three patients received cadaveric LTx at this age period. They developed well after this operation, and no recurrences were observed within follow-up for 13 years [9].

LTx from living donors is the most effective method in these cases. Living donors for the LTx should be in healthy condition, but sometimes there is no time to wait for another donor, except for subjects heterozygous for the mutated gene. A symptom-free carrier may be a donor for LTx, if OTC enzyme activity is high enough, and if no other options exist. The mutation carrier must undergo careful and comprehensive examination. OTC activity in liver biopsy samples must be tested to determine the suitability of heterozygote to be a donor [10]. According to Wakiya, T, the OTC activity of late-onset patients requiring LTx, ranges from 4.4% to 18.7%. Meanwhile, in those cases where LTx is not necessary, the residual enzyme activity ranges from 33% to 38% [11]. Rahayatri et al. [12] reported two 5-year-old girls who received liver transplants from heterozygous mutation carriers. The OTC activity in the first case and in her donor was 15% and 62%, respectively. She developed hyperammonemia within 2 months after the surgery. OTC activity in the second case and the donor was 9.7% and 42.6%, respectively. She developed hyperammonemia within 12 days after the surgery. Following continuous intravenous/venous hemodialysis, they were performing well without intensive care [12].

However, this method has potential risks. The enzyme activity in selected biopsy samples cannot represent its activity in other parts of the liver. Hence, one cannot accurately predict, whether the transplanted liver lobe exhibits sufficient activity, nor to predict whether total enzyme activity retained in the left liver is sufficient for heterozygous carrier donors.

Transplantation of hepatocytes may be another treatment option. Enosawa et al. reported an 11-day-old baby who underwent hepatocyte transplantation. The patient needed urgent LTx, but there was no source of liver, thus requiring hepatocyte transplantation. The patient was later in good condition and without recurrence within 3 months after the operation [13]. For the patients with poor overall clinical conditions, hepatocyte transplantation is less risky than liver grafting. Following hepatocyte transplantation, biochemical parameters of a 12-year-old patient with repeated metabolic decompensation showed decreased levels of plasma ammonia and increased urea production. However, the patient died because of a nosocomial fungal sepsis [14].

Surgical methods

Orthotopic LTx is still the best choice in OTCD. It has fewer complications than auxiliary LTx [5]. Over recent years, a domino cross-auxiliary LTx has been tried in the clinical setting. This method is based on exchanging part of liver tissue with patients suffering from other metabolic diseases aiming to achieve metabolic complementation. It does not require additional organ donation. Of the three OTCD patients in China, subjected to domino cross-auxiliary LTx, two cases recovered well after the operation, without any complications during the follow-up period. One patient experienced occult graft rejection resulting into graft dysfunction and eventual disease recurrence [15]. The domino cross-auxiliary LTx is a feasible method, without any problems caused by the operation itself.

Post-transplant management

Due to long-term therapy with immunosuppressive drugs and postoperative weakness, one should notice prevention of postsurgical infections, which may cause failure of this intervention and death of the patient.

Following transplantation, the liver function should be tested regularly, to discern graft injury. The graft-derived cell-free DNA in blood may be of similar discriminative value, it was also able to differentiate between the trend for graft injury and normal liver function. However, this technique is not as convenient as routine liver function tests [16]. The peak blood ammonia level of >356 μmol/L predicted poor neurodevelopmental outcomes in the patients undergoing LTx [17].

Clinical effect

According to the data from United Network for Organ Sharing (UNOS) database including 403 patients with urea cycle disorders (46.2% were OTCD) who underwent transplantation, the 1-, 3-, and 5-year graft survival rates were 90.4%, 86.3%, and 85.2%, respectively. Increased mass of the liver graft and male sex are related to decreased risk of graft loss [8]. In Japan, the 1-, 5-, 10-, and 15-year graft survival rates comprised 91.2%, 87.9%, 87.0%, and 79.3% among pediatric patients with metabolic disorders (OTCD, 20.6% of total) as shown by Kasahara et al. [18].

The 1-, 5-, and 10-year overall survival rates among 278 UCD patients who underwent LTx between 1987 and 2010 were 93%, 89%, and 87%, respectively, according to the UNOS database [19]. However, the article only stated that most UCD patients are OTCD, without any specific data on OTCD patients.

13 of 69 Chinese OTCD patients received LTx, at a median age of 3 years and one-year survival rate of 100% [20]. In Japan, the 1-, 5-, 10- and 15-year survival rates in 194 pediatric patients with metabolic disorders (OTCD=40) who underwent living donor LTx, were 91.2%, 87.9%, 86.1%, and 74.4% [18].

Hence, LTx can improve long-term survival rates of the patients, prevent recurrent hyperammonemia, and reduce the blood ammonia level. However, it did not improve neurodevelopmental outcomes in the patients with severe symptomatics, because hyperammonemia exerts early brain damage. Urgent LTx in another UCD, i.e., arginine succinate synthase deficiency, may improve the longitudinal cognitive and behavioural outcomes [17].

Conclusions

LTx can improve the long-term survival rate of patients with OTCD, but it cannot reverse the nervous system damage that occurred previously, and cannot improve cognitive impairment. However, neurodevelopment may normally proceed after LTx if it is performed early in childhood. The patients with late-onset disease should also be transplanted when required. Donorship of heterozygote carriers is still risky and should only be used when there are no other options. Hepatocyte transplantation can be tried if necessary. Prevention of infection, long-term monitoring of liver function and blood ammonia are required post-transplant.

Conflict of interest

The authors declare that they have no conflicts of interest.

References

Summar ML, Dobbelaere D, Brusilow S, Lee B. Diagnosis, symptoms, frequency and mortality of 260 patients with urea cycle disorders from a 21-year, multicentre study of acute hyperammonaemic episodes. Acta Paediatr. 2008; 97(10):1420-1425. doi: 10.1111/j.1651-2227.2008.00952.x
Msall M, Batshaw ML, Suss R, Brusilow SW, Mellits ED. Neurologic outcome in children with inborn errors of urea synthesis. Outcome of urea-cycle enzymopathies. N Engl J Med. 1984; 310(23):1500-1505. doi: 10.1056/NEJM198406073102304
Haberle J, Burlina A, Chakrapani A, Dixon M, Karall D, Lindner M, et al. Suggested guidelines for the diagnosis and management of urea cycle disorders: First revision. J Inherit Metab Dis. 2019; 42(6): 1192-1230. doi: 10.1002/jimd.12100
Kim IK, Niemi AK, Krueger C, Bonham CA, Concepcion W, Cowan TM, et al. Liver transplantation for urea cycle disorders in pediatric patients: a single-center experience. Pediatr Transplant. 2013; 17(2): 158-167. doi: 10.1111/petr.12041
Morioka D, Kasahara M, Takada Y, Shirouzu Y, Taira K, Sakamoto S, et al. Current role of liver transplantation for the treatment of urea cycle disorders: a review of the worldwide English literature and 13 cases at Kyoto University. Liver Transpl. 2005; 11(11):1332-1342. doi: 10.1002/lt.20587
Division of Genetics and Metabolism, Child Diseases and Health Care Branch, Chinese Association for Maternal and Child Health. Consensus on diagnosis and treatment of ornithine trans-carbamylase deficiency, J Zhejiang Univ (Med Sci), 2020; 49(5):539-547
(In Chinese). doi: 10.3785/j.issn.1008-9292.2020.04.11
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Ziogas IA, Wu WK, Matsuoka LK, Pai AK, Hafberg ET, Gillis LA, et al. Liver transplantation in children with urea cycle disorders: the importance of minimizing waiting time. Liver Transpl. 2021, May 31. doi: 10.1002/lt.26186
Zhu Z, Sun L, Wei L, et al. Liver transplantation for the treatment of hyperammonemia due to urea cycle disorder: report of four cases. Zhonghua Er Ke Za Zhi (Chinese Journal of Pediatrics). 2015; 53(2): 136-139 (In Chinese). doi: 10.1159/000416533
Wakiya T, Sanada Y, Urahashi T, Ihara Y, Yamada N, Okada N, et al. Living donor liver transplantation from an asymptomatic mother who was a carrier for ornithine transcarbamylase deficiency. Pediatr Transplant. 2012; 16(6):E196-200. doi: 10.1111/j.1399-3046.2012.01716.x
Wakiya T, Sanada Y, Urahashi T, Ihara Y, Yamada N, Okada N, et al. Impact of enzyme activity assay on indication in liver transplantation for ornithine transcarbamylase deficiency. Mol Genet Metab. 2012; 105(3): 404-407. doi: 10.1016/j.ymgme.2011.12.019
Rahayatri TH, Uchida H, Sasaki K, Shigeta T, Hirata Y, Kanazawa H, et al. Hyperammonemia in ornithine transcarbamylase-deficient recipients following living donor liver transplantation from heterozygous carrier donors. Pediatr Transplant. 2017; 21(1).
doi: 10.1111/petr.12848
Enosawa S, Horikawa R, Yamamoto A, Sakamoto S, Shigeta T, Nosaka S, et al., Hepatocyte transplantation using a living donor reduced graft in a baby with ornithine transcarbamylase deficiency: a novel source of hepatocytes. Liver Transpl. 2014; 20(3): 391-393. doi: 10.1002/lt.23800
Ribes-Koninckx C, Ibars ER, Calzado Agrasot MA, Bonora-Centelles A, Miquel BP, Vila Carbó JJ, et al. Clinical outcome of hepatocyte transplantation in four pediatric patients with inherited metabolic diseases. Cell Transplant. 2012; 21(10): 2267-2282. doi: 10.3727/096368912X637505
Qu W, Wei L, Zhu ZJ, Sun LY, Liu Y, Zeng ZG. Considerations for use of domino cross-auxiliary liver transplantation in metabolic liver diseases: A review of case studies. Transplantation. 2019; 103(9):1916-1920. doi: 10.1097/TP.0000000000002602
Ng HI, Sun LY, Zhu ZJ. Application of graft-derived cell-free DNA in ornithine transcarbamylase deficiency patient after living donor liver transplantation: Two case reports. Medicine (Baltimore). 2018; 97(51): e13843. doi: 10.1097/MD.0000000000013843
Kido J, Matsumoto S, Haberle J, Inomata Y, Kasahara M, Sakamoto S, et al. Role of liver transplantation in urea cycle disorders: Report from a nationwide study in Japan. J Inherit Metab Dis. 2021. doi: 10.1002/jimd.12415
Kasahara M, Sakamoto S, Horikawa R, Koji U, Mizuta K, Shinkai M, et al. Living donor liver transplantation for pediatric patients with metabolic disorders: the Japanese multicenter registry. Pediatr Transplant. 2014; 18(1): 6-15. doi: 10.1111/petr.12196
Yu L, Rayhill SC, Hsu EK, Landis CS. Liver transplantation for urea cycle disorders: analysis of the united network for organ sharing database. Transplant Proc. 2015; 47(8): 2413-2418. doi: 10.1016/j.transproceed.2015.09.020
Lu D, Han F, Qiu W, Zhang H, Ye J, Liang L, et al. Clinical and molecular characteristics of 69 Chinese patients with ornithine transcarbamylase deficiency. Orphanet J Rare Dis. 2020; 15(1): 340. doi: 10.1186/s13023-020-01606-2

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Introduction

Indications for surgery

Donor selection

Surgical methods

Post-transplant management

Clinical effect

Conclusions

Conflict of interest

The authors declare that they have no conflicts of interest.

References

Summar ML, Dobbelaere D, Brusilow S, Lee B. Diagnosis, symptoms, frequency and mortality of 260 patients with urea cycle disorders from a 21-year, multicentre study of acute hyperammonaemic episodes. Acta Paediatr. 2008; 97(10):1420-1425. doi: 10.1111/j.1651-2227.2008.00952.x
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Джингуа Вэй, Бо Хюи

Департамент неврологии, Госпиталь Сиджин, 4-й Военно-Медицинский университет, Сиань, Китай

Дефицит орнитин-транскарбамилазы (ДОТК) представляет собой наследственное заболевание с нарушением цикла обмена мочевины, характеризующееся высокой летальностью. Это генетическое нарушение обмена веществ проявляется гипераммониемией. Лекарства и гемодиализ могут снизить уровень аммиака в крови у пациентов. Трансплантация печени может улучшить долгосрочную выживаемость пациентов, но не может излечить необратимые повреждения нервной системы, возникшие ранее, и не может улучшить когнитивные функции. Если трансплантацию печени проводят в раннем детстве, впоследствии нервное развитие может быть нормальным. При необходимости пациентам с поздним дебютом также следует проводить трансплантацию. Гетерозиготность по ДОТК у донора все же представляет существенный риск, и ее следует использовать только тогда, когда нет других вариантов. При необходимости можно попытаться сделать трансплантацию гепатоцитов. После трансплантации необходима профилактика инфекции, длительный контроль функции печени и содержания аммиака в крови. Трансплантация печени должна рассматриваться для всех пациентов с генетическим ДОТК. Окончательное решение о том, следует ли и как использовать этот режим лечения, зависит от индивидуальной клинической ситуации.

Ключевые слова

Дефицит орнитин-транскарбамилазы, нарушение цикла мочевины, трансплантация печени.

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Jingya Wei, Bo Hui

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Department of Neurology, Xijing Hospital, Fourth Military Medical University, Xi’an, China

Correspondence:
Dr. Jingya Wei, Department of Neurology, Xijing Hospital, Fourth Military Medical University, 15 Changle-xi Road, Xi’an 710032, Shaanxi province, China
Phone: +86 29 8477 1055
E-mail: iamtrn@126.com

Citation: Wei J, Hui B. Liver transplantation in the treatment of ornithine transcarbamylase deficiency. Cell Ther Transplant 2021; 10(3-4): 26-29.

Ornithine transcarbamylase deficiency (OTCD) is a genetic disorder causing disturbed urea metabolic cycle with a high mortality rates. It’s a genetic metabolic disease manifesting as hyperammonemia. Drugs and hemodialysis may reduce blood ammonia levels in the patients. Liver transplantation may improve the long-term survival rate of patients, but it cannot reverse the nervous system damage that has occurred before, and cannot improve cognition. If the liver transplant is performed early in childhood, neurodevelopment may be normal at later terms. Late-onset patients should also be transplanted when required. Heterozygosity for OTCD in the donor is still risky and should only be used when there are no other options. Hepatocyte transplantation can be tried if necessary. Prevention of infection, long-term monitoring of liver function and blood ammonia are required posttransplant. Liver transplantation should be considered for all patients with genetic OTCD. The final decision of whether and how to use this treatment mode depends on individual clinical circumstances.

Keywords

Ornithine transcarbamylase deficiency, urea cycle disorder, liver transplantation, hepatocyte transplantation.

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Jingya Wei, Bo Hui

Keywords

Ornithine transcarbamylase deficiency, urea cycle disorder, liver transplantation, hepatocyte transplantation.

Keywords

Ornithine transcarbamylase deficiency, urea cycle disorder, liver transplantation, hepatocyte transplantation.

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Department of Neurology, Xijing Hospital, Fourth Military Medical University, Xi’an, China

Citation: Wei J, Hui B. Liver transplantation in the treatment of ornithine transcarbamylase deficiency. Cell Ther Transplant 2021; 10(3-4): 26-29.

Department of Neurology, Xijing Hospital, Fourth Military Medical University, Xi’an, China

Citation: Wei J, Hui B. Liver transplantation in the treatment of ornithine transcarbamylase deficiency. Cell Ther Transplant 2021; 10(3-4): 26-29.

Джингуа Вэй, Бо Хюи

Ключевые слова

Дефицит орнитин-транскарбамилазы, нарушение цикла мочевины, трансплантация печени.

Ключевые слова

Дефицит орнитин-транскарбамилазы, нарушение цикла мочевины, трансплантация печени.

Департамент неврологии, Госпиталь Сиджин, 4-й Военно-Медицинский университет, Сиань, Китай

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Introduction

It is generally known that intestinal microbiota is a symbiotic community including many types of bacteria, fungi and viruses. It is a dynamic biological system with an average weight of 2-3 kg, producing many metabolites (metabolic substances, vitamins, neurotransmitters, etc.) necessary for existence and growth of the host organism. The gut microbiota interacts with intestinal epithelial cell layers which are exposed both to endogenous pathogenic (e.g., blood-borne) viruses, and to intestinal bacterial populations. In turn, the gut microbed strains are affected by various bacteriophage populations causing their lysis. The surviving bacteria may acquire mobile gene elements, including those providing resistance to antibiotics (Fig. 1). These polyresistant bacteria are an important cause of life-threatening infections in immunocompromised patients, e.g., after intensive cytostatic therapy and hematopoietic stem cell transplantation (HSCT).

Figure 1. Intestinal epithelium is exposed to endogenous host viruses (bottom), and interacts with gut bacteria (light green) which could be lysed by bacteriophages (top left). Some of them may harbor and transfer antibiotic resistance genes to the bacteria (top right)

Moreover, the host immune system develops in permanent contact with the surrounding microbial and viral antigens, especially with the endogenous intestinal microbiota, which includes all these components [1]. Microbial and viral antigens of the intestinal microbiota, passing through the epithelial barriers of the mucous membranes, penetrate into the regional blood vessels and lymph nodes, form an adaptive B- and T-cell immune response, being a key factor in the normal maturation and functioning of the immune system.

For decades, the main attention of bacteriologists was paid to cultivated, mainly aerobic microorganisms – Escherichia, Klebsiella, Enterococci that were studied in details for decades. Cultivable anaerobic gut bacteria were also exhaustively studied over last decades. However, with development of high-throughput DNA diagnostics, the spectrum of known microbial bacteria extended to sufficient degree. Currently, >1000 bacterial species are detectable in normal gut microbiota. Hence, over the past 10-20 years, the novel molecular biology approaches (multiple PCR, high-throughput DNA sequencing) enabled detailed classifying hundreds of species of anaerobic intestinal bacteria, which dominate the intestinal microbiota.

Human viral community (virome) is exhibiting even higher taxonomic and genetic complexity. Formerly, the main interest was drawn to the viruses of eukaryotic cells which could be pathogenic to humans. The modern NGS approach allows to detect both known viruses (herpes, anelloviruses, picobirnaviruses) and a number of previously unknown viral DNA sequences [2].

However, intestinal human virome is dominated by bacteriophages. These are largely represented by Caudiovirales. [3]. This order of phages includes 3 families (Myoviridae; Siphoviridae, and Podoviridae).

Along with double-stranded DNA phages, minor populations of single-stranded DNA and RNA phages are detectable in human gut virome which are also specific for distinct bacterial species as reviewed by Carding et al. [3].

The issues of viral sequences in bacterial and human cells (e.g., prophages, retroviral elements etc.) are also detectable by metagenomics but will not be covered here, because of undefined clinical significance and still undefined systemic approach. Hence, the question about functions and significance of virome abundance and diversity in healthy subjects and GIT disorders is still open.

Current methodology

Unlike the bacterial microbiota, viral intestinal population (gut virome) has been studied to a much lesser extent. Whereas bacterial species have the common target gene for sequencing, i.e., 16SrRNA (the main object for NGS analysis), the viruses lack such a common marker gene, thus hampering easy assessment of their diversity in biological samples.

Currently, there is a broad diagnostic choice in clinical virology, starting with cytopathogenic tests, large arrays of immune diagnostic sets, and modern whole-scale panels of PCR assays. To diagnose some pathogenic viruses (up to 10-15 species), multiplex PCR was developed, and it is commonly used in clinical laboratories. However, these commercial PCR panels cannot cover the entire spectrum of potential viral agents, usually targeting up to 10-12 pathogens.

Therefore, the most comprehensive approach to studying the entire viral community is whole-genome screening of viral sequences by means of NGS followed by extensive bioinformatics. E.g., a random metagenomic analysis may also allow detection of human pathogenic viruses. Methodology of metagenomic studies are well reviewed in [4].

Diversity of human viruses and bacteriophages

A number of endogenous viruses persisting lifelong may be found in stools under certain conditions, e.g., in immunocompromised patients or during immunosuppressive therapy.

Herperviruses in gut are often activated in the patients with inflammatory bowel diseases. E.g., the Japanese group, using high-capacity multiplex PCR with microchip electrophoresis, has detected as much as 191 different bacterial species and 206 viruses in 215 stool samples (71.7% positivity) from immunocompromised patients and subjects with ulcerative colitis [5]. Among viral pathogens, Epstein-Barr virus (EBV) was revealed in 90 samples (30.0%); HHV-6, in 53 cases (17.7%), and cytomegalovirus (CMV) in 37 specimens (12.3%).

Most often, however, human intestinal microbiome is extensively studied in search of the viruses known to be pathogenic (i.e., noroviruses, rotaviruses, astroviruses, adenoviruses etc.). Biological diversity of human pathogenic viruses was first studied in Asian countries, with high incidence of gastroenteritis in pediatric setting [6]. The authors examined stool samples from 7 children positive for picobirnavirus and identified, by means of metagenomics, enterovirus, gyrovirus, parechovirus in these samples, which are potentially pathogenic in gastroenteritis. In addition, a metagenomic study of stool microbiota allows detecting bacterial-viral associations (for example, C.difficile associated with a number of viruses) in intestinal syndromes as shown by a group from the USA [7]. Metagenomic analysis was also used for NGS analysis of stool samples in gastroenteritis, and, except of common noroviruses, additional pathogens were found from the genus Astroviridae and Caliciviridae [8].

Gut human virome after HSCT

A limited number of works concerned presence of intestinal viruses posttransplant. E.g., Legoff et al. have detected different viruses in stool and plasma following HSCT using electrospray ionization with mass-spectrometric [9]. The workers have revealed high adenovirus (AdV) viral load in stool samples. In an earlier study, AdV DNA was found in stools of 21 HSCT patients with AdV infection, from a total group of 182 patients. Of note, time dynamics of AdV viral loads in stool specimens was predictive for AdV viraemia, thus suggesting intestinal source to be the primary site of the viral infection [10].

Cytomegalovirus (CMV) viral load was assessed in stool of HSCT as possible marker of acute intestinal graft-versus-host disease posttransplant [11]. CMV DNA was found in 20 of 121 HSCT recipients. However, the authors did not find any correlation between CMV DNA loads and intestinal graft-versus-host disease (aGVHD), as well between viral contents in plasma and stools.

In view of scarce NGS-based virome studies in HSCT, it is very important to detect and realize significance of multiple viral species in progression of intestinal syndrome. Over the past 5 years, several papers have been published on the metagenomics of viruses after HSCT [12]. The authors traced the virome dynamics in 44 HSCT recipients using metagenomics techniques (NexTera, HiSeq platforms). Following transplantation (i.e., during transient immune deficiency), Anelloviridae, herpes viruses, papilloma and polyoma viruses, especially picobirnavirus were “flourishing” in intestinal GVHD. Moreover, decreased detection rates were noted for bacteriophages, except for Siphoviridae. A similar work was carried out by a Dutch group [13]. The authors used the original ViroCap system to study fecal samples, with a large panel of probes for 34 families of DNA and RNA viruses (a total of 337 species). After enrichment of viral DNA in the samples, the NGS procedures were performed. At the same time, it was possible to identify, along with known noro- and adenoviruses, also rhinovirus, herpesvirus-7, VK virus, astrovirus at higher sensitivity, than with conventional PCR tests. This approach revealed new associations between the findings of viral sequences and intestinal GVHD. Temporal changes of the patient's microbiota after GVHD and weekly fecal microbiota transplantation in a single patient was studied by Chinese workers [14]. Biodiversity of bacterial species gradually increased after successful TFM, whereas the spectrum of viruses, in general, expanded with time after FMT, e.g., Caudivirales content was increased.

Intestinal phageome

Current metagenomic approaches allowed to look for the whole spectrum of virome, including human viruses and bacteriophages in human microbiota which seems to become a feasible task of clinical significance [15].

For more than 100 years, the bacteriophages were extensively studied using bacteriolysis in classical cultures, morphological and, later molecular PCR methods. Therefore, current criteria for bacteriophage classification are based on their biological properties (lytic or temperate forms; bacterial targets), morphology, main location site etc. [16].

Some of the bacteriophages are widely used in clinical practice to combat antibiotic-resistant bacteria [17].

However, the full-scale analysis of multiple phage populations became available only few years ago, with an advent of high-throughput metagenomic sequencing performed at various NGS platforms [18].

This approach makes it possible to assess the entire community of pathogenic viruses, especially, different bacteriophage species in fecal samples. Different bacteriophages are, generally, specific for distinct bacterial species [19]. Therefore, spectrum and content of intestinal bacteriophages, by definition, depends on the dynamics of the bacterial hosts in the microbiota, and vice versa. Dietary habits, age and antibiotic therapy may influence composition and dynamics of both bacteria and their phages. E.g., starting from birth, the Caudovirales content and phage biodiversity change significantly with age [18].

Shotgun metagenomic methods allow evaluating the entire population of genes in a sample (though at different detection efficiencies). E.c., French authors have applied this technique to study the intestinal bacterial microbiota upon exposure to antimicrobial drug (cefprozil) Immediately after therapy, the total content of metagenomic sequences was expected to decrease. However, 3 months after the therapy, new previously absent gene sequences appeared in the intestinal microbiota and, what is important, the content of antibiotic resistance signatures increased, especially in individuals with initially low biodiversity of the intestinal microbiota. [20]. Different mechanisms of horizontal gene transfer via bacteriophages are shown in Fig. 2.

Figure 2. Horizontal gene transfer can commonly occur through conjugation and natural transformation. Additionally, it may occur through transduction, where resistance is transmitted via bacteriophage. (From [21])

Metagenomic studies of intestinal phageome and resistance genes

Previous knowledge of intestinal virome was, mostly, based on classical studies of bacteriophages detectable by their bacteriolytic effects. Tremendous information on intestinal phages accumulated over XX century. The data on eukaryotic cell viruses are also quite extensive, mostly concerning distinct pathogenic viral species.

Current technical advances, i.e., next-generation sequencing (NGS) enabled coverage of the whole intestinal virome. Metagenomics makes it possible to identify and evaluate both temporal dynamics of phage populations, and their relationship with antibiotic resistance genes that promoting colonization of intestines by pathogenic bacterial strains.

Over the past 3-5 years, the work was started with searching phage sequences and antibiotic resistance genes using new generation sequencing (NGS) methods. Thus, Fernández-Orth et al. investigated DNA from samples of intestinal microbiota in healthy individuals and after treatment with ciprofloxacin, using deep sequencing methods (MySec, Illumina). Assembly of the sequences obtained was evaluated using Kraken software. The samples were found to contain from 4 to 266 viruses. Caudovirales predominated among bacteriophages, and the phages of Siphoviridae and Myoviridae families were also identified. Antibiotic resistance genes were also found in bacterial DNA, and their content was significantly increased after treatment with ciprofloxacin [22].

In other study, bioinformatic analysis of multiple viral sequences from human intestinal microbiome was carried out 4 weeks after a course of antibiotics. The authors found a significant increase in the number of gene signatures (scaffolds) of antibiotic-resistant genes after antibiotic therapy [23].

However, current evidence show that the antibiotic resistance genes can be inserted into plasmids and other mobile genetic elements, which can be transmitted both vertically and by horizontal transfer within the bacterial population, which is essential for accumulation of resistant strains within the intestinal microbiota. Such evidence has been obtained recently. For example, gene sequences were screened for 254 strains of Klebsiella pneumoniae, which most often acquires the drug resistance genes [24]. They showed that most of the studied strains contained intact prophage sequences. An additional analysis of 42 K.pneumoniae strains showed that these phages belong to the families Myoviridae, Siphoviridae, and Podoviridae. Interestingly, no virulence genes were detected in these prophages; however, in 2% of cases, these prophages also encoded genes related to antibiotic resistance factors.

Probable bacteria-phage interactions in HSCT patients

However, most of these clinical studies dealt with the state and ways of restoring the bacterial component of the microbiota, while missing possible role of bacteriophages in severe intestinal dysbiosis. The latter direction can also be promising, as shown by the data of NGS studies on the stability of intestinal bacteriophage populations during fecal transplantation [25]. Meanwhile, there are still no proven positive results from phage therapy in severe intestinal dysbiosis. It is believed that in the future it will be possible to develop modified bacteriophages adapted to specific resistant bacteria [26]. So far, however, there is a process of accumulating information about the bacterial-viral complex of the intestinal microbiota in severe intestinal syndromes of infectious origin.

Posttransplant period is often associated with severe colitis often associated to persistent infection with K.pneumoniae, pathogenic E.coli, C.difficile as reviewed in [27]. Meanwhile, treatment of bacterial infections using species-specific bacteriophages, in particular – those against Staphylococci, E. coli, etc. has been successfully used for decades. The history of these developments is well described [17]. However, the desirable clinical effects were temporary, often due to the development of resistance to phage therapy [19]. British scientists have discovered that optimal combinations of several bacteriophages are most effective in suppressing and preventing phage resistance of C.difficile, as was previously shown experimentally [28]. In hamster experiments, treatment with optimized phage mixtures led to rapid decrease in the C.difficile colonization. Clinical transplantation of intestinal microbiota also suggests possible clinical effects of non-bacterial pathogens. E.g., Ott et al. [29] administered sterile filtrates of donor stool through a nasal cannule to the patients with Clostridium difficile infection. Usage of this bacteria-free drug in 5 patients led to long-term normalization of intestinal disorder, as well as appropriate changes in bacterial and intestinal microbiota. The authors suggest that bacteriophages from the stool filtrate may cause similar positive effects. Hence, these findings enable search and identification of intestinal bacteriophages associated with positive and persistent effects of colitis therapy, especially at the present time, when effective methods of metagenomic DNA sequencing are developed for such studies.

Conclusion

Gut microbiota is a complex symbiosis of bacteria, viruses and fungi. However, unlike the bacterial microbiota (bacteriome), the viral gut community (gut virome) is studied to much lesser degree, due to absence of common target gene for nucleic acid sequencing in viruses. Over last years, the whole-genome screening techniques using next-generation sequencing (NGS) promoted our knowledge in the field. This approach allowed to estimate the biodiversity of human viruses and bacteriophages in the individual samples of intestinal microbiota in health and disease.

Studies of the virome changes after HSCT are now launched, however, being at initial stage. Meanwhile, the changes in bacteriophage community (phageome) and its diversity post-transplant may explain both therapy-associated changes of bacteriome, and development of bacterial antibiotic resistance, due to phage-mediated transfer of antibiotic resistance genes.

Conflicts of interest

None conflicts of interest are declared.

Acknowledgements

The authors are much appreciated to the Pediatric Research and Clinical Center for Infectious Diseases, and dedicate the present article to the 95^th anniversary of this institution.

References

Shi N, Li N, Duan X, Niu H. Interaction between the gut microbiome and mucosal immune system Mil Med Res 2017; 4:14.
doi: 10.1186/s40779-017-0122-9
Smits SL, Schapendonk CM, van Beek J, Vennema H, Schürch AC, Schipper D, et al. New viruses in idiopathic human diarrhea cases, the Netherlands. Emerg Infect Dis. 2014; 20(7):1218-22. doi: 10.3201/eid2007.140190
Carding SR, Davis N, Hoyles L. Review article: the human intestinal virome in health and disease. Aliment Pharmacol Ther. 2017; 46(9):800-815. doi: 10.1111/apt.14280
Gu W, Miller S, Chiu CY. Clinical Metagenomic Next-Generation Sequencing for Pathogen Detection. Annu Rev Pathol. 2019; 14:319-338. doi: 10.1146/annurev-pathmechdis-012418-012751
Nahar S, Iraha A, Hokama A, Uehara A, Parrott G, Ohira T, et al. Evaluation of a multiplex PCR assay for detection of cytomegalovirus in stool samples from patients with ulcerative colitis. World J Gastroenterol. 2015; 21(44):12667-75. doi: 10.3748/wjg.v21.i44.12667
Sun G, Zang Q, Gu Y, Niu G, Ding C, Zhang P. Viral metagenomics analysis of picobirnavirus-positive feces from children with sporadic diarrhea in China. Arch Virol. 2016; 161 (4): 971-5. doi: 10.1007/s00705-015-2726-2
Zhou Y, Wylie KM, El Feghaly RE, Mihindukulasuriya KA, Elward A, Haslam DB, Storch GA, Weinstock GM. Metagenomic Approach for Identification of the Pathogens Associated with Diarrhea in Stool Specimens. J Clin Microbiol. 2016; 54 (2): 368-75.
doi: 10.1128/JCM.01965-15
Fernandez-Cassi X, Martínez-Puchol S, Silva-Sales M, Cornejo T, Bartolome R, Bofill-Mas S, Girones R. Unveiling Viruses Associated with Gastroenteritis Using a Metagenomics Approach. Viruses. 2020; 12 (12): 1432. doi: 10.3390/v12121432
Legoff J, Feghoul L, Mercier-Delarue S, Dalle JH, Scieux C, Chérot J, et al. Broad-range PCR-electrospray ionization mass spectrometry for detection and typing of adenovirus and other opportunistic viruses in stem cell transplant patients. J Clin Microbiol. 2013; 51(12):4186-92. doi: 10.1128/JCM.01978-13
Jeulin H, Salmon A, Bordigoni P, Venard V. Diagnostic value of quantitative PCR for adenovirus detection in stool samples as compared with antigen detection and cell culture in haematopoietic stem cell transplant recipients. Clin Microbiol Infect. 2011;17(11):1674-80. doi: 10.1111/j.1469-0691.2011.03488.x
Bueno F, Albert E, Giménez E, Piñana JL, Pérez A, Gómez MD, et al., 2020. Cytomegalovirus DNA load monitoring in stool specimens for anticipating the occurrence of intestinal acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation: Is it of any value? Transpl Infect Dis. 2020; 22(6):e13440. doi: 10.1111/tid.13440
Legoff J, Resche-Rigon M, Bouquet J, Robin M, Naccache SN, Mercier-Delarue S, et al. The eukaryotic gut virome in hematopoietic stem cell transplantation: new clues in enteric graft-versus-host disease. Nat Med. 2017; 23 (9): 1080-1085. doi: 10.1038/nm.4380
Jansen SA, Nijhuis W, Leavis HL, Riezebos-Brilman A, Lindemans CA, Schuurman R. Broad virus detection and variant discovery in fecal samples of hematopoietic transplant recipients using targeted sequence capture metagenomics. Front Microbiol. 2020; 11: 560179. doi: 10.3389/ fmicb.2020.560179
Zhang F, Zuo T, Yeoh YK, Cheng FWT, Liu Q, Tang W, et al. Longitudinal dynamics of gut bacteriome, mycobiome and virome after fecal microbiota transplantation in graft-versus-host disease. Nat Commun. 2021; 12 (1): 65. doi: 10.1038/s41467-020-20240-x
Wang W, Jovel J, Halloran B, Wine E, Patterson J, Ford G, et al. Metagenomic analysis of microbiome in colon tissue from subjects with inflammatory bowel diseases reveals interplay of viruses and bacteria. Inflamm Bowel Dis. 2015; 21 (6): 1419-27.
doi: 10.1097/MIB.0000000000000344
Principi N, Silvestri E, Esposito S Advantages and Limitations of Bacteriophages for the Treatment of Bacterial Infections. Front. Pharmacol. 2019;10:513. doi: 10.3389/fphar.2019.00513
Brüssow H. Phage therapy for the treatment of human intestinal bacterial infections: soon to be a reality? Exp Rev Gastroenterol Hepatol. 2017. doi: 10.1080/17474124.2017.1342534
Townsend EM, Kelly L, Muscatt G, Box JD, Hargraves N, Lilley D, Jameson E. The human gut phageome: Origins and roles in the human gut microbiome. Front Cell Infect Microbiol. 2021; 11: 643214. doi: 10.3389/fcimb.2021.643214
Oechslin F. Resistance development to bacteriophages occurring during bacteriophage therapy. Viruses 2018, 10, 351.
doi: 10.3390/v10070351
Raymond F, Déraspe M, Boissinot M, Bergeron MG, Corbeil J. Partial recovery of microbiomes after antibiotic treatment. Gut Microbes. 2016; 7 (5): 428-34. doi: 10.1080/ 19490976.2016.1216747
Schroeder M, Brooks BD, Brooks AE. The Complex Relationship between Virulence and Antibiotic Resistance. Genes. 2017; 8(1):39. https://doi.org/10.3390/genes8010039
Fernández-Orth D, Miró E, Brown-Jaque M, Rodríguez-Rubio L, Espinal P, Rodriguez-Navarro J, et al. Faecal phageome of healthy individuals: presence of antibiotic resistance genes and variations caused by ciprofloxacin treatment. J Antimicrob Chemother. 2019; 74 (4): 854-864. doi: 10.1093/jac/dky540
Górska A, Peter S, Willmann M, Autenrieth I, Schlaberg R, Huson DH. Dynamics of the human gut phageome during antibiotic treatment Comput Biol Chem. 2018; 74: 420-427. doi: 10.1016/j.compbiolchem.2018.03.011
Baliga P, Shekar M, Kallappa GS. Genome-wide identification and analysis of chromosomally integrated putative prophages associated with clinical Klebsiella pneumoniae strains. Curr Microbiol 2021; 78 (5): 2015-2024. doi: 10.1007/s00284-021-02472-2
Broecker F, Russo G, Klumpp J, Moelling K. Stable core virome despite variable microbiome after fecal transfer. Gut Microbes. 2017; 8 (3): 214-220. doi: 10.1080/19490976.2016.1265196
Paule A, Frezza D, Edeas M. Microbiota and phage therapy: Future challenges in medicine. Med Sci (Basel). 2018; 6 (4): 86.
doi: 10.3390/medsci6040086
Goloshchapov OV, Kucher MA, Chukhlovin AB. Gut microbiome in hematopoietic stem cell transplantation: patient-and treatment-related factors. Cell Ther Transpant. 2018; 7(4): 16-28. doi: 10.18620/ctt-1866-8836-2018-7-4-16-28
Nale JY, Spencer J, Hargreaves KR, Buckley AM, Trzepiński P, Douce GR, Clokie MR. Bacteriophage combinations significantly reduce Clostridium difficile growth in vitro and proliferation in vivo. Antimicrob Agents Chemother. 2015; 60 (2): 968-981.
doi: 10.1128/AAC.01774-15
Ott SJ, Waetzig GH, Rehman A, Moltzau-Anderson J, Bharti R, Grasis JA, et al. Efficacy of sterile fecal filtrate transfer for treating patients with Clostridium difficile infection. Gastroenterology. 2017; 152 (4): 799-811.e7. doi: 10.1053/ j.gastro.2016.11.010

" ["~DETAIL_TEXT"]=> string(29610) "

Introduction

Current methodology

Diversity of human viruses and bacteriophages

A number of endogenous viruses persisting lifelong may be found in stools under certain conditions, e.g., in immunocompromised patients or during immunosuppressive therapy.

Gut human virome after HSCT

Intestinal phageome

Some of the bacteriophages are widely used in clinical practice to combat antibiotic-resistant bacteria [17].

However, the full-scale analysis of multiple phage populations became available only few years ago, with an advent of high-throughput metagenomic sequencing performed at various NGS platforms [18].

Metagenomic studies of intestinal phageome and resistance genes

Probable bacteria-phage interactions in HSCT patients

Conclusion

Conflicts of interest

None conflicts of interest are declared.

Acknowledgements

The authors are much appreciated to the Pediatric Research and Clinical Center for Infectious Diseases, and dedicate the present article to the 95^th anniversary of this institution.

References

Shi N, Li N, Duan X, Niu H. Interaction between the gut microbiome and mucosal immune system Mil Med Res 2017; 4:14.
doi: 10.1186/s40779-017-0122-9
Smits SL, Schapendonk CM, van Beek J, Vennema H, Schürch AC, Schipper D, et al. New viruses in idiopathic human diarrhea cases, the Netherlands. Emerg Infect Dis. 2014; 20(7):1218-22. doi: 10.3201/eid2007.140190
Carding SR, Davis N, Hoyles L. Review article: the human intestinal virome in health and disease. Aliment Pharmacol Ther. 2017; 46(9):800-815. doi: 10.1111/apt.14280
Gu W, Miller S, Chiu CY. Clinical Metagenomic Next-Generation Sequencing for Pathogen Detection. Annu Rev Pathol. 2019; 14:319-338. doi: 10.1146/annurev-pathmechdis-012418-012751
Nahar S, Iraha A, Hokama A, Uehara A, Parrott G, Ohira T, et al. Evaluation of a multiplex PCR assay for detection of cytomegalovirus in stool samples from patients with ulcerative colitis. World J Gastroenterol. 2015; 21(44):12667-75. doi: 10.3748/wjg.v21.i44.12667
Sun G, Zang Q, Gu Y, Niu G, Ding C, Zhang P. Viral metagenomics analysis of picobirnavirus-positive feces from children with sporadic diarrhea in China. Arch Virol. 2016; 161 (4): 971-5. doi: 10.1007/s00705-015-2726-2
Zhou Y, Wylie KM, El Feghaly RE, Mihindukulasuriya KA, Elward A, Haslam DB, Storch GA, Weinstock GM. Metagenomic Approach for Identification of the Pathogens Associated with Diarrhea in Stool Specimens. J Clin Microbiol. 2016; 54 (2): 368-75.
doi: 10.1128/JCM.01965-15
Fernandez-Cassi X, Martínez-Puchol S, Silva-Sales M, Cornejo T, Bartolome R, Bofill-Mas S, Girones R. Unveiling Viruses Associated with Gastroenteritis Using a Metagenomics Approach. Viruses. 2020; 12 (12): 1432. doi: 10.3390/v12121432
Legoff J, Feghoul L, Mercier-Delarue S, Dalle JH, Scieux C, Chérot J, et al. Broad-range PCR-electrospray ionization mass spectrometry for detection and typing of adenovirus and other opportunistic viruses in stem cell transplant patients. J Clin Microbiol. 2013; 51(12):4186-92. doi: 10.1128/JCM.01978-13
Jeulin H, Salmon A, Bordigoni P, Venard V. Diagnostic value of quantitative PCR for adenovirus detection in stool samples as compared with antigen detection and cell culture in haematopoietic stem cell transplant recipients. Clin Microbiol Infect. 2011;17(11):1674-80. doi: 10.1111/j.1469-0691.2011.03488.x
Bueno F, Albert E, Giménez E, Piñana JL, Pérez A, Gómez MD, et al., 2020. Cytomegalovirus DNA load monitoring in stool specimens for anticipating the occurrence of intestinal acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation: Is it of any value? Transpl Infect Dis. 2020; 22(6):e13440. doi: 10.1111/tid.13440
Legoff J, Resche-Rigon M, Bouquet J, Robin M, Naccache SN, Mercier-Delarue S, et al. The eukaryotic gut virome in hematopoietic stem cell transplantation: new clues in enteric graft-versus-host disease. Nat Med. 2017; 23 (9): 1080-1085. doi: 10.1038/nm.4380
Jansen SA, Nijhuis W, Leavis HL, Riezebos-Brilman A, Lindemans CA, Schuurman R. Broad virus detection and variant discovery in fecal samples of hematopoietic transplant recipients using targeted sequence capture metagenomics. Front Microbiol. 2020; 11: 560179. doi: 10.3389/ fmicb.2020.560179
Zhang F, Zuo T, Yeoh YK, Cheng FWT, Liu Q, Tang W, et al. Longitudinal dynamics of gut bacteriome, mycobiome and virome after fecal microbiota transplantation in graft-versus-host disease. Nat Commun. 2021; 12 (1): 65. doi: 10.1038/s41467-020-20240-x
Wang W, Jovel J, Halloran B, Wine E, Patterson J, Ford G, et al. Metagenomic analysis of microbiome in colon tissue from subjects with inflammatory bowel diseases reveals interplay of viruses and bacteria. Inflamm Bowel Dis. 2015; 21 (6): 1419-27.
doi: 10.1097/MIB.0000000000000344
Principi N, Silvestri E, Esposito S Advantages and Limitations of Bacteriophages for the Treatment of Bacterial Infections. Front. Pharmacol. 2019;10:513. doi: 10.3389/fphar.2019.00513
Brüssow H. Phage therapy for the treatment of human intestinal bacterial infections: soon to be a reality? Exp Rev Gastroenterol Hepatol. 2017. doi: 10.1080/17474124.2017.1342534
Townsend EM, Kelly L, Muscatt G, Box JD, Hargraves N, Lilley D, Jameson E. The human gut phageome: Origins and roles in the human gut microbiome. Front Cell Infect Microbiol. 2021; 11: 643214. doi: 10.3389/fcimb.2021.643214
Oechslin F. Resistance development to bacteriophages occurring during bacteriophage therapy. Viruses 2018, 10, 351.
doi: 10.3390/v10070351
Raymond F, Déraspe M, Boissinot M, Bergeron MG, Corbeil J. Partial recovery of microbiomes after antibiotic treatment. Gut Microbes. 2016; 7 (5): 428-34. doi: 10.1080/ 19490976.2016.1216747
Schroeder M, Brooks BD, Brooks AE. The Complex Relationship between Virulence and Antibiotic Resistance. Genes. 2017; 8(1):39. https://doi.org/10.3390/genes8010039
Fernández-Orth D, Miró E, Brown-Jaque M, Rodríguez-Rubio L, Espinal P, Rodriguez-Navarro J, et al. Faecal phageome of healthy individuals: presence of antibiotic resistance genes and variations caused by ciprofloxacin treatment. J Antimicrob Chemother. 2019; 74 (4): 854-864. doi: 10.1093/jac/dky540
Górska A, Peter S, Willmann M, Autenrieth I, Schlaberg R, Huson DH. Dynamics of the human gut phageome during antibiotic treatment Comput Biol Chem. 2018; 74: 420-427. doi: 10.1016/j.compbiolchem.2018.03.011
Baliga P, Shekar M, Kallappa GS. Genome-wide identification and analysis of chromosomally integrated putative prophages associated with clinical Klebsiella pneumoniae strains. Curr Microbiol 2021; 78 (5): 2015-2024. doi: 10.1007/s00284-021-02472-2
Broecker F, Russo G, Klumpp J, Moelling K. Stable core virome despite variable microbiome after fecal transfer. Gut Microbes. 2017; 8 (3): 214-220. doi: 10.1080/19490976.2016.1265196
Paule A, Frezza D, Edeas M. Microbiota and phage therapy: Future challenges in medicine. Med Sci (Basel). 2018; 6 (4): 86.
doi: 10.3390/medsci6040086
Goloshchapov OV, Kucher MA, Chukhlovin AB. Gut microbiome in hematopoietic stem cell transplantation: patient-and treatment-related factors. Cell Ther Transpant. 2018; 7(4): 16-28. doi: 10.18620/ctt-1866-8836-2018-7-4-16-28
Nale JY, Spencer J, Hargreaves KR, Buckley AM, Trzepiński P, Douce GR, Clokie MR. Bacteriophage combinations significantly reduce Clostridium difficile growth in vitro and proliferation in vivo. Antimicrob Agents Chemother. 2015; 60 (2): 968-981.
doi: 10.1128/AAC.01774-15
Ott SJ, Waetzig GH, Rehman A, Moltzau-Anderson J, Bharti R, Grasis JA, et al. Efficacy of sterile fecal filtrate transfer for treating patients with Clostridium difficile infection. Gastroenterology. 2017; 152 (4): 799-811.e7. doi: 10.1053/ j.gastro.2016.11.010

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Голощапов1, Алексей Б. Чухловин1,2, Олег С. Глотов2" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(140) "

Олег В. Голощапов¹, Алексей Б. Чухловин^1,2, Олег С. Глотов²

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¹ НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
² Детский научно-практический центр инфекционных болезней ФМБА, 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) "28407" ["VALUE"]=> array(2) { ["TEXT"]=> string(4017) " Микробиота кишечника (сложный симбиоз бактерий, грибов и вирусов) – это динамическая биологическая система, необходимая для существования и роста человеческого организма. Состав и соотношение бактериальных популяций серьезно нарушаются при тяжелых колитах и болезни «трансплантат против хозяина» (GVHD), возникающих после трансплантации гемопоэтических стволовых клеток (HSCT), особенно при развитии устойчивых к антибиотикам бактериальных штаммов. В отличие от хорошо известной бактериальной микробиоты, изученной с помощью классической бактериологии и секвенирования гена 16S рРНК, вирусные популяции кишечной микробиоты (например, бактериофагов) в этих клинических условиях изучены недостаточно из-за отсутствия общего вирусного гена, пригодного для сравнительного молекулярно-генетического анализа. Оценка соотношений вирусной и бактериальной кишечной микробиоты возможна с помощью метагеномных методов анализа множества видов ДНК в образцах биоматериала. Объектом клинического исследования являются пациенты с инфекционными осложнениями, вызванными массивным антибактериальным и цитостатическим лечением. Особое внимание следует обратить на тяжелый колит с инфекцией C.difficile и устойчивой к антибиотикам K. pneumoniae, а также другими патогенами, как при трансплантации фекальной микробиоты (FMT), так и без нее. Обычная оценка кишечной микробиоты будет осуществляться путем секвенирования следующего поколения (NGS) на основе генного разнообразия 16S рДНК для бактериальных генов и метагеномного анализа NGS, чтобы оценить соотношение различных вирусов эукариотических клеток и, в частности, бактериофагов в случае дисбактериоза кишечника. Следует установить типичные нарушения кишечного вирома, а также их роль в колонизации кишечными бактериями, устойчивыми к антибиотикам, после интенсивной антибиотикотерапии и химиотерапии. <h2>Ключевые слова</h2> Кишечные инфекции, трансплантация, иммунологические осложнения, кишечная микробиота, вирусы, бактериофаги, антибиотикорезистентность, секвенирование нового поколения (NGS), ген 16S rRNA, метагеномика. " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3915) "

Микробиота кишечника (сложный симбиоз бактерий, грибов и вирусов) – это динамическая биологическая система, необходимая для существования и роста человеческого организма. Состав и соотношение бактериальных популяций серьезно нарушаются при тяжелых колитах и болезни «трансплантат против хозяина» (GVHD), возникающих после трансплантации гемопоэтических стволовых клеток (HSCT), особенно при развитии устойчивых к антибиотикам бактериальных штаммов. В отличие от хорошо известной бактериальной микробиоты, изученной с помощью классической бактериологии и секвенирования гена 16S рРНК, вирусные популяции кишечной микробиоты (например, бактериофагов) в этих клинических условиях изучены недостаточно из-за отсутствия общего вирусного гена, пригодного для сравнительного молекулярно-генетического анализа. Оценка соотношений вирусной и бактериальной кишечной микробиоты возможна с помощью метагеномных методов анализа множества видов ДНК в образцах биоматериала. Объектом клинического исследования являются пациенты с инфекционными осложнениями, вызванными массивным антибактериальным и цитостатическим лечением.

Особое внимание следует обратить на тяжелый колит с инфекцией C.difficile и устойчивой к антибиотикам K. pneumoniae, а также другими патогенами, как при трансплантации фекальной микробиоты (FMT), так и без нее. Обычная оценка кишечной микробиоты будет осуществляться путем секвенирования следующего поколения (NGS) на основе генного разнообразия 16S рДНК для бактериальных генов и метагеномного анализа NGS, чтобы оценить соотношение различных вирусов эукариотических клеток и, в частности, бактериофагов в случае дисбактериоза кишечника. Следует установить типичные нарушения кишечного вирома, а также их роль в колонизации кишечными бактериями, устойчивыми к антибиотикам, после интенсивной антибиотикотерапии и химиотерапии.

Ключевые слова

Кишечные инфекции, трансплантация, иммунологические осложнения, кишечная микробиота, вирусы, бактериофаги, антибиотикорезистентность, секвенирование нового поколения (NGS), ген 16S rRNA, метагеномика.

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Oleg V. Goloshchapov¹, Alexei B. Chukhlovin^1,2, Oleg S. Glotov²

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¹ RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia
² Children's Scientific and Clinical Center for Infectious Diseases of the Federal Medical and Biological Agency, St. Petersburg, Russia

Correspondence:
Dr. Alexei B. Chukhlovin, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, 6-8 L. Tolstoy St, 197022, St. Petersburg, Russia
Phone: +7 (921) 325-00-94
E-mail: alexei.chukh@mail.ru

Citation: Goloshchapov OV, Chukhlovin AB, Glotov OS. Possible role of intestinal human viruses and bacteriophages following hematopoietic stem cell transplantation: a mini-review. Cell Ther Transplant 2021; 10(3-4): 19-25.

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Gut microbiota (a complex community of bacteria, fungi and viruses) is a dynamic biological system adapted for co-existence and symbiosis with host organism. Composition and ratio of bacterial populations is severely impaired in severe colitis and graft-versus-host disease (GVHD) occurring after hematopoietic stem cell transplantation (HSCT), especially, upon development of antibiotic-resistant bacterial strains. In contrast to the well-known bacterial microbiota studied by classic bacteriology and 16S rRNA gene sequencing, the viral populations of intestinal microbiota (e.g., bacteriophages) in are poorly studied in these clinical conditions, due to absence of a common viral gene suitable for comparative molecular genetic analysis. Assessing the ratios for viral and bacterial intestinal microbiota is feasible by means of metagenomic methods assaying multiple DNA species in the samples of biomaterial. As an object of clinical research, the patients with infectious complications caused by massive antibacterial and cytostatic treatment. Special attention should be drawn to severe colitis with C.difficile infection and antibiotic-resistant K.pneumonia and other pathogens with/without fecal microbiota transplantation (FMT). Conventional assessment of intestinal microbiota will be accomplished by next-generation sequencing (NGS) based on 16S rDNA gene diversity for bacterial genes, and metagenomic NGS analysis, in order to assess the ratio of various viruses of eukaryotic cells and, in particular, bacteriophages in cases of gut dysbiosis. Typical disturbances of the gut virome should be established, as well as role of bacteriophages in emergence of antibiotic-resistant intestinal bacteria after intensive antibiotic and chemotherapy.

Keywords

Intestinal microbiota, gut microbiota, viruses, bacteriophages, transplantation, immune complications, antibiotic resistance, NGS sequencing, 16S rRNA gene, metagenomics.

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Goloshchapov1, Alexei B. Chukhlovin1,2, Oleg S. Glotov2 " ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(104) "

Oleg V. Goloshchapov¹, Alexei B. Chukhlovin^1,2, Oleg S. Glotov²

Keywords

Intestinal microbiota, gut microbiota, viruses, bacteriophages, transplantation, immune complications, antibiotic resistance, NGS sequencing, 16S rRNA gene, metagenomics.

Keywords

Intestinal microbiota, gut microbiota, viruses, bacteriophages, transplantation, immune complications, antibiotic resistance, NGS sequencing, 16S rRNA gene, metagenomics.

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Олег В. Голощапов¹, Алексей Б. Чухловин^1,2, Олег С. Глотов²

Ключевые слова

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Introduction

During the development of malignant neoplasia, a specific cellular environment is formed in the chronic inflammation site termed "inflammatory microenvironment of the tumour" (TME). This cell community consists of tumour-associated macrophages (MF), dendritic cells (DC), myeloid suppressor cells (MSC), neutrophils (NF), mast cells, natural killer cells (NK), T- and B-lymphocytes, cancer-associated fibroblasts (CAF) and endothelial cells. The interaction between tumour cells, myeloid cells and lymphocytes is a dynamic, bidirectional process and includes intercellular contacts, constant exchange of secreted soluble molecules, factors, vesicles, due to which an autonomous system is established that regulates tumour growth [1-5].

Neoplastic progression is associated with lack of oxygen, deficiency of nutrients causing hypoxia and development of metabolic acidosis in the tumour microenvironment. These factors promote selection of tumour cells with the gene mutations that allow them to survive under more severe microenvironmental conditions. Such adaptation of tumour cells is accompanied by increased production of various growth factors, cytokines, chemokines, which together present a triggering factor for enhancement of angiogenesis, metastases, and inhibition of local immune response. In turn, the normal TME cells also begin to secrete factors promoting tumour progression. As a result, a closed-circuit regulatory system is formed [6]. E.g., the content of IL-4 increases in TME, thus inducing differentiation of macrophages to the second-type (M2) resident cells. The M2 subpopulation may account for up to 50 % of the tumour mass and contribute to activation of pro-tumourigenic processes accompanied by the synthesis of IL-1, IL-1RA, IL-4, IL-6, IL-10, IL-12, L-arginine, prostaglandin E2, TNF-α, TGF-β, VEGF-A, and a variety of chemokines and their receptors CCL1, CCL5, CCL17, CCL22, CCL24, CCR2, CXCL10, CXCL16 [7-9]. These mediators are involved in angiogenesis, immunosuppression, and metastasis.

In tumour cells, increased production of some amino acid metabolism enzymes is revealed, e.g., of indolamine 2,3-dioxygenase, arginase-1. Activation of iNOS, as well as STAT3 transcription factor is noted, thereby initiating the differentiation of dendritic cells into tolerogenic tumour-associated dendritic cells (TADC) [10]. These cells produce TGF-β which promotes immunosuppression by stimulating Th2, Th17 and T regulatory cells [11].

Of interest, differentiation of neutrophils in the TME structures depends on the stage of the disease. Thus, the normally pro-inflammatory neutrophils differentiate at later phase to an immunosuppressive phenotype under the influence of TGF-β and angiotensin II [12]. The tumour-associated neutrophils synthesise collagenase IV, heparanase, elastase and matrix metalloproteinases (MMPs) which contribute to extracellular matrix degradation, tumour cell invasion and metastasis. The secreted proteinases destroy extracellular matrix, and degrade the pro-inflammatory cytokines, thus causing anti-inflammatory effects [13]. Neutrophils also produce oncostatin M, which enhances angiogenesis, as well as CXCL1, CXCL8, CCL-3, CXCL6, TGF-β, and prostaglandin E2 synthesis, thus supporting the neoplastic progression [14].

The CSF-1, HIF-1α, CCL2, CCL7, CXCL1 peptide factors synthesised by the TME cell populations are able to alter the metabolism of myeloid cells, leading to transition to MSC [15]. MSC enhance the synthesis of reactive oxygen species, arginase-1, prostaglandin E2, IL-4, IL-6, inhibit the function of T-lymphocytes [16], support the stemness of tumour cells [17], increase angiogenesis and metastasis [18]. It should be noted that MSC create background for spreading the tumour not only locally, but also to the target organ, inducing expression of adhesion molecules on the surface of endotheliocytes, e.g., E-selectin, intercellular adhesion molecules 1 (ICAM-1), and vascular cell adhesion molecules 1 (VCAM-1), promoting residence of tumour cells in the target organ [19].

M2 macrophages and MSCs are the main producers of IL-1β, which initiates a whole spectrum of procarcinogenic effects [20–23]. IL-1β provides both direct and indirect effects upon angiogenesis, by inducing the synthesis of various cytokines and angiogenesis factors [24]. Direct effects of IL-1β include activation of FGF-β expression in endothelial cells [24], VEGF-A and its receptors [25], regulation of endothelial progenitor cells, thus contributing to neovascularisation [25]. IL-1β also affects Bv8, CCL2, and CCL3 secretion, leading to (i) enhanced synthesis of VEGF-A, PLGF, bFGF by endothelial cells, (ii) VEGF-A secretion by myeloid cells (CD34+ or Flk-1+) [26], (iii) FGF1 secretion by mononuclear cells [27], (iv) IL-8 secretion by macrophages [28]. In general, IL-1β may affect cell differentiation, causing synthesis of either pro-inflammatory, or angiogenetic factors [28]. Immunosuppressive effect of IL-1β proceeds via stimulated synthesis of anti-inflammatory factors (IL-10, TGF-β, arginase-1) by tumour-associated macrophages and MSCs. This effect results into suppression of T cell and M1 activities [28], and the non-canonical signalling pathway of the NF-κB transcription factor is triggered, thus, in turn, suppressing antitumour immunity of T-regulatory cells [29]. The effect of IL-1β was shown to be associated with PD-L1 overexpression, an additional factor of immunity inhibition [29].

The role of immune cells in TME may be either to suppress tumour growth (antitumour TME), or to promote tumour growth (immunosuppressive TME). Thus, depending on the TME factors and type of malignancy, the immune cells may exert pro- or antitumour effects (Fig. 1) [30].

Figure 1. Influence of various immune cell populations upon TME

Abbreviations: NK, natural killers; Neu, neutrophils; MI, type I macrophages; DC, dendritic cells.

Cancer-associated fibroblasts (CAF) synthesise factor(s) inducing differentiation of macrophages to M2 and depletion of CD8+ T cells, which also stimulates proliferation, invasion and metastasis of tumour cells [31]. Along with cytokine production, tumour cells may activate pro-tumourigenic processes, due to metabolic acidosis in the extracellular matrix. E.g., acidification of extracellular matrix triggers p53-dependent apoptosis of surrounding cells and degradation of the basement membrane [32], along with increased secretion of cathepsin B, metalloproteinases, urokinase plasminogen activator, hydrolysing components of the extracellular matrix [33]. Also, acidification of extracellular matrix alters the lysosomal distribution, thus further enhancing secretion of proteinases causing destruction of extracellular matrix [34] and disruption of intercellular adhesion contacts by degradation of E-cadherin [35].

Several studies suggest acidosis to be a factor of immune therapy efficiency, as shown in murine models of melanoma and pancreatic adenocarcinoma, where the increased TME acidity correlated with inhibited antitumour T cell-mediated immunity, associated with lower efficacy of immune drugs [36, 37].

Increased acidity of TME leads to decreased efficiency of anticancer drugs, due to decreased transfer of drugs into the cells. For example, anthracyclines (doxorubicin), anthraquinones and alkaloids are weak bases and require optimal pH range (7.5-9.5) for their transmembrane transport [38-40]. Under these conditions, activity of a well-known glycoprotein transporter (pGP) is enhanced, thus promoting efflux of anticancer drugs from malignant cells. This effect was observed in tumour cells adapted for low extracellular pH, with acquired TP53 gene mutations [41–43]. These adaptive processes cause multidrug resistance and limit the choice of therapeutic options.

Hence, malignant cells may stimulate differentiation of tumour-associated immune cells to immunosuppressive phenotypes by synthesising a wide range of signalling molecules. In turn, these immune cells produce anti-inflammatory factors, growth factors, proteinases, enhance expression of adhesion molecules, causing invasion and metastasis of tumours, activation of angiogenesis. TME acidification is not only a factor leading to selection of the most resistant and aggressive tumour phenotypes, but it also induces destruction of intercellular contacts and extracellular matrix, which ultimately triggers the processes of invasion and metastasis.

Mutual influence of tumour cells and normal TME populations promotes development of cell associations, and their extracellular milieu protects from external impacts, e.g., anticancer therapy, immune surveillance. Even a small number of tumour cells forms a microenvironment resistant to antitumour therapy, especially if they are represented by stem or ‘dormant’ cells. Hence, a prevalence of the distinct component of the cellular microenvironment presumes differentiated approach to treatment. The strategic purpose in oncology is to transform cancer into a long-term chronic disease which is well controlled by the low-toxicity approaches. To implement this task, three areas of research could be highlighted: (i) a search for specific key target molecules, in order to create targeted drugs; (ii) personalisation of treatment programs based on molecular and cellular characteristics of the tumour, and individual clinical prognosis; (iii) use of nanomaterials when creating novel drugs, thus providing higher efficiency of treatment. The latter approach may increase concentrations of active substances in the tumour foci and reduce the drug toxicity. Long-term studies provide convincing evidence that carcinogenesis is a multistage multicomponent process, including disturbances of apoptosis, proliferation, angiogenesis and cell metabolism leading to the formation of altered pathological microenvironment.

Multimodality of carcinogenesis requires usage of combined treatment methods aimed at different molecular targets. In the past ten years, a series of nanomaterials has been developed in various laboratories around the world that have great potential for therapeutic use in oncology, e.g., liposomes, polymer carriers, carbon nanoparticles, iron oxide and gold nanoparticles. Currently, there is a technical opportunity of creating structures that would deliver active substances to the target cells and undergo biodegradation. However, the mentioned nanocarriers have a number of disadvantages. Liposomes, polymers, dendrimers can provide a significant decrease in overall toxicity of cytotoxic drugs, but they have a low potential in terms of targeted delivery. Carbon nanomaterials make it possible to create multicomponent and multitarget therapeutic constructs. Graphene and its derivatives are considered the most promising carbon nanomaterials for these purposes.

Current experience with graphene carriers

Initial experiments with unmodified graphene demonstrated its systemic toxicity [44,45] associated with accumulation in lungs [46], reticuloendothelial system including liver and spleen [47, 48] and provoking an inflammatory response [49]. Recent studies have shown that modified graphene oxide is promising for manipulating the tumour microenvironment; however, an analysis of the literature suggests that research in this area has just begun. For example, the use of graphene oxide functionalised with polyethylene glycol (GO-PEG) in photodynamic therapy led to a decrease in the interleukin-4-dependent polarisation of M2 in macrophages of the tumour microenvironment. The antitumour action of GO-PEG was to reduce the migration and invasion of subcutaneous osteosarcoma cells in mice [50]. In [51], the combined effect of low-frequency ultrasound therapy and graphene oxide-doxorubicin (GO-DOX) conjugate on local damage to endothelial cells lining the neovascular network was shown. This effect increased the penetration of the GO-DOX conjugate into the interstitial space of mouse liver carcinoma through damaged capillaries. Over past few years, a series of works was published at the Department of General and Bioorganic Chemistry (Pavlov University, St. Petersburg) which demonstrated an opportunity of reducing toxicity to acceptable level, due to functionalisation of the graphene carrier [52-54]. Moreover, the graphene-based nanomaterials (GBN) have been shown to have a number of advantages: stimulation of immune response, inhibition of tumour stem cells, regulation of angiogenesis and hypoxia [55]. In particular, it should be noted that the GBNs exhibit photodynamic and photothermal activity, and can be effectively used as nanoplatforms for targeted delivery of cytostatic drugs.

Figure 2. General structure of graphene oxide

Graphene is known to consist of sp²-hybridised carbon atoms forming two-dimensional nanolayers, while graphene oxide (GO) contains various oxygen-containing oxygen functional groups: (i) carboxyl, carbonyl, and lactol, located at the edges of GO layers; (ii) epoxy and hydroxyl groups distributed on the surface of the GO plane [56-61] (Fig. 2). Reduced GO (rGO) is a variant of GO in which most of the oxygen-containing functional groups are reduced by means of hydrazine hydrate or biomolecules [54, 62].

A graphene monolayer was obtained in 2004 by A. Geim and K. Novoselov [63], while GO was first synthesised in 1859 by B. Brodie by oxidising graphite using a mixture of oxidising agents (potassium chlorate and fuming nitric acid) [64]. However, the most effective method was developed by W. Hammers and R. Offeman in 1957, with a mixture of sulphuric acid, sodium nitrate and potassium permanganate [65]. GO functionalisation can be carried out using various reactions (Fig. 3): amidation, esterification, 1,3-dipolar cycloaddition, halogenation, as well as through non-covalent functionalisation through the formation of hydrogen bonds, π-π stacking and hydrophobic interactions. These reactions make it possible to obtain unique nanomaterials having a medical potential in cancer treatment [66], delivery of drugs and biomolecules [67, 68], development of biosensors [69], as well as substances with antiviral [70], antibacterial [71] and antifungal activity [72]. Among GBN, GO has the greatest potential for use in medicine for the following reasons: (i) GO contains various functional groups that allow further surface functionalisation; (ii) functionalisation of GO increases its biocompatibility; (iii) the presence of oxygen-containing functional groups ensures stability of aqueous GO dispersions.

Figure 3. Basic ways to functionalise graphene oxide

Analysis of the literature revealed a number of research works devoted to synthesis and biological activity of GBN-based conjugates. Zhang et al. [73] reported that covalent GO functionalisation with sulphonic acid and folic acid (GO-SO3H-FA) groups increased the specific cytotoxicity for MCF-7 cells (breast cancer-derived strain). Conjugation of doxorubicin (DOX) and camptothecin (CPT) with GO through its non-covalent functionalisation (due to π-π stacking and hydrophobic interactions) significantly increases therapeutic efficacy as compared to individual drugs. The CPT and DOX loading in the mixed GO-SO₃H-FA-CPT-DOX conjugate was 4.5% and 400%, respectively.

Wang et al. [67] demonstrated that covalent functionalisation of GO with chlorotoxin (CTX) increases the efficiency of drug delivery to C6 glioma cells. At the same time, non-covalent DOX attachment with a loading of 570 mg DOX per gram of CTX-GO significantly increases efficiency of the conjugate (the release of the cytostatic drug was pH-dependent). Fan et al. [74] synthesised a covalent GO-based conjugate with adipic acid dihydrazide and sodium alginate (SA). Then, DOX.HCl was attached non-covalently to GO-SA. The maximum DOX loading was 1.8 mg per 1 mg GO-SA. The highest drug release rate was observed at pH 5.0. Cytotoxicity testing with HeLa (cervical carcinoma) cell line showed that the GO-SA conjugate is not cytotoxic, while GO-SA/DOX exhibits cytotoxicity due to the specific effect on CD44 receptors.

Qin et al. [75] synthesised GO non-covalently conjugated with polyvinylpyrrolidone (PVP, M=30 kDa), and then folic acid (FA) was covalently attached through the formation of an amide bond (carboxyl groups of GO and amino groups of FA). Next, the authors performed non-covalent DOX loading (due to π-π stacking and hydrophobic interactions).

The calculated value of the DOX loading on the FA-GO-PVP was 107.5 wt. %. The resulting conjugate demonstrated high antitumour efficacy against HeLa cells. Huang et al. [76] described the ability of FA-functionalised GO to efficiently bind the chlorine e₆ photosensitiser for photodynamic therapy. Tiwari et al. [77] used the GO-PVP noncovalent conjugate for double noncovalent addition of quercetin (QS) and gefitinib (GF) and compared it with the GO-PVP-QS and GO-PVP-GF conjugates. The authors found that the combined loading of the drugs showed higher cytotoxicity against PA-1 (ovarian cancer) cell line compared to individual drugs. The amount of QS and GF in GO-PVP-QS-GF was 20% and 46%, respectively.

Deb et al. [78] functionalised GO with polyethylene glycol (PEG), FA, and CPT via non-covalent π-π stacking interactions (CPT loading was 45%). The resulting conjugate (C=100 μg∙ml⁻¹) caused the death of 76% of cells compared with the control when using the MCF-7 cell line [78]. The same group functionalised GO with the natural polymer chitosan (CS) and FA, to deliver CPT and 3,3’-diindolylme- thane (DIM). The resulting conjugate (GO-CS-FA-CPT-DIM) demonstrated high cytotoxicity against the MCF-7 cell line (95.7% decrease in cell viability), which was significantly higher compared to individual DIM preparations (42.4%) and CPT (52.6%) [79]. Pei et al. [80] showed that simultaneous functionalisation of the GO surface with PEG (pGO) (pGO-CP-DOX, mass ratio: 1: 0.376: 0.376) with cisplatin (CP) and DOX leads to increased cytotoxicity towards Cal-27 (human squamous carcinoma) and MCF-7 cell lines. The authors observed higher inhibition of cell proliferation for the pGO-CP-DOX conjugate compared to individual preparations: IC₅₀ (MCF-7)=14.5 μg∙ml⁻¹ for pGO-CP-DOX, 22.5 μg∙ml⁻¹ for pGO-DOX, and 22 μg∙ml⁻¹ for pGO-CP [80]. Bullo et al. [81] demonstrated the ability of GO functionalisation using PEG, FA, and anticancer drugs: protocatechuic acid (23.5% PCA) and chlorogenic acid (18.3% CA). The authors investigated the effect of the GO-PEG-FA-PCA-CA conjugate on the HT29 (colon cancer) and HepG2 (liver cancer) cell lines. Cytotoxicity trials showed the following results: IC₅₀ (HT29)=50.7 μg∙ml⁻¹, IC₅₀ (HepG2)=40.4 μg∙ml⁻¹ [81]. Gong et al. [82] demonstrated that fluorinated graphene (FG) can be used to load a mixture of DOX and CPT after CS covalent functionalisation; DOX and CPT loading were 110% and 25%, respectively. The resulting FG-CS-DOX-CPT conjugate demonstrated a 60% and 75% decrease in the viability of HeLa cells with simultaneous laser irradiation (wavelength 808 nm) [82]. Gong et al. [83] evaluated the ability of non-covalent FG conjugation with a cytostatic DOX loading as high as 200%. The FG-DOX conjugate at 30 μg∙ml⁻¹ drug content reduced HeLa cell line viability to 94% after 48 h of incubation [83].

In an in vivo study, Shim et al. [84] showed that rGO functionalised with low-molecular weight heparin (LHT7) acts as a targeted drug for the delivery of DOX. The rGO-LHT7-DOX conjugate with rGO: DOX mass ratios of 2, 1, 0.5, 0.1 demonstrated a high antitumour effect at the KB human carcinoma cell line (cell viability was decreased by 61.1%), along with significant decrease in tumour size by (92.5±3.1)% [84]. Table 1 shows the results of studying cytotoxic conjugates based on GBN and cytostatic drugs.

Table 1. Cytotoxicity of GBN and non-covalently linked cytostatic drugs

Conclusion

Current data provide sufficient results concerning molecular and cellular events providing mutual influence of tumour cells and TME cells, as well as factors of cancer progression. It has been shown that the tumour cells per se and their cellular TME create an integrated system that promotes tumour progression and development of multiple drug resistance.

Thus, the following requirements must be met for modern therapeutic agents: targeted action, polyfunctionality with respect to ability of loading various molecules on the GBN surface, low toxicity, opportunity of selective inactivation of immunosuppressive components in the TME. The last issue deserves special attention. The chance to resolve this complex problem is shown by the example of GBN usage.

List of abbreviations

IL – interleukin
TNF-α – tumour necrosis factor alpha
TGF-β1 – transforming growth factor receptor-β1
VEGF-A – vascular endothelial growth factor A
CAF – cancer-associated fibroblasts
CCL – C-C motif ligand
CCR2 – C-C chemokine receptor type 2
CPT – camptothecin
CSF-1 – the colony stimulating factor 1
CTX – chlorotoxin
CXCL – the chemokine (C-X-C motif) ligand
DOX – doxorubicin
FA – folic acid
GBN – graphene-based nanomaterials
GO – graphene oxide
iNOS – Inducible nitric oxide synthase
bFGF – basic fibroblast growth factor
FGF1 – fibroblast growth factor 1
HIF-1α – hypoxia inducible factor 1 subunit alpha
PD-L1 – ligand of programmed death-1 receptor
PLGF – placental growth factor
STAT3 – signal transducer and activator of transcription 3
Th – T helper cells
TME – tumour microenvironment

Acknowledgement

This work was financially supported by the Ministry of Health of the Russian Federation (state assignment Э.03-2021; 121040200136-0).

Conflict of interests

The authors declared no potential conflict of interest.

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Bullo S, Buskaran K, Baby R, Dorniani D, Fakurazi S, Hussein MZ. Dual drugs anticancer nanoformulation using graphene oxide-PEG as nanocarrier for protocatechuic acid and chlorogenic acid. Pharm Res. 2019; 36:91. doi: 10.1007/s11095-019-2621-8
Gong P, Zhao Q, Dai D, Zhang S, Tian Z, Sun L, et al. Functionalized ultrasmall fluorinated graphene with high NIR absorbance for controlled delivery of mixed anticancer drugs. Chem- A Eur J. 2017; 23:17531-17541. doi: 10.1002/chem.201702917
Gong P, Du J, Wang D, Cao B, Tian M, Wang Y, et al. Fluorinated graphene as an anticancer nanocarrier: An experimental and DFT study. J Mater Chem B. 2018; 6:2769-2777. doi: 10.1039/c8tb00102b
Shim G, Kim JY, Han J, Chung SW, Lee S, Byun Y, et al. Reduced graphene oxide nanosheets coated with an anti-angiogenic anticancer low-molecular-weight heparin derivative for delivery of anticancer drugs. J Control Release. 2014; 189:80-89.
doi: 10.1016/j.jconrel.2014.06.026
Rosli NF, Fojtů M, Fisher AC, Pumera M. Graphene oxide nanoplatelets potentiate anticancer effect of cisplatin in human lung cancer cells. Langmuir. 2019; 35:3176-3182. doi: 10.1021/acs.langmuir.8b03086
Pooresmaeil M, Namazi H. β-Cyclodextrin grafted magnetic graphene oxide applicable as cancer drug delivery agent: Synthesis and characterization. Mater Chem Phys. 2018; 218:62-69. doi: 10.1016/j.matchemphys.2018.07.022
Ma N, Liu J, He W, Li Z, Luan Y, Song Y, et al. Folic acid-grafted bovine serum albumin decorated graphene oxide: An efficient drug carrier for targeted cancer therapy. J Colloid Interface Sci. 2017; 490:598-607. doi: 10.1016/j.jcis.2016.11.097
Tian J, Luo Y, Huang L, Feng Y, Ju H, Yu BY. Pegylated folate and peptide-decorated graphene oxide nanovehicle for in vivo targeted delivery of anticancer drugs and therapeutic self-monitoring. Biosens Bioelectron. 2016; 80:519-524. doi: 10.1016/j.bios.2016.02.018
Javanbakht S, Namazi H. Doxorubicin loaded carboxymethyl cellulose/graphene quantum dot nanocomposite hydrogel films as a potential anticancer drug delivery system. Mater Sci Eng C. 2018; 87:50-59. doi: 10.1016/j.msec.2018.02.010
Karki N, Tiwari H, Pal M, Chaurasia A, Bal R, Joshi P, et al. Functionalized graphene oxides for drug loading, release and delivery of poorly water soluble anticancer drug: A comparative study. Colloids Surfaces B Biointerfaces. 2018; 169:265-272.
doi: 10.1016/j.colsurfb.2018.05.022

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Introduction

Figure 1. Influence of various immune cell populations upon TME

Abbreviations: NK, natural killers; Neu, neutrophils; MI, type I macrophages; DC, dendritic cells.

Current experience with graphene carriers

Figure 2. General structure of graphene oxide

Figure 3. Basic ways to functionalise graphene oxide

Table 1. Cytotoxicity of GBN and non-covalently linked cytostatic drugs

Conclusion

List of abbreviations

Acknowledgement

This work was financially supported by the Ministry of Health of the Russian Federation (state assignment Э.03-2021; 121040200136-0).

Conflict of interests

The authors declared no potential conflict of interest.

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Pei X, Zhu Z, Gan Z, Chen J, Zhang X, Cheng X, et al. PEGylated nano-graphene oxide as a nanocarrier for delivering mixed anticancer drugs to improve anticancer activity. Sci Rep. 2020; 10:1-15. doi: 10.1038/s41598-020-59624-w
Bullo S, Buskaran K, Baby R, Dorniani D, Fakurazi S, Hussein MZ. Dual drugs anticancer nanoformulation using graphene oxide-PEG as nanocarrier for protocatechuic acid and chlorogenic acid. Pharm Res. 2019; 36:91. doi: 10.1007/s11095-019-2621-8
Gong P, Zhao Q, Dai D, Zhang S, Tian Z, Sun L, et al. Functionalized ultrasmall fluorinated graphene with high NIR absorbance for controlled delivery of mixed anticancer drugs. Chem- A Eur J. 2017; 23:17531-17541. doi: 10.1002/chem.201702917
Gong P, Du J, Wang D, Cao B, Tian M, Wang Y, et al. Fluorinated graphene as an anticancer nanocarrier: An experimental and DFT study. J Mater Chem B. 2018; 6:2769-2777. doi: 10.1039/c8tb00102b
Shim G, Kim JY, Han J, Chung SW, Lee S, Byun Y, et al. Reduced graphene oxide nanosheets coated with an anti-angiogenic anticancer low-molecular-weight heparin derivative for delivery of anticancer drugs. J Control Release. 2014; 189:80-89.
doi: 10.1016/j.jconrel.2014.06.026
Rosli NF, Fojtů M, Fisher AC, Pumera M. Graphene oxide nanoplatelets potentiate anticancer effect of cisplatin in human lung cancer cells. Langmuir. 2019; 35:3176-3182. doi: 10.1021/acs.langmuir.8b03086
Pooresmaeil M, Namazi H. β-Cyclodextrin grafted magnetic graphene oxide applicable as cancer drug delivery agent: Synthesis and characterization. Mater Chem Phys. 2018; 218:62-69. doi: 10.1016/j.matchemphys.2018.07.022
Ma N, Liu J, He W, Li Z, Luan Y, Song Y, et al. Folic acid-grafted bovine serum albumin decorated graphene oxide: An efficient drug carrier for targeted cancer therapy. J Colloid Interface Sci. 2017; 490:598-607. doi: 10.1016/j.jcis.2016.11.097
Tian J, Luo Y, Huang L, Feng Y, Ju H, Yu BY. Pegylated folate and peptide-decorated graphene oxide nanovehicle for in vivo targeted delivery of anticancer drugs and therapeutic self-monitoring. Biosens Bioelectron. 2016; 80:519-524. doi: 10.1016/j.bios.2016.02.018
Javanbakht S, Namazi H. Doxorubicin loaded carboxymethyl cellulose/graphene quantum dot nanocomposite hydrogel films as a potential anticancer drug delivery system. Mater Sci Eng C. 2018; 87:50-59. doi: 10.1016/j.msec.2018.02.010
Karki N, Tiwari H, Pal M, Chaurasia A, Bal R, Joshi P, et al. Functionalized graphene oxides for drug loading, release and delivery of poorly water soluble anticancer drug: A comparative study. Colloids Surfaces B Biointerfaces. 2018; 169:265-272.
doi: 10.1016/j.colsurfb.2018.05.022

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Малкова1,2, Сергей В. Агеев1,2, Абделсаттар О. Е. Абделхалим2,3, Олег Е. Молчанов4, Дмитрий Н. Майстренко4, Константин Н. Семенов1,2,4, Владимир В. Шаройко1,2,4" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(364) "

Анна М. Малкова^1,2, Сергей В. Агеев^1,2, Абделсаттар О. Е. Абделхалим^2,3, Олег Е. Молчанов⁴, Дмитрий Н. Майстренко⁴, Константин Н. Семенов^1,2,4, Владимир В. Шаройко^1,2,4

" ["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) "28396" ["VALUE"]=> array(2) { ["TEXT"]=> string(976) "1 Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия 2 Институт химии, Санкт-Петербургский государственный университет, Санкт-Петербург, Россия 3 Отдел исследования окружающей среды, Национальный центр социальных и криминологических исследований, Гиза, Арабская Республика Египет 4 Российский научный центр радиологии и хирургических технологий имени A. M. Гранова, Санкт-Петербург, Россия" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(898) "

¹ Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова, Санкт-Петербург, Россия
² Институт химии, Санкт-Петербургский государственный университет, Санкт-Петербург, Россия
³ Отдел исследования окружающей среды, Национальный центр социальных и криминологических исследований, Гиза, Арабская Республика Египет
⁴ Российский научный центр радиологии и хирургических технологий имени A. M. Гранова, Санкт-Петербург, Россия

Развитие и прогрессирование неоплазий происходит одновременно с изменениями окружающей стромы. Раковые клетки могут функционально формировать свое микроокружение за счет секреции различных цитокинов, хемокинов и формирования кислой среды. Данные факторы способствуют дифференциации иммунных клеток по иммуносупрессивному фенотипу, стимулируют синтез ряда ферментов обмена аминокислот, факторов роста, молекул адгезии, что промотирует инвазию, ангиогенез и метастазирование, а также снижает эффективность действия противоопухолевых препаратов и лучевой терапии. Для повышения эффективности химиотерапии возможно использование мультитаргетных углеродных наноматериалов. В частности, наноматериалы на основе модифицированного графена позволяют создавать многокомпонентные терапевтические конструкции, включающие макромолекулы, полимеры и эффекторные агенты. Первоначальные эксперименты с немодифицированными графенами продемонстрировали их токсичность, связанную с их накоплением в паренхиматозных органах и инициированием воспалительных процессов. В последние несколько лет вышла серия работ, в которых продемонстрирована возможность снижения токсичности оксида графена за счет функционализации. В данном обзоре обобщены экспериментальные данные по созданию ковалентных и нековалентных конъюгатов на основе оксида графена и показана их эффективность in vitro на различных опухолевых клеточных линиях. Отдельно представлены немногочисленные данные по влиянию наноматериалов на основе оксида графена на опухолевое микроокружение.

Ключевые слова

Опухоль, микроокружение, прогрессирование, цитокины, ацидоз, иммунная система, углеродные наноматериалы.

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Anna M. Malkova^1,2, Sergei V. Ageev^1,2, Abdelsattar O. E. Abdelhalim^2,3, Oleg E. Molchanov⁴, Dmitrii N. Maistrenko 4, Konstantin N. Semenov^1,2,4, Vladimir V. Sharoyko^1,2,4

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¹ Pavlov University, St. Petersburg, Russia
² Institute of Chemistry, St. Petersburg State University, Saint Petersburg, Russia
³ National Center for Social and Criminological Research, Giza, Arab Republic of Egypt
⁴ A. M. Granov Russian Research Centre for Radiology and Surgical Technologies, St. Petersburg, Russia

Correspondence:
Dr. Vladimir V. Sharoyko, Pavlov University, 6-8 L. Tolstoy St., 197022, St. Petersburg, Russia
Phone: +7 (981) 936-41-51
E-mail: sharoyko@gmail.com

Citation: Malkova AM, Ageev SV, Abdelhalim AOE et al. Mutual influence of malignant cells and cellular microenvironment: prospects for manipulating tumour microenvironment with nanomaterials. Cell Ther Transplant 2021; 10(3-4): 8-18.

Development and progression of neoplasia occurs in parallel with changes in the surrounding stroma. Cancer cells may functionally reshape their microenvironment by secreting various cytokines, chemokines and generation of acidic medium. These factors contribute to differentiation of immune cells into immunosuppressive phenotype, stimulate the synthesis of a number of amino acid metabolism enzymes, growth factors, adhesion molecules, which promote invasion, angiogenesis and metastasis, and also reduce efficiency of anticancer drugs and radiation therapy. To increase effectiveness of the chemotherapy, multitargeted carbon nanomaterials may be applied. In particular, nanomaterials based on modified graphene make it possible to create multicomponent therapeutic constructs, including macromolecules, polymers, and effector agents. Initial experiments with unmodified graphenes demonstrated their toxicity associated with their accumulation in parenchymal organs and initiation of inflammatory processes. In the past few years, a series of works has been published in which the possibility of reducing the toxicity of graphene oxide through functionalisation has been demonstrated. This review summarises the experimental data on the creation of covalent and non-covalent conjugates based on graphene oxide and demonstrates their in vitro efficacy on various tumour cell lines. Separately, there are few data on the effect of nanomaterials based on graphene oxide on the tumour microenvironment.

Keywords

Tumour, microenvironment, progression, cytokines, acidosis, immune system, carbon nanomaterials.

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Malkova1,2, Sergei V. Ageev1,2, Abdelsattar O. E. Abdelhalim2,3, Oleg E. Molchanov4, Dmitrii N. Maistrenko 4, Konstantin N. Semenov1,2,4, Vladimir V. Sharoyko1,2,4" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(244) "

Anna M. Malkova^1,2, Sergei V. Ageev^1,2, Abdelsattar O. E. Abdelhalim^2,3, Oleg E. Molchanov⁴, Dmitrii N. Maistrenko 4, Konstantin N. Semenov^1,2,4, Vladimir V. Sharoyko^1,2,4

Keywords

Tumour, microenvironment, progression, cytokines, acidosis, immune system, carbon nanomaterials.

Keywords

Tumour, microenvironment, progression, cytokines, acidosis, immune system, carbon nanomaterials.

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Correspondence:
Dr. Vladimir V. Sharoyko, Pavlov University, 6-8 L. Tolstoy St., 197022, St. Petersburg, Russia
Phone: +7 (981) 936-41-51
E-mail: sharoyko@gmail.com

Ключевые слова

Опухоль, микроокружение, прогрессирование, цитокины, ацидоз, иммунная система, углеродные наноматериалы.

Ключевые слова

Опухоль, микроокружение, прогрессирование, цитокины, ацидоз, иммунная система, углеродные наноматериалы.

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Introduction

Systemic light chain (AL) amyloidosis is a form of plasma cell disorders, characterized by overproduction of immunoglobulin light chains by clonal plasma cells (PS) or lymphocytes and their deposition in organs and tissues in the form of an insoluble fibrillar protein-amyloid. Cardiac involvement is the main predictor of patient outcome. The goal of therapy is to rapidly and profoundly suppress production of amyloidogenic light chains [1-2].

Autologous hematopoietic stem cell transplantation (ASCT) has been used in the treatment of systemic AL amyloidosis since 1994. Long-term follow-up demonstrate 15-year overall survival in 50% of patients who achieved complete hematological response (CR) after ASCT [3-4]. However, 80% of patients with newly diagnosed systemic AL amyloidosis are ineligible for ASCT.

For a long time, oral melphalan and dexamethasone (MDex) were considered a standard of care in AL amyloidosis, but the addition of proteasome inhibitor- bortezomib, significantly increased the efficacy of treatment [5]. However, bortezomib, cyclophosphamide and dexamethasone (CyBorD) regime currently is the standard of care for newly diagnosed patients. According to a large European retrospective study, the frequency of hematological response (HR) on CyBorD regime is 65%, cardiac response – 33%, renal response –15%, median overall survival (OS) was 72 months [6-8].

Despite higher frequency of clinical responses, the addition of bortezomib did not improve prognosis in the patients with IIIb heart stage, according to the Mayo Clinic classification (NT-proBNP >8500 ng/l), and 40% of these patients still die within 6 months after the diagnosis. Therefore, the question of the optimal regimens for these patients is still open.

Patients and methods

We analyzed the response to induction therapy in 105 newly diagnosed patients with systemic AL amyloidosis, treated at RM Gorbacheva Research Institute within a period from 2004 to 2021 [6]. All the patients signed informed consent for the use of personal data for research purposes. Their median age was 63 years (31-81). The percentage of men and women was 53% and 47%, respectively. Isolated AL amyloidosis was documented in 72% (n=76) of cases; in combination with multiple myeloma, in 27% (n=29). At the time of diagnosis, 62% of patients had three or more organs involved. The incidence of organ involvement was as follows: kidneys, 88% (n=93); heart, 87% (n=92); liver, 40% (n=43); nervous system, 48% (n=51); gastrointestinal tract, (GIT) 27% (n=29); lungs, 11% (n=12), and other organs (thyroid gland, lymph nodes, adrenal glands, etc.), 20% (n=21). In the patients with established Mayo stage, the following distribution was observed: stage I, 22% (n=20); stage II, 52% (n=47); stage III, 26% (n=24). The median NT-proBNP level was 1892 ng/l (35 to 34772), 15 patients had IIIb stage (NT-proBNP >8500 ng/l). Renal involvement was documented in 94 patients at the following severity distribution: stage I, 23% (n=22); stage II, 48% (n=45); stage III, 29% (n=27).

In our study, we assessed the efficacy of CyBorD compared with other treatment regimens. All consecutive patients were divided into 3 groups: group 1 was treated with CyBorD (26%, n=28); group 2 received other bortezomib-based regimens (bortezomib/dexamethasone (VD), bortezomib/melphalan/dexamethasone (BMDex)), 59% (n=62); group 3 included bortezomib-free regimens (melphalan/dexamethasone (MDex), cyclophosphamide/prednisolone, corticosteroids), 14% (n=15). Patients with autologous ASCT were excluded. The median number of therapeutic rounds in all groups was 4. The main patients’ characteristics are presented in Table 1.

Table 1. Patients characteristics

Clinical definitions

Hematological response (HR) evaluation was based on serum and urine immunofixation and determination of the level of free light chains (FLC) by nephelometry. Complete remission (CR) definition included negative serum and urine immunofixation and normal FLC ratio, very good partial response (VGPR) was based on difference between involved and uninvolved concentrations of free light chains (dFLС) <40 mg/L. Partial response (PR) was defined as a decrease of dFLC by >50%. Organ response was evaluated by changes in biomarkers: NT-proBNP for the heart, proteinuria for the kidney and alkaline phosphatase for the liver. Relapse or progression was defined as loss of previously achieved response, or organ progression, or increase in dFLС by 50% from the best response.

Statistical analysis

Descriptive statistics was used for the patient data evaluation. Chi-square test was used to compare response between the groups. Kaplan-Meier method and log-rank test was used to compare survival estimates. Cumulative incidence estimates were used to evaluate hematologic and organ responses. Gray’s test was applied to compare cumulative incidences between the groups. All the survival and cumulative incidence parameters were calculated from the date of systemic therapy initiation. For progression-free survival, the outcome measures were death or hematological relapse/progressive disease. Relapse/progressive disease were considered a competing risk for organ response. Multivariate analysis was done with proportional hazard analysis for survival estimates and Fyne-Gray regression for cumulative incidences. Variables with significance of <0.015 were selected for multivariate analysis.

Results

The 3-year OS was 70.3% (95% СI 61-80), the median follow-up was 27.8 months (22 days to 11 years). In the univariate analysis, unfavorable factors for OS were as follows: age over 70 years (p=0.007); male gender (p=0.015, 64% versus 86%); Mayo stage IIIb [OS was 48% (95% CI 21-75) vs 60% (95% CI 25-95) vs 72% (95% CI 59-85), and 79% (95% CI 58-100) in comparison with Mayo stages IIIа, II and I, respectively (p=0.07)]; renal injury stage III [65% (95% CI 46-84) vs 73% (95% CI 54-92) vs 79% (95% CI 68-90) compared with stages I and II, respectively, p<0.0001]. Improved 3-year OS was documented in the presence of hematological response [91% (95% CI 83-99) vs 40% (95% CI 25-54), p<0.001] (Figure 1B) and organ responses [93% (95% CI 86-100) vs 55% (95% CI 38-72), p=0.0003] in patients with cardiac response vs non-responders, [92% (95% CI 85-99) vs 77% (95% CI 60-94), p<0.0001, and 100% vs 33% (95% CI 4-62), p=0.0002 in the patients with renal and liver responses, respectively. Assessment of overall survival risk factors is presented in Table 2.

Table 2. Risk factors assessment for 3-year overall survival

Notes: NS, nervous system; GIT, gastrointestinal tract

Figure 1. Kinetics of hematologic and organ responses in the study group (A). Impact of hematologic response on overall survival (B)

The 3-year OS in CyBorD group was 95% (95% CI 85-99) versus 85% (95% CI 73-97) in other bortezomib-containing regimens, and 63% (95% CI 44-82) in non-bortezomib regimens (p=0.0337). In the multivariate analysis, when corrected for other confounding factors, any treatment except CyBorD was associated with worse 3-year OS (HR 4.9, 95% CI 1.4-17.2, p=0.012). Other factors which impacted the survival were: bone marrow plasma cell (BMPC) counts >2.5% (HR 0.2, 95% CI 0.1-0.5, p=0.0002), and NtproBNP levels >2500 ng/l OS (HR 4.6, 95% CI 1.0-20.6, p=0.04, Figure 2A).

The 3-year progression-free survival (PFS) in CyBorD group was 79% (95%CI 63-95), versus 48% (95%CI 35-61) in group 2, and 55% (95%CI 30-80) in group 3 (p=0.28).

Overall response rate (ORR) was 70% (n=74), and median time to HR was 10.3 (9-14.6) months.

Figure 2. Forest plot of multivariate analyses of 3-year overall survival (A), and hematological response (B)

The percentage of patients who had HR was significantly higher in the CyBoRD group, 94% (95% CI 84-99) vs 84% in group 2 (95% CI 73-95), and 63% in group 3 (95% CI 26-100), p=0.033. The HR was achieved earlier at the bortezomib-containing regimens, with median time to response of 9.6 (5.3-15), and 10 (7.7-12.4) months in groups 1 and 2 vs 32.7 (6.4-32.7) months in group 3.

Figure 3. Summary of the best hematologic responses according to the study groups

Group 1: CyBorD; group 2: other bortezomib-containing regimens; group 3: non-bortezomib treatments.
Abbreviations: Partial response (PR); Very good partial response (VGPR); Complete response (CR)

The frequency of CR was comparable between the groups: 52% (11/21), 76% (30/39) and 60% (3/5). VGPR was achieved in 19% (4/21), 8% (3/39), 20% (1/5) and PR 28% (6/21), 15% (6/39), 20% (1/5), in groups 1, 2 and 3 respectively (Fig. 3, p>0.05).

In the univariate analysis, gender, age, number of affected organs, presence of multiple myeloma did not affect frequency of hematological remission. Surprisingly, in the multivariate analysis, the cumulative HR incidence was significantly lower in patients with the presence of PC >2.5% (HR 0.67, 95%CI 0.54-0.83, p=0.0002) and it was the only significant factor (Fig. 2B).

The organ response (OR) was assessed over a 3-year period from the start of therapy (Fig. 1A). Assessment of heart response by cardiac biomarkers was possible in 77 patients (23, 45 and 9 patients in groups 1, 2, and 3, respectively). Cardiac responses were observed in 38 (49%) cases. The median time to response was 19.3 (12.8-70) months.

The percentage of cardiac responses was higher in CyBorD group, i.e., 78% (95% CI 59-97) vs 55% (95% CI 36-74) and 16 % (95% CI 16-44), in groups 2 and 3, respectively (p=0.050). In CyBorD group, the time to cardiac response was also shorter: 13 months versus 36 months versus not reached (p=0.050).

Renal responses were observed in 46 (63%) of 73 patients with median time to response 12 (9.5-18.3) months. The frequency of responses in groups 1, 2 and 3 was the following: 90% (95% СI 73-99), 92% (95% СI 81-99, and 57% (95% СI 22-92), p=0.01. The shortest median time to response was also in CyBorD group, i.e., 7 (2.7-11.9) vs 16.5 (10-29) months in group 2. For the group 3, median response was not reached at 3-year interval. Liver responses were documented in 11 (45%) of 24 patients, median time to response was 25.5 (13.3-70.7) months. The frequency of response in groups 1, 2 and 3 was 40% (95% CI 40-81), 77% (95% CI 42-99) and 100%, p=0.084. The median time to liver response was comparable among groups.

Discussion

According to the previous studies, overall response rate (ORR) to bortezomib-based treatment varies from 60% to 94%, and CR rates vary from 23% to 71%. Multicenter retrospective European study included 230 AL amyloidosis patients, and concluded that upfront CyBorD was unable to overcome poor outcomes in Mayo stage III patients, with median OS of 4.6 months. Also, long-term organ responses are rarely reported for bortezomib-based treatments [7].

A recent prospective observational study data, with 915 systemic AL amyloidosis patients, showed that upfront bortezomib confers durable hematologic responses [9]. The main goal of this study was to assess the impact of deep HR upon the patients’ outcomes. A dFLC <10 mg/L was evaluated as а new predictor of response depth ("stringent dFLC response"). All the patients were treated with bortezomib, and it was CyBorD regimen in 94.9% of cases. The median age, gender, number of therapy courses was comparable to our group of patients. The only difference was higher percentage of patients with stage III heart disease (50%), while percentage of patients with stage IIIb was comparable to our study (13%). In this retrospective study, median OS was 72 months. Overall response rate was 65%, with 49% of deep responses (CR, VGPR, stringent dFLC responses). Median time to next treatment (TNT) was not reached, and 55% had not proceeded to further treatment at 7 years [9]. Patients with stringent dFLC responses had significantly better OS and TNT and impressive organ responses than did those with lesser responses. The incidence of cardiac response was 61% compared to 45% with lesser responses (p=0.005).

Therefore, achievement of a stringent dFLC response may be a potential new therapy goal in AL. Our results are comparable to published data, and show a highly frequent HR, organ responses and improvement in OS with bortezomib-based treatments. Of note, like in the other studies [6, 10], we demonstrated that CyBorD was superior to other bortezomib-containing regimens not only in terms of time to organ response and probability of such response, but also for OS. Nonetheless, patients with IIIb stage still have a significantly lower OS.

The main limitation of our study were the absence of FLC analysis and cardiac biomarkers in some patients at the time of diagnosis and at the moment of data evaluation thus complicating the Mayo stage assessment, depth of hematological response and heart response, and could explain statistical insignificance for some comparisons.

However, absence of effective second-line treatments for a long time limited practical applications of the response criteria. Recent advances with introduction of daratumumab make the evaluation of response crucial for the prognosis and planning of therapies. According to the ANDROMEDA study, addition of daratumumab to the CyBorD regimen increased the rate of HR and organ response. Cardiac and renal response was achieved in the first 6 months of therapy with daratumumab in 41.5% versus 22.2% and 53.0% versus 23.9%, respectively [11].

Another unusual finding of this study is a correlation between the BMPC infiltration and outcomes in patients with AL amyloidosis. Upon analysis of our subgroups, higher percentage of BMPC was a significant factor of improved OS but negative factor for HR (p=0.0002). The significance of increased BMPCs in biology of AL amyloidosis is not clear. According to the literature, the patients with more than 10% BMPC had more frequent cardiac involvement (86% vs 63%), a significantly shorter PFS time (18 vs 48 months), and reduced OS (33 months vs not reached) [13]. However, in our study the high BMPC infiltration in patients with multiple myeloma and AL amyloidosis had an opposite effect on OS survival and HR rate, probably, due to low frequency of multiple myeloma cases in the study group. The issue of amyloidosis biology with high BMPC, but without multiple myeloma, should be yet to be understood.

Conclusions

CyBorD is an effective upfront option for the patients with systemic AL amyloidosis. However, the presence of a progressive heart damage remains a predictor of early mortality in these patients. Currently, only early diagnosis can improve the outcomes of these patients, so we need a good collaboration between hematologists, general physician, cardiologists and nephrologists, to recognize the disease before advanced stages. Risk stratification and response monitoring should be based on measurements of cardiac markers and markers of hematologic response.

Appropriate treatment should begin as soon as possible with rapidly acting regimens.

Acknowledgments

The authors acknowledge the laboratories of Histopathology, Immunology, specialists in echocardiography for their help with assessment of diagnosis as well as Charity foundation "AdVita" for help in purchasing reagents for the "Freelite" testing.

The authors declare no conflicts of interest.

References

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doi: 10.1016/j.bbmt.2019.08.016
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Introduction

Patients and methods

Table 1. Patients characteristics

Clinical definitions

Statistical analysis

Results

Table 2. Risk factors assessment for 3-year overall survival

Notes: NS, nervous system; GIT, gastrointestinal tract

Figure 1. Kinetics of hematologic and organ responses in the study group (A). Impact of hematologic response on overall survival (B)

The 3-year progression-free survival (PFS) in CyBorD group was 79% (95%CI 63-95), versus 48% (95%CI 35-61) in group 2, and 55% (95%CI 30-80) in group 3 (p=0.28).

Overall response rate (ORR) was 70% (n=74), and median time to HR was 10.3 (9-14.6) months.

Figure 2. Forest plot of multivariate analyses of 3-year overall survival (A), and hematological response (B)

Figure 3. Summary of the best hematologic responses according to the study groups

Group 1: CyBorD; group 2: other bortezomib-containing regimens; group 3: non-bortezomib treatments.
Abbreviations: Partial response (PR); Very good partial response (VGPR); Complete response (CR)

Discussion

Conclusions

Appropriate treatment should begin as soon as possible with rapidly acting regimens.

Acknowledgments

The authors declare no conflicts of interest.

References

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Основная цель терапии – быстрое и глубокое подавление продукции амилоидогенных легких цепей, а поражение сердца при этом заболевании является основным предиктором выживаемости пациентов. Терапия на основе бортезомиба, циклофосфамида и дексаметазона (CyBorD) в последнее время считается стандартом лечения впервые выявленных пациентов. Однако, количество исследований режима CyBorD с оценкой долгосрочного гематологического и органного ответа ограничено. В нашем исследовании мы проанализировали ответ на индукционную терапию у 105 пациентов с впервые выявленным системным AL амилоидозом, не являющихся кандидатами на проведение аутологичной трансплантации гемопоэтических стволовых клеток (АТГСК). Вся терапия была разделена на 3 группы: 1 – CyBorD, 2 – другие схемы на основе бортезомиба и 3 группа – схемы без бортезомиба. Общая 3-х летняя выживаемость составила 70,3% с медианой наблюдения 27,8 месяцев (22 дня-11 лет). Неблагоприятными факторами в отношении прогноза при однофакторном анализе были возраст старше 70 лет (p=0,007), мужской пол (p=0,015), стадия Mayo IIIb (p=0,07) и III (p<0,0001) стадия поражения почек. В многофакторном анализе применение любых других режимов, помимо CyBorD, негативно сказывалось на показателях 3-х летней выживаемости (ОР 4,9, 95% CI 1,4-17,2, p=0,012). 3-летняя беспрогрессивная выживаемость при использовании схемы CyBorD составила 79% против 48% в группе 2, и 55% в группе 3 (p=0,28). Общая частота ответов составила 70% (n=74). Процент пациентов с гематологическим ответом был достоверно выше в группе CyBoRD, 94% против 84% и 63% в группах 2 и 3, соответственно (p=0,033), как и медиана времени до ответа (9,6, 95% ДИ 5,3-15 месяцев). Органные ответы были оценены за 3-х летний период от начала терапии. Процент кардиальных и почечных ответов так же был выше в группе CyBorD: для сердца он составил 78% против 55% и 16% (p=0,050) в 1, 2, 3 группах соответственно, а для почек 90% против 92% против 57% (p=0,01). В общей группе, гематологический (медиана 10 месяцев) и почечный ответ (медиана 12 месяцев) наблюдались раньше, чем кардиальный и печеночный ответы (медиана 26 месяцев). Наши результаты сопоставимы с ранее опубликованными данными европейских исследований и показывают высокую частоту ГО и органных ответов, улучшение общей выживаемости при использовании схемы CyBorD. Органные ответы при этом наблюдались существенно позже, чем гематологические. <h2>Ключевые слова</h2> Системный AL амилоидоз, CyBoRD, бортезомиб." 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Кудяшева, Ольга В. Пирогова, Валентина В. Порунова, Светлана В. Толстова, Анна Г. Смирнова, Иван С. Моисеев, Александр Д. Кулагин" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(251) "

Ольга В. Кудяшева, Ольга В. Пирогова, Валентина В. Порунова, Светлана В. Толстова, Анна Г. Смирнова, Иван С. Моисеев, Александр Д. Кулагин

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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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Системный амилоидоз легких цепей (AL) – одна из форм плазмоклеточных дискразий, характеризующаяся гиперпродукцией свободных легких цепей иммуноглобулинов клональными плазматическими клетками и их отложением в органах и тканях в виде нерастворимого фибриллярного белка-амилоида. Основная цель терапии – быстрое и глубокое подавление продукции амилоидогенных легких цепей, а поражение сердца при этом заболевании является основным предиктором выживаемости пациентов. Терапия на основе бортезомиба, циклофосфамида и дексаметазона (CyBorD) в последнее время считается стандартом лечения впервые выявленных пациентов. Однако, количество исследований режима CyBorD с оценкой долгосрочного гематологического и органного ответа ограничено.

В нашем исследовании мы проанализировали ответ на индукционную терапию у 105 пациентов с впервые выявленным системным AL амилоидозом, не являющихся кандидатами на проведение аутологичной трансплантации гемопоэтических стволовых клеток (АТГСК). Вся терапия была разделена на 3 группы: 1 – CyBorD, 2 – другие схемы на основе бортезомиба и 3 группа – схемы без бортезомиба.

Общая 3-х летняя выживаемость составила 70,3% с медианой наблюдения 27,8 месяцев (22 дня-11 лет). Неблагоприятными факторами в отношении прогноза при однофакторном анализе были возраст старше 70 лет (p=0,007), мужской пол (p=0,015), стадия Mayo IIIb (p=0,07) и III (p<0,0001) стадия поражения почек. В многофакторном анализе применение любых других режимов, помимо CyBorD, негативно сказывалось на показателях 3-х летней выживаемости (ОР 4,9, 95% CI 1,4-17,2, p=0,012). 3-летняя беспрогрессивная выживаемость при использовании схемы CyBorD составила 79% против 48% в группе 2, и 55% в группе 3 (p=0,28). Общая частота ответов составила 70% (n=74). Процент пациентов с гематологическим ответом был достоверно выше в группе CyBoRD, 94% против 84% и 63% в группах 2 и 3, соответственно (p=0,033), как и медиана времени до ответа (9,6, 95% ДИ 5,3-15 месяцев). Органные ответы были оценены за 3-х летний период от начала терапии. Процент кардиальных и почечных ответов так же был выше в группе CyBorD: для сердца он составил 78% против 55% и 16% (p=0,050) в 1, 2, 3 группах соответственно, а для почек 90% против 92% против 57% (p=0,01). В общей группе, гематологический (медиана 10 месяцев) и почечный ответ (медиана 12 месяцев) наблюдались раньше, чем кардиальный и печеночный ответы (медиана 26 месяцев). Наши результаты сопоставимы с ранее опубликованными данными европейских исследований и показывают высокую частоту ГО и органных ответов, улучшение общей выживаемости при использовании схемы CyBorD. Органные ответы при этом наблюдались существенно позже, чем гематологические.

Ключевые слова

Системный AL амилоидоз, CyBoRD, бортезомиб.

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Olga V. Kudyasheva, Olga V. Pirogova, Valentina V. Porunova, Svetlana V. Tolstova, Anna G. Smirnova, 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. Olga V. Kudyasheva, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, 6-8 L. Tolstoy St, 197022, St. Petersburg, Russia
E-mail: bmt.myeloma@gmail.com

Citation: Kudyasheva OV, Pirogova OV, Porunova VV. Comparison of bortesomib-based induction regimens with other treatment modalities in patients with newly diagnosed systemic light chain amyloidosis ineligible for autologous stem cell transplantation. Cell Ther Transplant 2021; 10(3-4): 38-45.

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Systemic light chain (AL) amyloidosis is a form of plasma cell disorders, characterized by overproduction of immunoglobulin light chains by clonal plasma cells and their deposition in organs and tissues as an insoluble fibrillar protein-amyloid. Suppression of amyloid production is the main goal of therapy, whereas cardiac involvement is the main predictor of survival. Therapeutic regimen containing bortezomib, cyclophosphamide and dexamethasone (CyBorD) was recently introduced as the standard of care for newly diagnosed patients. However, there are only few longitudinal comparative studies of this regimen with evaluation of organ responses.

In our study we analyzed the response to induction therapy in 105 patients with newly diagnosed patients with systemic AL amyloidosis ineligible for autologous stem cell transplantation (ASCT). All the patients were divided into three groups: group 1 received CyBorD; group 2 was treated with other bortezomib-based regimens, and group 3 received bortezomib-free regimens.

The 3-year OS was 70.3% (95% СI 61-80) with the median follow-up of 27.8 months (22 days to 11 years). Unfavorable factors for OS were as follows: age >70 years (p=0.007), male gender (p=0.015), Mayo stage IIIb (p=0.07) and renal damage stage III (p<0.0001). In the multivariate analysis, all other treatments than CyBorD were associated with decreased 3-year OS values (HR 4.9, 95% CI 1.4-17.2, p=0.012). 3-year progression-free survival (PFS) in CyBorD group was 79% (95% CI 63-95), vs 48% (95% CI 35-61) in group 2, and 55% (95% CI 30-80) in group 3 (p=0.28). Overall response rate (ORR) was 70% (n=74). The percentage of patients who showed hematological response was significantly higher in the CyBoRD group, 94% vs 84% in group 2 and 63% in group 3 (p=0.033), and median time to response in this group was 9.6 (5.3-15) months. The organ response (OR) was assessed over a 3-year period. The percentage of heart and renal responses was higher in CyBorD group. For cardiac responses, the rate was 78% vs 55% vs 16% (p=0.05) for groups 1, 2 and 3 respectively. Renal responses were observed in 90% vs 92% vs 57% of the patients (p=0.01). Overall median time of hematologic response (median, 10 months) and renal response (median, 12 months) occurred earlier than cardiac and hepatic responses (median, 26 months).

In summary, our results are comparable with previously published studies, demonstrating faster hematological response and organ responses after CyBorD treatment, which is translated into improved overall survival. Organ responses were observed significantly later than hematologic response.

Keywords

Systemic AL amyloidosis, CyBoRD, bortezomib.

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Kudyasheva, Olga V. Pirogova, Valentina V. Porunova, Svetlana V. Tolstova, Anna G. Smirnova, Ivan S. Moiseev, Alexander D. Kulagin" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(145) "

Olga V. Kudyasheva, Olga V. Pirogova, Valentina V. Porunova, Svetlana V. Tolstova, Anna G. Smirnova, Ivan S. Moiseev, Alexander D. Kulagin

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Keywords

Systemic AL amyloidosis, CyBoRD, bortezomib.

Keywords

Systemic AL amyloidosis, CyBoRD, bortezomib.

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

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Ключевые слова

Системный AL амилоидоз, CyBoRD, бортезомиб.

Ключевые слова

Системный AL амилоидоз, CyBoRD, бортезомиб.

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Introduction

In 2020, the COVID-19 pandemic has affected virtually all activities, both in Russia and globally [1-5]. The most significant damage occurred to the healthcare system. The first case of COVID-19 in St. Petersburg was registered on March 8, 2020. The nation-wide lockdown had been imposed in Russian Federation since March 30, 2020. Therefore, COVID-19 has become a real challenge for oncology and hematology services in Russia. The main task was to preserve the availability and quality of highly specialized medical care. Hematopoietic stem cell transplantation (HSCT) is a life-saving procedure for hematological patients. Despite the global trend towards a decrease in transplantation activity due to the pandemic, we tried to retain its capacity by introducing preventive measures and optimizing anti-infectious control in our Center. In the present study, we aim to present the workflow at the largest Russian transplant center in the era of COVID-19 pandemic.

Patients and methods

This work represents an observational study. The main methodology was to collect the data on clinical capacities of our transplant center from April 2020 to July 2021. Since the beginning of the COVID-19 pandemic, a series of measures have been taken at our Center to prevent spreading of the SARS-CoV-2 virus. Appropriate measures at the inpatient units included were as follows: a part of staff members was transferred to remote work; weekly PCR screening of the personnel and patients was arranged; the staff movement in the clinic was minimized, along with mandatory usage of personal protection equipment (PPE). Protection measures for outpatients included mandatory PCR screening of the patients before hospital admission, remote supervision of patients in permissible situations.

The main objectives included studying the influence of COVID-19 pandemic on the workflow of our HSCT Center, and assessing efficiency of the anti-epidemic measures taken. The main tasks were to estimate the rates of transplant-related mortality, incidence of COVID-19 infection in HSCT recipients and the characteristics of this group, to assess possibility of maintaining HSCT performance during the pandemic. The Kaplan-Meier method was used to estimate overall survival (OS) and transplant-related mortality (TRM). The log-rank test used for comparison of cumulative TRM incidence. All the calculations were performed using R version 3.3.2.

Results

Medical staff/Healthcare professionals

The medical staff of the center consists of 494 employees. The median age is 35 years (range 19 to 77). The key aspect was to preserve safety and efficiency of healthcare professionals. None of the employees were directly involved in COVID hospitals/red zones. Some of the staff switched to remote work, psychologists for example, who continued to work with the patients online. A total of 27 employees over 65 years old, including 10 medical doctors and 7 nurses, were transferred to self-isolation. In April 2020, due to limited diagnostic facilities, we were able to perform PCR testing for SARS-CoV-2 among employees only when they manifested with fever or respiratory symptoms. But already in May 2020, we started with weekly screening of clinical staff. During the COVID-19 pandemic, we performed a total of 21,702 PCR tests. Due to optimization of laboratory work, the PCR data became available within 24 hours. The symptom-free employees with positive PCR test results or those with mild clinical signs were sent to self-isolation. Employees with signs of respiratory failure were admitted to the specialized hospital for therapy. The movements of personnel within the clinic were minimized as much as possible. Regular use of personal protective equipment was mandatory.

From April 2020 to July 2021, a total of 252 (54.9%) of healthcare professionals suffered and recovered from COVID-19, including 83 physicians (51.2%) and 120 nurses (57.7%) who developed antiviral IgG antibodies in 44.4% and 48.1% of the cases, respectively. Other medical and non-medical staff members had documented disease in 55% (n=49) with antibody response in 37% of the cases (Fig. 1). The median time between the first positive and the first negative PCR test was 16.5 days (range 2 to 65). There were no COVID-19-related deaths among healthcare professionals in our Center.

Figure 1. Number of healthcare workers infected with SARS-CoV-2 from the start of pandemic

The largest number of COVID-19 cases among our staff was observed during the second wave of COVID-19 (autumn 2020), which correlated with general course of the pandemic in the Russian Federation (Fig. 2).

Figure 2. Time dynamics of confirmed cases in RM Gorbacheva Memorial Institute compared to general trends for the Russian Federation

Red curve, dynamics of confirmed cases in Russian Federation; blue curve, time course of confirmed cases in RM Gorbacheva Memorial Institute (St. Petersburg)

By July 1, 2021, 119 employees at our Center (25.9%) have been vaccinated: physicians, 43.2% (n=70); nurses, 15.8% (n=33); other medical and non-medical staff, 18% (n=16). Thus, 69.7% of employees (n=320) were immunized against COVID-19, including physicians (82.1%, n=133), nurses (66.8%, n=139), other medical and non-medical staff (54%, n=48) as shown in Fig. 3.

Figure 3. Dynamic of immune response in health-care workers in RM Gorbacheva Memorial Institute through each COVID-19 wave

Figure 4. Transplant activity in 2019 and 2020

Figure 5. Comparison of HSC donors in 2019 and 2020

Transplant activity in 2020

A total of 419 HSCTs performed in 2020, included 136 autologous and 283 allogeneic transplants. By comparison, 415 transplantations were performed in 2019, of which 144 and 271 were autologous and allogeneic, respectively (Fig. 4).

Due to closed access to international bone marrow donor registries, the HSCT structure was redistributed in favor of unrelated donors from the Russian registry and haploidentical donors (Fig. 5). During the pandemic from April 2020 to July 2021, 27 allogeneic grafts were cryopreserved and 24 (88.9%) of them were transfused to HSCT recipients. In 3 cases, graft transfusion was not performed due to recipient death: one patient deceased with COVID-19, two patients, due to progression of the underlying disease. However, we tried to use non-cryopreserved allogeneic grafts whenever possible, and succeeded in 90% of allografts. The reason for this practice is provided by the data from our center, published in 2018 showing higher frequency of primary graft failure with a cryopreserved allogeneic graft [6]. COVID-19-positive cases were recorded in eight donors, of which 6 were scheduled for adult patients and 2, for children. Of these cases, 4 donors were from the Russian unrelated donor registry; 3 donors were haploidentical, and a matched related donor was used in one case. In 4 patients, HSCT was postponed for a 1 to 8 weeks. During this period, no progression of the underlying disease was observed; in these patients, HSCT procedure was performed without complications. In 3 cases, the donor was changed to a haploidentical. In 1 case, a positive PCR test was received after bone marrow harvest, which did not affect the stem cell harvesting or HSCT procedure in any way. Upon receiving a PCR-positive test, donors were sent to self-isolation, and transplantation was postponed due to the absence of alternative donors.

HSCT recipients

Almost half of the HSCTs performed in 2020 were patients with acute leukemias, i.e., AML, 20.8% (n=87) and ALL, 26% (n=109). The detailed diagnosis distribution of HSCT recipients is presented in Table 1.

Table 1. Comparison of diagnosis structure in 2019 and 2020

Figure 6. Structure of initial diagnoses in the study group

From April 2020 to July 2021, COVID-19 was diagnosed in 39 HSCT recipients with ALL 11 (28%), AML 10 (25.5%), aplastic anemia 5 (13%), Hodgkin's lymphoma 3 (8%), non-Hodgkin lymphomas 2 (5%), multiple myeloma 3 (8%), multiple sclerosis 2 (5%) and 1 (2.5%) each with diagnoses of mucopolysaccharidosis type 1, chronic myeloid leukemia and CNS embryonal tumors (Fig. 6). During the pandemic, COVID-19 hospital has been deployed at the University, thus enabling continued specific therapies using distant consultation approach for HSCT patients who developed SARS-CoV-2 infection. It should be noted that immunosuppressive therapy with calcineurin and mTOR inhibitors as part of the GVHD prophylaxis was continued during the COVID-19 infection.

The overall group characteristics

The median age of infected patients was 27 years (4-66). There were 25 males (64.1%) and 14 females (35.9%). The majority of patients (n=29, 74.3%) had 0 points of the HCT CI comorbidity index. Allogeneic and autologous HSCT was performed in 31 (79.5%) and 8 (20.5%) patients, respectively. The HSC source were both PBSC (n=22, 56.4%), and bone marrow (n=17, 43.6%). Reduced-intensity conditioning (RIC) was used in 27 (69.3%) patients; MAC, in 12 cases (30.7%). Thirty patients (76.9%) were in complete remission of the underlying disease at the time of HSCT.

he median time between HSCT and COVID-19 infection was 68 days (-1 to +2093). At the time of COVID-19 onset, 33 patients (84.6%) were in remission of underlying disease. Most patients had ECOG status of 0-1 point at the onset of infection [11/18, (28.2%/46.1%)]. The median cycle threshold value (Ct) for the PCR of the first positive test was 31.8 (14.2-39.2). Two (5.1%) patients had an active acute graft-versus-host disease (GVHD) and 8 (20.5%) patients had chronic GVHD. The median duration of immunosuppressive therapy at the time of COVID-19 development was 36 days (-1 to +340).

Coronavirus infection was asymptomatic in 23 (59%) patients. Febrile fever was recorded in 16 (27%) patients; cough, in 8 (14%); respiratory failure, in 4 (7%); diarrhea, in 3 (5%); emetic syndrome, in 1 (2%); hypotension in 1 (2 %); rhinopharyngitis, in 1 (2%); anorexia, in 1 (2%). The median level of leukocytes was 3.6×10⁹/L (0-14.7), neutrophils – 1.6×10⁹/L (0-11.9), lymphocytes – 0.9×10⁹/L (0-3.2), platelets – 115×10⁹/L (6-298), hemoglobin – 98 g/L (58-155).

Seventeen (43.6%) patients were admitted to the hospital, and 22 (56.4%) were observed as outpatients. The median hospital stay was 15.5 days (1-47). Eight (20.5%) patients died. The median duration of COVID-19 before death was 20 days (1 to 47). After the infection, 21 (53.8%) patients were in remission of the underlying disease, 9 (23.1%) were in progression. In 6 (15.4%) patients, the disease staging was not performed due to a lethal outcome, in 2 (5.1%) patients with diagnoses of MPS type 1 and MS, the staging was not applicable. The disease status at the follow-up point was unknown in 1 patient (2.6%). The median period from the diagnosis of coronavirus infection to the follow-up term was 105 days (1-337).

The incidence of COVID-19 among HSCT recipients from April 2020 to July 2021 was 7.3% (n=39), in allo-HSCT, 8.6% (n=31); in auto-HSCT, 4.5% (n=8). A total of 536 HSCTs were performed during this period. The overall 100-day survival rate among HSCT recipients since the diagnosis of the COVID-19 was 79.5% (95% CI 0.609-0.884), as shown in Fig. 7A. The mortality rate was 20.5% (n=8). Among 8 patients, 50% (n=4) died in the early post-transplant period up to +100 days, and 37.5% (n=3) of them had pancytopenia at the time of the COVID-19 onset. The causes of death were COVID-19 infection (n=4, 50%), secondary infectious complications (n=2, 25%), relapse of the underlying disease (n=1, 12.5%), hemorrhagic complications (n=1, 12.5%).

The 100-day cumulative incidence of transplant-related mortality (TRM) among all HSCT recipients was 7% (95%CI 0.9-0.95) and 8.7% (95%CI 0.88-0.93) in 2019 and 2020, respectively (p=0.35) (Fig. 7B). The 100-day cumulative incidence of TRM among auto-HSCT recipients was 1.4% and 3.8% (95%CI 0.9-0.98) in 2019 and 2020, respectively (p=0.33) (Fig. 8B). The 100-day cumulative incidence of TRM among allo-HSCT recipients was 13.9% and 14.9% (95% CI 0.8-0.89) in 2019 and 2020 respectively (p=0.79) as seen from Fig. 8А.

Figure 7. Overall 100-day survival rate since the COVID-19 diagnosis (A), and 100-day cumulative incidence of transplant-related mortality (B) among all HSCT recipients

Figure 8. Comparison of 100-day transplant related mortality among allo-HSCT (A) and auto-HSCT (B) recipients in 2019 and 2020

Discussion

A number of published works to the similar topic point to decreased transplant activity in HSCT centers around the world during the COVID-19 pandemic [7-12]. We tried, however, to keep the same transplant activity. Despite the mortality rate of 20.5% in the group of HSCT recipients, diagnosed with COVID-19, the one-year TRM did not change significantly compared to 2019. In our opinion, the reason for these results is, firstly, low incidence of COVID-19 infection among HSCT recipients in our Center, and, secondly, maintenance of HSCT activity during the pandemic. This became possible due to the measures taken to limit spreading of SARS-CoV-2, as well as redistribution of the donor structure in favor of unrelated donors from the Russian registry, as well as participation of haploidentical donors.

Conclusions

Our experience confirms that with appropriate patient care resources, thorough screening and selection of donors, regular screening of patients and staff, vaccination, proper use of personal protective equipment, it is possible to maintain the same transplant activity during a pandemic without significantly increased TRM.

Financial support

This work was financially supported by the Ministry of Science and Higher Education of the Russian Federation (Agreement № 075-15-2021-1086, contract № RF----193021X0015). No conflicts of interest are declared.

Acknowledgement

Special thanks to the nurses, patients and their relatives.

References

Varma A, Kosuri S, Ustun C, Ibrahim U, Moreira J, Bishop M, et al. COVID-19 infection in hematopoietic cell transplantation: age, time from transplant and steroids matter. Leukemia 34, 2809-2812 (2020). doi: 10.1038/s41375-020-01019-x
Sultan AM, Mahmoud, HK, Fathy GM, Abdelfattah N. The outcome of hematopoietic stem cell transplantation patients with COVID-19 infection. Bone Marrow Transplant. 2021; 56, 971-973. doi: 10.1038/s41409-020-01094-9
Passamonti F, Cattaneo C, Arcaini L, Bruna R, Cavo M, Merli F, et al. Clinical characteristics and risk factors associated with COVID-19 severity in patients with haematological malignancies in Italy: a retrospective, multicentre, cohort study. Lancet Haematol. 2020; published online Aug 13. doi: 10.1016/S2352-3026(20)30251-9
Orchard K, Dignan FL, Lee J, Pearce R, Desai M, McFarlane E, et al. The NICE COVID-19 rapid guideline on haematopoietic stem cell transplantation: development, implementation and impact. Br J Haematol. 2021; 192:467-473. https://doi.org/10.1111/bjh.17280
Ljungman P, Mikulska M, de la Camara R, Basak G, Chabannon C, Corbacioglu S, et al. The challenge of COVID-19 and hematopoietic cell transplantation; EBMT recommendations for management of hematopoietic cell transplant recipients, their donors, and patients undergoing CAR T-cell therapy. Bone Marrow Transplant. 2020; 55, 2071–2076. https://doi.org/10.1038/s41409-020-0919-0
Babenko EV, Moiseev IS, Kanunnikov MM, Alyanskiy AL, Pevcov DE, Frolova AV, et al. Pair-matched study of cryopreserved versus native graft in adult and pediatric recipients of allogeneic hematopoietic stem cell transplantation. Cell Ther Transplant. 2018 7(1), 45–53. doi: 10.18620/ctt-1866-8836-2018-7-2-45-53
Xu Z-L, Huang X-J. COVID-19 & allogeneic transplant: Activity and preventive measures for best outcomes in China. Adv Cell Gene Ther. 2020;00:e94. doi: 10.1002/acg2.94
Ueda Oshima M, Sandmaier BM, Petersdorf E, Flowers M, Hill G, Lee S, et al. Blood and marrow transplantation during the emerging COVID-19 pandemic: the Seattle approach. Bone Marrow Transplant. 2021; 56, 305-313. doi: 10.1038/s41409-020-01068-x
Maurer K, Saucier A, Kim HT, Acharya U, Mo CC, Porter J, et al. COVID-19 and hematopoietic stem cell transplantation and immune effector cell therapy: a US cancer center experience. Blood Adv. 2021; 5 (3): 861-871. doi: 10.1182/bloodadvances.2020003883
Kanellopoulos A, Ahmed MZ, Kishore B, Lovell R, Horgan C, Paneesha S, et al. COVID-19 in bone marrow transplant recipients: reflecting on a single centre experience. Br J Haematol. 2020; l, 190: e67-e70. https://doi.org/10.1111/bjh.16856
del Campo PL, López AR, de la Cruz Benito B, de Paz Arias R, de Soto Álvarez T, Sánchez Vadillo I, et al. Hematopoietic cell transplantation during COVID-19 pandemic: experience from a tertiary hospital in Madrid. Exp Rev Hematol. (2021); 14:1, 1-5.
doi: 10.1080/17474086.2021.1858789
Coll E, Fernández-Ruiz M, Sánchez-Álvarez JE, Martínez-Fernández JR, Crespo M, Gayoso J, et al. COVID-19 in transplant recipients: The Spanish experience. Am J Transplant. 2021, 21: 1825-1837. https://doi.org/10.1111/ajt.16369

" ["~DETAIL_TEXT"]=> string(20675) "

Introduction

Patients and methods

Results

Medical staff/Healthcare professionals

Figure 1. Number of healthcare workers infected with SARS-CoV-2 from the start of pandemic

Figure 2. Time dynamics of confirmed cases in RM Gorbacheva Memorial Institute compared to general trends for the Russian Federation

Red curve, dynamics of confirmed cases in Russian Federation; blue curve, time course of confirmed cases in RM Gorbacheva Memorial Institute (St. Petersburg)

Figure 3. Dynamic of immune response in health-care workers in RM Gorbacheva Memorial Institute through each COVID-19 wave

Figure 4. Transplant activity in 2019 and 2020

Figure 5. Comparison of HSC donors in 2019 and 2020

Transplant activity in 2020

HSCT recipients

Table 1. Comparison of diagnosis structure in 2019 and 2020

Figure 6. Structure of initial diagnoses in the study group

The overall group characteristics

Figure 7. Overall 100-day survival rate since the COVID-19 diagnosis (A), and 100-day cumulative incidence of transplant-related mortality (B) among all HSCT recipients

Figure 8. Comparison of 100-day transplant related mortality among allo-HSCT (A) and auto-HSCT (B) recipients in 2019 and 2020

Discussion

Conclusions

Financial support

Acknowledgement

Special thanks to the nurses, patients and their relatives.

References

Varma A, Kosuri S, Ustun C, Ibrahim U, Moreira J, Bishop M, et al. COVID-19 infection in hematopoietic cell transplantation: age, time from transplant and steroids matter. Leukemia 34, 2809-2812 (2020). doi: 10.1038/s41375-020-01019-x
Sultan AM, Mahmoud, HK, Fathy GM, Abdelfattah N. The outcome of hematopoietic stem cell transplantation patients with COVID-19 infection. Bone Marrow Transplant. 2021; 56, 971-973. doi: 10.1038/s41409-020-01094-9
Passamonti F, Cattaneo C, Arcaini L, Bruna R, Cavo M, Merli F, et al. Clinical characteristics and risk factors associated with COVID-19 severity in patients with haematological malignancies in Italy: a retrospective, multicentre, cohort study. Lancet Haematol. 2020; published online Aug 13. doi: 10.1016/S2352-3026(20)30251-9
Orchard K, Dignan FL, Lee J, Pearce R, Desai M, McFarlane E, et al. The NICE COVID-19 rapid guideline on haematopoietic stem cell transplantation: development, implementation and impact. Br J Haematol. 2021; 192:467-473. https://doi.org/10.1111/bjh.17280
Ljungman P, Mikulska M, de la Camara R, Basak G, Chabannon C, Corbacioglu S, et al. The challenge of COVID-19 and hematopoietic cell transplantation; EBMT recommendations for management of hematopoietic cell transplant recipients, their donors, and patients undergoing CAR T-cell therapy. Bone Marrow Transplant. 2020; 55, 2071–2076. https://doi.org/10.1038/s41409-020-0919-0
Babenko EV, Moiseev IS, Kanunnikov MM, Alyanskiy AL, Pevcov DE, Frolova AV, et al. Pair-matched study of cryopreserved versus native graft in adult and pediatric recipients of allogeneic hematopoietic stem cell transplantation. Cell Ther Transplant. 2018 7(1), 45–53. doi: 10.18620/ctt-1866-8836-2018-7-2-45-53
Xu Z-L, Huang X-J. COVID-19 & allogeneic transplant: Activity and preventive measures for best outcomes in China. Adv Cell Gene Ther. 2020;00:e94. doi: 10.1002/acg2.94
Ueda Oshima M, Sandmaier BM, Petersdorf E, Flowers M, Hill G, Lee S, et al. Blood and marrow transplantation during the emerging COVID-19 pandemic: the Seattle approach. Bone Marrow Transplant. 2021; 56, 305-313. doi: 10.1038/s41409-020-01068-x
Maurer K, Saucier A, Kim HT, Acharya U, Mo CC, Porter J, et al. COVID-19 and hematopoietic stem cell transplantation and immune effector cell therapy: a US cancer center experience. Blood Adv. 2021; 5 (3): 861-871. doi: 10.1182/bloodadvances.2020003883
Kanellopoulos A, Ahmed MZ, Kishore B, Lovell R, Horgan C, Paneesha S, et al. COVID-19 in bone marrow transplant recipients: reflecting on a single centre experience. Br J Haematol. 2020; l, 190: e67-e70. https://doi.org/10.1111/bjh.16856
del Campo PL, López AR, de la Cruz Benito B, de Paz Arias R, de Soto Álvarez T, Sánchez Vadillo I, et al. Hematopoietic cell transplantation during COVID-19 pandemic: experience from a tertiary hospital in Madrid. Exp Rev Hematol. (2021); 14:1, 1-5.
doi: 10.1080/17474086.2021.1858789
Coll E, Fernández-Ruiz M, Sánchez-Álvarez JE, Martínez-Fernández JR, Crespo M, Gayoso J, et al. COVID-19 in transplant recipients: The Spanish experience. Am J Transplant. 2021, 21: 1825-1837. https://doi.org/10.1111/ajt.16369

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Несмотря на глобальную тенденцию к снижению трансплантационной активности на фоне пандемии COVID-19, мы старались ее сохранить, внедряя профилактические меры и оптимизируя инфекционный контроль в нашем центре. <h3>Материалы и методы</h3> Это наблюдательное исследование. Мы собрали данные о работе нашего трансплантационного центра с апреля 2020 года по июль 2021 года в течение двух волн пандемии. Основной задачей было изучение влияния пандемии COVID-19 на работу центра ТГСК, включая заболеваемость сотрудников и реципиентов ТГСК, а также трансплантационную активность. <h3>Результаты</h3> Первый случай заражения COVID-19 в Санкт-Петербурге был зарегистрирован 8 марта 2020 года. 30 марта 2020 года в Российской Федерации был объявлен всеобщий режим самоизоляции. Вторая волна COVID-19 началась в октябре 2020 года. Основным инструментом инфекционного контроля, помимо требований государственных органов, был еженедельный скрининг персонала и пациентов. Всего за период с мая 2020 по июль 2021 было проведено 21702 ПЦР исследований. На 1 июля 2021 года 69,7% сотрудников были иммунизированы в результате перенесенной инфекции или вакцинированы. В 2020 году, на который пришлась первая волна пандемии, нам удалось провести 419 ТГСК: 136 аутологичных и 283 аллогенных. Для сравнения: в 2019 году выполнено 415 трансплантаций, из них 144 аутологичных и 271 аллогенных соответственно. В 2020 году структура доноров для ТГСК была перераспределена в пользу неродственных из Российского реестра и гаплоидентичных доноров. Заболеваемость COVID-19 среди реципиентов ТГСК в период с апреля 2020 года по июль 2021 года составила 7,3% (n=39), после алло-ТГСК – 8,6% (n=31), после ауто-ТГСК – 4,5% (n=8). Медиана возраста пациентов с COVID-19 составила 27 лет (4-66). Медиана времени развития COVID-19 после ТГСК составила 68 дней (-1-2093). У большинства пациентов – 29 (74,3%) индекс коморбидности HCT CI на момент трансплантации был равен 0. Источником стволовых клеток были как ПСКК – 22 (56,4%), так и КМ – 17 (43,6%). У большинства пациентов на момент проведения ТГСК была полная ремиссия основного заболевания (n=30, 76,9%). Общая 100-дневная выживаемость среди реципиентов ТГСК с момента постановки диагноза COVID-19 составила 79,5% (95% ДИ 0,609-0,884). Летальность составила 20,5% (n=8). Причины смерти: инфекция COVID-19 – 50% (n=4), вторичные инфекционные осложнения – 25% (n=2), рецидив основного заболевания – 12,5% (n=1), геморрагические осложнения – 12, 5% (n=1). 100-дневная кумулятивная частота трансплантационной летальности среди всех реципиентов ТГСК составила 7% (95% ДИ 0,9-0,95) и 8,7% (95% ДИ 0,88-0,93) в 2019 и 2020 годах соответственно (p=0,35). <h3>Выводы</h3> Благодаря профилактическим мерам, регулярному скринингу ПЦР, а также использованию доноров, как из Российского регистра, так и гаплоидентичных, нам удалось сохранить трансплантационную активность на прежнем уровне. 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Синяев, Марина О. Попова, Юлия А. Рогачева, Анна А. Спиридонова, Мария Ю. Аверьянова, Александр Л. Алянский, Белла И. Аюбова, Елена В. Бабенко, Евгений А. Бакин, Ильдар М. Бархатов, Максим П. Богомольный, Татьяна А. Быкова, Алина А. Витрищак, Мария Д. Владовская, Юлия Ю. Власова, Алиса Г. Волкова, Асмик Г. Геворгян, Татьяна Л. Гиндина, Олег В. Голощапов, Кирилл А. Екушов, Мария А. Эстрина, Наталья Е. Иванова, Максим А. Кучер, Алексей Б. Чухловин, Кирилл В. Лепик, Инна В. Маркова, Наталья Б. Михайлова, Елена В. Морозова, Анна А. Осипова, Олеся В. Паина, Дмитрий Э. Певцов, Анна Г. Смирнова, Александр Н. Швецов, Лилия В. Стельмах, Галина Н. Столбенко, Людмила С. Зубаровская, Сергей Н. Бондаренко, Иван С. Моисеев, Александр Д. Кулагин" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1327) "

Александр А. Синяев, Марина О. Попова, Юлия А. Рогачева, Анна А. Спиридонова, Мария Ю. Аверьянова, Александр Л. Алянский, Белла И. Аюбова, Елена В. Бабенко, Евгений А. Бакин, Ильдар М. Бархатов, Максим П. Богомольный, Татьяна А. Быкова, Алина А. Витрищак, Мария Д. Владовская, Юлия Ю. Власова, Алиса Г. Волкова, Асмик Г. Геворгян, Татьяна Л. Гиндина, Олег В. Голощапов, Кирилл А. Екушов, Мария А. Эстрина, Наталья Е. Иванова, Максим А. Кучер, Алексей Б. Чухловин, Кирилл В. Лепик, Инна В. Маркова, Наталья Б. Михайлова, Елена В. Морозова, Анна А. Осипова, Олеся В. Паина, Дмитрий Э. Певцов, Анна Г. Смирнова, Александр Н. Швецов, Лилия В. Стельмах, Галина Н. Столбенко, Людмила С. Зубаровская, Сергей Н. Бондаренко, Иван С. Моисеев, Александр Д. Кулагин

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" ["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) "28427" ["VALUE"]=> array(2) { ["TEXT"]=> string(6316) "Трансплантация гемопоэтических стволовых клеток (ТГСК) – это жизнеспасающая процедура при онкологических, гематологических и доброкачественных заболеваниях. Несмотря на глобальную тенденцию к снижению трансплантационной активности на фоне пандемии COVID-19, мы старались ее сохранить, внедряя профилактические меры и оптимизируя инфекционный контроль в нашем центре. <h3>Материалы и методы</h3> Это наблюдательное исследование. Мы собрали данные о работе нашего трансплантационного центра с апреля 2020 года по июль 2021 года в течение двух волн пандемии. Основной задачей было изучение влияния пандемии COVID-19 на работу центра ТГСК, включая заболеваемость сотрудников и реципиентов ТГСК, а также трансплантационную активность. <h3>Результаты</h3> Первый случай заражения COVID-19 в Санкт-Петербурге был зарегистрирован 8 марта 2020 года. 30 марта 2020 года в Российской Федерации был объявлен всеобщий режим самоизоляции. Вторая волна COVID-19 началась в октябре 2020 года. Основным инструментом инфекционного контроля, помимо требований государственных органов, был еженедельный скрининг персонала и пациентов. Всего за период с мая 2020 по июль 2021 было проведено 21702 ПЦР исследований. На 1 июля 2021 года 69,7% сотрудников были иммунизированы в результате перенесенной инфекции или вакцинированы. В 2020 году, на который пришлась первая волна пандемии, нам удалось провести 419 ТГСК: 136 аутологичных и 283 аллогенных. Для сравнения: в 2019 году выполнено 415 трансплантаций, из них 144 аутологичных и 271 аллогенных соответственно. В 2020 году структура доноров для ТГСК была перераспределена в пользу неродственных из Российского реестра и гаплоидентичных доноров. Заболеваемость COVID-19 среди реципиентов ТГСК в период с апреля 2020 года по июль 2021 года составила 7,3% (n=39), после алло-ТГСК – 8,6% (n=31), после ауто-ТГСК – 4,5% (n=8). Медиана возраста пациентов с COVID-19 составила 27 лет (4-66). Медиана времени развития COVID-19 после ТГСК составила 68 дней (-1-2093). У большинства пациентов – 29 (74,3%) индекс коморбидности HCT CI на момент трансплантации был равен 0. Источником стволовых клеток были как ПСКК – 22 (56,4%), так и КМ – 17 (43,6%). У большинства пациентов на момент проведения ТГСК была полная ремиссия основного заболевания (n=30, 76,9%). Общая 100-дневная выживаемость среди реципиентов ТГСК с момента постановки диагноза COVID-19 составила 79,5% (95% ДИ 0,609-0,884). Летальность составила 20,5% (n=8). Причины смерти: инфекция COVID-19 – 50% (n=4), вторичные инфекционные осложнения – 25% (n=2), рецидив основного заболевания – 12,5% (n=1), геморрагические осложнения – 12, 5% (n=1). 100-дневная кумулятивная частота трансплантационной летальности среди всех реципиентов ТГСК составила 7% (95% ДИ 0,9-0,95) и 8,7% (95% ДИ 0,88-0,93) в 2019 и 2020 годах соответственно (p=0,35). <h3>Выводы</h3> Благодаря профилактическим мерам, регулярному скринингу ПЦР, а также использованию доноров, как из Российского регистра, так и гаплоидентичных, нам удалось сохранить трансплантационную активность на прежнем уровне. Заболеваемость COVID-19 среди реципиентов ТГСК составила 7,3%. Несмотря на то, что летальность от COVID-19 среди реципиентов ТГСК составила 20,5%, пандемия не повлияла на трансплантационную летальность среди всех реципиентов ТГСК в нашем центре. <h2>Ключевые слова</h2> Пандемия, COVID-19, SARS-CoV-2, трансплантация гемопоэтических стволовых клеток." ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(6120) "

Трансплантация гемопоэтических стволовых клеток (ТГСК) – это жизнеспасающая процедура при онкологических, гематологических и доброкачественных заболеваниях. Несмотря на глобальную тенденцию к снижению трансплантационной активности на фоне пандемии COVID-19, мы старались ее сохранить, внедряя профилактические меры и оптимизируя инфекционный контроль в нашем центре.

Материалы и методы

Это наблюдательное исследование. Мы собрали данные о работе нашего трансплантационного центра с апреля 2020 года по июль 2021 года в течение двух волн пандемии. Основной задачей было изучение влияния пандемии COVID-19 на работу центра ТГСК, включая заболеваемость сотрудников и реципиентов ТГСК, а также трансплантационную активность.

Результаты

Первый случай заражения COVID-19 в Санкт-Петербурге был зарегистрирован 8 марта 2020 года. 30 марта 2020 года в Российской Федерации был объявлен всеобщий режим самоизоляции. Вторая волна COVID-19 началась в октябре 2020 года. Основным инструментом инфекционного контроля, помимо требований государственных органов, был еженедельный скрининг персонала и пациентов. Всего за период с мая 2020 по июль 2021 было проведено 21702 ПЦР исследований. На 1 июля 2021 года 69,7% сотрудников были иммунизированы в результате перенесенной инфекции или вакцинированы.

В 2020 году, на который пришлась первая волна пандемии, нам удалось провести 419 ТГСК: 136 аутологичных и 283 аллогенных. Для сравнения: в 2019 году выполнено 415 трансплантаций, из них 144 аутологичных и 271 аллогенных соответственно. В 2020 году структура доноров для ТГСК была перераспределена в пользу неродственных из Российского реестра и гаплоидентичных доноров.

Заболеваемость COVID-19 среди реципиентов ТГСК в период с апреля 2020 года по июль 2021 года составила 7,3% (n=39), после алло-ТГСК – 8,6% (n=31), после ауто-ТГСК – 4,5% (n=8). Медиана возраста пациентов с COVID-19 составила 27 лет (4-66). Медиана времени развития COVID-19 после ТГСК составила 68 дней (-1-2093). У большинства пациентов – 29 (74,3%) индекс коморбидности HCT CI на момент трансплантации был равен 0. Источником стволовых клеток были как ПСКК – 22 (56,4%), так и КМ – 17 (43,6%). У большинства пациентов на момент проведения ТГСК была полная ремиссия основного заболевания (n=30, 76,9%). Общая 100-дневная выживаемость среди реципиентов ТГСК с момента постановки диагноза COVID-19 составила 79,5% (95% ДИ 0,609-0,884). Летальность составила 20,5% (n=8). Причины смерти: инфекция COVID-19 – 50% (n=4), вторичные инфекционные осложнения – 25% (n=2), рецидив основного заболевания – 12,5% (n=1), геморрагические осложнения – 12, 5% (n=1). 100-дневная кумулятивная частота трансплантационной летальности среди всех реципиентов ТГСК составила 7% (95% ДИ 0,9-0,95) и 8,7% (95% ДИ 0,88-0,93) в 2019 и 2020 годах соответственно (p=0,35).

Выводы

Благодаря профилактическим мерам, регулярному скринингу ПЦР, а также использованию доноров, как из Российского регистра, так и гаплоидентичных, нам удалось сохранить трансплантационную активность на прежнем уровне. Заболеваемость COVID-19 среди реципиентов ТГСК составила 7,3%. Несмотря на то, что летальность от COVID-19 среди реципиентов ТГСК составила 20,5%, пандемия не повлияла на трансплантационную летальность среди всех реципиентов ТГСК в нашем центре.

Ключевые слова

Пандемия, COVID-19, SARS-CoV-2, трансплантация гемопоэтических стволовых клеток.

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Aleksandr A. Siniaev, Marina O. Popova, Yulia A. Rogacheva, Anna A. Spiridonova, Maria Y. Averyanova, Alexander L. Alyanskiy, Bella I. Ayubova, Elena V. Babenko, Evgenii A. Bakin, Ildar M. Barkhatov, Maxim P. Bogomolny, atiana A. Bykova, Alina A. Vitrischak, Maria D. Vladovskaya, Yulia Y. Vlasova, Alisa G. Volkova, Asmik G. Gevorgian, Tatiana L. Gindina, Oleg V. Goloshchapov, Kirill A. Ekushov, Maria A. Estrina, Natalia E. Ivanova, Maxim A. Kucher, Alexei B. Chukhlovin, Kirill V. Lepik, Inna V. Markova, Natalia B. Mikhailova, Elena V. Morozova, Anna A. Osipova, Olesya V. Paina, Dmitrii E. Pevtsov, Anna G. Smirnova, Alexandr N. Shvetsov, Lilia V. Stelmakh, Galina N. Stolbenko, Ludmila S. Zubarovskaya, Sergey N. Bondarenko, 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. Aleksandr A. Siniaev, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transpantation, Pavlov University, 6-8 L. Tolstoy St., 197022, St. Petersburg, Russia
E-mail: drsiniaev@yandex.ru

Citation: Siniaev AA, Popova MO, Rogacheva YA et al. Journey of a hematopoietic stem cell transplantation center through COVID-19 pandemic: one-year experience. Cell Ther Transplant 2021; 10(3-4): 30-37.

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Hematopoietic stem cell transplantation (HSCT) is a life-saving procedure for oncological, hematological and non-malignant disorders. Despite global trend for a decrease of transplantation activity in view of the COVID-19 pandemic, we tried to maintain it by taking preventive measures and optimizing infection control in our center.

Patients and methods

This is an observational study. We collected the performance data of our transplant center from April 2020 to July 2021, i.e., during two waves of the pandemic. The main objectives were to study the influence of COVID-19 pandemic on the workflow of the HSCT center, including morbidity among employees and HSCT recipients, as well as on the transplant activity.

Results

The first case of COVID-19 infection in St. Petersburg was recorded on March 8, 2020. On March 30, 2020, a national lockdown had been imposed in the Russian Federation. The second wave of COVID-19 started in October 2020. Weekly screening of staff and patients was the main diagnostic tool, in addition to the governmental requirements. In sum, a total of 21702 PCR tests for SARS-CoV-2 were performed over the study period. As for July 1, 2021, 69.7% of employees became immune to the virus, due to previous COVID-19 disease, or by vaccination. In 2020, we managed to perform 419 HSCT, including 136 autologous and 283 allogeneic transplants. For comparison, 415 HSCTs were carried out in 2019, with 144 autologous and 271 allogeneic transplants. In 2020, the HSC donorship was shifted towards unrelated donors from the Russian Registry and haploidentical donors. Incidence of COVID-19 among HSCT recipients between April 2020 and July 2021 was 7.3% (n=39), being 8.6% (n=31) after allogeneic HSCT, and 4.5% (n=8) following auto-HSCT. The median age of patients with COVID-19 was 27 years (4-66). The median term for the COVID-19 onset was 68 days post-transplant (-1 to +2093). In most patients – 29 (74.3%) the HCT CI comorbidity index at the time of transplantation was 0. The stem cell source were either peripheral blood stem cells (n=22, 56.4%), or bone marrow (n=17, 43.6%). Most of the patients achieved complete remission of the underlying disease at the time of HSCT (n=30, 76.9%). The overall 100-day survival rate among HSCT recipients since the diagnosis of the COVID-19 was 79.5% (95% CI 0.609 – 0.884). The mortality rate was 20.5% (n=8). The causes of death were as follows: COVID-19 – 50% (n=4); secondary infectious complications, 25% (n=2); relapse of the underlying disease, 12.5% (n=1); hemorrhagic complications, 12.5% (n=1). The 100-day cumulative incidence of transplant-related mortality (TRM) among all HSCT recipients was 7% (95% CI 0.9 – 0.95) and 8.7% (95% CI 0.88 – 0.93) in 2019 and 2020, respectively (p=0.35).

Conclusions

Due to preventive measures, regular PCR screening, as well as the use of donors from the Russian Registry or haploidentical donors, we managed to maintain HSCT activity at the same level. The COVID-19 morbidity of HSCT recipients was 7.3%, their mortality rate – 20.5%. In summary, the pandemic did not affect transplant-related mortality among the HSCT recipients in our center.

Keywords

Pandemic, COVID-19, SARS-CoV-2, HSC transplantation.

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Siniaev, Marina O. Popova, Yulia A. Rogacheva, Anna A. Spiridonova, Maria Y. Averyanova, Alexander L. Alyanskiy, Bella I. Ayubova, Elena V. Babenko, Evgenii A. Bakin, Ildar M. Barkhatov, Maxim P. Bogomolny, atiana A. Bykova, Alina A. Vitrischak, Maria D. Vladovskaya, Yulia Y. Vlasova, Alisa G. Volkova, Asmik G. Gevorgian, Tatiana L. Gindina, Oleg V. Goloshchapov, Kirill A. Ekushov, Maria A. Estrina, Natalia E. Ivanova, Maxim A. Kucher, Alexei B. Chukhlovin, Kirill V. Lepik, Inna V. Markova, Natalia B. Mikhailova, Elena V. Morozova, Anna A. Osipova, Olesya V. Paina, Dmitrii E. Pevtsov, Anna G. Smirnova, Alexandr N. Shvetsov, Lilia V. Stelmakh, Galina N. Stolbenko, Ludmila S. Zubarovskaya, Sergey N. Bondarenko, Ivan S. Moiseev, Alexander D. Kulagin" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(783) "

" } ["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) "28431" ["VALUE"]=> array(2) { ["TEXT"]=> string(3620) "Hematopoietic stem cell transplantation (HSCT) is a life-saving procedure for oncological, hematological and non-malignant disorders. Despite global trend for a decrease of transplantation activity in view of the COVID-19 pandemic, we tried to maintain it by taking preventive measures and optimizing infection control in our center. <h3>Patients and methods</h3> This is an observational study. We collected the performance data of our transplant center from April 2020 to July 2021, i.e., during two waves of the pandemic. The main objectives were to study the influence of COVID-19 pandemic on the workflow of the HSCT center, including morbidity among employees and HSCT recipients, as well as on the transplant activity. <h3>Results</h3> The first case of COVID-19 infection in St. Petersburg was recorded on March 8, 2020. On March 30, 2020, a national lockdown had been imposed in the Russian Federation. The second wave of COVID-19 started in October 2020. Weekly screening of staff and patients was the main diagnostic tool, in addition to the governmental requirements. In sum, a total of 21702 PCR tests for SARS-CoV-2 were performed over the study period. As for July 1, 2021, 69.7% of employees became immune to the virus, due to previous COVID-19 disease, or by vaccination. In 2020, we managed to perform 419 HSCT, including 136 autologous and 283 allogeneic transplants. For comparison, 415 HSCTs were carried out in 2019, with 144 autologous and 271 allogeneic transplants. In 2020, the HSC donorship was shifted towards unrelated donors from the Russian Registry and haploidentical donors. Incidence of COVID-19 among HSCT recipients between April 2020 and July 2021 was 7.3% (n=39), being 8.6% (n=31) after allogeneic HSCT, and 4.5% (n=8) following auto-HSCT. The median age of patients with COVID-19 was 27 years (4-66). The median term for the COVID-19 onset was 68 days post-transplant (-1 to +2093). In most patients – 29 (74.3%) the HCT CI comorbidity index at the time of transplantation was 0. The stem cell source were either peripheral blood stem cells (n=22, 56.4%), or bone marrow (n=17, 43.6%). Most of the patients achieved complete remission of the underlying disease at the time of HSCT (n=30, 76.9%). The overall 100-day survival rate among HSCT recipients since the diagnosis of the COVID-19 was 79.5% (95% CI 0.609 – 0.884). The mortality rate was 20.5% (n=8). The causes of death were as follows: COVID-19 – 50% (n=4); secondary infectious complications, 25% (n=2); relapse of the underlying disease, 12.5% (n=1); hemorrhagic complications, 12.5% (n=1). The 100-day cumulative incidence of transplant-related mortality (TRM) among all HSCT recipients was 7% (95% CI 0.9 – 0.95) and 8.7% (95% CI 0.88 – 0.93) in 2019 and 2020, respectively (p=0.35). <h3>Conclusions</h3> Due to preventive measures, regular PCR screening, as well as the use of donors from the Russian Registry or haploidentical donors, we managed to maintain HSCT activity at the same level. The COVID-19 morbidity of HSCT recipients was 7.3%, their mortality rate – 20.5%. In summary, the pandemic did not affect transplant-related mortality among the HSCT recipients in our center. <h2>Keywords</h2> Pandemic, COVID-19, SARS-CoV-2, HSC transplantation." ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3462) "

Patients and methods

Results

Conclusions

Keywords

Pandemic, COVID-19, SARS-CoV-2, HSC transplantation.

Patients and methods

Results

Conclusions

Keywords

Pandemic, COVID-19, SARS-CoV-2, HSC transplantation.

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

" } ["AUTHOR_RU"]=> array(37) { ["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) "28425" ["VALUE"]=> array(2) { ["TEXT"]=> string(1339) "Александр А. Синяев, Марина О. Попова, Юлия А. Рогачева, Анна А. Спиридонова, Мария Ю. Аверьянова, Александр Л. Алянский, Белла И. Аюбова, Елена В. Бабенко, Евгений А. Бакин, Ильдар М. Бархатов, Максим П. Богомольный, Татьяна А. Быкова, Алина А. Витрищак, Мария Д. Владовская, Юлия Ю. Власова, Алиса Г. Волкова, Асмик Г. Геворгян, Татьяна Л. Гиндина, Олег В. Голощапов, Кирилл А. Екушов, Мария А. Эстрина, Наталья Е. Иванова, Максим А. Кучер, Алексей Б. Чухловин, Кирилл В. Лепик, Инна В. Маркова, Наталья Б. Михайлова, Елена В. Морозова, Анна А. Осипова, Олеся В. Паина, Дмитрий Э. Певцов, Анна Г. Смирнова, Александр Н. Швецов, Лилия В. Стельмах, Галина Н. Столбенко, Людмила С. Зубаровская, Сергей Н. Бондаренко, Иван С. Моисеев, Александр Д. Кулагин" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1327) "

" } ["SUMMARY_RU"]=> array(37) { ["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) "28427" ["VALUE"]=> array(2) { ["TEXT"]=> string(6316) "Трансплантация гемопоэтических стволовых клеток (ТГСК) – это жизнеспасающая процедура при онкологических, гематологических и доброкачественных заболеваниях. Несмотря на глобальную тенденцию к снижению трансплантационной активности на фоне пандемии COVID-19, мы старались ее сохранить, внедряя профилактические меры и оптимизируя инфекционный контроль в нашем центре. <h3>Материалы и методы</h3> Это наблюдательное исследование. Мы собрали данные о работе нашего трансплантационного центра с апреля 2020 года по июль 2021 года в течение двух волн пандемии. Основной задачей было изучение влияния пандемии COVID-19 на работу центра ТГСК, включая заболеваемость сотрудников и реципиентов ТГСК, а также трансплантационную активность. <h3>Результаты</h3> Первый случай заражения COVID-19 в Санкт-Петербурге был зарегистрирован 8 марта 2020 года. 30 марта 2020 года в Российской Федерации был объявлен всеобщий режим самоизоляции. Вторая волна COVID-19 началась в октябре 2020 года. Основным инструментом инфекционного контроля, помимо требований государственных органов, был еженедельный скрининг персонала и пациентов. Всего за период с мая 2020 по июль 2021 было проведено 21702 ПЦР исследований. На 1 июля 2021 года 69,7% сотрудников были иммунизированы в результате перенесенной инфекции или вакцинированы. В 2020 году, на который пришлась первая волна пандемии, нам удалось провести 419 ТГСК: 136 аутологичных и 283 аллогенных. Для сравнения: в 2019 году выполнено 415 трансплантаций, из них 144 аутологичных и 271 аллогенных соответственно. В 2020 году структура доноров для ТГСК была перераспределена в пользу неродственных из Российского реестра и гаплоидентичных доноров. Заболеваемость COVID-19 среди реципиентов ТГСК в период с апреля 2020 года по июль 2021 года составила 7,3% (n=39), после алло-ТГСК – 8,6% (n=31), после ауто-ТГСК – 4,5% (n=8). Медиана возраста пациентов с COVID-19 составила 27 лет (4-66). Медиана времени развития COVID-19 после ТГСК составила 68 дней (-1-2093). У большинства пациентов – 29 (74,3%) индекс коморбидности HCT CI на момент трансплантации был равен 0. Источником стволовых клеток были как ПСКК – 22 (56,4%), так и КМ – 17 (43,6%). У большинства пациентов на момент проведения ТГСК была полная ремиссия основного заболевания (n=30, 76,9%). Общая 100-дневная выживаемость среди реципиентов ТГСК с момента постановки диагноза COVID-19 составила 79,5% (95% ДИ 0,609-0,884). Летальность составила 20,5% (n=8). Причины смерти: инфекция COVID-19 – 50% (n=4), вторичные инфекционные осложнения – 25% (n=2), рецидив основного заболевания – 12,5% (n=1), геморрагические осложнения – 12, 5% (n=1). 100-дневная кумулятивная частота трансплантационной летальности среди всех реципиентов ТГСК составила 7% (95% ДИ 0,9-0,95) и 8,7% (95% ДИ 0,88-0,93) в 2019 и 2020 годах соответственно (p=0,35). <h3>Выводы</h3> Благодаря профилактическим мерам, регулярному скринингу ПЦР, а также использованию доноров, как из Российского регистра, так и гаплоидентичных, нам удалось сохранить трансплантационную активность на прежнем уровне. Заболеваемость COVID-19 среди реципиентов ТГСК составила 7,3%. Несмотря на то, что летальность от COVID-19 среди реципиентов ТГСК составила 20,5%, пандемия не повлияла на трансплантационную летальность среди всех реципиентов ТГСК в нашем центре. <h2>Ключевые слова</h2> Пандемия, COVID-19, SARS-CoV-2, трансплантация гемопоэтических стволовых клеток." ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(6120) "

Материалы и методы

Результаты

Выводы

Ключевые слова

Пандемия, COVID-19, SARS-CoV-2, трансплантация гемопоэтических стволовых клеток.

Материалы и методы

Результаты

Выводы

Ключевые слова

Пандемия, COVID-19, SARS-CoV-2, трансплантация гемопоэтических стволовых клеток.

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Introduction

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the most common primary liver malignancy worldwide [1, 2]. The incidence of HCC has tripled in the United States during the past three decades, with an annual increase of 4.5% [3]. Additionally, the mortality rates associated with this disease have continued to rise [3, 4]. In Egypt, malignant liver tumors represent 1.7% of all malignancies and HCC constitutes more than 70% of these malignancies [5]. Hospital-based studies have reported an overall increase in relative frequency of all liver cancers in Egypt (mainly, HCC), from approximately 4% in 1993 to 7.3% in 2003 [6].

Currently, since introduction of Milan criteria (MC) of liver transplantation (LTx), this treatment has proven to be an excellent therapeutic option for HCC [7]. Due to the organ shortage, not all transplant-eligible HCC patients undergo LT at the optimal timing. Scarcity of liver grafts and, therefore, longer waiting time result into the disease progression. The predicted probability of dropping from waiting list is estimated as 12% for the patients with 6-month delay of tumor treatment [8, 9].

In view of sufficient organ shortage, the need for a model to select, prioritize and identify HCC patients with fruitful outcome became crucial. The established transplant criteria, like Milan and UCSF criteria have been well validated and were used as the guideline to select the patients for LTx, especially deceased donor LT [10-12]. Lymphovascular invasion and histological grade of tumor were found to be the most relevant tumor variables to the outcome of HCC patients. Despite that, LT for HCC currently relies on morphological criteria, i.e., number of tumor nodes?, size, and total tumor volume to select HCC patients for LT [6, 13-16].

Unfortunately, most HCC patients are beyond the MC at the time of presentation. Therefore, downstaging to the values fitting for MC is attempted in selected patients. Downstaging is usually performed by a variety of techniques called collectively locoregional therapies (LRT). LRT include radiofrequency ablation (RFA), transarterial chemoembolization (TACE), transarterial radioembolization (TARE), alone or a combination. Downstaging offers many advantages, including decreasing tumor burden and causing less aggressive tumor biology [17]. In 2001, Yao et al. reported the first successful LTx following the HCC downstaging. They showed that successful downstaging of HCC is feasible with a good post LTx outcome [18]. Subsequently, several groups obtained similar outcomes by using different protocols [18-23]. The shortage of the organ grafts requires proper evaluation of the downstaging LRT upon outcomes of HCC treated by LTx, thus determining the aim of our study.

Materials and methods

A cohort of 115 adult patients underwent LT for the presence of hepatocellular carcinoma (HCC) at our institution between August 2006 and December 2019. Approval from our institutional Research Ethical Committee was obtained before conduction of this study. Cases of pediatric LT or liver retransplantation were excluded from this study.

LTx was performed using both cadaveric and living donor liver transplantation (LDLT). Cases from LDLT were first- and second-degree relatives of their respective patients. HCC was diagnosed by contrast-enhanced computed tomography (CT) and/or abdominal magnetic resonance imaging (MRI). The disease staging was done by chest CT, cranial CT, and technetium-99m bone scintigraphy, to exclude extra-hepatic disease. HCC size, number, tumor grade, and lymph vascular invasion were diagnosed by an experienced pathologist.

For histopathological examination, the 7-point sampling procedure was employed as follows: (1) At least four tissue samples were biopsied from the junction of HCC with nearby hepatic tissue in a 1:1 proportion at 12, 3, 6, 9 o’clock locations, (2) at least one sample should be taken from intratumoral region to allow for molecular subtyping, (3) Aiming to exclude the presence of microvascular invasion, satellite, or dysplastic nodules, samples were also obtained from hepatic tissue ≤ 1 cm and >1 cm from HCC margin (adjacent and distant peritumoral locations respectively). (4) The size of tissue blocks was confirmed to be approximately 1.5 cm – 2.0 cm × 1.0 cm × 0.3 cm, (5) All the specimens were tagged according to the sampling locations.

Liver explant is defined as the native liver of the recipient which was removed in toto by the surgical team as a preparatory step for implanting a new whole liver, or a liver lobe during LTx procedure. Total tumor volume (TTV) was defined as the sum of individual tumor lesion volume; the tumor volume was estimated using the formula (T= {(4/3) π, r3} where r equals the maximum diameter of the lesion measured in cm). Presence of mixed HCC and cholangiocarcinoma was a criterion for excluding the case from our study.

Based on the usage of pre-transplant downstaging LRT, patients were divided into the following groups:
• Group A: Patients within Milan criteria (MC) who did not receive pretransplant downstaging LRT.
• Group B: Patients beyond MC who, therefore, received downstaging pretransplant LRT.

Our center currently adopts MC for HCC as the standard criteria for LTx. Any patient who is beyond MC is usually considered for a downstaging protocol by means of one or more locoregional therapies to downstage the tumor to the values fitting within MC. LTx for the downstaged patients is considered after subsequent confirmation of the absence of extrahepatic disease. Pretransplant locoregional therapies included RFA, TACE and TARE.

Evaluation of the response to locoregional therapy was done according to the mRECIST criteria [24]. Accordingly, complete response (CR) was defined as disappearance of any arterial enhancement in all target lesions. Meanwhile, partial response (PR) was defined by at least a 30% reduction in the sum of diameters of enhancing lesions. Progressive disease (PD) was identified as an increase for, at least, 20% in the sum of diameters of enhancing lesions. Finally, stable disease (SD) was defined as cases that do not qualify for either (PR) or (PD) [24].

A triple immunosuppression protocol was used for the LT recipients, including calcineurin inhibitor (CNI), corticosteroids and mycophenolate mofetil. Significance of differences and correlations between distinct tumor variables, effects of LRT downstaging, and posttransplant outcomes were assessed by t-test, Chi-square test, one-way ANOVA test, and Pearson’s correlation criterion. P-value of <0.05 was considered statistically significant. Kaplan-Meier curves were used to express patient survival, graft survival, and tumor-free survival and its significance was determined by log-rank test.

Results

A cohort of 115 patients underwent LTx between August 2006 and December 2019 at our center. Presence of HCC was the primary indication for LTx. Table 1 is demonstrating pretransplant, transplant, and explant variables for the studied HCC lesions.

Table 1. Pretransplant, transplant and explant characteristics of the studied HCC patients

Note: *, percentage of non necrotic HCC cases

The degree of tumor differentiation and vascular invasion could not be assessed in 15 cases (13% of lesions) due to complete necrosis of the lesion caused by LRT prior to LTx. Follow-up period ranged from 24.3-149.9 months, with a mean of 45.98±33.3 months. The overall 5-year patient and tumor-free survival, and graft survival rate were 79.7%, 90.4% and 88.2%, respectively (Fig. 1).

Figure 1. Overall and tumor-free survival, graft survival following LTx for HCC patients

Initially, 136 patients presented with HCC during the study period. Fig. 2 illustrates their distribution, according to their initial HCC burden, LRT and LTx.

Figure 2. Distribution of HCC patients by their clinical condition during the study period

Note: * Tumor response was assessed according to mRECIST Criteria

Twenty-one patients dropped out while awaiting LT, thus representing 15.4% dropout for the total HCC group. Therefore, thirteen patients from group A were not transplanted, i.e., 8 patients were delisted due to worsening of their clinical state, and 5 patients, due to progression of HCC beyond the MC (9.3% and 5.8% of HCC patients within MC, respectively).

On the other hand, fifty-five patients were subjected to downstaging LRT, and only 42 of them were eligible for transplant since they showed, at least, partial response. The remaining thirteen patients were excluded from the waiting list, due to stable or progressive disease following the use of LRT. Seventy-three patients had HCC within MC (63.5% of transplanted HCC patients), while the remaining 36.5% were beyond MC (42 patients). Only number of HCC nodules and TTV exhibited significant difference between both groups (Table 2).

Table 2. Comparison of different pretransplant variables between both groups

Note: *, percentage within the corresponding group; **, after exclusion of 11 cases with total tumor necrosis

Figure 3. Patient survival curves for group A and B patients following LTx

Figure 4. Tumor-free survival curves for group A and B patients following LTx

Figure 5. Graft survival curves for group A and B patients following LTx

Group A slightly differed from group B as regards the long-term outcomes, but this marginal difference did not reach the level of statistical significance. Patient survival was slightly better in Group A (78.6% vs 74.4% at 5 years), with p value of 0.57 (log-rank test). Similarly, tumor-free survival was slightly better in group A (83.6% vs 74.2%) at the 5-year interval (p=0.35). On the other hand, graft survival was almost the same 90.1% vs 90.5% at the 5 years interval in group A and B respectively (p=0.83). Kaplan-Meier graphs for patient, tumor free and graft survival are illustrated in Fig. 3, 4 and 5, respectively.

Twenty-five recipients (21.7%) died during the follow-up period. 15 were in group A, and 10, in group B. The causes of death among those recipients are listed in Table 3. The total number of mortalities was statistically insignificant between the groups A and B at p=0.82.

HCC recurrence was reported in a total of 11 patients (9.6% of transplanted HCC patients). Six cases were reported in group A and five, in group B. Recurrence rates were 8.2% and 11.9 % in group A and B, respectively (p=0.53).

Five patients diagnosed with HCC recurrence showed initially lymphovascular invasion in their liver explants, poor tumor differentiation was found in four cases, five patients had moderate tumor differentiation, and 7 patients showed total tumor volume (TTV) of >115 cm³. HCC recurrence was significantly related to the presence of vascular invasion and poor degree of differentiation. Moreover, both features were significantly related to patient survival. Vice versa, transplant criteria and tumor volume >115 cm³ showed no significant relation to the patients’ survival or tumor recurrence (Table 4).

Seven patients presented solely with distant metastases in lungs (n=6), bones (n=1), and the remaining four patients developed intrahepatic tumor recurrence. Treatment for these cases was scheduled as supportive therapy, along with palliative use of sorafenib if possible.

Discussion

Currently, LTx offers the best curative chance for patients with HCC on the top of liver cirrhosis, when a liver graft is available [7-9]. Our results correspond with such an opinion, i.e., the overall 5-year patient survival, graft survival, and tumor-free survival were 79.7%, 90.4%, and 88.2%, respectively. We observed LTx dropout rate of 15.1% for the patients with tumors that corresponded to Milan criteria. The institutional data showed dropout of 11.0%, and 57.4% at 6 and 12 months for those patients who initially were within MC [8].

Lack of organs for transplants led to development of prioritizing models to use the limited graft pool very efficiently and successfully. In this context, the accumulated evidence of excellent outcomes in the patients transplanted for HCC who fits the Milan criteria lead to adoption of the 22-point bonus system by UNOS [7-9]. There are endless debates on whether a transplant center should embark on adopting MC or more liberal criteria [10-12]. This might indicate that none of the single morphology-based transplant criteria is sufficient when predicting best transplant outcomes in HCC patients, thus raising a need for inclusion of some biological tumor factors into the predictive models [6, 13-16].

There have been numerous reports on the tumor downstaging approaches. However, these data are limited by the small number of patients and/or the use of varying downstaging protocols [17-23]. HCC progression in the patients being on waiting list for LTx was found to be an important prognostic factor. It was observed that tumor recurrence after LTx increased from 12% in the patients remaining within MC (either spontaneously or following bridging therapy), to 45% for those with tumor progression beyond the MC [24, 25]. Different criteria were developed to assess the response of HCC to LRT, with mRECIST assessment criteria being the commonly adopted [23, 26-29].

Morphological HCC criteria including TTV >115 cm³, or being within MC parameters were not shown to significantly influence post-LTx outcome in our HCC patients. Meanwhile, poor tumor differentiation and presence of lymphatic microvascular invasion proved to exert statistically significant influence upon patient survival and HCC recurrence. This finding highlights the importance of biological factors versus morphological variables in determining long-term outcomes following LTx.

Multiplicity of criteria for LTx might partially demonstrate insufficiency of tumor morphologic criteria alone to precise prediction of post-LTx outcomes. The current staging systems for HCC consider only gross tumor morphology. Tumor size and volume appear to reflect the more sufficient biological features of malignancies. Jonas et al. found that tumor diameter and number of HCC lesions in association with pathologic tumor grade predicted the presence of vascular invasion only in HCC lesions >5 cm [13, 15]. Moreover, molecular subtyping appears to be a useful approach to more individualized management of malignant tumors in general, this is also true in the context of HCC. Various studies concentrate now on genetic profiling of HCC lesions. E.g., Marsh et al. investigated DNA mutations in HCC lesions and found the fractional allelic loss (FAI, an index of mutation accumulation), and vascular invasion were the strongest predictors of tumor-free survival [14, 15].

Downstaging LRT was used to reverse HCC patients to the clinical stage fitting Milan criteria. This strategy proved to be successful in more than 75% of cases; 23.6% were not considered a successful downstaging, due to persistence of stable or progressing disease, according to mRECIST criteria.

The patients successfully downstaged to the condition within MC showed the rates of overall and recurrence-free survival comparable to the patients who corresponded to Milan criteria, being transplanted without initial LRT. In the light of organ shortage, LRT offers an opportunity to downstage HCC to clinical stage within MC, along with selection of more biologically favorable tumors.

Retrospective pattern and relatively small number are among the limitations of our study, thus requiring further studies to confirm such results and to define the role of LRT as a bridge for LTx, aiming for prevention of HCC progression while awaiting LTx.

The era of molecular HCC typing will soon have its influence on HCC management, and introduction of one or more biological markers to the HCC transplant criteria is one of the ways to improve its future therapy.

Conclusion

The overall results of LTx for HCC at our institution showed an excellent outcome. Presence of lymphatic vascular invasion and poor tumor differentiation are the main factors affecting the long-term post-LTx outcomes. This finding again highlights the importance of biological tumor criteria along with commonly adopted morphological criteria. LRT offers an opportunity to downstage HCC to the clinical state which fits MC, along with choosing more biologically favorable tumors. The successfully downstaged HCC patients who fitted MC, showed overall and recurrence-free survival rates comparable to those who were initially transplanted within MC and without LRT.

Conflict of interest

Authors have neither conflict of interest, nor financial issues to be disclosed.

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