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15Cellular Therapy and Transplantation (CTT). Vol. 12, No. 2, 2023 doi: 10.18620/ctt-1866-8836-2023-12-2-15-22 Submitted: 06 June 2023, accepted: 23 June 2023
Salvage second allogeneic stem cell transplantation for primary and secondary graft failure in adult patients
Tatiana A. Rudakova, Ekaterina S. Yakimenko, Nikita P. Volkov, Anastasia V. Beinarovich, Dmitriy K. Zhogolev, Yulia A. Rogacheva, Maria V. Barabanshikova, Yulia Yu. Vlasova, Alexander L. Alyanskiy, Maria D. Vladovskaya, Oleg V. Goloshchapov, Marina O. Popova, Elena V. Morozova, Ivan S. Moiseev, Alexander D. Kulagin
RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, Russia
Dr. Tatiana A. Rudakova, RM Gorbacheva Research Institute E-mail: t_a_rudakova@mail.ru
of Pediatric Oncology, Hematology and Transplantology, Pavlov University, St. Petersburg, 197922, Russia
Citation: Rudakova TA, Yakimenko ES, Volkov NP et al. Salvage second allogeneic stem cell transplantation for primary and secondary graft failure in adult patients. Cell Ther Transplant 2023; 12(2): 15-22.
Summary
We have evaluated clinical outcomes in 49 patients who received unmanipulated allogeneic hematopoietic stem cell transplantation (allo-HSCT) as a salvage treatment for primary (PGF) and secondary graft failure (SGF). The median age of patients was 31 years. Indications for the first allo-HSCT were malignant (n=43, 88%) and nonmalignant diseases (n=6, 12%). Thirteen patients with malignant diseases (27%) were in the active phase of disease. Patients with PGF received a second graft, at a median interval of 43 days (34-82) after allo-HSCT. The second allo-HSCT (HSCT2) were performed from hap-loidentical (n=42, 86%), HLA-matched related (n=2, 4%) and unrelated (n=5, 10%) donors. Donor-specific antibodies (DSA) before the 1st allo-HSCT (HSCT1) were examined in 21 cases, and detected in 7 patients. Donor change in 2nd HSCT was performed in 23 cases. Following HSCT2, the neutrophil counts exceeding 0.5x109/L were achieved in 21(43%) patients with a cumulative
incidence (CI) of 33% (95% CI, 19-48) and median en-graftment time of 29 (1-41) days; blood platelet counts over 50x109/L were achieved in 11(22%) patients. The 3rd allo-HSCT was required in 14 patients. A total of 34 patients died, the cause of death in 31 cases was infection, in three cases - relapse of the underlying disease. The one-year relapse-free survival rate after HSCT2 was 65% (95% CI 51-79), the one-year event-free survival rate) was 20% (95%CI, 11-37) with relapce, acute graft-ver-sus-host disease (aGvHD) grade 3-4 considered as event. One-year overall survival (OS) was 33% (95% CI, 22-50), 5 year OS was 28% (95% CI, 18-45). Source of the graft was the only factor which showed an association with OS: usage of peripheral blood stem cells (50%; 95%, CI 31-66) versus bone marrow (26%; 95% CI 2-65, p=0.049).
Keywords
Graft failure, hematopoietic stem cell transplantation, allogeneic, secondary, efficiency, outcomes.
Introduction
Despite advances in the field of allo-HSCT, primary and secondary graft failure (resp., PGF and SGF) remain a challenging problem with respect to life-threatening pancytopenia, prolonged hospitalization, adverse outcomes and the absence of established treatment guidelines. The incidence of this complication is reported to be from 3% to 30%, depending on numerous factors including the diagnosis, status
of the disease, stem cell dose, type of HSCT, cellular and humoral rejection factors, viral infections [1]. The risk of PGF is reported to vary from 5% with myeloablative conditioning (MAC) to 10% with RIC or non-myeloablative preparative regimens (RIC) [2, 3, 4]. Al-Shaibani et al. report 100-day overall survival of 22% and 64% in primary and secondary graft failure, respectively [5].
PGF is characterized by the lack of neutrophil recovery (absolute neutrophil count <0.5 x 10*9/L), combined with the
lack of donor chimerism in bone and/or peripheral blood cells (<5%) and should be distinguished from poor graft function, or cytopenia with full donor chimerism [6, 7, 8]. SGF is mono- or pancytopenia requiring transfusion of blood products, or growth factor support after achievement of sustained engraftment [6].
When PGF or SGF occurs, the treatment options available are limited and often associated with poor outcomes [9]. For patients who experience graft failure after allo-HSCT, a second transplantation may be necessary to salvage the treatment outcome. However, the efficacy and safety of second transplantations in this setting are not well established, and there are only limited data available on this topic.
The aim of the present study was to report the outcomes in a series of 49 second allo-HSCTs performed for primary or secondary graft failure, and to assess the efficacy of the procedure.
Materials and methods
Clinical features of the patients with GF
A retrospective study was conducted to evaluate the series of HSCT2 performed in 2015-2023 for primary and secondary graft failure (respectively, PGF and SGF) after allo-HSCT in 49 patients with malignant (n=43) and non-malignant diseases (n=6). PGF was defined as absolute neutrophil count (ACN) less 0.5x107L by day +28 after HSCT, with donor chimerism <5%. SGF was defined as cytopenia with loss of donor chimerism to less 10% with no signs of relapse in case of malignant disease.
The median age of the patients was 31 years (range 18-60). Table 1 outlines the clinical characteristics of 49 recipients of HSCT2. There was a predominance of patients with acute myeloid leukemia (n=21; 44%) and other myeloproliferative neoplasms (n=15; 31%). Almost one-third of patients with malignant disorders had active underlying disease prior to HSCT (n=13; 27%).
Conditioning regimens
The first transplant was performed with fludarabine (180 mg/m2) combined with oral busulfan (n=45), or fludarabine and other agents (n=4). Busulfan dosage was 12-14 mg/kg in 15 patients; in older patients or patients with comorbidities, or in severe aplastic anemia, the dose of busulfan was reduced to 10 mg/kg in 16 cases and 8 mg/kg in 14 cases.
Conditioning regimens for the 2nd HSCT included fludarabine (120 mg/m2) and cyclophosphamide (200 mg/m2) in 41 patients; fludarabine and melphalan (100 mg/m2) in 4 patients; fludarabine and tiotepa (n=3) and fludarabine with treosulfan (n=1).
GvHD prophylaxis
GvHD prophylaxis in the 1st HSCT was cyclophosphamide 50 mg/kg on days +3 and +4 (PtCy) alone, or in combination with other agents (n=43; 88%), anti-thymocyte globulin (n=4; 8%), TCR alfa/beta T cell depletion (n=2; 4%). In the 2nd HSCT, the patients received PtCy with or without other immunosuppressive drugs (n=37), bendamustine (n=8) or calcineurin inhibitors (n= 4).
Second transplantation
The second transplants were performed at a median interval of 43 days (range 30-137) from the first transplants, with median follow up time of 118 days (range: 36-2573). Donors for the second HSCT were haploidentical family members (n=41, 84%), mismatched unrelated donors (MMUD, n=2; 4%), matched unrelated donors (MUD, n=4, 8%), matched related donors (MRD, n=2; 4%). Secondary donor was the same in 26 patients; in 20 and 3 cases another family member or another MUD was chosen respectively.
PGF was the indication for 2nd HSCT (33 cases; 67%), and SGF patients were transplanted in 16 cases (33%). The majority of donors were haploidentical for both the first and the second HSCT. PBSC grafts were prevalent over bone marrow
Table 1. Demographic and clinical characteristics of the patients subjected to second HSCT
Characteristic Patients
Median age, years (range) 31 (18-60)
Sex: female/male (%)
Diagnoses, n(%)
Acute lymphoblastic leukemia 7 (14)
Acute myeloid leukemia 21 (44)
Primary/postpolycytemic myelofibrosis 3 (6)
Myelodysplastic syndrome 5 (10)
Atypical Chronic myeloid leukemia 2 (4)
Chronic myeloid leukemia 5 (10)
Severe acquired aplastic anemia 5 (10)
Primary immunodefficiency 1 (2)
Active status of malignant disease at the moment of HSCTI, n(%) 13 (30)
Donor change, n(%) 23 (47)
HSC source change, n(%) 29 (59)
as the stem cell source in both 1st and 2nd transplants. A detailed description of HSCT1 and HSCT2 patients is presented in Table 2.
Statistical analysis
Patient and transplant characteristics were evaluated by means of descriptive statistics. The Wilcoxon rank-sum test was used for continuous and Chi-square test for categorical factors. All patients were followed longitudinally until death, or last follow-up. Cumulative incidence rates and their 95% confidence intervals were estimated for engraftment (death before Day +30 and relapse before Day+30 were regarded as the competing risks), and for aGvHD with death and relapse as competing risks. Kaplan-Meier analysis was used to estimate overall survival (OS), and event-free survival, with relapse, acute GvHD grade III-IV, or the 3rd HSCT as an event. All statistical procedures were performed with R free software package v.4.3.0.
Results
Blood recovery and early complications
Neutrophil engraftment was documented in 21 pts with cumulative incidence (CI) of 59% (95%CI, 37-77) and median time of 29 days (range, 1-55). Blood platelet counts of 20x109/L were achieved in 11 patients on day 27 (range 12190), and the levels of 50x109/L were observed on day 31 (range 22-579) in 9 patients.
A total of 34 pts died during the follow-up period. In 31 cases, the lethal outcome was caused by infectious complications, and 3 patients died with relapse of primary disease. Early death (before D+30) occurred in 11 (22%) cases, with infectious cause of death in 10 patients (including one case of SARS-CoV2 infection), and one case of veno-occlusive
Table 2. Transplant details at the 1st and 2nd HSCTs in the patients with post-transplant graft failure
Characteristic HSCT1 HSCT2
Donor, n (%)
Haploidentical 27 (55) 41 (84)
MMUD 10 (20) 2 (4)
MUD 9 (18) 4 (8)
MRD 3 (6) 2 (4)
Graft source
PB 26 (53) 38 (78)
BM 22 (45) 11 (22)
both 1 (2) -
PBSC: median (range)
Number of NC*, 108 8.0 (3.5-17.7) 14.8 (3.8-156.6)
Number of CD34+, 106 5.6 (2.3-10.0) 7 (1.3-12.4)
Number of CD3+, 107 16.8 (1.2 -54.7) 18.85 (6-60.3)
BM: median (range)
Number of NC, 108 3.1 (1.39-5.0) 12.6 (2.0-42.3)
Number of CD34+, 106 2.79 (1.57-5.0) 2 (0.8-4.95)
Number of CD3+, 107 2.6 (0.4-8.8) 3.2 (1.5-4.7)
Note: NC, nucleated cells
disease. The overall survival (OS) was 34% (95% CI; 22-50) at one year after the 1st HSCT, and 28% (95%CI; 18-45) at 5 years after the 1st HSCT (Fig. 1).
Figure 1. Overall survival rate of HSCT2 recipients at 5-year following the 1st allo-HSCT
Non-relapse mortality rate (NRM) was 65% (95% CI, 5179) at one year after the 2nd HSCT. Event-free survival rate was 19.5% (95% CI; 10-35) at one year post-transplant (with relapse, acute GvHD III-IV or the 3rd HSCT considered an event. Infectious episodes were documented in 42 cases, while 38 patients had active infection at the time of the 2HSCT (Fig. 2). Fourteen patients underwent the 3rd HSCT, due to primary graft failure in 11 cases, and secondary graft failure in three patients.
Early post-transplant toxicity manifested as mucositis 1-3 grade (n=22; 34%), cystitis (n=6; 23%), cytokine release syndrome (n=6; 9%), venoocclusive disease (n=6; 9%), throm-botic microangiopathy (n=2; 1%), hemorrhagic complications (n=16; 25%). Cumulative incidence of acute GvHD was 25% (95% CI, 13-37). Acute GvHD grade III-IV occurred in 9 patients (18%) with involvement of the skin (n=7) and gastrointestinal tract (n=2).
Infectious landscape
Majority of patients (47 of 49) had, at least, one infectious condition after HSCT1. Five patients had separate or combined bacterial, fungal and viral episodes of infections after HSCT1; 12 patients had bacterial and viral episodes. In 8 cases, bacterial and fungal episodes were documented. A total of 33 patients exhibited active bacterial infection at the time of HSCT2, while 5 patients had active bacterial and viral infection, and one patient had active combined bacterial, fungal and viral infection at the time of HSCT2 (Fig. 2). Ten patients were free of clinical infection prior to HSCT2, and engraftment rate after HSCT2 in the patients with active infection was 42% (95%CI; 24-59) versus 65% (95%CI; 1790), p=0.57, while overall survival was 27% (95%CI; 16-47) for the group with active infection vs. 30% (95%CI; 15-47) for the group with no infection at the time of HSCT2 (p=0.8).
A total of 45 patients experienced, at least, one infectious episode after HSCT2. Of them, a single bacterial pathogen was revealed in 6 cases, 4 patients had only viral infections, isolated fungal infection was found in one case. 15 patients had both bacterial and viral infections; bacterial and fungal episodes were documented in 9 cases, combined bacterial, fungal and viral infections were registered in 10 cases. A total of 27 patients had mixed infection, of them 10 cases were caused by bacterial and fungal pathogens; 11, by bacterial and viral agents; 4, by bacterial, fungal and viral pathogens, and, 2 by viral and fungal agents. Reactivation of cytomegalovirus (CMV) was observed most frequently, occurring in
19 patients (39%), with reactivation before D+30 in 10 cases. Meanwhile, HHV6 was detected in 11 cases (22%), with early reactivation in five patients. Eight patients had other significant infections, e.g., BK virus (n=6), JC virus (n=1), SARS-CoV-2 (n=1).
Since prolonged aplasia may be associated with viral infection, we evaluated the influence of early viral reactivation occurring upon the engraftment period after HSCT2. There was no difference for engraftment rates in the subgroups with vs. without early CMV or HSV6 reactivation, 53 % (95%CI; 13-82) vs. 42% (95%CI; 26-59), p=0.84.
Donor-specific antibodies (DSA)
In 20 patients, blood serum samples were tested prior to transplant for DSA using solid-phase immunoassays. Seven patients proved to be DSA-positive (35%) and 13 patients were DSA-negative (65%). Of the 7 DSA-positive patients, three achieved engraftment at HSCT2.
Macrophages
BM aspirates were obtained from all 49 patients at a similar time period, i.e., between 2-3 weeks, both after first and second HSCT. All specimens showed reduced cellularity. As seen from Fig. 3, the median macrophage count before the second HSCT was 7.7% (range: 0.6-100) in non-engrafted patients vs. 16.5% (0.6 to 60) in engrafted ones (p=0.45). Median macrophage count after the second HSCT was 45.5% (range: 10-100) in non-engrafted patients vs. 3.75% (range: 0.04-26) in engrafted ones (p-value=0.29).
Upon univariate analysis, PBSC as a graft source compared to BM proved to be the only factor associated with better engraftment, OS and NRM rates, i.e., 50% (95%CI; 15-65) versus 26% (95%CI; 21-66, p=0.04); 41% versus 9%, p=0.04; 26% (95%CI, 12-42) vs. 57% (95%CI; 20-82, p=0.06), respectively.
Figure 2. Incidence of infectious complications among the patients subjected to HSCT2 (A, Infectious episodes during the first post-transplant period; B, infections by the date of HSCT2)
Discussion
Second HCT is frequently used to treat GF occurring after allo-HSCT. We report similar, or slightly better outcomes of HSCT2 as salvage therapy for primary and secondary GF than it was published elsewhere by Schriber et al., and Lund et al. [10, 11] who analyzed cohorts with mixed diagnoses, whereas the recent, less heterogeneous cohort studies show higher rate of engraftment (73-98%), lower rate of acute GvHD III-IV grade (8-17%) [12-14]. Nevertheless, rates of overall survival and NRM in our study were concordant with those in a study performed on behalf of the Acute Leukemia Working Party of the EBMT [12].
Infections are reported to be the main cause of death in the setting of salvage second allo-HSCT [11, 12, 14]. Our study confirms this statement by 63% (n=31) of lethal infectious complications after HSCT2. Bacterial infections were prevalent in our study. Although there is evidence of an effect of viral reactivation on the bone marrow function, our study found no association between viral reactivation and engraft-ment [15-17]. Post-transplant toxicity profile was acceptable with rate of VOD and TMA being not higher than in general transplant population [18, 19].
Recently, the donor-specific antibodies (DSA) have been found to be predictive of primary GF in the setting of HLA haploidentical mismatched family transplants, especially in multiply transfused patients [20]. In our study, the proportion of haploidentical allo-HSCT was relatively high. However, due to retrospective nature of the analysis, not all hap-loidentical cases were tested for DSA, which present a clear limitation of our study, along with small group size.
A number of studies propose "seed, soil and climate" model to describe factors influencing engraftment and functioning of the hematopoietic stem cell graft [21, 22]. The available data suggest a hypothesis about complex mechanisms which may be activated during GF involving both soluble mole-
cules and cellular components [23, 24]. Since macrophages are known to be effector cells of IFNy-mediated inflammatory pathway, we suggested macrophage count to be an indirect marker of primary graft failure [25, 26]. No statistically significant association between macrophage counts and en-graftment was demonstrated in our study, but there was a tendency to higher macrophage numbers in non-engrafted patients after HSCT2. That finding also might result from concomitant triggers of allo-immunity, such as viral reactivation or severe bacterial infections [27].
There are several obvious limitations in this study. First, this is a retrospective study conducted at a single referral center. Second, we studied a small patient group with high heterogeneity in primary diagnoses of allo-HSCT recipients, different factors of prognosis and outcomes after allo-HSCT. Due to these limitations, only univariate analysis was performed. Usage of PBSC as a graft source proved to be the only factor, supported with a number of previous reports which showed statistically significant association with better engraftment and overall survival [28, 29].
Conclusion
Thus, being a salvage treatment of life-threatening GF, HSCT2 with RIC is a feasible treatment option which can rescue about a third of patients with primary and secondary GF after HSCT1. However, NRM remains high, mainly due to infectious complications. Further studies aiming at improved engraftment, reduction of infection rates and transplant-related toxicity are warranted, attempting for better outcomes in the patients with post-transplantation graft failure.
Conflict of interests
The authors have declared no competing interests.
Figure 3. Macrophage counts before (A) and after HSCT2 (B) with or without engraftment (abscissa). Ordinate, macrophage counts in bone marrow (%)
Compliance with ethical standards
All human clinical studies have been approved by the appropriate institutional Ethics Committee and have been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. All medical procedures performed were in accordance with the Ethical Standards of the responsible committee on human experimentation (institutional and national), and with the Helsinki Declaration of 1975, as revised in 2008.
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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
Резюме
Мы оценивали клинические исходы у 49 пациентов, перенесших аллогенную трансплантацию немани-пулированных гемопоэтических стволовых клеток (алло-ТГСК) в качестве лечения спасения при первичной (ПНТ) и вторичной недостаточности трансплантата (ВНТ). Средний возраст больных составил 31 год. Показаниями к первой алло-ТГСК были злокачественные новообразования (п=43, 88%) и незлокачественные заболевания (п=6, 12%). Тринадцать больных со злокачественными заболеваниями (27%) находились в активной фазе заболевания. Пациентам с ПНТ была проведена вторая ТГСК со средним интервалом 43 дня (34-82) после первичной алло-ТГСК. Вторую алло-ТГСК (ТГСК2) выполняли от гаплоидентичных (п=42, 86%), ИЬА-совместимых родственных (п=2, 4%) и неродственных (п=5, 10%) доноров. Донор-специфические антитела (ДСА) перед первой алло-ТГСК (ТГСК1) исследовали в 21 случае, и они были выявлены у 7 пациентов. Смена донора при 2-й ТГСК произведена в 23 случаях. После ТГСК2 количество нейтрофилов, превышающее 0,5х109/л, было достигнуто у 21 (43%) пациента с кумулятивной частотой (С1), равной 33% (95% С1: 19-48) и средним временем приживления трансплантата 29 (1-41) сут.; количество тромбоцитов более 50х109/л было отмечено у 11 пациентов (22%).
3-я алло-ТГСК потребовалась у 14 пациентов. Всего умерло 34 больных, причиной смерти в 31 случае стала инфекция, в трех случаях - рецидив основного заболевания. Годичная безрецидивная (бессобытийная) выживаемость после ТГСК2 составила 65% (95% С1 51-79), годичная безрецидивная выживаемость) - 20% (95% С1 11-37), при этом рецидив и острая реакция «трансплантат против хозяина» (оРТПХ) 3-4 степени расценивались как событие. Однолетняя общая выживаемость (ОВ) составила 33% (95% С1 22-50), 5-летняя ОВ - 28% (95% С1 1845). Клеточный источник трансплантата был единственным фактором, который показал связь с ОВ: использование стволовых клеток периферической крови (50%; 95%, С1: 31-66) по сравнению с костным мозгом (26%; 95%, С1 2-65, р=0,049).
Ключевые слова
Недостаточность трансплантата, трансплантация гемопоэтических стволовых клеток, аллогенная, вторичная, эффективность, исходы.
