Graft-versus-host Disease Prophylaxis Strategy Research Articles

Unrelated donor transplantation with post-transplant cyclophosphamide versus ATG for myelodysplastic neoplasms

Prospective randomized trials have reported a benefit for anti-thymocyte globulin (ATG)-based graft-versus-host disease (GvHD) prophylaxis in the setting of allogeneic hematopoietic stem cell transplantation (Allo-HSCT) with unrelated donors (UD). However, the optimal GvHD prophylaxis strategy has been recently challenged by the increasing use of post-transplant cyclophosphamide (PTCY). We report from the EBMT registry the outcomes of 960 patients with myelodysplastic neoplasms (MDS) undergoing allo-HSCT from UD with PTCY or ATG as GvHD prophylaxis. Primary outcomes were overall survival (OS) and progression-free survival (PFS). Disease characteristics were similar in both groups. Day 28 neutrophil engraftment was significantly better with ATG (93% vs 85%, p<0.001). With a median follow-up of 4.4 years (95% confidence interval [CI] 4.2 - 4.8), 5-year OS was 58% (95% CI 50-65) with PTCY and 49% (95% CI 46-53%) in the ATG group, p=0.07. 5-year PFS was higher for PTCY with 53% (95% CI 45-60) vs 44% (95% CI 40-48) for ATG, p=0.043. Grade II-IV aGvHD incidence was lower using PTCY (23% [95% CI 17-29%] vs 30% [95% CI 27-33%]), p=0.044 while there was no difference in incidence of cGvHD at 5 years. Multivariable analyses confirmed better OS and PFS with PTCY, with a HR for ATG of 1.32 (1 - 1.74), p=0.05, and a better PFS for PTCY with a HR for ATG of 1.33 (1.03 - 1.73), p=0.03. This study suggests that GvHD prophylaxis using PTCY instead of ATG in this setting remains a valid option. Further prospective randomized studies would be essential to confirm these results.

Higher Infused CD34+ Cell Dose Does Not Influence Clinical Outcomes in Allogeneic Peripheral Blood Stem Cell Transplantation Using Post-Transplant Cyclophosphamide in Children with High-Risk Leukemia

Background: The impact of infused graft cell dose on outcomes, including graft-versus-host disease (GVHD) and relapse, which have been major challenges in allogeneic hematopoietic stem cell transplantation (HSCT), remains unclear. Post-transplant cyclophosphamide (PTCy) has emerged as an effective and safe GVHD prophylaxis strategy, with improved GVHD incidence and relapse-free survival (RFS). Early practice of unmanipulated peripheral blood stem cell transplantation (PBSCT) using PTCy was commonly performed with a restriction on the CD34 + cell dose to minimize the risk of GVHD. However, recent studies demonstrated the protective effect of CD34 + cells on relapse, with no association with GVHD, thereby raising questions about the optimal cell dose. In this context, we aimed to study the impact of infused cell dose on outcomes in children with high-risk leukemia who underwent allogeneic PBSCT using PTCy. Methods: A retrospective analysis was conducted on 50 pediatric patients (median age at diagnosis : 9.3 years, range, 0.3-17.3) with hematologic malignancy (33 acute myeloid leukemia, 12 acute lymphoblastic leukemia, and 4 myelodysplastic syndrome/myeloproliferative neoplasm, 1 other) in first or second remission between 2019 and 2023. They received their first allogeneic PBSCT and donors included matched or mismatched unrelated donors (n=12) and haploidentical family donors (n=38). Conditioning was myeloablative, and PTCy-based GVHD prophylaxis (50mg/kg/day on days 3 and 4) was used for all patients. The patients were divided into three groups based on infused CD34 + cell dose: high dose group (&amp;gt;10 × 10 6/kg, N=10), intermediate dose group (5-10 × 10 6/kg, N=24), and low dose group (&amp;lt;5 × 10 6/kg, N=16). Results: The median age at HSCT was 11.6 years (range, 0.7-24.9). The median dose of infused CD34 + cells and CD3 + cells was 6.5 x 10 6/kg and 48.6 x 10 7/kg, respectively. There was a tendency for the mean dose of infused CD3 + cells to increase in the group with higher infused CD34 + cell dose: 47.6 x 10 7/kg for low dose group, 57.5 x 10 7/kg for intermediate dose group, and 73.4 x 10 7/kg for high dose group ( P=0.053). Patients receiving a higher dose of CD34+ cells had significantly shorter median time to neutrophil engraftment (13 days in high dose group vs. 14 days in intermediate dose group vs. 17 days in low dose group, P&amp;lt;0.001). The time to platelet engraftment was similar among the three groups. There was no difference among high dose, intermediate dose, and low dose groups in the cumulative incidence (CI) of day+100 grades II-IV acute GVHD and moderate to severe chronic GVHD (grades II to IV acute GVHD: 60.0% vs. 63.6% vs. 73.3% [ P=0.988], respectively; moderate to severe chronic GVHD: 22.2% vs. 29.2% vs. 25.0% [ P=0.961], respectively). With a median observation period of 20.4 months (range, 3.0-46.8) from transplant, RFS and overall survival (OS) showed a non-significant trend towards a higher survival rate in the high dose group compared to the other groups (RFS: 76.2% in high dose group vs. 62.1% in intermediate dose group vs. 62.6% in low dose group, P=0.694; OS: 88.9% in high dose group vs. 63.0% in intermediate dose group vs. 76.0% in low dose group, P=0.788). Conclusions: Higher number of infused CD34 + cell dose was associated with faster neutrophil engraftment. For patients in the high dose group (CD34 + cell dose &amp;gt; 10 x 10 6/kg with a relatively higher number of CD3 + cells), a non-significant trend toward a higher survival rate was observed, with no detrimental impact on GVHD. PBSCT in a pediatric patient from an unrelated or haploidentical adult donor may result in a high infused cell dose. Our findings suggest that restricting the number of infused CD34 + cell dose may not be necessary in the setting of allogeneic PBSCT with PTCy. Larger cohort studies are needed to confirm the potential benefits and drawbacks of a higher cell dose in children who receive PBSCT within a PTCy setting.

Comparison between Post-Transplant Cyclophosphamide Use and Conventional Prophylaxis of Graft-Versus-Host Disease: A Retrospective Study

Introduction: In order to modify the immune response balance between donor and recipient in the context of haploidentical transplantation, the use of post-transplant cyclophosphamide (PTCy), which reduces the population of recipient alloreactive T cells, has become the preferred strategy for graft-versus-host disease (GVHD) prophylaxis. Recently, this approach has also been tested and validated in HLA-matched related or unrelated transplants, as well as in unrelated transplants with HLA mismatch. However, high doses of PTCy can cause cardiac toxicity, hemorrhagic cystitis, and potentially increase the incidence of viral infections. Therefore, comparative studies are needed to evaluate the outcomes of PTCy use compared to other conventional GVHD prophylaxis strategies. Objective: To evaluate the outcomes of patients undergoing allogeneic peripheral blood stem cell transplantation (PBSCT) and to compare the use of post-transplant cyclophosphamide with other GVHD prophylaxis strategies. Patients and Methods: Retrospective analysis of consecutive patients transplanted between March 2014 and March 2023 at two transplant centers. The median follow-up was 24 months (range: 3-116 months). Results: A total of 118 adult patients undergoing PBSCT were included. There were 70 HLA-matched related donors, 28 HLA-matched unrelated donors, and 20 unrelated donors with one HLA mismatch. The median age was 52 years (range: 18 to 80), with a majority being male (51%). The most common diagnoses were acute myeloid leukemia (37%), acute lymphoblastic leukemia (18%), and myelodysplastic syndrome (18%). The disease risk index (DRI) was considered low or intermediate in 53% of cases, high in 31%, and very high in 16%. The majority of patients (76%) had a low risk of transplant-related complications (HCT-CI). Most patients received reduced-intensity conditioning regimens (78%), and the majority (72%) received some sort of T-cell depletion, with 36 (31%) patients receiving PTCy and 49 (41%) receiving ATG. No significant differences were found between the groups (PTCy vs. non-PTCy) in overall survival at 24 months (65% vs. 61%, p = 0.71, respectively), disease-free survival at 24 months (55% vs. 53%, p = 0.76), non-relapse mortality at 24 months (21% vs. 23%, p = 0.84), relapse rate at 24 months (24% vs. 24%, p = 0.61), neutrophil engraftment at 30 days (89% vs. 93%, p = 0.49), and incidence of grade II-IV acute GVHD at 100 days (31% vs. 29%, p = 0.99), grade III-IV acute GVHD at 100 days (6% vs. 12%, p = 0.22), chronic GVHD at 24 months (42% vs. 50%, p = 0.51), and moderate/severe chronic GVHD at 24 months (19% vs. 23%, p = 0.66). There was also no difference in the incidence of infections, including viral infections and cytomegalovirus reactivation. Conclusions: The use of PTCy demonstrated similar clinical outcomes to other GVHD prophylaxis strategies, without an increased risk of infections or mortality. Therefore, PTCy can be considered a viable, safe, and cost-effective option for GVHD prophylaxis in the context of HLA-matched and HLA-mismatched transplants.

Corticosteroids as graft-versus-host disease prophylaxis for allogeneic hematopoietic cell transplant recipients with calcineurin inhibitor intolerance

Background aimsAlthough calcineurin inhibitors (CNIs) have a well-established role in the prevention of graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT), their use can be limited by significant toxicities, which may result in premature treatment discontinuation. The optimal management of patients with CNI intolerance is unknown. The objective of this study was to determine the effectiveness of corticosteroids as GVHD prophylaxis for patients with CNI intolerance. MethodsThis retrospective single-center study included consecutive adult patients with hematologic malignancies who underwent myeloablative peripheral blood allogeneic HCT with anti-thymocyte globulin, CNI, and methotrexate GVHD prophylaxis in Alberta, Canada. Multivariable competing-risks regression was used to compare cumulative incidences of GVHD, relapse, and non-relapse mortality between recipients of corticosteroid versus continuous CNI prophylaxis, and multivariable Cox proportional hazards regression was applied to compare overall survival, relapse-free survival (RFS) and moderate-to-severe chronic GVHD and RFS. ResultsAmong 509 allogeneic HCT recipients, 58 (11%) patients developed CNI intolerance and were switched to corticosteroid prophylaxis at median 28 days (range 1-53) after HCT. Compared with patients who received continuous CNI prophylaxis, recipients of corticosteroid prophylaxis had significantly greater cumulative incidences of grade 2-4 acute GVHD (subhazard ratio [SHR] 1.74, 95% confidence interval [CI] 1.08–2.80, P = 0.024), grade 3–4 acute GVHD (SHR 3.22, 95% CI 1.55–6.72, P = 0.002), and GVHD-related non-relapse mortality (SHR 3.07, 95% CI 1.54–6.12, P = 0.001). There were no significant differences in moderate-to-severe chronic GVHD (SHR 0.84, 95% CI 0.43–1.63, P = 0.60) or relapse (SHR 0.92, 95% CI 0.53–1.62, P = 0.78), but corticosteroid prophylaxis was associated with significantly inferior overall survival (hazard ratio [HR] 1.77, 95% CI 1.20–2.61, P = 0.004), RFS (HR 1.54, 95% CI 1.06–2.25, P = 0.024), and chronic GVHD and RFS (HR 1.46, 95% CI 1.04–2.05, P = 0.029). ConclusionsAllogeneic HCT recipients with CNI intolerance are at increased risks of acute GVHD and poor outcomes despite institution of corticosteroid prophylaxis following premature CNI discontinuation. Alternative GVHD prophylaxis strategies are needed for this high-risk population.

Real-World Data Showing Trends and Outcomes by Race and Ethnicity in Allogeneic Hematopoietic Cell Transplantation: A Report from the Center for International Blood and Marrow Transplant Research

The use of HLA-mismatched donors could enable more patients with ethnically diverse backgrounds to receive allogeneic hematopoietic cell transplantation (HCT) in the United States. However, real-world trends and outcomes following mismatched donor HCT for diverse patients remain largely undefined. We conducted this study to determine whether the use of mismatched donor platforms have increased the access to allogeneic HCT for ethnically diverse patients, particularly through the application of novel graft-versus-host disease (GVHD) prophylaxis regimens, and whether outcomes for diverse patients are comparable to those of non-Hispanic White patients. This observational cross-sectional study used real-world data from the Center for International Blood and Marrow Transplant Research (CIBMTR) registry. All patients receiving their first allogeneic HCT in the United States between 2009 and 2020 were included, with a focus on transplantations performed in 2020. Data from patients undergoing allogeneic HCT using bone marrow, peripheral blood, or cord blood from HLA-matched or mismatched related and unrelated donors were analyzed. Specifically, relative proportion of allogeneic HCT was generated as percentage of total for donor type and for patient age, disease indication, GVHD prophylaxis, and race and ethnicity. Causes of death were summarized using frequencies, and the Kaplan-Meier estimator was used for estimating overall survival. Compared to matched related donor and matched unrelated donor HCT, more ethnically diverse patients received mismatched unrelated donor, haploidentical donor, and cord blood HCT. Although matched unrelated donor remains the most common donor type, the use of haploidentical donors has increased significantly over the last 5 years. Paralleling this increase in haploidentical HCT is the increased use of post-transplantation cyclophosphamide (PTCy) as GVHD prophylaxis. Relative to previous transplantation eras, the most contemporary era is associated with the highest survival rates following allogeneic HCT irrespective of patient race and ethnicity. Nonetheless, disease relapse remains the primary cause of death for both adult and pediatric allogeneic HCT recipients by donor type and across all patient racial/ethnic groups. Ethnically diverse patients are undergoing allogeneic HCT at higher rates, largely through the use of alternative donor platforms incorporating PTCy. Maintaining access to potential life-saving allogeneic HCT using alternative donors and novel GVHD prophylaxis strategies and improving HCT outcomes, particularly disease relapse, remain urgent clinical needs.

Post-Transplant Cyclophosphamide, Tacrolimus, and Mycophenolate Mofetil As the New Standard for Graft-Versus-Host Disease (GVHD) Prophylaxis in Reduced Intensity Conditioning: Results from Phase III BMT CTN 1703

Introduction: Controlling both GVHD and disease relapse is essential for allogeneic hematopoietic cell transplantation (alloHCT) success. For three decades, the standard GVHD prophylaxis strategy has been a calcineurin inhibitor such as tacrolimus (Tac) plus methotrexate (MTX). Although several approaches have been tried in recent years to improve upon Tac/MTX, intensifying immunosuppression frequently comes with an increased risk of serious infections or relapse and usually no effect on chronic GVHD even if acute GVHD is reduced. The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) previously completed a phase II study comparing three novel GVHD prophylaxis regimens to contemporaneous controls receiving Tac/MTX (BMT CTN 1203) in order to determine the most promising novel GVHD prophylaxis approach with reduced intensity conditioning (RIC). The most promising GVHD prophylaxis regimen in BMT CTN 1203 was a 3-drug combination of post-transplant cyclophosphamide (PTCy), tacrolimus, and mycophenolate mofetil (PTCy/Tac/MMF). Here, we report the results of the randomized phase III study comparing outcomes of alloHCT in those randomized to receive PTCy/Tac/MMF versus standard Tac/MTX. Patients and Methods: Eligible adults (age 18+) with hematologic malignancies undergoing RIC alloHCT with an 6/6 matched related (N=128), 8/8 matched unrelated (N=288), or 7/8 single mismatch (N=15) peripheral blood stem cell donor, satisfactory organ function, and adequate performance status were randomized 1:1 to receive PTCy/Tac/MMF (N=214) or Tac/MTX (N=217), stratified by transplant center and Disease Risk Index (DRI). The primary endpoint of the study was GVHD/relapse or progression-free survival (GRFS), a time-to-event outcome defined as grade III-IV acute GVHD, chronic GVHD requiring systemic immune suppression, disease relapse or progression, or death by any cause. The primary hypothesis was that PTCy/Tac/MMF has a ≥15% higher GRFS at 1 year than Tac/MTX in the intent-to-treat population. Secondary endpoints included the incidence/severity of acute and chronic GVHD, engraftment/chimerism, relapse/progression, infections, and survival. Results: The 2 study arms were well balanced by patient sex, age, Karnofsky performance status, disease risk, comorbidities, donor match, conditioning regimen, and post-transplant maintenance therapy (Figure panel A). In the multivariate Cox regression model of the primary endpoint, the PTCy treatment group had a significantly lower hazard of GRFS than Tac/MTX (hazard ratio 0.641, 95% confidence interval [CI] 0.492 to 0.835, p=0.001). The adjusted 1-year GRFS rate was 52.7% (95% CI: 45.8%, 59.2%) for the PTCy arm and 34.9% (95% CI: 28.6%, 41.3%) for the control arm, Figure panel B). The lower proportion of GRFS events in the PTCy arm was due to a reduction in both acute and chronic GVHD. The Day 100 grade III-IV acute GVHD was 6.3% vs 14.7% (p=0.001), and chronic GVHD rate at 1 year was 21.9% vs 35.1% (p=0.005) for PTCy vs Tac/MTX, respectively. There was no difference in the relapse/progression rate at 1 year (20.8% vs 20.2%, p=0.9), or OS rate at 1 year post transplant (76.8% vs 72.6% , p=0.3), in PTCy vs Tac/MTX. The cumulative incidence of engraftment was lower for PTCy for neutrophils ≥ 500/mm3 by day +28 (90.3% vs 93.4%, p=0.03), platelets ≥ 50,000/mm3 by day +100 (79.5% vs 83.7%, p<0.001), and lymphocytes ≥ 1000/mm3 by 1 year (47.1% vs 63.2%, p<0.001). Grade 3 infection rates were similar between the arms (12.2% for PTCy vs 13.3%, p=0.8) but grade 2 infections were greater for PTCy (33.7% vs 23.5%, p=0.002). There was no difference in CMV reactivation between the treatment arms (7.3% for PTCy vs 7.1%, p=0.8). There was no significant difference in proportion of chimerism at day +100 (>95% donor in 68.6% for PTCy vs 67.8%, p=0.2) or secondary graft failure between the arms (2.9% for PTCy vs 0.9%, p=0.2). Conclusions: BMT CTN 1703 met its primary endpoint, demonstrating a higher 1-year GRFS with PTCy/Tac/MMF compared to Tac/MTX owing to significant improvements in GVHD risk without increased risk of relapse or death. PTCy/Tac/MMF, which has become standard of care for mismatched transplants, should also become the standard of care for GVHD prophylaxis from closely-matched donors receiving reduced intensity conditioning. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Controversies and expectations for the prevention of GVHD: A biological and clinical perspective.

Severe acute and chronic graft versus host disease (GVHD) remains a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation. Historically, cord blood and matched sibling transplantation has been associated with the lowest rates of GVHD. Newer methods have modified the lymphocyte components to minimize alloimmunity, including: anti-thymocyte globulin, post-transplant cyclophosphamide, alpha/beta T cell depletion, and abatacept. These agents have shown promise in reducing severe GVHD, however, can be associated with increased risks of relapse, graft failure, infections, and delayed immune reconstitution. Nonetheless, these GVHD prophylaxis strategies have permitted expansion of donor sources, especially critical for those of non-Caucasian decent who previously lacked transplant options. This review will focus on the biologic mechanisms driving GVHD, the method by which each agent impacts these activated pathways, and the clinical consequences of these modern prophylaxis approaches. In addition, emerging novel targeted strategies will be described. These GVHD prophylaxis approaches have revolutionized our ability to increase access to transplant and have provided important insights into the biology of GVHD and immune reconstitution.

Haploidentical Transplant Using Selective Ex-Vivo Tcrαβ Depleting and Memory T Cell Add-Back Results in More Favorable Gvhd-Free /Relapse Free Survival (GRFS) As Compared to Post-Transplant Cyclophosphamide for Adults with Hematological Malignancies - a Comparative Analysis of 170 Patients in a Multicenter Study in Singapore

Background: Outcome after haploidentical (Haplo) hematopoietic cell transplantation (HCT) is encouraging and has become alternative option to treat patients with high-risk hematological malignancies without human leukocyte antigen (HLA) matched donor. Currently, ex-vivo T-cell depletion (TCD) and unmanipulated graft with post-transplant cyclophosphamide (PTCy) remain the most commonly employed graft-versus-host disease (GVHD) prophylaxis strategies in patients receiving Haplo-HCT. The aim of this study is to compare the clinical outcome of adult patients with hematological malignancies receiving Haplo-HCT using these two different GVHD prophylaxis strategies. Methods: We analysed 170 adults’ patients receiving haploidentical peripheral blood stem cell transplant for various hematological malignancies between Jan 2011 and July 2022, following myeloablative (MAC, n=21) or reduced intensity conditioning (RIC, N=149) regimen. 100 patients received Haplo-HCT with selective ex-vivo T cell (TCRαβ and CD45RA+) depleted grafts for GVHD prophylaxis (Haplo-TCD) (Koh LP et al. ASH 2018), whereas 70 patients received unmanipulated, T-cell-replete graft followed by PTCy (Haplo-PTCy), in combination with tacrolimus and mycophenolate mofetil for GVHD prophylaxis. Results: Median time to neutrophil recovery was 12 days (range, 8-25) and 18 days (range 13-29) for patients receiving Haplo-TCD and Haplo-PTCY, respectively (p<0.001). Primary graft failure was seen in 1 patient in each of the 2 groups. Cumulative incidence (C.I.) of non-relapse mortality (NRM) (22% vs 25%; p=0.508), relapse (22% vs 26%; p=0.561), day 180 grade 2-4 acute GVHD (aGVHD) (35% vs 33%; p=0.539), day 180 grade 3-4 aGVHD (11% vs 3%; p=0.508) were not significantly different between the Haplo-TCD and Haplo-PTCy cohorts. However, C.I. of chronic GVHD (cGVHD) at 2 years was significantly lower in Haplo-TCD as compared with Haplo-PTCy (4% vs 26%, P<0.001). At a median follow up of 19.7 months (range 0.3- 67.1) in surviving patients, the 2-year overall (OS), event-free (EFS), and GVHD-free/relapse-free (GRFS) survival were 62% vs 49% (p=0.083), 56% vs 42% (p=0.309) and 54% vs 31% (p=0.006) for Haplo-TCD and Haplo-PTCy, respectively. Multivariable analysis showed that disease risk index (DRI), HCT-Comorbidity Index (HCT-CI) and GVHD prophylaxis strategies were independent risk factors for OS, EFS and GRFS. In contrast, NRM was only influenced by HCT-CI (p=0.007), whereas relapse was only influenced by DRI (p=0.0001). Notably, Haplo-TCD was associated with significantly lower risk of cGVHD in multivariable analysis (HR 0.14; 95% CI 0.04-0.15; p=0.0011), and this translates into significantly more favorable GRFS as compared to Haplo-PTCy (Figure 1). We performed propensity scoring for matching and identified 54 patients in each cohort. With propensity score matching, the use haplo-TCD retained its significant prognostic impact with lower risk of cGVHD (HR 0.08; 95% CI 1-62; p=0.016), and resulting in more favorable 5 years GRFS (50% vs 30%; p=0.03) as compared to Haplo-PTCy recipients (Figure 2). There was no significant difference in OS, EFS, CI of relapse, NRM, acute GVHD 2-4 and 3-4 between the 2 groups. Conclusions: As compared to unmanipulated graft and PTCy, Haplo-HCT using ex-vivo TCRαβ and CD45RA+ depleted graft resulted in comparable outcome, with the additional advantage of earlier neutrophil engraftment, lower risk of cGVHD and more favorable GRFS. The difference in the post-transplant outcome with these two GVHD prophylaxis strategies warrants further investigation and confirmation in prospective controlled trials. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Graft-Versus-Host-Disease Prophylaxis with ATG or Ptcy in Patients with Lymphoproliferative Disorders Undergoing Reduced Intensity Conditioning Regimen 9/10 Mmud HCT

Introduction: Post-transplant cyclophosphamide (PTCY) has been introduced as a graft-versus-host disease (GvHD) prophylaxis in haploidentical setting with successful results. As a result, PTCY has been applied to other settings such as in mismatched and matched unrelated hematopoietic cell transplant (HCT). However, T-cell depletion with anti-thymocyte globulin (ATG) remains the main strategy in one antigen HLA-mismatched unrelated donor (9/10 MMUD). Data comparing the two GvHD prophylaxis strategies in patients undergoing MMUD 9/10 for lymphoproliferative disease are limited. Methods: We compared PTCY versus ATG as GvHD prophylaxis in patients with lymphoproliferative disease undergoing a first 9/10 MMUD HCT with a reduced intensity conditioning regimen from 2010 to 2021. Adult patients in all disease status for which high-resolution HLA-allele typing was available in the European Society for Blood and Marrow Transplantation (EBMT) data registry were included. Patients receiving PTCY were matched to patients receiving ATG according to the following variables: age, disease status at transplant, female to male donor status, stem cell source and CMV serology. Results: A total of 411 patients were identified (n=341 for ATG group and n=70 for PTCY group). According to the above mentioned variables, 106 patients receiving ATG were identified and matched with 58 patients receiving PTCY. Among the group of 164 patients paired up, diagnosis was Hodgkin Lymphoma in most of the cases (19% and 38% in the ATG and PTCY group, respectively). The median age was 54 (range 21-69) and 52 (range 22-69) years old in the ATG and PTCY group, respectively (p= NS). The majority of patients underwent a previous autologous HCT (72% in the ATG and 68% in the PTCY group, respectively). Disease state at HCT was complete remission in 71% of the patients in both ATG and PTCY group. The most frequent GvHD prophylaxis in the ATG group was cyclosporine A (CsA) and methotrexate (MTX) (n=51; 48%), followed by CsA and mycophenolate mofetil (MMF) (n=31; 29%). In the PTCY group, the majority of patients (n=30; 52%) received CsA and MMF, while tacrolimus and MMF (n=27; 46%) represented the second most used associated immunosuppressive agents. The median follow-up was 5.1 (CI: 3.8-6.7) years for the ATG group and 1.7 (CI 0.9-2.4) years in the PTCY group. The cumulative incidence of neutrophil engraftment was 97% (CI:90.5-99.1) and 100% in ATG and PTCY groups, respectively (p=0.08). Grade III-IV acute GVHD at 100 day was not significantly different between the two groups 11.3% (CI:6-18.6) versus 17.4% (CI: 8.1-29.7) in the ATG and PTCY group, respectively; p=0.60). No differences were observed in 1-y relapse incidence (22.3% (CI: 11.5-27.6) versus 17.3% (CI: 7.4-30.5), p=0.32) and non-relapse mortality (19% versus 32%, p=0.20). GvHD-free, relapse-free survival was not different across the two groups (43.5% (CI: 33.2-53.3) in ATG and 46.9% (CI: 31.2-61.2) in PTCY, p=0.88). The cumulative incidence of 1-year extensive chronic GvHD was 14.4% (CI: 7.8-22.9) in the ATG group and 5.3% (CI: 0.9-15.9) in the PTCY group, respectively (p=0.21). The 1 year-progression free survival was 58.9% (CI: 47.9-68.3) in patients receiving ATG and 50.7% (CI: 34.3-65) in those receiving PTCY (p=0.74) and 1-year overall survival was 65.9% (CI: 55.4-74.4) in the ATG group versus 55.2% (CI: 38.8-68.9) in the PTCY group (p=0.69). Forty-seven patients died in the ATG group, 20 died in the PTCY group. The main cause of death was transplant related complications (n=27 in ATG and n=14 in PTCY patients, respectively) followed by relapse of disease (n=13 in ATG and n=4 in PTCY group). Conclusions: In patients with lymphoproliferative diseases undergoing 9/10 MMUD HSCT, PTCY as GVHD prophylaxis might be a safe option providing similar results to ATG prophylaxis. Due to the limited number of patients, prospective randomized trials are needed to allow better understand the effectiveness of adding PTCY into different platforms, including MMUD 9/10 HSCT.

Comparison of Allogeneic Hematopoietic Cell Transplantation Outcomes from Younger Matched Unrelated Donor Versus Older Sibling Donor for Acute Myeloid Leukemia

Background: Aging population has resulted in an increase in the incidence of acute myeloid leukemia (AML). The median age of diagnosis for AML is 68 years. Allogeneic hematopoietic cell transplant (alloHCT) is a curative modality for patients with AML, however, disease relapse remains a major issue. Human leukocyte antigen (HLA)-matched sibling donors (MSD) are considered the preferred donor type in clinical practice. However, with increasing median age of patients, sibling donors for these patients are likely to be older as well, often with higher comorbidities. Prior registry studies demonstrated that older donor age is associated with inferior survival. A recent study in older MDS patients demonstrated reduced relapse risk with improved disease-free survival (DFS) with younger matched unrelated donors (MUD). However, the impact of donor age and type on alloHCT outcomes in AML patients remains unknown. Methods: This retrospective cohort study accessed data from the Center for International Blood and Marrow Transplant Research database (CIBMTR) in AML patients 50 years or older undergoing alloHCT from older (>50) MSDs or younger (<35) MUDs between 2011 and 2018. The study included common allograft types, conditioning regimens, and graft-versus-host-disease (GVHD) prophylaxis strategies. Other exclusion criteria were recipients of ex vivo T-cell depleted grafts, mismatched unrelated donor, cord blood or identical twin transplants. The primary outcome, compared between the 2 donor age groups, was relapse risk, and secondary outcomes included non-relapse mortality (NRM), DFS, and overall survival (OS). Cumulative incidence estimates were calculated for competing risks outcomes. To evaluate potential risk factors, multivariable cox regression was used, and relevant transplant-related covariates were considered. Interactions between the main effect (donor age group) and significant risk factors were tested. Fine and gray model was used for NRM and relapse. Results: Among 4684 eligible patients in the study cohort, 1736 underwent alloHCT with an older MSD (median age, 61 [range: 50-80]) whereas 2948 received transplant from a younger MUD (median age, 63 [range: 50-84]). In multivariable analysis, younger MUDs conferred a significantly decreased risk of relapse (HR 0.86; 95% CI, 0.77-0.96; p=.005) as compared to older MSDs (Table 1; Figure 1). The adjusted cumulative incidence of relapse at 5 years was significantly lower with younger MUDs (35%; 95% CI, 33-37%) versus older MSDs (41%; 95% CI, 38%-43%) (p=.003) (Table 2). NRM was reported in 2 subgroups of transplant years (2011-2015 and 2016-2018) as there was significant interaction between the main effect (MUD vs MSD) and alloHCT year (p=.003). Younger MUDs conferred an increased NRM (HR 1.24; 95% CI, 1.04-1.49; p=.016) compared to older MSDs in the earlier period of 2011-2015, whereas the NRM was lower with younger MUDs in the latter period of 2016-2018 (HR, 0.78, 95% CI, 0.64-0.96; p=.017) (Table1; Figure 1). While there was no difference in the adjusted cumulative incidence of NRM at 5 years in the latter period (17% vs 20%; p=.147), NRM was significantly higher in AML patients who underwent alloHCT between 2011 and 2015 from a younger MUD (28%; 95% CI, 25-30%) compared to older MSDs (24%; 95% CI, 20%-27%; p=.045) (Table2). There was no difference in OS or DFS rates of alloHCT with younger MUDs vs older MSDs (OS: HR 1.02; 95% CI, 0.94-1.12; p=.607; DFS: HR 0.92; 95% CI, 0.85-1.01; p=.073) (Table 1; Figure 1). While the adjusted 5-year OS probability was 47% in each of the 2 cohorts (p=0.95), the adjusted 5-year DFS probability was 44% with younger MUDs (95% CI, 42%-46%) as compared to 41% with older MSDs (95% CI, 38%-43%; p=.04) (Table2). Conclusions: This large study from a prospectively collected registry data found significant relapse reduction in AML patients who underwent alloHCT with younger MUDs as compared to older MSDs and highlights that a younger MUD donor type exerts a stronger GVL effect and should be preferred when available. The higher NRM associated with younger MUDs has decreased in recent years, likely due to enhanced GVHD prophylaxis, infection preemption and preventative strategies, and supportive cares measures translating into improved leukemia-free survival. The results aid in donor selection and younger MUDs should be preferred in AML patients at a higher risk for post-alloHCT relapse. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Younger Matched Unrelated Donors Confer a Decreased Relapse Risk As Compared to Older Sibling Donors for Adult B-Cell ALL Patients Undergoing Allogeneic Hematopoietic Cell Transplantation

Background: The incidence of acute lymphoblastic leukemia (ALL) has increased due to aging population and the median age at diagnosis is 56 years among adults. Allogeneic hematopoietic cell transplant (alloHCT) offers cure for ALL patients, however, disease relapse remains a major issue. Human leukocyte antigen (HLA)-matched sibling donors (MSD) are considered the ideal donor type, mainly due to lower incidence and severity of graft-versus-host-disease (GVHD) and improved disease-free survival (DFS) in ALL. However, siblings are also likely to be older, often with higher comorbidities, and adult ALL patients typically undergo reduced-intensity conditioning and need novel strategies to reduce the post-alloHCT relapse risk. While recent data have suggested relapse reduction and survival benefit with younger matched unrelated donors (MUD) in AML and MDS, the impact of donor age on alloHCT outcomes in adult ALL patients remain unknown. Methods: This retrospective cohort study from the Center for International Blood and Marrow Transplant Research database (CIBMTR) data in B-cell ALL patients 50 years or older, undergoing alloHCT from older (>50) MSDs or younger (<35) MUDs between 2011 and 2018, included common allograft types (PB vs BM), conditioning regimens (RIC/NMA vs MAC), and graft-versus-host-disease (GVHD) prophylaxis strategies (FK-based vs CSA-based vs. others). Other exclusion criteria were recipients of ex vivo T-cell depleted grafts, recipients of mismatched unrelated donors, cord blood or identical twin transplants. The primary outcome, compared between the 2 donor age groups, was relapse risk whereas secondary outcomes included non-relapse mortality (NRM), DFS, and overall survival (OS). Cumulative incidence estimates were calculated for competing risks outcomes, including NRM and relapse. The Kaplan-Meier method was used to estimate the probabilities for survival. To evaluate potential risk factors, multivariable cox regression was used, and relevant transplant-related covariates were considered. Interactions between the main effect (donor age group) and significant risk factors were tested. Fine and Gray model was used for NRM and relapse. Given the multicenter nature of the database, center effect was tested for OS by fitting a gamma frailty model. Results: Among 925 eligible patients in the study cohort, 386 underwent alloHCT with an older MSD (median age, 59 [range: 50-75]) whereas 539 received transplant from a younger MUD (median age, 60 [range: 50-77]). In multivariable analysis, younger MUDs conferred a significantly decreased risk of relapse (HR 0.68; 95% CI, 0.53-0.87; p=.002) versus older MSDs (Table 1; Figure 1). The adjusted cumulative incidence of relapse at 5 years was significantly lower with younger MUDs compared to older MSDs (26% vs 37%; p=.001) (Table 2). Younger MUDs conferred an increased NRM compared to older MSDs (HR 1.38; 95% CI, 1.05-1.82; p=.02) (Table1; Figure 1). The adjusted cumulative incidence of NRM at 5 years was also significantly higher in B-ALL patients who underwent alloHCT from younger MUDs compared to older MSDs (31% vs 22%; p=.006) (Table2). There were no differences in OS or DFS rates of alloHCT with younger MUDs vs older MSDs (OS: HR 1.09; 95% CI, 0.90-1.32; p=.37; DFS: HR 0.95; 95% CI, 0.79-1.14; p=.57) (Table 1; Figure 1). The adjusted 5-year OS probability was 48% in younger MUDs (95% CI, 43%-52%) and 51% among older MSDs (95% CI, 45%-56%; p=0.37). The adjusted 5-year DFS probability was 44% with younger MUDs (95% CI, 40%-49%) compared to 42% with older MSDs (95% CI, 37%-47%; p=.59) (Table2). Conclusions: This is the largest study to date performed in a mature, prospectively collected registry cohort that aids in donor selection and found significant relapse reduction in adult B-ALL patients who underwent alloHCT with younger MUDs as compared to older MSDs. The results highlight that younger MUD donor type exerts a stronger GVL effect and should be preferred in patients at a higher risk for post-alloHCT relapse. The higher NRM associated with younger MUDs will need enhanced GVHD prophylaxis, infection preemption and preventative strategies, and supportive cares measures to consolidate the leukemia-free survival. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Total Marrow and Lymphoid Irradiation with Post-Transplantation Cyclophosphamide for Patients with AML in Remission

Graft-versus-host disease (GVHD) has remained the main cause of post-transplantation mortality and morbidity after allogeneic hematopoietic cell transplantation (alloHCT), adding significant economic burden and affecting quality of life. It would be desirable to reduce the rate of GVHD among patients in complete remission (CR) without increasing the risk of relapse. In this study, we have tested a novel conditioning regimen of total marrow and lymphoid irradiation (TMLI) at 2000 cGy, together with post-transplantation cyclophosphamide (PTCy) for patients with acute myeloid leukemia in first or second CR, to attenuate the risk of chronic GVHD by using PTCy, while using escalated targeted radiation conditioning before allografting to offset the possible increased risk of relapse. The primary objective was to evaluate the safety/feasibility of combining a TMLI transplantation conditioning regimen with a PTCy-based GVHD prophylaxis strategy, through the assessment of adverse events in terms of type, frequency, severity, attribution, time course, duration, and complications, including acute GVHD, infection, and delayed neutrophil/platelet engraftment. Secondary objectives included estimation of non-relapse mortality (NRM), overall survival (OS), relapse-free survival, acute and chronic GVHD, and GVHD-relapse-free survival (GRFS). A patient safety lead-in was first conducted to ensure there were no unexpected toxicities and was expanded on the basis of lack of dose-limiting toxicities. The patient safety lead-in segment followed 3 + 3 dose expansion/(de-)escalation rules based on observed toxicity through day 30; the starting dose of TMLI was 2000 cGy, and a de-escalation to 1800 cGy was considered. After the safety lead-in segment, an expansion cohort of up to 12 additional patients was to be studied. TMLI was administered on days −4 to 0, delivered in 200 cGy fractions twice daily. The radiation dose delivered to the liver and brain was kept at 1200 cGy. Cyclophosphamide was given on days 3 and 4 after alloHCT, 50 mg/kg each day for GVHD prevention; tacrolimus was given until day 90 and then tapered. Among 18 patients with a median age of 40 years (range 19-56), the highest grade toxicities were grade 2 Bearman bladder toxicity and stomatitis. No grade 3 or 4 Bearman toxicities or toxicity-related deaths were observed. The cumulative incidence of acute GVHD grade 2 to 4 and moderate-to-severe chronic GVHD were 11.1% and 11.9%, respectively. At a median follow up of 24.5 months, two-year estimates of OS and relapse-free survival were 86.7% and 83.3%, respectively. Disease relapse at 2 years was 16.7%. The estimates of NRM at 2 years was 0%. The GVHD/GRFS rate at 2 years was 59.3% (95% confidence interval, 28.8-80.3). This chemotherapy-free conditioning regimen, together with PTCy and tacrolimus, is safe, with no NRM. Preliminary results suggest an improved GRFS rate.

Antithymocyte globulin plus post-transplant cyclophosphamide combination as graft-versus-host disease prophylaxis in haploidentical peripheral blood stem cell transplantation for hematological malignancies.

Post-transplant cyclophosphamide (PT-Cy) and calcineurin inhibitors used in peripheral blood haplo-identical stem cell transplantation (haploSCT) increase the risk of acute/chronic graft-versus-host disease (GVHD). Whether ATG/PT-Cy is feasible for Asian patients undergoing haploSCT is unclear, and an optimal strategy for GVHD prophylaxis is needed. We retrospectively analyzed 61 hematologic malignancy patients who underwent peripheral blood haploSCT using ATG/PT-Cy from January 2013 to December 2018. We also compared the effects of ATG/PT-Cy (ATG group; n = 61) with historical data from patients who underwent haploSCT using sirolimus/PT-Cy (non-ATG group; n = 22). Cumulative incidences of grades II-IV acute GVHD and moderate to severe chronic GVHD did not differ significantly. The ATG group had higher incidence of Epstein-Barr virus (EBV) reactivation, but neither group had post-transplant lymphoproliferative disorders. The ATG group also had a higher OS rate (2-year OS in ATG group vs. non-ATG group: 43.4% vs. 27.3%, respectively; P = 0.071). ATG/PT-Cy is an acceptable strategy for GVHD prophylaxis in Asian patients undergoing haploSCT.

Omission of day +11 methotrexate dose and allogeneic hematopoietic cell transplantation outcomes: results of a systematic review/meta-analysis.

Allogeneic hematopoietic cell transplantation (allo-HCT) is potentially curative for patients with malignant and benign hematologic conditions. Graft-versus-host disease (GVHD) is a known complication of allo-HCT that results in significant morbidity and mortality. A common GVHD prophylaxis strategy combines a calcineurin inhibitor with methotrexate. When mucositis and organ toxicity develop, the day +11 dose is frequently omitted to limit further organ damage. The potential impact of this practice on allo-HCT outcomes is unclear as published data show conflicting results. Thus, we performed a systematic review/meta-analysis of the available literature to assess the impact of omitting day +11 methotrexate on allo-HCT recipients. Data were extracted in relation to benefits (overall survival [OS], progression-free survival [PFS]) and harms (acute and chronic GVHD, non-relapse mortality [NRM], and relapse). Pooled OS rate favored those who received day +11 methotrexate vs. those who did not (HR = 1.21; 95% CI = 1.02-1.43; p = 0.03). There was no significant difference in pooled rates of PFS (HR = 0.96; 95% CI = 0.60-1.52; p = 0.85), acute GVHD (HR = 1.03; 95% CI = 0.35-2.98; p = 0.96), chronic GVHD (HR = 0.83; 95% CI = 0.44-1.57; p = 0.57), NRM (HR = 0.86; 95% CI = 0.67-1.11; p = 0.25), and relapse (HR = 0.97; 95% CI = 0.75-1.26; p = 0.83) between the two groups. Large prospective multicenter studies are needed to better define the significance of day +11 methotrexate omission.

Anti-thymocyte globulin with CsA and MMF as GVHD prophylaxis in nonmyeloablative HLA-mismatched allogeneic HCT.

Nonmyeloablative regimens are used for allogeneic hematopoietic cell transplantation (HCT) of older or medically unfit patients, but successful outcome is still hindered by graft-versus-host disease (GVHD), especially in the setting of HLA-mismatched HCT. New GVHD prophylaxis strategies are emerging, including the triple drug strategy, that improve the GVHD-free and relapse-free survival (GRFS). Because the impact of ATG in HLA-mismatched Flu-TBI-based nonmyeloablative HCT has not been investigated, we did a retrospective analysis in three Dutch centers. 67 patients were evaluable, with a median age of 56 years. Overall survival, relapse-free survival and GRFS at 4 years were 52%, 43%, and 38%, respectively. NRM findings and cumulative incidence of relapse at 4 years were 26% and 31%, respectively. At 1-year grade II-IV had occurred in 40% of the patients, and the incidence of moderate-severe chronic GVHD incidence was 16%. Acknowledging the limitations of retrospective analyses, we conclude that the use of ATG for HLA-mismatched truly nonmyeloablative Flu-TBI HCT is feasible and results in acceptable long term outcomes, especially with regards to GRFS. We consider ATG in combination with cyclosporin and mycophenolate mofetil as an alternative for the triple drug strategy that uses sirolimus for GVHD prophylaxis in this particular setting.

Optimizing outcomes for haploidentical hematopoietic stem cell transplantation in severe aplastic anemia with intensive GVHD prophylaxis: a review of current findings

ABSTRACT Introduction: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has resulted in increased levels of disease-free survival in severe aplastic anemia (SAA). Haploidentical transplantation (haplo-SCT) was previously not recommended due to unacceptable incidences of graft-versus-host disease (GvHD) and graft failures. With the advent of intensive GvHD prophylaxis strategies, the outcomes obtained with haplo-SCT for SAA have gradually improved. Areas covered: A comprehensive search considered PubMed reported articles before 1 February 2021, presented abstracts, and clinical trials pertaining to haplo-HSCT for SAA. This manuscript covers modern approaches with intensive GvHD prophylaxis in haplo-SCT for SAA. The representative methods consist of granulocyte colony stimulating factor (G-CSF) plus ATG-based and posttransplantation cyclophosphamide (PT-Cy)-based protocols. Expert opinion: Currently, haplo-SCT has become a feasible option for treating SAA. The G-CSF/ATG-based protocol included the largest sample size and reported comparable survival rates with identical siblings. The PT-Cy protocol resulted in a relatively lower incidence of GvHD and seemingly poorer but continuously improved engraftment with augmented conditioning. The optimized outcomes are constantly updated with the modification of the conditioning regimen, donor selection, graft source and GvHD prophylaxis. In the future, we should pay more attention to quality of life in addition to survival, and personalized haplo-SCT may improve outcomes.

Sirolimus versus cyclosporine in haploidentical stem cell transplantation with posttransplant cyclophosphamide and mycophenolate mofetil as graft-versus-host disease prophylaxis.

Sirolimus has emerged as an alternative to calcineurin inhibitors‐based (CNI) graft‐versus‐host disease (GVHD) prophylaxis. This retrospective study compares the outcome of 133 consecutive adult patients with haematological malignancies undergoing haploidentical stem cell transplantation with posttransplant cyclophosphamide (PTCy) and mycophenolate mofetil (MMF), combined with cyclosporine A (PTCy–CsA–MMF, n = 67) or sirolimus (PTCy–Sir–MMF, n = 66) as GVHD prophylaxis strategy. The median follow‐up was 48 (range 22–83) and 13 (range 3–33) months, respectively. PTCy–CsA–MMF was associated in multivariate analyses with a higher risk of acute kidney injury (HR 2.1, 95% CI, 1.21–3.57, p = .008) and thrombotic microangiopathy (HR 12.5, 95% CI, 1.66–93.5, p = .014), whereas PTCy–Sir–MMF was associated with a higher risk of hepatic sinusoidal obstruction syndrome (SOS) (HR 10.8, 95% CI, 1.52–77, p = .018), especially late‐onset forms, which totally resolved and none of the patients needed discontinuation of sirolimus. Two SOS‐related deaths were detected, both in the PTCy–CsA–MMF subgroup. Both GVHD prophylaxis strategies were otherwise comparable in terms of engraftment, GVHD incidence and survival.

The utility of hyperbaric oxygen therapy in post-transplant cyclophosphamide-induced hemorrhagic cystitis: a case report and review of the\xa0literature

BackgroundTo date, there are only a few case reports of cyclophosphamide (Cy)-induced hemorrhagic cystitis (HC) in adult or pediatric allogeneic stem cell transplant (SCT) patients treated successfully with hyperbaric oxygen (HBO). In all the reported cases, Cy was used as a part of the conditioning regimen, rather than post-transplant for graft-versus-host-disease (GVHD) prophylaxis. More recently, the risk of HC in allogeneic SCT is further increased by the widespread use of post-transplantation cyclophosphamide (PTCy) as a highly effective strategy for GVHD prophylaxis. This is the first case reported of PTCy-induced HC successfully treated with HBO to the best of our knowledge.Case presentationIn this article, we present a 58-year-old Caucasian male case of allogeneic SCT complicated by severe HC following PTCy, which was successfully treated with HBO, eliminating the need for cystectomy.ConclusionHBO can be a safe, noninvasive, alternative treatment modality for PTCy-induced HC developing in allogeneic SCT patients.

Impact of patient: donor HLA disparity on reduced-intensity-conditioned allogeneic stem cell transplants from HLA mismatched unrelated donors for AML: from the ALWP of the EBMT.

Patients with acute myeloid leukaemia (AML) who lack a matched sibling or unrelated donor commonly undergo transplantation from a donor matched at 9/10 HLA-A, -B, -C, -DRB1, -DQB1 alleles, and it is unclear if a specific locus mismatch is preferable to any other. We therefore studied 937 patients with AML in complete remission transplanted using a reduced intensity conditioning regimen from an unrelated donor mismatched at a single allele. In a multivariate analysis, patient age, adverse karyotype and patient cytomegalovirus (CMV) seropositivity were correlated with decreased leukaemia free survival (LFS) and overall survival (OS). There was no significant difference in LFS or OS between patients transplanted from donors mismatched at HLA-A, -B, -C or -DRB1 in comparison to a HLA-DQB1 mismatched transplant. In a multivariate analysis, patients transplanted with a HLA-A mismatched donor had higher rates of acute graft-versus-host disease (GVHD) and non-relapse mortality (NRM) than patients transplanted with a HLA-DQB1 mismatched donor. Patient CMV seropositivity was associated with an increase in NRM and acute GVHD and reduced LFS and OS, regardless of donor CMV status. For CMV seropositive patients lacking a fully matched donor, alternative GVHD and CMV prophylaxis strategies should be considered.

IFNL4 and donor selection for matched unrelated donor haematopoietic stem-cell transplantation

IFNL4 and donor selection for matched unrelated donor haematopoietic stem-cell transplantation