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Mycophenolate Mofetil: A Friend or a Foe with PTCy and Tacrolimus Prophylaxis in HLA-Matched donors?
Mehta, R. S., Saliba, R. M., Hayase, E., Jenq, R. R., Abraham, S., Rashid, A., Rondon, G., Al-Atrash, G., Bashir, Q., Hosing, C. M., et al
Transplantation and cellular therapy. 2022
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Abstract
Adapted from the haploidentical literature, post-transplantation cyclophosphamide (PTCy) is increasingly being used with HLA-matched donors, generally with a calcineurin inhibitor, such as tacrolimus (Tac) with or without mycophenolate mofetil (MMF). Owing to its immunosuppressive, potentially antitumor, and antimicrobial properties, MMF is an attractive drug; however, it remains unclear how much benefit is gained when used with PTCy/Tac. To assess that, we compared PTCy/Tac (n=242) to PTCy/Tac/MMF (n= 144) in recipients of HLA-matched donors. In multivariate analysis, the PTCy/Tac/MMF group had a significantly higher risk of grade II-IV acute graft-versus-host disease (GVHD; hazard ratio (HR) 2.1, 95% confidence interval (CI) 1.6-2.8, p<0.001), and steroid-refractory/dependent acute GVHD (HR 4.8, 95% CI 2.4-9.6, p<0.001), yet a significantly lower risk of relapse (HR 0.5, 95% CI, 0.3-0.9, p=0.009) and better progression-free survival (PFS; HR 0.7, 95% CI 0.5-0.9, p=0.04). There was no difference in the risk of grade III-IV acute GVHD, chronic GVHD, non-relapse mortality, or overall survival. MMF was associated with prolonged neutrophil engraftment by 2 days, and a higher risk of bacterial infections. In an exploratory stool microbiome analysis (n=16), we noted a higher relative abundance of β-glucuronidase-producing bacteria in the MMF group, which may have a role in the pathogenesis of MMF-related GVHD. Our data suggest that the addition of MMF to PTCy/Tac for HLA-matched donor HCT does not provide any advantage for GVHD prevention. Further studies are needed to decipher this mechanism, and understand its role with PTCy-based prophylaxis.
PICO Summary
Population
Adults with haematological malignancy who had first transplant with HLA-matched donor (n=386)
Intervention
Post-transplant cyclophosphamide with tacrolimus and mycophenalate mofetil (PTCy/Tac/MMF, n= 144)
Comparison
Post-transplant cyclophosphamide with tacrolimus only (PTCy/Tac, n=242)
Outcome
In multivariate analysis, the PTCy/Tac/MMF group had a significantly higher risk of grade II-IV acute graft-versus-host disease (GVHD; hazard ratio (HR) 2.1, 95% confidence interval (CI) 1.6-2.8), and steroid-refractory/dependent acute GVHD (HR 4.8, 95% CI 2.4-9.6), yet a significantly lower risk of relapse (HR 0.5, 95% CI, 0.3-0.9) and better progression-free survival (PFS; HR 0.7, 95% CI 0.5-0.9). There was no difference in the risk of grade III-IV acute GVHD, chronic GVHD, non-relapse mortality, or overall survival. MMF was associated with prolonged neutrophil engraftment by 2 days, and a higher risk of bacterial infections. In an exploratory stool microbiome analysis (n=16), we noted a higher relative abundance of β-glucuronidase-producing bacteria in the MMF group, which may have a role in the pathogenesis of MMF-related GVHD.
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Post-Transplantation Cyclophosphamide vs Tacrolimus and Methotrexate Graft-versus-Host Disease Prophylaxis For HLA-Matched Donor Transplantation
Mehta, R. S., Saliba, R. M., Rondon, G., Al-Atrash, G., Bashir, Q., Hosing, C. M., Kebriaei, P., Khouri, I., Nieto, Y., Oran, B., et al
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND The use of post-transplantation cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis is increasing in patients undergoing HLA-matched sibling (MSD) or unrelated (MUD) donor hematopoietic cell transplantation (HCT), but data about its comparative efficacy against the traditional GVHD prophylaxis are scarce. OBJECTIVES Two broad questions assessed in this study were: (a) comparison of PTCy-based GVHD prophylaxis vs Tac/MTX (without ATG) in the MSD and (b) comparison of PTCy-based GVHD prophylaxis vs Tac/MTX (with ATG) in the MUD group. STUDY DESIGN This retrospective single-center study analyzed the outcomes of 964 patients who received Tac/MTX (n=578) vs PTCy-based (n=386) GVHD prophylaxis. All MUD recipients in the Tac/MTX group also received ATG; thus, separate analyses were conducted for MSD (n=412) and MUD (n=552) cohorts. In the MUD cohort, 306 patients received Tac/MTX/ATG and 246 received PTCy-based GVHD prophylaxis. In the MSD cohort, 272 received Tac/MTX and 140 received PTCy-based prophylaxis. RESULTS Both PTCy groups included somewhat older patients than the Tac/MTX groups and more patients had myeloid malignancy (85-90% vs 59-64%, respectively). A majority of patients in all groups received myeloablative conditioning and peripheral blood graft. Both PTCy groups had a significantly delayed neutrophil engraftment, higher risk of hemorrhagic cystitis, and higher risk of bacterial infections than the Tac/MTX groups. The risks of viral infections and related deaths were significantly higher in Tac/MTX group in the MUD cohort. In multivariate analysis, the risk of grade III-IV acute GVHD was similar in PTCy and Tac/MTX groups in both MSD and MUD cohorts, but the risk of chronic GVHD was significantly lower with PTCy in the MSD cohort. PTCy was associated with a significantly lower risk of non-relapse mortality and better progression-free survival in the MUD. PTCy was associated with improved GRFS in both MSD and MUD groups. CONCLUSIONS Our data suggest a benefit of using PTCy-based GVHD prophylaxis in both MSD (vs Tac/MTX) and MUD (vs Tac/MTX/ATG) HCT.
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Azithromycin may increase hematologic relapse rates in matched unrelated donor hematopoietic cell transplant recipients who receive anti-thymocyte globulin, but not in most other recipients
Sheshadri, A., Saliba, R., Patel, B., Ahmed, T., Bueno, L. C., Arain, M. H., Mehta, R. S., Popat, U. R., Hosing, C. M., Rondon, G., et al
Bone marrow transplantation. 2020
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Haploidentical Transplantation with Post-Transplantation Cyclophosphamide for High-Risk Acute Lymphoblastic Leukemia
Srour, S. A., Milton, D. R., Bashey, A., Karduss-Urueta, A., Al Malki, M. M., Romee, R., Solomon, S., Nademanee, A., Brown, S., Slade, M., et al
Biology of Blood & Marrow Transplantation. 2017;23(2):318-324
Abstract
Haploidentical transplantation performed with post-transplantation cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis has been associated with favorable outcomes for patients with acute myeloid leukemia and lymphomas. However, it remains unclear if such approach is effective for patients with acute lymphoblastic leukemia (ALL). We analyzed outcomes of 109 consecutively treated ALL patients 18 years of age and older at 5 institutions. The median age was 32 years and the median follow-up for survivors was 13 months. Thirty-two patients were in first complete remission (CR1), while the rest were beyond CR1. Neutrophil engraftment occurred in 95% of the patients. The cumulative incidences of grades II to IV and III and IV acute GVHD at day 100 after transplantation were 32% and 11%, respectively, whereas chronic GVHD, nonrelapse mortality, relapse rate, and disease-free survival (DFS) at 1 year after transplantation were 32%, 21%, 27%, and 51%, respectively. Patients in CR1 had 52% DFS at 3 years. These results suggest that haploidentical transplants performed with PTCy-based GVHD prophylaxis provide a very suitable alternative to HLA-matched transplantations for patients with ALL.
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Results of a 2-arm, phase 2 clinical trial using post-transplantation cyclophosphamide for the prevention of graft-versus-host disease in haploidentical donor and mismatched unrelated donor hematopoietic stem cell transplantation
Gaballa, S., Ge, I., El Fakih, R., Brammer, J. E., Kongtim, P., Tomuleasa, C., Wang, S. A., Lee, D., Petropoulos, D., Cao, K., et al
Cancer. 2016;122(21):3316-3326
Abstract
BACKGROUND High-dose, post-transplantation cyclophosphamide (PTCy) to prevent graft-versus-host disease (GVHD) has improved outcomes in haploidentical (HAPLO) stem cell transplantation (SCT). However, it remains unclear whether this strategy is effective in SCT from 1-antigen human leukocyte antigen (HLA)-mismatched unrelated donors (9/10 MUD) and how the outcomes of these patients compare with those of haploidentical transplantation recipients. METHODS A parallel, 2-arm, nonrandomized phase 2 clinical trial was conducted of melphalan-based reduced-intensity conditioning with PTCy, tacrolimus, and mycophenolate mofetil to prevent GVHD in patients with high-risk hematologic malignancies who underwent HAPLO (n = 60) or 9/10 MUD (n = 46) SCT. RESULTS The 1-year overall and progression-free survival rates were 70% and 60%, respectively, in the HAPLO arm and 60% and 47%, respectively, in the 9/10 MUD arm. The day +100 cumulative incidence of grade II to IV acute GVHD and grade III to IV acute GVHD was 28% and 3%, respectively, in the HAPLO arm and 33% and 13%, respectively, in the 9/10 MUD arm. The 2-year cumulative incidence of chronic GVHD was 24% in the HAPLO arm and 19% in the 9/10 MUD arm. The 1-year cumulative incidence of nonrelapse mortality was 21% in the HAPLO arm and 31% in the 9/10 MUD arm, and the 1-year relapse rate was 19% in the HAPLO arm and 25% in the 9/10 MUD arm. CONCLUSIONS Although this was a nonrandomized study and could not serve as a direct comparison between the 2 groups, the authors conclude that PTCy-based GVHD prophylaxis is effective for both HAPLO and 9/10 MUD SCTs. Prospective randomized trials will be required to compare the efficacies of alternative donor options for patients lacking HLA-matched donors. Cancer 2016;122:3316-3326. © 2016 American Cancer Society. Copyright © 2016 American Cancer Society.
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6.
Post-transplantation cyclophosphamide versus conventional graft-versus-host disease prophylaxis in mismatched unrelated donor haematopoietic cell transplantation
Mehta, R. S., Saliba, R. M., Chen, J., Rondon, G., Hammerstrom, A. E., Alousi, A., Qazilbash, M., Bashir, Q., Ahmed, S., Popat, U., et al
British Journal of Haematology. 2016;173(3):444-55
Abstract
Post-transplantation cyclophosphamide (PTCy) is an effective strategy to prevent graft-versus-host disease (GVHD) after haploidentical haematopoietic cell transplantation (HCT). We determined the efficacy of PTCy-based GVHD prophylaxis in human leucocyte antigen (HLA)-mismatched unrelated donor (MMUD) HCT. We analysed 113 adult patients with high-risk haematological malignancies who underwent one-antigen MMUD transplantation between 2009 and 2013. Of these, 41 patients received PTCy, tacrolimus and mycophenolate mofetil (MMF) for GVHD prophylaxis; 72 patients received conventional prophylaxis with anti-thymocyte globulin, tacrolimus and methotrexate. Graft source was primarily bone marrow (83% PTCy vs. 63% conventional group). Incidence of grade II-IV (37% vs. 36%, P = 0.8) and grade III-IV (17% vs. 12%, P = 0.5) acute GVHD was similar at day 100. However, the incidence of grade II-IV acute GVHD by day 30 was significantly lower in the PTCy group (0% vs. 15%, P = 0.01). Median time to neutrophil (18 days vs. 12 days, P < 0.001) and platelet (25.5 days vs. 18 days, P = 0.05) engraftment was prolonged in PTCy group. Rates of graft failure, chronic GVHD, 2-year non-relapse mortality, relapse, progression-free survival or overall survival were similar. Our results demonstrate that PTCy, tacrolimus and MMF for GVHD prophylaxis is safe and produced similar results as conventional prophylaxis in patients with one antigen HLA-MMUD HCT. Copyright © 2016 John Wiley & Sons Ltd.