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Sirolimus is an acceptable alternative to tacrolimus for graft-versus-host disease prophylaxis after haploidentical peripheral blood stem cell transplantation with post-transplant cyclophosphamide
Elmariah, H., Otoukesh, S., Kumar, A., Ali, H., Arslan, S., Shouse, G., Pourhassan, H., Nishihori, T., Faramand, R., Mishra, A., et al
Transplantation and cellular therapy. 2023
Abstract
BACKGROUND Graft-versus-host disease (GVHD) prophylaxis with post-transplant cyclophosphamide (PTCy), tacrolimus (TAC) and mycophenolate mofetil (MMF) for allogeneic haploidentical donor (haplo) hematopoietic cell transplantation (HCT) results in comparable outcomes to matched unrelated donor transplantation. A phase II study from Moffitt Cancer Center substituting sirolimus (SIRO) in place of TAC reported comparable rates of grade II-IV acute GVHD. Many centers have substituted SIRO for TAC in this setting based on a preferred side effect profile, though comparative data is limited. OBJECTIVE The objective of this study is to compare outcomes of haplo HCT with PTCy/SIRO/MMF versus PTCy/TAC/MMF. STUDY DESIGN We retrospectively compared haplo HCT outcomes with PTCy/SIRO/MMF versus PTCy/TAC/MMF. Included were all consecutive patients receiving haplo donor T cell replete peripheral blood stem cell graft HCT for hematologic malignancies at Moffitt Cancer Center or the City of Hope National Medical Center between 2014 and 2019. RESULTS A total of 423 patients were included, of which 84 (20%) received SIRO and 339 (80%) received TAC. Median age for all patients was 54 (range 18 to 78) years, and median follow-up for entire study cohort was 30 months. SIRO group had a higher proportion of patients ≥60 years (58% versus 34%, P = <.01), and the groups also differed in diagnosis type, conditioning regimen, and cytomegalovirus serostatus. There were no significant differences in the rates of grade II-IV acute GVHD (45% versus 47%, P = .6) at day +100 or chronic GVHD (47% versus 54%, P = .79) at 2 years post-HCT. In multivariate analysis, neutrophil engraftment at day +30 was significantly better with TAC (OR = 0.30, CI 0.1 to 0.83, P = .02) with a median time to engraftment of 17 days versus 18 days for SIRO, but platelet engraftment was similar in both groups. Otherwise, in multivariate analysis, GVHD prophylaxis type had no significant influence on acute or chronic GVHD, nonrelapse mortality, relapse, GVHD-free relapse-free survival, disease free survival, or overall survival after peripheral blood haplo HCT. CONCLUSIONS These findings suggest that SIRO is a comparable alternative to TAC in combination with PTCy/MMF for GVHD prophylaxis, resulting in overall similar clinical outcomes despite delay in engraftment after peripheral blood haplo HCT. While TAC remains the standard of care, SIRO may be substituted based on the side effect profile of these medications with consideration of patient medical comorbidities at HCT.
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Outcomes Following Intolerance to Tacrolimus/Sirolimus Graft-Versus-Host Disease Prophylaxis for Allogeneic Hematopoietic Cell Transplantation
Mirza, A. S., Tandon, A., Jenneman, D., Cao, S., Brimer, T., Kumar, A., Kidd, M., Khimani, F., Faramand, R., Mishra, A., et al
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND Although tacrolimus and sirolimus (TAC/SIR) is an accepted graft-versus-host disease (GVHD) prophylaxis following allogeneic hematopoietic cell transplant (HCT), toxicity from this regimen can lead to premature discontinuation of immunosuppression. There are limited studies reporting outcomes and subsequent treatment of patients with TAC/SIR intolerance. OBJECTIVES To assess outcomes of patients with TAC/SIR intolerance and guide subsequent management after intolerance. STUDY DESIGN We retrospectively analyzed transplant outcomes of consecutive adult patients at Moffitt Cancer Center who received allogeneic HCT with TAC/SIR as GVHD prophylaxis from 2009 to 2018. TAC/SIR intolerance was defined as discontinuation due to toxicity of either TAC or SIR before post-transplant day 100. RESULTS 777 patients met the inclusion criteria. Median follow-up was 22 (0.2-125) months. Intolerance occurred in 13% (n = 104) of patients at a median of 30 (range 5-90) days. The most common causes of intolerance were acute kidney injury (n = 53 [51%]), thrombotic microangiopathy (n = 31 [28%]), and veno-occlusive disease (n = 23 [22%]). The cumulative incidence of grade 2 to 4 acute GVHD at 100 days in TAC/SIR-intolerant patients was 50% (95% CI, 39%-64%) and 25% (95% CI, 22%-29%) in patients tolerant to this regimen (P < .0001). In multivariate analyses, grade 2 to 4 acute GVHD was significantly higher in TAC/SIR-intolerant patients (HR 2.40; 95% CI, 1.59-3.61; P < .0001). Similarly, in multivariate analyses, TAC/SIR-intolerant patients had more chronic GVHD (HR 1.48, 95% CI, 1.03-2.12; P = .03). The non-relapse mortality (NRM) at 1 year in TAC/SIR-intolerant patients was 47% (95% CI, 38%-59%) and 12% (95% CI, 10%-15%) in those tolerant to the regimen (P < .0001). The 2-year relapse free survival of TAC/SIR-intolerant patients was 35% (95% CI, 25%-44%) and 60% (95% CI, 57%-65%) among TAC/SIR-tolerant patients, (HR 2.30; 95% CI, 1.61-3.28; P < .0001). Intolerance stratified by early (≤30 days) versus late (31-100 days) significantly affected the cumulative incidence of acute GVHD at 75% (early [95% CI, 59%-94%]) versus 33% ([late] 95% CI, 21%-50%) (P = .001) as well as the cumulative incidence of NRM at 61% ([early] 95% CI, 48%-77%) versus 35% ([late] 95% CI, 24%-51%) (P = .006). After developing TAC/SIR intolerance, most patients were switched to an alternative 2-drug regimen (71/104 [68%]), with the most common being mycophenolate mofetil in addition to continuing TAC or SIR (68/71 [96%]). CONCLUSIONS Overall, TAC/SIR intolerance was associated with poorer outcomes. Early intolerance contributed to higher risk of acute GVHD, increased NRM, and inferior survival. Patients with early intolerance were often switched to an alternative agent, and patients with late intolerance tended to be continued on single-drug therapy without substitution. Single-drug versus 2-drug regimens after intolerance did not appear to affect outcomes. Management strategies to mitigate the risks of intolerance are warranted.
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Omission of day +11 methotrexate dose and allogeneic hematopoietic cell transplantation outcomes: results of a systematic review/meta-analysis
Kharfan-Dabaja, M. A., Reljic, T., Kumar, A., Yassine, F., Keller, K., Fernandez, A., Murthy, H., Ayala, E., Aljurf, M., Iqbal, M.
Bone marrow transplantation. 2021
Abstract
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.
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Antithymocyte globulin for graft-versus-host disease prophylaxis: an updated systematic review and meta-analysis
Kumar, A., Reljic, T., Hamadani, M., Mohty, M., Kharfan-Dabaja, M. A.
Bone marrow transplantation. 2018
Abstract
Graft-versus-host disease (GVHD) remains a limiting factor for successful allogeneic hematopoietic cell transplantation (allo-HCT). Conflicting data exist on the benefit of ATG on post-transplant survival. We performed a systematic review of randomized controlled trials (RCTs) to assess benefits and harms of thymoglobulin and Fresenius (re-branded as Grafalon) ATG formulations in patients undergoing allo-HCT for a variety of hematologic malignancies and bone marrow failure syndromes. A comprehensive search of MEDLINE, EMBASE, and Cochrane Library was performed. Data on methodological quality, benefits, and harms were extracted for each trial and pooled under a random-effects model. Eight RCTs (1134 patients) met the inclusion criteria. Methodological quality ranged from moderate to very low. Pooled results showed no difference in overall survival (OS) with the use of ATG (hazard ratio (HR) = 0.97; 95% confidence interval (CI) = 0.74-1.28; P = 0.83). ATG reduced grade II/III acute GVHD (risk ratio (RR) = 0.61; 95% CI = 0.48-0.77; P < 0.0001), grade III/IV acute GVHD (RR = 0.52; 95% CI = 0.34-0.81; P = 0.004), and chronic GVHD (RR = 0.52; 95% CI = 0.40-0.69; P < 0.00001) without an increase in non-relapse mortality (NRM) (RR = 0.91; 95% CI = 0.74-1.13; P = 0.40). Future studies with better methodological quality are needed to provide conclusive answers related to optimal dosing and timing of ATG for prevention of GVHD.
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Antithymocyte globulin for acute-graft-versus-host-disease prophylaxis in patients undergoing allogeneic hematopoietic cell transplantation: a systematic review
Kumar, A., Mhaskar, A. R., Reljic, T., Mhaskar, R. S., Kharfan-Dabaja, M. A., Anasetti, C., Mohty, M., Djulbegovic, B.
Leukemia. 2012;26(4):582-8
Abstract
Graft-versus-host-disease (GVHD) is a major complication associated with allogeneic hematopoietic cell transplantation (allo-HCT). Antithymocyte globulin (ATG) is recommended for GVHD prophylaxis following allo-HCT, however, evidence on efficacy of ATG is conflicting. Accordingly, we undertook a systematic review. All phase III randomized controlled trials (RCTs) comparing ATG versus control for prevention of GVHD in patients undergoing allo-HCT were eligible. Medline and Cochrane databases were searched. Data on methodological quality, benefits and harms were extracted for each trial and pooled under a random effects model. Seven RCTs enrolling 733 patients met inclusion criteria. Pooled results showed no difference for overall survival with use of ATG (hazard ratio was 0.91; 95% confidence intervals (CI), 0.75-1.10; P = 0.32). There was a significant benefit for prevention of grade III/IV acute GVHD (risk ratio (RR) = 0.51; 95% CI, 0.27-0.94; P = 0.03). There was no benefit associated with ATG use for prevention of either grade II (RR = 0.79; 95% CI, 0.48-1.30; P = 0.35) or grade I acute GVHD (RR = 1.42; 95% CI, 0.75-2.69; P = 0.28). Use of ATG was not associated with significant reduction in non-relapse mortality (RR = 0.74; 95% CI, 0.53-1.03; P = 0.08). Future trials with adequate sample size are required to provide more definitive answers.