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A Calcineurin Inhibitor Free Graft Versus Host Disease Prophylaxis for Patients Undergoing Matched Related and Matched Unrelated Donor Allogeneic Hematopoietic Cell Transplant
Iqbal, M., Nieto, F. A. M., Brannick, K. M., Li, Z., Murthy, H., Foran, J., Roy, V., Kharfan-Dabaja, M. A., Ayala, E.
Transplantation and cellular therapy. 2023
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Editor's Choice
Abstract
Post-transplantation cyclophosphamide (PTCy) and calcineurin inhibitor (CNI) based graft versus host disease (GVHD) prophylaxis has shown lower rates of acute and chronic GVHD when compared with the traditional prophylaxis of CNI and methotrexate (MTX) in matched related (MRD) and matched unrelated donor (MUD) allogeneic hematopoietic cell transplant (allo-HCT). The combination of PTCy with sirolimus as a CNI-free GVHD prophylaxis has shown promising results with cumulative rates of grade II-IV acute and chronic GVHD in the range of 15-27% and 20-27%, respectively, in patients undergoing MRD, MUD and haploidentical allo-HCT. We report a single center, nonrandomized comparison of patients undergoing matched donor allo-HCT receiving PTCy in combination with sirolimus (PTCy-Siro) with those receiving the standard GVHD prophylaxis of tacrolimus and MTX (Tac-MTX). One hundred and sixteen consecutive patients who had undergone a MRD or MUD allo-HCT between January 2018 to January 2021 and received either PTCy with sirolimus or tacrolimus with methotrexate as GVHD prophylaxis regimens were eligible for inclusion. Out of a total of 116 patients undergoing MRD and MUD allo-HCT, 29 received PTCy-Siro and 87 Tac-MTX. Patients receiving PTCy-Siro had a significantly shorter median time to immunosuppression withdrawal at 138 (37-312) vs 232(66-1120) days for patients receiving Tac-MTX (p=<0.001). No significant difference was observed between the two arms for incidence of grade II to IV acute GVHD, grade III to IV acute GVHD, steroid refractory acute GVHD or clinical infections. At a median follow up of 1.1 (range: 0-1.8) years, patients receiving PTCy-Siro were significantly less likely to have chronic GVHD with 2-year freedom from GVHD of 75% (95%CI: 58-98%) vs 20% (95%CI 10-40%), p=0.005.
PICO Summary
Population
Adults from a single centre in USA undergoing matched-related or matched-unrelated donor allogeneic HSCT (n=116)
Intervention
Post-transplant cyclophosphamide in combination with sirolimus (PTCy-Siro, n=29)
Comparison
Tacrolimus and methotrexate (Tac-MTX, n=87)
Outcome
Patients receiving PTCy-Siro had a significantly shorter median time to immunosuppression withdrawal at 138 (37-312) vs 232(66-1120) days for patients receiving Tac-MTX. No significant difference was observed between the two arms for incidence of grade II to IV acute GVHD, grade III to IV acute GVHD, steroid refractory acute GVHD or clinical infections. At a median follow up of 1.1 (range: 0-1.8) years, patients receiving PTCy-Siro were significantly less likely to have chronic GVHD with 2-year freedom from GVHD of 75% (95%CI: 58-98%) vs 20% (95%CI 10-40%)
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2.
A phase 2 trial of GVHD prophylaxis with PTCy, sirolimus, and MMF after peripheral blood haploidentical transplantation
Bejanyan, N., Pidala, J. A., Wang, X., Thapa, R., Nishihori, T., Elmariah, H., Lazaryan, A., Khimani, F., Davila, M. L., Mishra, A., et al
Blood advances. 2021;5(5):1154-1163
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Editor's Choice
Abstract
The introduction of posttransplant cyclophosphamide (PTCy) made performing allogeneic hematopoietic cell transplantation (HCT) from HLA haplotype-incompatible donors possible. In a setting of PTCy and tacrolimus/mycophenolate mofetil (MMF) as a graft-versus-host disease (GVHD) prophylaxis, a peripheral blood (PB) graft source as compared with bone marrow reduces the relapse rate but increases acute GVHD (aGVHD) and chronic GVHD (cGVHD). This phase 2 trial assessed sirolimus and MMF efficacy following PTCy as a GVHD prophylaxis after PB haploidentical HCT (haplo-HCT). With 32 evaluable patients (=18 years) enrolled, this study had 90% power to demonstrate a reduction in 100-day grade II-IV aGVHD to 20% from the historical benchmark of 40% after haplo-HCT using PTCy/tacrolimus/MMF. At a median follow-up of 16.1 months, the primary end point of the trial was met with a day-100 grade II-IV aGVHD cumulative incidence of 18.8% (95% confidence interval [CI], 7.5% to 34.0%). There were no graft-failure events and the 1-year probability of National Institutes of Health (NIH) moderate/severe cGVHD was 18.8% (95% CI, 7.4% to 34.0%), nonrelapse mortality was 18.8% (95% CI, 7.4% to 34.0%), relapse was 22.2% (95% CI, 9.6% to 38.2%), disease-free survival was 59.0% (95% CI, 44.1% to 79.0%), GVHD-free relapse-free survival was 49.6% (95% CI, 34.9% to 70.5%), and overall survival was 71.7% (95% CI, 57.7% to 89.2%) for the entire cohort. These data demonstrate that GVHD prophylaxis with sirolimus/MMF following PTCy effectively prevents grade II-IV aGVHD after PB haplo-HCT, warranting prospective comparison of sirolimus vs tacrolimus in combination with MMF following PTCy as GVHD prophylaxis after PB HCT. This trial was registered at www.clinicaltrials.gov as #NCT03018223.
PICO Summary
Population
Adult patients who received a haploidentical stem cell transplant (n=32)
Intervention
Post-transplant cyclophosphamide (PTCy) and tacrolimus/mycophenolate mofetil (MMF) as a graft-versus-host disease (GVHD) prophylaxis
Comparison
None
Outcome
At a median follow-up of 16.1 months, the primary end point of the trial was met with a day-100 grade II-IV aGVHD cumulative incidence of 18.8%. There were no graft-failure events and the 1-year probability of National Institutes of Health (NIH) moderate/severe cGVHD was 18.8%, nonrelapse mortality was 18.8%, relapse was 22.2% , disease-free survival was 59.0%, GVHD-free relapse-free survival was 49.6% and overall survival was 71.7% for the entire cohort.
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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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Post-Transplant cyclophosphamide is associated with increase in Non-CMV Herpesvirus infections in Acute leukemia and MDS patients
Singh, A., Dandoy, C. E., Chen, M., Kim, S., Mulroney, C. M., Kharfan-Dabaja, M. A., Ganguly, S., Maziarz, R. T., Kanakry, C. G., Kanakry, J. A., et al
Transplantation and cellular therapy. 2021
Abstract
BACKGROUND There is increasing use of post-transplant cyclophosphamide (PTCy) for GVHD prophylaxis for both haploidentical and fully matched transplants. Published studies have reported an increased incidence of CMV infection with the use of PTCy. Limited data exist regarding the incidence and outcomes of infection with non-CMV herpes viruses (NCHV) in this setting. OBJECTIVE The aim of this study was to evaluate the cumulative incidence of NCHV infections and the association of NCHV infections with transplant-specific outcomes in patients receiving haploidentical transplant with PTCy(HaploCy), matched sibling donor transplant with PTCy (SibCy) or matched sibling donor transplant with calcineurin inhibitor based prophylaxis (SibCNI). We hypothesized that, like CMV infection, patients receiving haploidentical transplant with PTCy will have higher risk of NCHV infections. STUDY DESIGN Using the CIBMTR database, we analyzed patients (HaploCy, n=757; SibCNI, n=1605; SibCy, n=403) receiving first hematopoietic stem-cell transplant between 2012 and 2017 for acute myeloid leukemia, acute lymphoblastic leukemia and myelodysplastic syndrome. RESULTS The cumulative incidence of non-CMV herpes virus infection at six months post-transplant in the HaploCy, SibCy and SibCNI were 13.9% (99%CI=10.8-17.3%), 10.7% (99%CI=7.1-15%), and 5.7% (99%CI=4.3-7.3%), p<0.001 respectively. This was primarily due to a higher frequency of HHV-6 viremia reported in patients receiving PTCy. Incidence of Epstein-Barr viremia was low in all groups and no cases of post-transplant lymphoproliferative disorder were seen in PTCy groups. The incidence of non-CMV herpes virus organ disease was low in all three cohorts. Development of NCHV infection was associated with increased treatment-related mortality, particularly in the HaploCy group. There was no association with the development of GVHD, relapse, and disease-free survival. Patients in PTCy cohorts who did not develop non-CMV herpes virus infection had lower rates of cGVHD. CONCLUSIONS This study demonstrates that the use of PTCy is associated with increased risk of NCHV infection. Development of NCHV infection is associated with increased non-relapse mortality, especially in HaploCY group. Prospective trials should consider viral surveillance strategies in conjunction with assessment of immune reconstitution for better understanding of the clinical relevance of viral reactivation in different transplant settings.
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Risk Factors for Graft-versus-Host Disease in Haploidentical Hematopoietic Cell Transplantation Using Post-Transplant Cyclophosphamide
Im, A., Rashidi, A., Wang, T., Hemmer, M., MacMillan, M. L., Pidala, J., Jagasia, M., Pavletic, S., Majhail, N. S., Weisdorf, D., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
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Editor's Choice
Abstract
Post-transplant cyclophosphamide (PTCy) has significantly increased the successful use of haploidentical donors with relatively low incidence of GVHD. Given its increasing use, we sought to determine risk factors for GVHD after haploidentical hematopoietic cell transplantation (haploHCT) using PTCy. Data from the Center for International Blood and Marrow Transplant Research on adult patients with AML, ALL, MDS, or CML who underwent PTCy-based haploHCT (2013-2016) were analyzed and categorized into 4 groups based on myeloablative (MA) or reduced intensity (RIC) conditioning and bone marrow (BM) or peripheral blood (PB) graft source. 646 patients were identified (MA-BM=79, MA-PB=183, RIC-BM=192, RIC-PB=192). The incidence of grade 2-4 aGVHD at 6 months was highest in MA-PB (44%), followed by RIC-PB (36%), MA-BM (36%), and RIC-BM (30%) (p=0.002). The incidence of chronic GVHD at 1 year was 40%, 34%, 24%, and 20%, respectively (p<0.001). In multivariable analysis, there was no impact of stem cell source or conditioning regimen on grade 2-4 acute GVHD; however, older donor age (30-49 versus <29 years) was significantly associated with higher rates of grade 2-4 acute GVHD (HR 1.53, 95% CI 1.11-2.12, p=0.01). In contrast, PB compared to BM as a stem cell source was a significant risk factor for the development of chronic GVHD (HR 1.70, 95% CI 1.11-2.62, p=0.01) in the RIC setting. There were no differences in relapse or overall survival between groups. Donor age and graft source are risk factors for acute and chronic GVHD, respectively, after PTCy-based haploHCT. Our results indicate that in RIC haploHCT, the risk of chronic GVHD is higher with PB stem cells, without any difference in relapse or overall survival.
PICO Summary
Population
Adult patients with AML, ALL, MDS, or CML who underwent PTCy-based haploHCT (n=646)
Intervention
Myeloablative conditioning with a bone marrow graft source (MA-BM, n=79), Myeloablative conditioning with a peripheral blood graft source (MA-PB, n=183)
Comparison
Reduced intensity conditioning with a bone marrow graft source, (RIC-BM, n=192) Reduced intensity conditioning with a peripheral blood graft source, (RIC-PB, n=192).
Outcome
The incidence of grade 2-4 aGVHD at 6 months was highest in MA-PB (44%), followed by RIC-PB (36%), MA-BM (36%), and RIC-BM (30%). The incidence of chronic GVHD at 1 year was 40%, 34%, 24%, and 20%, respectively. In multivariable analysis, there was no impact of stem cell source or conditioning regimen on grade 2-4 acute GVHD; however, older donor age (30-49 versus <29 years) was significantly associated with higher rates of grade 2-4 acute GVHD. In contrast, PB compared to BM as a stem cell source was a significant risk factor for the development of chronic GVHD in the RIC setting. There were no differences in relapse or overall survival between groups.
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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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Tacrolimus plus sirolimus with or without ATG as GVHD prophylaxis in HLA-mismatched unrelated donor allogeneic stem cell transplantation
Kharfan-Dabaja, M. A., Parody, R., Perkins, J., Lopez-Godino, O., Lopez-Corral, L., Vazquez, L., Caballero, D., Falantes, J., Shapiro, J., Orti, G., et al
Bone Marrow Transplantation. 2017;52(3):438-444
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Abstract
HLA-matched related or unrelated donors are not universally available. Consequently, patients can be offered hematopoietic stem cell transplantation (HSCT) from alternative donors, including mismatched unrelated donors (MMURD), known to cause a higher incidence of acute GVHD (aGVHD) and chronic GVHD. In vivo T-cell-depletion strategies, such as antithymocyte globulin (ATG) therapy, significantly decrease the risk of GVHD. We performed a multicenter, retrospective study comparing tacrolimus (TAC) and sirolimus (SIR) with or without ATG in 104 patients (TAC-SIR=45, TAC-SIR-ATG=59) who underwent MMURD HSCT. Use of ATG was associated with a lower incidence, albeit not statistically significant, of grades 2-4 aGVHD (46% vs 64%, P=0.09), no difference in grades 3-4 aGVHD (10% vs 15%, P=0.43), a trend for a lower incidence of moderate/severe chronic GVHD (16% vs 37%, P=0.09) and more frequent Epstein-Barr virus reactivation (54% vs 18%, P=0.0002). There were no statistically significant differences in 3-year overall survival (OS) (TAC-SIR-ATG=40% (95% confidence interval (CI)=24-56%) vs TAC-SIR=54% (95% CI=37-70%), P=0.43) or 3-year cumulative incidence of relapse/progression (TAC-SIR-ATG=40% (95% CI=28-58%) vs TAC-SIR=22% (95% CI=13-39%), P=0.92). An intermediate Center for International Blood & Marrow Transplant Research disease risk resulted in a significantly lower non-relapse mortality and better OS at 3 years. Our study suggests that addition of ATG to TAC-SIR in MMURD HSCT does not affect OS when compared with TAC-SIR alone.
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In vivo IL-12/IL-23p40 neutralization blocks Th1/Th17 response after allogeneic hematopoietic cell transplantation
Pidala, J., Beato, F., Kim, J., Betts, B., Jim, H., Sagatys, E., Levine, J. E., Ferrara, J. L., Ozbek, U., Ayala, E., et al
Haematologica. 2017
Abstract
T helper 1 and T helper 17 lymphocytes mediate acute graft vs. host disease. Interleukin 12 is critical for T helper 1 differentiation and interleukin 23 for T helper 17 maintenance. Interleukin 12 and 23 are heterodimeric cytokines that share the p40 subunit (IL-12/IL-23p40). In a randomized, blinded, placebo-controlled trial, we examined the biologic impact and clinical outcomes following IL-12/IL-23p40 neutralization using ustekinumab. 30 patients received peripheral blood mobilized hematopoietic cell transplantation from HLA-matched sibling or unrelated donors, received sirolimus plus tacrolimus as graft vs. host disease prophylaxis, and were randomized to ustekinumab vs. placebo with 1:1 allocation after stratification by donor type. The primary endpoint of the trial was the mean % Treg on day 30 post-HCT. Ustekinumab was delivered by subcutaneous injection on day -1 and day +20 after transplantation. On day 30 post-transplant, no significant difference in % Treg was observed. Ustekinumab suppressed serum IL-12/IL-23p40 levels. Host-reactive donor alloresponse at day 30 and 90 after transplantation was polarized with significant reduction in IL-17 and IFN-gamma production and increase in IL-4. No toxicity attributed to ustekinumab was observed. Overall survival and NIH moderate/severe chronic graft vs. host disease-, relapse-free survival were significantly improved among ustekinumab-treated patients. No significant improvements were observed in acute or chronic graft vs. host disease, relapse, or non-relapse mortality. These data provide first evidence that IL-12/IL-23p40 neutralization can polarize donor anti-host alloresponse in vivo and provide initial clinical efficacy evidence to be tested in subsequent trials. This trial was registered as NCT01713400.
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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.