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1.
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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2.
Phase 2 multicenter trial of ofatumumab and prednisone as initial therapy of chronic graft-vs-host disease
Lazaryan, A., Lee, S. J., Arora, M., Kim, J., Betts, B. C., Khimani, F., Nishihori, T., Bejanyan, N., Liu, H., Kharfan-Dabaja, M. A., et al
Blood advances. 2021
Abstract
Standard initial therapy of chronic graft vs. host disease (cGVHD) with glucocorticoids results in suboptimal and transient responses in a significant number of patients. Safety and feasibility of anti-CD20 directed B-cell therapy with ofatumumab (1000 mg IV on days 0 and 14) and prednisone (1 mg/kg/day) was previously established in our phase I trial (n=12). We now report the mature results of the phase II expansion of the trial (n=38). The overall NIH severity of cGVHD was moderate (63%) or severe (37%) with 74% of all patients affected by the overlap subtype of cGVHD and 82% by prior acute cGVHD. The combined therapy was generally well tolerated, with some anticipated infusion reactions to ofatumumab, and common toxicities of glucocorticoids. Total B-cell depletion following therapy was profound, with marginal recovery within first 12 months from initial therapy. The observed 6 month clinician-reported and 2014 NIH-defined overall response rates (ORR=complete + partial response[CR/PR]) of 62.5% (1-sided lower 90% confidence interval=51.5%) were not superior to pre-specified historic benchmark of 60%. Post-hoc comparison of 6 month NIH response suggested benefit compared to more contemporaneous NIH-based benchmark of 48.6% with frontline sirolimus/prednisone (CTN 0801 trial). Baseline cGVHD features (organ involvement, severity, initial IS agents) were not significantly associated with 6-month ORR. The median time to initiation of second-line therapy was 5.4 months (range 0.9-15.1 months). Failure-free survival (FFS) was 64.2% (95% CI 46.5-77.4%) at 6 months and 53.1% (95% CI 35.8-67.7%) at 12 months, whereas FFS with CR/PR at 12 months of 33.5% exceeded a benchmark of 15% in post-hoc analysis, and was associated with greater success in steroid discontinuation by 24 months (odds ratio 8 (95% CI 1.21-52.7). This single-arm phase II trial demonstrated acceptable safety and potential efficacy of the upfront use of ofatumumab in combination with prednisone in cGVHD. This trial is registered at www.clinicaltrials.gov as NCT01680965.
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3.
Ruxolitinib resistance or intolerance in steroid-refractory acute graft-versus-host disease - a real-world outcomes analysis
Abedin, S., Rashid, N., Schroeder, M., Romee, R., Nauffal, M., Alhaj Moustafa, M., Kharfan-Dabaja, M. A., Palmer, J., Hogan, W., Hefazi, M., et al
British journal of haematology. 2021
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Abstract
Ruxolitinib for steroid-refractory acute graft-versus-host disease (SR-aGVHD) results in resistance or intolerance in 1/5 of patients. Outcomes of such patients are undefined. We identified these patients in a multicentre review and reported outcomes. Ruxolitinib-resistant aGVHD was identified in 48/307 patients. Among patients receiving additional therapy, the overall response rate to next therapy was 36%. Median survival was 21 days. Ruxolitinib intolerance led to treatment discontinuation in 16/307 patients. Ten intolerant patients received additional therapy with 50% experiencing continued improvement of aGVHD. Median survival was 50 days in these patients. These data serve as a baseline for future SR-aGVHD studies.
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4.
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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5.
Hypoalbuminaemia segregates different prognostic subgroups within the refined standard risk acute graft-versus-host disease score
Kharfan-Dabaja, M. A., Sheets, K., Kumar, A., Murthy, H. S., Nishihori, T., Tsalatsanis, A., Mina, A., Mathews, J., Ayala, E., Chavez, J., et al
British journal of haematology. 2018;180(6):854-862
Abstract
Hypoalbuminaemia has been previously described to predict worse non-relapse mortality (NRM) and inferior overall survival (OS) in allogeneic haematopoietic cell transplant (allo-HCT) recipients. Here, we evaluate the role of hypoalbuminaemia (<35 g/l) at time of onset of acute graft-versus-host disease (aGVHD) when incorporated into the refined aGVHD score. The study population consisted of 522 patients, median age 53 (18-75) years, who underwent an allo-HCT mostly for haematological malignancies. Standard risk (SR) aGVHD comprised 467 patients (89%) and the number of high risk (HR) cases was 55 (11%). Median follow-up for all surviving patients was 26 (3-55) months. Two-year OS was significantly better in patients with SR aGVHD with a serum albumin ≥35 g/l compared to SR with albumin <35 g/l [70% (95% CI = 64-76%) vs. 49% (95% CI = 42-56%), P < 0·0001]. Also, patients with SR aGVHD and a serum albumin level of ≥35 g/l had a significantly lower NRM at 1-year post-transplantation [6% (95% CI = 3-10%) vs. 25% (95% CI = 20-32%), P < 0·0001]. After our findings are validated in a large cohort of patients, we propose that hypoalbuminaemia should be incorporated into the refined aGVHD risk score to further its ability to predict outcomes within this group.
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6.
GvHD after umbilical cord blood transplantation for acute leukemia: an analysis of risk factors and effect on outcomes
Chen, Y. B., Wang, T., Hemmer, M. T., Brady, C., Couriel, D. R., Alousi, A., Pidala, J., Urbano-Ispizua, A., Choi, S. W., Nishihori, T., et al
Bone Marrow Transplantation. 2017;52(3):400-408
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Abstract
Using the Center for International Blood and Marrow Transplant Research (CIBMTR) registry, we analyzed 1404 umbilical cord blood transplantation (UCBT) patients (single (<18 years)=810, double (18 years)=594) with acute leukemia to define the incidence of acute GvHD (aGvHD) and chronic GvHD (cGvHD), analyze clinical risk factors and investigate outcomes. After single UCBT, 100-day incidence of grade II-IV aGvHD was 39% (95% confidence interval (CI), 36-43%), grade III-IV aGvHD was 18% (95% CI, 15-20%) and 1-year cGvHD was 27% (95% CI, 24-30%). After double UCBT, 100-day incidence of grade II-IV aGvHD was 45% (95% CI, 41-49%), grade III-IV aGvHD was 22% (95% CI, 19-26%) and 1-year cGvHD was 26% (95% CI, 22-29%). For single UCBT, multivariate analysis showed that absence of antithymocyte globulin (ATG) was associated with aGvHD, whereas prior aGvHD was associated with cGvHD. For double UCBT, absence of ATG and myeloablative conditioning were associated with aGvHD, whereas prior aGvHD predicted for cGvHD. Grade III-IV aGvHD led to worse survival, whereas cGvHD had no significant effect on disease-free or overall survival. GvHD is prevalent after UCBT with severe aGvHD leading to higher mortality. Future research in UCBT should prioritize prevention of GvHD.
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7.
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.