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A phase II randomized, placebo-controlled, multicenter trial to evaluate the efficacy of cytomegalovirus PepVax vaccine in preventing cytomegalovirus reactivation and disease after allogeneic hematopoietic stem cell transplant
Nakamura, R., La Rosa, C., Yang, D., Hill, J. A., Rashidi, A., Choe, H., Zhou, Q., Lingaraju, C. R., Kaltcheva, T., Longmate, J., et al
Haematologica. 2024
Abstract
Not available.
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Flares of Acute Graft-Versus-Host Disease (GVHD): A Mount Sinai Acute GVHD International Consortium (MAGIC) Analysis
Akahoshi, Y., Spyrou, N., Hoepting, M. Dr med, Aguayo-Hiraldo, P., Ayuk, F. A., Chanswangphuwana, C., Choe, H. K., Eder, M., Etra, A. M., Grupp, S. A., et al
Blood advances. 2024
Abstract
The absence of a standardized definition for GVHD flares and data on its clinical course are significant concerns. We retrospectively evaluated 968 patients across 23 Mount Sinai Acute GVHD International Consortium (MAGIC) transplant centers who achieved complete response (CR) or very good partial response (VGPR) within 4 weeks of treatment. The cumulative incidence of flares within 6 months was 22% and flares were associated with a higher risk of non-relapse mortality (NRM) (adjusted Hazard Ratio [aHR] 4.84 [95% CI, 3.19-7.36], P < 0.001). Compared to the initial GVHD, flares were more severe (Grades III/IV: 41% vs. 16%, P < 0.001) and had more frequent lower gastrointestinal (LGI) involvement (55% vs. 32%, P < 0.001). At CR/VGPR, elevated MAGIC biomarkers predicted the future occurrence of a flare, along with its severity and LGI involvement. In multivariate analyses, higher Ann Arbor (AA) biomarker scores at CR/VGPR were significant risk factors for flares (AA2 vs. AA1: aHR, 1.81 [95% CI, 1.32-2.48], P = 0.001; AA3 vs. AA1: aHR, 3.14 [95% CI, 1.98-4.98], P < 0.001), as were early response to initial treatment (aHR, 1.84 [95% CI, 1.21-2.80], P = 0.004) and HLA-mismatched unrelated donor (aHR, 1.74 [95% CI, 1.00-3.02], P = 0.049). MAGIC biomarkers also stratified the risk of NRM both at CR/VGPR and at the time of flare. We conclude that GVHD flares are common and carry a significant mortality risk. The occurrence of future flares can be predicted by serum biomarkers that may serve to guide adjustment and discontinuation of immunosuppression.
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3.
Lack of RBC transfusion independence by Day 30 following allogeneic hematopoietic stem cell transplant strongly predicts inferior survival and high non-relapse mortality in acute myeloid leukemia patients
Yuan, S., Yang, D., Nakamura, R., Al Malki, M. M., Salhotra, A., Afkhami, M., Wang, S.
Transfusion. 2024
Abstract
BACKGROUND Studies have suggested that acute myeloid leukemia (AML) patients with incomplete hematologic recovery undergoing allogeneic stem cell transplantation (allo-HSCT) had inferior overall survival (OS). STUDY DESIGN AND METHODS This single-center, retrospective study of AML patients evaluated the relationship between red blood cell (RBC) and platelet (PLT) transfusion requirements during the first 30 days and long-term outcomes after allo-HSCT through multivariate analyses. RESULTS A total of 692 AML patients received peripheral blood stem cells (89.2%), marrow (5.6%), or umbilical cord (5.2%) from matched related (37.4%), unrelated (49.1%), or haploidentical (8.2%) donors in 2011-2017. Transfusion requirements during the first 30 days for RBC (89.5% transfused, median 3, range 1-18 units) or PLT (98.2% transfused, median 6, range 1-144 units) were variable. By Day 30, 56.7% (95% confidence interval [CI]: 52.8-60.3%) and 86.1% (95% CI: 83.2-88.5%) had achieved RBC and PLT transfusion independence, respectively. Median follow-up among survivors (n = 307) was 7.1 years (range: 2.7-11.8). Lack of RBC transfusion independence by Day 30 was strongly and independently associated with worse 5-year OS (39.2% vs. 59.6%, adjusted hazard ratio [HR] 1.83, 95% CI: 1.49-2.25), leukemia-free survival (35.8% vs. 55.5%, HR = 1.75, 95% CI: 1.43-2.14), and NRM (29.7% vs. 13.7%, HR = 2.05, 95% CI: 1.45-2.89) (p < .001). There was no difference in relapse rates among patients who achieved or did not achieve RBC (p = .34) or PLT (p = .64) transfusion independence. CONCLUSION Prolonged RBC dependence predicted worse survival and NRM rates, but not increased relapse. Posttransplant surveillance of such patients should be adjusted with more attention to non-relapse complications.
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Post-Transplantation Cyclophosphamide-Based Graft-versus-Host Disease Prophylaxis
Bolaños-Meade, J., Hamadani, M., Wu, J., Al Malki, M. M., Martens, M. J., Runaas, L., Elmariah, H., Rezvani, A. R., Gooptu, M., Larkin, K. T., et al
The New England journal of medicine. 2023;388(25):2338-2348
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Editor's Choice
Abstract
BACKGROUND In patients undergoing allogeneic hematopoietic stem-cell transplantation (HSCT), a calcineurin inhibitor plus methotrexate has been a standard prophylaxis against graft-versus-host disease (GVHD). A phase 2 study indicated the potential superiority of a post-transplantation regimen of cyclophosphamide, tacrolimus, and mycophenolate mofetil. METHODS In a phase 3 trial, we randomly assigned adults with hematologic cancers in a 1:1 ratio to receive cyclophosphamide-tacrolimus-mycophenolate mofetil (experimental prophylaxis) or tacrolimus-methotrexate (standard prophylaxis). The patients underwent HSCT from an HLA-matched related donor or a matched or 7/8 mismatched (i.e., mismatched at only one of the HLA-A, HLA-B, HLA-C, and HLA-DRB1 loci) unrelated donor, after reduced-intensity conditioning. The primary end point was GVHD-free, relapse-free survival at 1 year, assessed in a time-to-event analysis, with events defined as grade III or IV acute GVHD, chronic GVHD warranting systemic immunosuppression, disease relapse or progression, and death from any cause. RESULTS In a multivariate Cox regression analysis, GVHD-free, relapse-free survival was significantly more common among the 214 patients in the experimental-prophylaxis group than among the 217 patients in the standard-prophylaxis group (hazard ratio for grade III or IV acute GVHD, chronic GVHD, disease relapse or progression, or death, 0.64; 95% confidence interval [CI], 0.49 to 0.83; P = 0.001). At 1 year, the adjusted GVHD-free, relapse-free survival was 52.7% (95% CI, 45.8 to 59.2) with experimental prophylaxis and 34.9% (95% CI, 28.6 to 41.3) with standard prophylaxis. Patients in the experimental-prophylaxis group appeared to have less severe acute or chronic GVHD and a higher incidence of immunosuppression-free survival at 1 year. Overall and disease-free survival, relapse, transplantation-related death, and engraftment did not differ substantially between the groups. CONCLUSIONS Among patients undergoing allogeneic HLA-matched HSCT with reduced-intensity conditioning, GVHD-free, relapse-free survival at 1 year was significantly more common among those who received cyclophosphamide-tacrolimus-mycophenolate mofetil than among those who received tacrolimus-methotrexate. (Funded by the National Heart, Lung, and Blood Institute and others; BMT CTN 1703 ClinicalTrials.gov number, NCT03959241.).
PICO Summary
Population
Adults with hematologic cancers undergoing HLA-matched related donor or a matched or 7/8 mismatched unrelated donor transplant, enrolled in an RCT in multiple centres in USA (n=431)
Intervention
Cyclophosphamide-tacrolimus-mycophenolate mofetil (experimental prophylaxis, n=214)
Comparison
Tacrolimus-methotrexate (standard prophylaxis (standard prophylaxis, n=217)
Outcome
GVHD-free, relapse-free survival was significantly more common among patients in the experimental-prophylaxis group than among the standard-prophylaxis group (hazard ratio for grade III or IV acute GVHD, chronic GVHD, disease relapse or progression, or death, 0.64; 95% confidence interval [CI], 0.49 to 0.83). At 1 year, the adjusted GVHD-free, relapse-free survival was 52.7% (95% CI, 45.8 to 59.2) with experimental prophylaxis and 34.9% (95% CI, 28.6 to 41.3) with standard prophylaxis. Patients in the experimental-prophylaxis group appeared to have less severe acute or chronic GVHD and a higher incidence of immunosuppression-free survival at 1 year. Overall and disease-free survival, relapse, transplantation-related death, and engraftment did not differ substantially between the groups.
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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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Haploidentical donor hematopoietic cell transplantation for myelodysplastic/myeloproliferative overlap neoplasms: results from a North American collaboration
Jain, T., Tsai, H. L., Elmariah, H., Vachhani, P., Karantanos, T., Wall, S. A., Gondek, L. P., Bashey, A., Keyzner, A., Tamari, R., et al
Haematologica. 2023
Abstract
Haploidentical donors offer a potentially readily available donor, especially for non-White patients, for hematopoietic cell transplantation (HCT). In this North American collaboration, we retrospectively analyzed outcomes of first HCT using haploidentical donor and posttransplantation cyclophosphamide (PTCy) in MDS/MPN-overlap neoplasms (MDS/MPN). We included 120 consecutive patients who underwent HCT using a haploidentical donor for MDS/MPN across 15 centers. Median age was 62.5 years and 38% were of non-White/Caucasian ethnicity. The median follow-up was 2.4 years. Graft failure was reported in 7/120 (6%) of patients. At 3 years, nonrelapse mortality (NRM) was 25% (95%CI 17-34%), relapse 27% (95%CI 18-36%), grade 3-4 acute graft versus host disease (GVHD) 12% (95%CI 6-18%), chronic GVHD requiring systemic immunosuppression 14% (95%CI 7-20%), progression-free survival (PFS) 48% (95%CI 39-59%), and overall survival (OS) 56% (95%CI 47-67%). On multivariable analysis, NRM was statistically significantly associated with advancing age at HCT (per decade increment, sdHR 3.28, 95%CI 1.30-8.25); relapse with the presence of mutation in EZH2/RUNX1/SETBP1 (sdHR 2.61, 95%CI 1.06-6.44); PFS with advancing age at HCT (per decade increment, HR 1.98, 95% 1.13-3.45); and OS with advancing age at HCT (per decade increment, HR 2.01, 95% CI 1.11-3.63) and splenomegaly at HCT/prior splenectomy (HR 2.20, 95%CI 1.04-4.65). Haploidentical donors are a viable option for HCT in MDS/MPN, especially for those disproportionately represented in the unrelated donor registry. Hence, donor mismatch should not preclude HCT for patients with MDS/MPN, an otherwise incurable malignancy. In addition to patient age, disease-related factors including splenomegaly and high-risk mutations dominate outcomes following HCT.
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WT1-mutated acute myeloid leukemia is sensitive to fludarabine-based chemotherapy and conditioning regimens
Aribi, A., Salhotra, A., Afkhami, M., Munteanu, A., Ali, H., Aldoss, I., Otoukesh, S., Al Malki, M. M., Sandhu, K. S., Koller, P., et al
Leukemia & lymphoma. 2023;:1-11
Abstract
We conducted a retrospective analysis of WT1-mutated acute myeloid leukemia (AML) patients who underwent allogeneic stem cell transplant. Thirty-seven patients with WT1-mutated AML were identified. Primary induction failure (40%) and early relapse rate (18%) after idarubicin/cytarabine (7 + 3) chemotherapy were observed. All patients with induction failure subsequently achieved CR with additional chemotherapy. There was no significant difference between outcomes after myeloablative vs. reduced intensity (Fludarabine/Melphalan [Flu/Mel]) conditioning regimens. RFS but not OS was significantly better in patients who received FLAG-IDA prior to transplant and/or a fludarabine-containing conditioning. In an independent ex vivo study, WT1-mutated AML samples exhibited greater sensitivity to fludarabine (p = 0.026) and melphalan (p = 0.0005) than non-WT1-mutated AML samples while there was no difference between sensitivity to cytarabine. Our data favor using a fludarabine-based induction for AML with WT1 mutation instead of 7 + 3. Fludarabine conditioning regimens for alloHCT showed better RFS but not OS.
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Phase 2 study of natalizumab plus standard corticosteroid treatment for high-risk acute graft-versus-host disease
Al Malki, M. M., London, K., Baez, J., Akahoshi, Y., Hogan, W. J., Etra, A. M., Choe, H. K., Hexner, E. O., Langston, A., Abhyankar, S. H., et al
Blood advances. 2023
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Editor's Choice
Abstract
GVHD of the gastrointestinal (GI) tract is the main cause of non-relapse mortality following allogeneic HCT. Ann Arbor (AA) scores derived from serum biomarkers at onset of GVHD quantify GI crypt damage; AA 2/3 scores correlate with resistance to treatment and higher non-relapse mortality (NRM). We conducted a multicenter, phase 2 study using natalizumab, a humanized monoclonal antibody that blocks T cell trafficking to the GI tract through the α4 subunit of α4β7 integrin, combined with corticosteroids as primary treatment for patients with new onset AA 2/3 GVHD. Seventy-five evaluable patients were enrolled and treated; 81% received natalizumab within 2 days of starting corticosteroids. Therapy was well tolerated with no treatment emergent adverse events (AEs) in more than 10% of patients. Outcomes for patients treated with natalizumab plus corticosteroids were compared to 150 well matched controls from the MAGIC database whose primary treatment was corticosteroids alone. There were no significant differences in overall or complete response between patients treated with natalizumab plus corticosteroids and corticosteroids alone controls (60% vs. 58%; P=0.67 and 48% vs. 48%; P=1.0, respectively) including relevant subgroups. There were also no significant differences in NRM or overall survival (OS) at 12 months in patients treated with natalizumab plus corticosteroids compared to controls treated with corticosteroids alone (38% vs 39%, P=0.80 and 46% vs 54%, P=0.48, respectively). In this multicenter biomarker-based phase 2 study, natalizumab combined with corticosteroids failed to improve outcome of patients with newly diagnosed high risk GVHD.
PICO Summary
Population
Adults with new onset high risk GvHD from 12 centres in USA (n=75)
Intervention
Natalizumab combined with corticosteroids (n=75)
Comparison
Matched controls from the MAGIC database whose primary treatment was corticosteroids alone (n=150)
Outcome
There were no significant differences in overall or complete response between patients treated with natalizumab plus corticosteroids and corticosteroids alone controls (60% vs. 58% and 48% vs. 48%, respectively) including relevant subgroups. There were also no significant differences in NRM or overall survival (OS) at 12 months in patients treated with natalizumab plus corticosteroids compared to controls treated with corticosteroids alone (38% vs 39% and 46% vs 54%, respectively).
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Tocilizumab for Cytokine Release Syndrome Management after Haploidentical Hematopoietic Cell Transplantation with Post-Transplant Cyclophosphamide-Based Graft-Versus-Host Disease Prophylaxis
Yao, J. M., Otoukesh, S., Kim, H., Yang, D., Mokhtari, S., Samara, Y., Blackmon, A., Arslan, S., Agrawal, V., Pourhassan, H., et al
Transplantation and cellular therapy. 2023
Abstract
BACKGROUND Cytokine release syndrome (CRS) is a common complication after haploidentical hematopoietic cell transplant (HaploHCT). Severe CRS after haploHCT leads to higher risk of non-relapse mortality (NRM) and worse overall survival (OS). Tocilizumab (TOCI) is an interleukin-6 receptor inhibitor and is commonly used as first-line for CRS management after chimeric antigen receptor T cell therapy, but the impact of TOCI administration for CRS management on Haplo HCT outcomes is not known. OBJECTIVES In this single center retrospective analysis, we compared HCT outcomes in patients treated with or without TOCI for CRS management after HaploHCT with post-transplant cyclophosphamide- (PTCy-) based graft-versus-host disease (GVHD) prophylaxis. STUDY DESIGN Of the 115 patients eligible patients who underwent HaploHCT at City of Hope between 2019 to 2021 and developed CRS, we identified 11 patients who received tocilizumab for CRS management (TOCI). These patients were matched with 21 patients who developed CRS but did not receive tocilizumab (NO-TOCI) based on age at the time of HCT (≤64 years or >65 years or older), conditioning intensity (MAC vs RIC/NMA), and CRS grading (1, 2 vs 3-4). Instead of 22 controls, we chose 21 patients because there was only one control matched with one TOCI treatment patient in one stratum. With only 11 patients in receiving tocilizumab for CRS treatment, matching with 21 patients who developed CRS but did not receive tocilizumab, we had 80% power to detect big differences (HR=3.4 or higher) in transplant outcomes using a two-sided 0.05 test. The power would be reduced to about 20-30% if the difference was moderate (HR=2.0) using the same test. RESULTS No CRS-related deaths were recorded in either group. Median time to neutrophil engraftment was 21 days (range: 16-43) in TOCI and 18 days (range 14-23) in NO-TOCI group (HR=0.55; 95% CI: 0.28-1.06, P=0.08). Median time to platelet engraftment was 34 days (range: 20-81) in TOCI and 28 days (range: 12-94) in NO-TOCI group (HR=0.56; 95% CI: 0.25-1.22, P= 0.19). Cumulative incidences of day +100 acute GVHD grades II-IV (P=0.97) and grades III-IV (P=0.47) were similar between the two groups. However, cumulative incidence of chronic GvHD at 1 year was significantly higher in patients receiving TOCI (64% vs 24%; P=0.05). Rates of NRM (P=0.66), relapse (P=0.83), disease-free survival (P=0.86), and overall survival (P=0.73) were similar at 1-year post-HCT between the two groups. CONCLUSIONS Tocilizumab administration for CRS management after HaploHCT appears to be safe with no short-term adverse effect and no effect on relapse rate. However, the significantly higher cumulative incidence of chronic GvHD, negates the high efficacy of PTCy on GvHD prophylaxis in this patient population. Therefore, using tocilizumab for CRS management in the HaploHCT population with PTCy maybe kept only for patients with severe CRS. The impact on such approach on long term outcome in HaploHCT with PTCy will need to be evaluated in a larger retrospective study or a prospective manner.
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The impact of SARS-CoV2 vaccines on the incidence of graft versus host disease in allogeneic hematopoietic stem cell transplant recipients: a single-center retrospective study
Ngo, D., Chen, J., Tinajero, J., Aribi, A., Arslan, S., Marcucci, G., Nakamura, R., Al Malki, M. M., Forman, S. J., Dadwal, S., et al
Stem cell research & therapy. 2023;14(1):95
Abstract
This study reports the incidence of chronic graft versus host disease (GvHD) in allogeneic hematopoietic stem cell transplant (alloHCT) recipients who received SARS-CoV2 vaccination. The overall rates of new and worsening chronic GvHD combined were 14%, with median time from vaccination to GVHD being approximately three to four weeks. A majority of the cases were of mild to moderate severity and primarily localized to either the skin, mouth, or joints. Prior chronic GVHD and recent transplant were associated with higher GVHD rates following COVID-19 vaccination. More prospective studies are needed to provide a definitive mechanism for the impact of SARS-CoV2 vaccination on alloHCT patients.