scholarly journals A Calcineurin Inhibitor Free Graft Versus Host Disease (GVHD) Prophylaxis for Patients Undergoing Matched Related (MRD) and Matched Unrelated Donor (MUD) Allogeneic Hematopoietic Cell Transplant (Allo-HCT)

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3893-3893
Author(s):  
Madiha Iqbal ◽  
Felipe Andres Mendieta Nieto ◽  
Kaitlyn M Brannick ◽  
Zhuo Li ◽  
Hemant S. Murthy ◽  
...  
Keyword(s):  
Median Time ◽  
Research Funding ◽  
Calcineurin Inhibitor ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Cell Transplant ◽  
Gvhd Prophylaxis ◽  
Grade Ii ◽  
Matched Donor

Abstract Introduction Post-transplantation cyclophosphamide (PTCy) and calcineurin inhibitor (CNI) based GVHD prophylaxis has shown lower rates of acute and chronic GVHD when compared with the traditional prophylaxis of calcineurin inhibitor (CNI) and methotrexate (MTX) in matched donor (related and unrelated) allo-HCT. The combination of PTCy with sirolimus as a calcineurin inhibitor-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 matched 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). Methods 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. The selection of PTCy with sirolimus or tacrolimus with methotrexate as GVHD prophylaxis regimen was based on physician choice. Primary endpoints were cumulative incidence of acute (grade II to IV) and chronic GVHD. Secondary endpoints were a) neutrophil and platelet engraftment; b) overall survival (OS); c) non-relapse mortality (NRM); d) relapse; e) clinical infections and f) time to immunosuppression (IS) withdrawal. Kaplan-Meier method was used to estimate 1-year and 2-year freedom from long term adverse events, including chronic GVHD, relapse, NRM and OS. All tests were two-sided with alpha level set at 0.05 for statistical significance. Results Out of a total of 116 patients undergoing MRD and MUD allo-HCT, 29 received PTCy/Siro and 87 Tac/MTX. Baseline characteristics were similar between the two arms except patients in PTCy/Siro were younger with median of 48 (range: 24-69) years vs. 61 (range: 20-73) years (p=0.004) in Tac/MTX. There was difference in primary indication for allo-HCT between the two arms with non-hodgkin lymphoma (NHL) being the most common in PTCy/Siro and acute myeloid leukemia (AML) in the Tac/MTX group. Patients receiving PTCy/Siro had a significantly higher median CD3 day 100 chimerism at 100 (90-100) vs. 90 (40-100) % (<0.001) and a significantly shorter median time to IS withdrawal at 138 (37-312) vs 232(66-1120) days for patients receiving Tac/MTX. There was no difference between the two arms for length of hospital stay and time to neutrophil engraftment, but PTCy/Siro had a significantly longer median time for platelet engraftment at 17.5 (12-74) vs.14 (11-38) days (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 (Table 1). After 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 (Figure 1). There was no difference between the two arms for OS, disease relapse or non-relapse mortality (Table 2). Conclusion In this study, the combination of PTCy/Siro is associated with a significantly lower risk of chronic GVHD when compared against the traditional GVHD prophylaxis of CNI and methotrexate, despite significantly earlier IS withdrawal. Other long-term outcomes of interest remained comparable between the two arms. Chronic GVHD contributes to significant morbidity and mortality in patients undergoing allo-HCT. Newer strategies to limit the impact of chronic GVHD are needed. The results of our study warrant validation in a large, multicenter, randomized prospective trial. Figure 1 Figure 1. Disclosures Murthy: CRISPR Therapeutics: Research Funding. Foran: gamida: Honoraria; takeda: Research Funding; novartis: Honoraria; trillium: Research Funding; boehringer ingelheim: Research Funding; OncLive: Honoraria; abbvie: Research Funding; certara: Honoraria; sanofi aventis: Honoraria; syros: Honoraria; taiho: Honoraria; revolution medicine: Honoraria; bms: Honoraria; servier: Honoraria; pfizer: Honoraria; actinium: Research Funding; aptose: Research Funding; kura: Research Funding; h3bioscience: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding.

Secondary Graft-Versus-Host Disease (GVHD) Prophylaxis with Oral Proteasome Inhibitor Ixazomib Is Associated with Low Incidence of Recurrent, Late Acute and Chronic GVHD and Facilitated Calcineurin Inhibitor Taper within the First Year Post Allogeneic Stem Cell Transplantation

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 41-42
Author(s):  
Natasia Rodriguez ◽  
Jasme Lee ◽  
Lisa Flynn ◽  
Fiona Murray ◽  
Sean Devlin ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Calcineurin Inhibitor ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Overlap Syndrome ◽  
Advisory Committees ◽  
Gvhd Prophylaxis ◽  
Grade Ii ◽  
Low Incidence

Background. GVHD is a frequent complication within the 1st year after allogeneic stem cell transplantation (allo-HCT). Recipients of reduced intensity (RI) and non-myeloablative (NMA) conditioning combined with calcineurin inhibitor (CNI)-based GVHD prophylaxis, frequently develop GVHD in the context of immunosuppression taper. Ixazomib is an oral proteasome inhibitor (PI) that has demonstrated immunomodulatory properties, inhibition of pro-inflammatory cytokines, anti-tumor activity, and has a wide safety profile. We hypothesized that secondary GVHD prophylaxis using ixazomib, will facilitate CNI taper without increase in GVHD frequency and severity, maintaining graft-versus-tumor (GVT) effect, and a safety profile. Methods. We conducted an open label, prospective, single-center pilot study between 11/16 and 03/19. Eligible patients were > 18 yrs old, had a hematologic malignancy treated with RI or NMA conditioning allo-HCT, received CNI-based GVHD prophylaxis, and were within day 100 to 150 post-HCT. Patients with active acute and/or chronic GVHD were excluded. Patients were treated with ixazomib 4 mg orally once weekly, each cycle consisting of 3 weeks on and 1 week off therapy, until completion of taper from prophylactic CNI or 1-year post-HCT was reached, whichever occurred first. Patients who developed grade II-IV acute GVHD, chronic GVHD, or died of transplant-related mortality (TRM) were deemed treatment failure. The primary endpoint was the efficacy of ixazomib for the prevention of recurrent or late grade II-IV acute GVHD or chronic GVHD at 1-year post-HCT. Additional endpoints included TRM, relapse rate, survival analysis, safety evaluation, and immune reconstitution. Results. A total of 18 patients (median age of 58 yrs) were accrued in the study. The majority were male, had a diagnosis of NHL, and received RI conditioning (Table 1). All patients had a PBSC graft, and 16 (89%) were 10/10 HLA-matched. The median time for initiation of ixazomib was 141.5 days post-HCT. Fourteen patients had no GVHD during the study period. The 4 patients who developed GVHD had severe overlap syndrome (n = 2), mild de novo chronic GVHD (n = 1), and recurrent grade II acute GVHD (n = 1). Notably, patients with severe overlap syndrome had limited chronic GVHD involvement affecting the mouth and/or eyes, and the severity score was driven by acute manifestations affecting the skin and GI tract. Six patients successfully discontinued CNI and 4 patients were tapering immunosuppression close to the end of study at 1-year post-HCT. The cumulative incidence (CI) of grade II-IV acute and chronic GVHD at 1-year post-HCT was 25% (95%CI: 7.2-48.1) (Fig. 1A). No patients died during the study and therefore, the CI of TRM at 1-year was 0%, and only 1 patient had malignant relapse (NHL). The CI of PFS and the composite endpoint GVHD-free/relapse-free survival (GRFS) at 1-year were 83% (95%CI: 58-100) and 73% (95%CI: 49-100, Fig 1B), respectively. All patients experienced at least 1 TEAE of any grade. Most AEs were grade 1 or 2, with the most common being cytopenia and elevation in ALT/AST. Drug-related SAEs were reported in 9 patients and included neutrophil and decreased WBC. Seven patients required ixazomib dose reduction due to side effects, and 5 patients were removed from the study due to toxicity (1 neutropenia, 3 GI, 1 skin rash). Of those, 1 had subsequent GVHD by day 365 post-HCT. Immune recovery at 3, 6 and 12 months post-HCT was evaluated. There was a rapid and sustained recovery in T-cell subpopulations and B cell reconstitution Fig 2. Conclusions. Secondary GVHD prophylaxis with ixazomib was associated with low incidence of recurrent and late acute and chronic GVHD within the 1st year post-HCT. This approach allowed CNI taper while preserving GVT effect without aggravating GVHD. No deaths occurred during the study period and the 1-year GRFS was high. Ixazomib was overall well tolerated and favored immune reconstitution post-HCT. Our findings support further development of this approach and provide a proof-of-concept for secondary GVHD prophylaxis. Disclosures Dahi: Kite: Consultancy. Giralt:TAKEDA: Research Funding; JAZZ: Consultancy, Honoraria; CELGENE: Consultancy, Honoraria, Research Funding; AMGEN: Consultancy, Research Funding; MILTENYI: Consultancy, Research Funding; KITE: Consultancy; NOVARTIS: Consultancy, Honoraria, Research Funding; OMEROS: Consultancy, Honoraria; ACTINUUM: Consultancy, Research Funding. Sauter:Bristol-Myers Squibb: Research Funding; GSK: Consultancy; Gamida Cell: Consultancy; Celgene: Consultancy, Research Funding; Kite - a Gilead Company: Consultancy; Precision Biosciences: Consultancy, Research Funding; Genmab: Consultancy; Novartis: Consultancy; Spectrum Pharamaceuticals: Consultancy; Sanofi-Genzyme: Consultancy, Research Funding; Juno Therapeutics: Consultancy, Research Funding. Perales:Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Medigene: Membership on an entity's Board of Directors or advisory committees, Other; NexImmune: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Other; Cidara Therapeutics: Other; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Nektar Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria; Miltenyi Biotec: Research Funding; Kite/Gilead: Honoraria, Research Funding; Incyte Corporation: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; MolMed: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ponce:Ceramedix: Membership on an entity's Board of Directors or advisory committees; Generon: Membership on an entity's Board of Directors or advisory committees; Kadmon: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding.

scholarly journals Use of Post-Transplant Cyclophosphamide (PTCy) with Mycophenolate Mofetil and Tacrolimus in HLA Matched Allogeneic Hematopoietic Cell Transplant Is Safe and Associated with Acceptable Transplant Outcomes

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1950-1950 ◽  
Author(s):  
Brian T Hess ◽  
Feng Gao ◽  
John F. DiPersio ◽  
Peter Westervelt ◽  
Ravi Vij ◽  
...  
Keyword(s):  
Research Funding ◽  
Acute Gvhd ◽  
Unrelated Donor ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant ◽  
Transplant Outcomes ◽  
Allogeneic Hematopoietic Cell Transplant ◽  
Transplant Patients ◽  
Gvhd Prophylaxis ◽  
Grade Ii

Abstract Background: The use of post-transplantation cyclophosphamide (PTCy) as a single agent for graft-versus-host disease (GVHD) prophylaxis in HLA matched transplant patients has had varied results. Two recent studies at Johns Hopkins University noted favorable incidences of both GVHD and non-relapse mortality (NRM) in both matched related and unrelated donor allogeneic hematopoietic cell transplant (allo-HCT) recipients (Kanakry CG, et al, JCO, 2013 and Kanakry CG et al, Blood, 2014). In contrast to this data, a phase II study at MD Anderson reported higher rates of grade II-IV acute GVHD and NRM, with worse overall survival in patients receiving PTCy as the sole GVHD prophylaxis compared to their matched cohort receiving a calcineurin-inhibitor (CNI) and methotrexate (MTX) as immunosuppression (Alousi AM et al, BBMT, 2015). Another study in Australia had to be stopped for safety reasons due to high GVHD and NRM when using PTCy as sole GVHD prophylaxis (Bradstock KF, BBMT, 2015). There is no published data on the use of MMF plus tacrolimus in combination with PTCy in HLA matched allo-HCT recipients. We hypothesized that addition of MMF and Tacrolimus to PTCy in HLA matched allo-HCT recipients will lead to significantly improved transplant outcomes. To answer this question we retrospectively analyzed data from patients who received this regimen at a single institution. Methods. We performed a retrospective analysis of 31 HLA matched allo-HCT patients who received PTCy at 50 mg/m2 on days +3 and +4 in addition to MMF and tacrolimus immunosuppression from December 2012 till June 2015 at Washington University School of Medicine in Saint Louis. All of these patients received G-CSF mobilized peripheral blood grafts. Patients included AML (n=13), ALL (n=5), MDS (n=5), CML (n=2), aplastic anemia (n=2) and NHL (n=1), myelofibrosis (n=1). Twelve of the patients underwent a matched related donor (MRD) transplant and 19 underwent a matched unrelated donor (MUD) transplant. Two of the MUD transplants had a HLA match grade of 8 of 10 and the other 17 were a 10 out of 10 match. Twenty-eight of the patients received a graft collected via peripheral blood stem cell mobilization and the other three had a donor graft collected via bone marrow harvest. Cumulative incidence of aGVHD was estimated using Gray's sub-distribution method to account for death without aGVHD as a competing event, and the cumulative incidences of non-relapse mortality (NRM) and relapse were estimated treating each other as competing event, while OS was estimated using Kaplan-Meier limit method. Results: This regimen was associated with acceptable GVHD in our patients. Incidence of grade II-IV acute GVHD was 28% (21.3% for MRD; 31.5% for MUD) at day 100 and 28% at 1 year. Incidence of Grade III-IV acute GVHD was 13.5% at both 100 days and 1 year. Limited chronic GVHD was 25.9% and extensive GVHD was 14.8% at 1 year. Similarly we found acceptable NRM and relapse in these patients, NRM was 10.2% and 19.7% at 100 days and 1 year respectively and cumulative incidence of relapse at 100 days and 1 year were 17.8% and 29.0% respectively. Overall survival at 1 year for all patients was 52%. Summary: Here we report favorable results from a regimen combining MMF and Tacrolimus on PTCy platform in HLA matched MRD and MUD transplant recipients. Relatively low GVHD and NRM results are particularly encouraging in view of almost exclusive use of G-CSF mobilized T cell replete grafts with much higher T cell content. Though limited by the relatively small number of patients, our results suggest combining MMF plus Tacrolimus with PTCy platform in HLA matched allogeneic transplant patients is safe and associated with acceptable transplant outcomes. Disclosures Vij: Onyx: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millennium: Honoraria, Speakers Bureau; BMS: Consultancy; Takeda: Consultancy, Research Funding; Novartis: Consultancy; Sanofi: Consultancy; Janssen: Consultancy; Merck: Consultancy. Uy:Novartis: Research Funding. Abboud:Teva Pharmaceuticals: Research Funding; Gerson Lehman Group: Consultancy; Merck: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees. Schroeder:Celgene: Other: Azacitidine provided for this trial by Celgene; Incyte: Consultancy. Jacoby:Sunesis: Research Funding; Novo Nordisk: Consultancy.

scholarly journals Results of a Phase III Double-Blind Study of the Addition of Tocilizumab Vs. Placebo to Cyclosporin/Methotrexate Gvhd Prophylaxis after HLA-Matched Allogeneic Stem Cell Transplantation

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 368-368 ◽  
Author(s):  
Glen A Kennedy ◽  
Siok-Keen Tey ◽  
Cameron Curley ◽  
Jason P Butler ◽  
Ashish Misra ◽  
...  
Keyword(s):  
Median Time ◽  
Research Funding ◽  
Acute Gvhd ◽  
Phase Iii ◽  
Control Group ◽  
Double Blind ◽  
Free Survival ◽  
Entire Cohort ◽  
Gvhd Prophylaxis ◽  
Grade Ii

Background: IL-6 mediates graft-vs.-host disease (GVHD) in experimental models of allogeneic stem cell transplantation. The addition of a humanized anti-IL-6R mAb (Tocilizumab; TCZ) to standard GVHD prophylaxis has shown in promise in reducing the incidence of acute GVHD in two prospective phase I/II clinical studies. Aims: To determine the efficacy of TCZ in preventing grade II-IV acute GVHD in patients with acute leukaemia or myelodysplasia undertaking 8/8 matched related sibling (MSD) or matched unrelated donor (MUD) allogeneic HPCT after myeloablative (MAC) or reduced intensity conditioning (RIC) across five Australian transplant centers. Methods: 145 patients (50 MSD and 95 MUD) were randomly assigned to either placebo or TCZ (8mg/kg; max dose 800mg) on day-1 of conditioning. Patients and physicians were both blinded to treatment. RIC patients all received Flu/Mel (n=81, 56%) while MAC patients received Cy/TBI (n=46, 32%) or Bu/Cy (n=18, 12%). All patients received T-replete PBPC grafts, and standard GVHD prophylaxis cyclosporine and day 1 (15mg/m2), 3, 6 and 11 (10mg/m2) methotrexate. The primary endpoint was incidence of grade II-IV acute GVHD. A planned substudy analyzed the MUD cohort. Secondary endpoints included day 180 grade II-IV acute GVHD free-survival (GVHD-FS), transplant-related mortality (TRM), progression-free survival (PFS), overall survival (OS), time to engraftment and rates of infection. The study was powered to observe a 50% reduction in the incidence of grade II-IV acute GVHD at day +100 for the entire and MUD cohorts, assuming a 50-55% baseline in the control group. Competing risk (death) regression adjusted hazard ratio (HR) was estimated to evaluate the GVHD-related outcomes in TCZ vs. placebo groups. Results: With a median follow up of 746 days, the overall incidence of grade II-IV GVHD at day 100 for the entire cohort was 36% vs. 27% for placebo vs. TCZ respectively (HR: 0.69; 95% CI 0.38-1.26; p=0.23), and 45% vs. 32% (HR: 0.61; 95% CI 0.31-1.22; p=0.16) for the MUD subgroup. The incidence of grade II-IV GVHD at day 180 for the entire cohort was 40% vs. 29% for placebo vs. TCZ respectively (HR: 0.68; 95% CI 0.38-1.22; p=0.19), and 48% vs. 32% (HR: 0.59; 95% CI 0.30-1.16; p=0.13) for the MUD subgroup. The incidence of severe grade III/IV GVHD at day 100 for the entire cohort was similar, 13% vs. 14% for placebo vs. TCZ respectively (HR: 1.04; 95% CI 0.42-2.61; p=0.93), and 10% vs. 14% for the MUD subgroup (HR: 1.42; 95% CI 0.41-4.95; p=0.59). A trend to improved GVHD-FS was noted in the TCZ-treated MUD subgroup, 52% vs. 68% for placebo vs. TCZ treated (HR: 1.70; 95% CI 0.86-3.37; p=0.13). For the entire cohort, TRM occurred in 8% of placebo-treated vs. 11% of TCZ-treated patients respectively (HR: 1.37; 95% CI 0.48-3.96; p=0.56); Progressions were similar at 25% vs. 33% (HR:1.44; CI 0.78-2.63, p=0.24) and OS was 79% vs. 71% (HR: 0.69; CI 0.35-1.34, p=0.27). No significant differences were seen in these outcomes in the MUD cohort. Day to neutrophil engraftment was marginally delayed in TCZ-treated patients, with median time to neutrophil ≥0.5 of 15 days (range 11-24 days) vs. 18 days (range 9-35 days) for placebo vs. TCZ-treated patients respectively (95% CI 1.3-4.7; p=0.001). Time to platelet engraftment was also marginally delayed in TCZ-treated patients, with median time to plts≥20 of 16 days (range 9-36 days) vs. 19 days (range 11-389 days) (95% CI 0.4-5.6; p=0.022). The median time to neutrophil and platelet engraftment in TCZ-treated patients were each 2 days slower in the MUD cohort (p=0.016 and p=0.22 for neutrophils and plts respectively). Two TCZ-treated patients died beyond day 30 (at day 31 and 32) with incomplete neutrophil recovery. The incidence of 1 or more grade 3 or higher liver toxicity (LT) was similar between groups, occurring in 14% of placebo-treated patients vs. 15% of TCZ-treated patients respectively (OR: 1.14; 95% CI 0.45-2.88; p=0.79). Grade 2 or higher infection adverse events occurred in 64% of placebo-treated patients vs. 71% of TCZ-treated patients respectively (OR: 1.34; 95% CI 0.67-2.71; p=0.41). Conclusion: In a phase III randomized, double-blind trial, TCZ administered at D-1 showed non-significant trends to reduced incidence of grade II-IV GVHD and improved acute GVHD-free survival in recipients of HLA-matched MUD donors, but no improvements in long term-survival. Study power was compromised by lower rates of acute GVHD in the control group than anticipated. Disclosures Ritchie: Novartis: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy; BMS: Research Funding; Takeda: Research Funding; Beigene: Research Funding; Imago: Research Funding; Sanofi: Honoraria. Gottlieb:Novartis: Consultancy; AbbVie: Consultancy; University of Sydney: Employment; Merck: Consultancy; Gilead: Consultancy; Haemalogix P/L: Membership on an entity's Board of Directors or advisory committees, Research Funding. Paul:Novo Nordisk: Consultancy, Research Funding; Sanofi: Consultancy, Speakers Bureau; Roche: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding, Speakers Bureau. Hill:Roche: Other: Investigator driven trial funding; Pharamcyclics: Consultancy, Research Funding; CSL: Consultancy, Research Funding; Implicit Bioscience: Consultancy, Research Funding. OffLabel Disclosure: Use of Tocilizumab for the prevention of acute GVHD

scholarly journals Post-Transplant Cyclophosphamide and Sirolimus in Matched Related and Unrelated Allogeneic Transplant with a Treosulfan-Based Conditioning

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4662-4662
Author(s):  
Jacopo Peccatori ◽  
Serena Albanese ◽  
Raffaella Greco ◽  
Francesca Lorentino ◽  
Fabio Giglio ◽  
...  
Keyword(s):  
High Risk ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Free Survival ◽  
Allogeneic Hsct ◽  
Post Transplant ◽  
Gvhd Prophylaxis

Abstract Introduction: Post transplant cyclophosphamide (PT-Cy) has recently emerged as a very promising pharmacological strategy to overcome human leukocyte antigen (HLA) barriers in the setting of haploidentical hematopoietic cell transplant (HCT). We recently reported a promising preliminary experience on the use of PT-Cy and sirolimus as graft-versus-host disease (GVHD) prophylaxis in matched allo-HSCT (Greco R et al, Blood 2016). Herein we describe long-term outcomes of matched allogeneic HSCT, using treosulfan-based conditioning, and GVHD prophylaxis with PT-Cy and sirolimus. Methods: In our center, we collected 104 adult patients (pts) receiving matched HSCT for high-risk hematological malignancies, mainly acute myeloid leukemia (n=43). Donor was matched related (MRD) for 45 pts, 10/10 matched unrelated (MUD) for 39 pts and 9/10 MUD for 20 pts. Median age was 48 years (range 19-78). At HSCT, 51% of patients were not in complete remission (CR), 39% were in CR1 and 11% in subsequent CR. Graft source was mainly PBSCs (95%). All pts received a conditioning regimen based on treosulfan and fludarabine; 89% received an intensified conditioning with the addition of melphalan. All pts received PT-Cy (50 mg/kg/day) on days 3 and 4. Sirolimus was given from day 5, and withdrawn 3 months after HSCT. Mycophenolate mofetil (MMF) was added from day 5 to day 30, only in MUD. All patients were treated according to current institutional programs upon written informed consent for transplant procedures. Results: Median follow up was over 16 months (range 3-51). Median CD34+ and CD3+ cell doses were 5.6x10^6/Kg (range, 1.5-10.9) and 2.0x10^8/Kg (range, 0.2-8.0), respectively. All the recipients of allo-HSCT experienced a sustained donor cell engraftment. The cumulative incidence of grades II-IV and III-IV acute GVHD at 100 days was 21% and 9%, respectively. The cumulative incidence of chronic GVHD was 25% at 2 years; we observed severe chronic GVHD only in 4% of pts. The cumulative incidences of relapse and non-relapse mortality (NRM) were 33% and 8% at 2 years, respectively. Two-year overall survival (OS) was 67% and progression free survival (PFS) 59%. The composite end point of GVHD-free/relapse-free survival (GRFS) was 52% at 2 years, in which events include grade 3-4 acute GVHD, systemic therapy-requiring chronic GVHD, relapse, or death. There was a longer OS, 2-year OS was 77% (p = 0.05), and a trend towards higher PFS and GRFS, 63% (p=0.07) and 58% (p=0.06) respectively, for pts with CR status at HSCT. We did not found a significant effect of HLA-matching (9/10 versus 10/10) or donor type (related versus unrelated) on major transplant outcomes (NRM, PFS, GRFS, relapse, acute and chronic GvHD). Conclusion: These outcomes confirmed that matched allogeneic HSCT using treosulfan-based chemotherapy, PT-Cy and sirolimus, is associated with low NRM and acceptable severe GVHD, providing relevant long-term survival in high-risk diseases. A randomized trial comparing this strategy with other kind of in-vivo T-cell depletion (i.e. ATG) is warranted. Disclosures Vago: Moderna TX: Research Funding; GENDX: Research Funding.

scholarly journals Higher Grade Cytokine Release Syndrome Is a Predictive Factor for Gvhd in Haploidentical Stem Cell Transplantation with Peripheral Blood Cell

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2881-2881
Author(s):  
Benjamin Bouchacourt ◽  
Valerio Maisano ◽  
Ana Benzaquen ◽  
Angela Granata ◽  
Sabine Furst ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Advisory Committees ◽  
Free Survival ◽  
Gvhd Prophylaxis ◽  
Grade Ii

Abstract Background: Early Cytokine Release Syndrome (CRS) is a common complication following haploidentical stem cell transplantation (Haplo-HSCT) induced by the proliferation of alloreactive T-Cells. CRS is occurring more frequently in patients receiving peripheral blood stem cells (PBSC) comparatively to bone marrow transplant, however its impact on outcome, notably graft versus host disease (GVHD) remain unclear. The main objective was to evaluate the impact of severity of CRS on the risk of GVHD. Patients and Methods: This retrospective single-center study included patients who had received a first haplo-HSCT for hematological malignancies, with PBSC as graft source. All patients received either a reduced-intensity conditioning (RIC) based on thiotepa (5mg/kg), busulfan (260 mg/m²) and fludarabine (120 mg/m²) [TBF], or a non-myeloablative conditioning (NMAC) based on fludarabine (150 mg/m²), cyclophosphamide (29 mg/kg) and 2 Gy TBI [CyFluTBI]. GVHD prophylaxis was based on PT-Cy 50 mg/kg (day+3 and +4) and cyclosporine A plus mycophenolate mofetil starting at day+5. All patients were given GSCF from day+5 to neutrophil recovery. Results: 241 consecutive patients were analyzed. One hundred patients (54%) had myeloid malignancies, and 111 (46%) had lymphoid malignancies. Most patients had intermediate or low risk DRI (n = 180, 75%) and HCT-CI was ≥ 3 for 159 patients (66%). Using ASTCT consensus criteria, 226 patients (94%) developed CRS, including 183 grade 1 and 43 grade ≥ 2. Transplantation and patient characteristics were not significantly different between patients with CRS grade 0-1 vs. ≥ 2, except for age. Indeed, patients with CRS grade ≥ 2 were significantly older than patients with CRS grade 0-1 (median 65 vs 60 yo respectively, p = 0.01). Patients with grade ≥ 2CRS had significantly higher cumulative incidence of day-100 grade II-IV acute GVHD (grade 0-1 vs. ≥ 2 : 28% and 44%, p = 0.028) and 4-year moderate to severe chronic GVHD (grade 0-1 vs. ≥ 2 : 16% and 30%, p = 0.024) compared to patients with grade 0-1 CRS (Figure 1). No difference in the cumulative incidence of relapse was observed between CRS groups (grade 0-1 vs. ≥ 2 : 22% and 21%, p = 0.802). By multivariate analysis, CRS grade ≥ 2 was the only factor associated with grade II-IV acute GVHD (HR = 1.99; 95%CI = [1.17-3.39], p = 0.011). CRS grade ≥ 2 was significantly associated with a higher risk of moderate to severe chronic GVHD (HR = 2.67; 95%CI = [1.36-5.21], p = 0.004) and poorer GVHD- and relapse-free survival (GRFS) (HR = 1.78 ; 95%CI = [1.19-2.67], p = 0.005). Progression free survival, overall survival and non-relapse mortality were not influenced by the severity of CRS. Conclusion: In the context of PBSC haplo-HSCT, the occurrence of grade ≥ 2 CRS following graft infusion is significantly associated with an increased risk of both acute and chronic GVHD. This may improve the early identification of patients with high risk of GVHD for whom specific enhanced GVHD prophylaxis should be investigated. Figure 1 Figure 1. Disclosures Chabannon: Sanofi SA: Other: Travel Support, Research Funding, Speakers Bureau; Bellicum Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau; Novartis: Speakers Bureau; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Terumo BCT: Speakers Bureau; Miltenyi Biotech: Research Funding; Fresenius Kabi: Research Funding; EBMT: Membership on an entity's Board of Directors or advisory committees. Blaise: Jazz Pharmaceuticals: Honoraria.

α4β7± Regulatory T Cells (Tregs) at Engraftment Predict Long-Term Graft-Versus-Host Disease (GVHD) Outcomes.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2237-2237
Author(s):  
Brian G Engelhardt ◽  
Madan Jagasia ◽  
Michael T Rock ◽  
Adetola A. Kassim ◽  
Bipin N. Savani ◽  
...  
Keyword(s):  
Stem Cell ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Clinical Severity ◽  
Unrelated Donor ◽  
Cell Transplant ◽  
Treg Population ◽  
Grade Ii ◽  
Neutrophil Engraftment

Abstract Abstract 2237 Poster Board II-214 Background: GVHD occurs unpredictably after allogeneic stem cell transplant (ASCT). GVHD is characterized by profound immune dysregulation, which suggests that abnormalities in suppressor lymphocytes known as Tregs may account for the clinical features of this disease. We have shown that the frequency of Tregs or α4β7± Tregs at neutrophil engraftment predict for recurrent grade II-IV GVHD or recurrent gut GVHD during the first 100 days of transplant, respectively. These data indicate that early lymphocyte populations may determine long-term immune-tolerance following ASCT. We hypothesized that Treg subsets present at engraftment would be associated with the occurrence, National Institutes of Health (NIH) phenotype, and severity of GVHD after day±100. Methods: Patients (pts) undergoing T cell replete ASCT were enrolled. GVHD after day±100 was classified prospectively as either: acute GVHD, overlap GVHD, or classic chronic GVHD using consensus criteria derived from the NIH. Clinical severity was determined by the modified Glucksberg criteria for acute GVHD and the NIH global assessment of severity for overlap/classic chronic GVHD. The frequency of CD45RO±CD25±Foxp3±CD127lo Tregs was quantified within the CD4± T-lymphocyte population at the time of neutrophil engraftment using polychromatic flow cytometry. Gut-homing Tregs were identified by the presence of α4β7±, and their frequency was expressed as a percentage of the total Treg population. Results: Treg analysis was performed at a median of 19 days post-transplant (range, 10-31) on 41 pts undergoing ASCT and surviving until day±100. Twenty-four (59%) pts received ablative conditioning and 17 (41%) pts received a reduced intensity regimen followed by matched related [N= 24 (59%)] or unrelated donor [N= 17 (41%)] ASCT. The stem cell source was peripheral blood, bone marrow, or cord blood for 30 (73%), 9 (22%), and 2 (5%) pts, respectively. GVHD prophylaxis consisted of calcineurin inhibitor and methotrexate [N=23 (56%)] or mycophenolate mofetil [N=18 (44%)]. The majority of patients had grade II-IV acute GVHD prior to day±100 [N=34 (83%)]. After a median follow-up of 15 months (range, 5-24) GVHD after day±100 occurred in 32 (78%) pts at a median of 152 days post ASCT (range, 103-533). GVHD phenotype was classified as: acute (N=19), overlap (N=9), or classic chronic (N=4). Grade III-IV acute and moderate to severe overlap/classic chronic GVHD occurred in 3 (7%) and 11 (27%) pts, respectively. Pts with GVHD after day±100 had lower frequencies of Tregs and α4β7± Tregs at engraftment (4.4% vs. 14.3%; P=0.145) and (9.9% vs. 20.7%; P=0.009), respectively. After excluding pts with gut GVHD, the association between α4β7± Tregs and GVHD after day±100 persisted (P=0.034). Median Treg percentages did not differ among GVHD phenotypes [acute (4.4%) vs. overlap (4.2%) vs. classic chronic (5%) vs. none (14.3%); P=0.464]. However, significant differences between α4β7± Treg frequencies and GVHD subtypes were noted [acute (11%) vs. overlap (9.6%) vs. classic chronic (11.6%) vs. none (20.7%); P=0.002]. α4β7± Treg differences were most apparent when pts with any acute GVHD (acute±overlap) were compared to pts without features of acute GVHD (none±classic chronic) (9.9% vs. 19.4%; P=0.009). Increased frequencies of Tregs and α4β7± Tregs at engraftment tended to be associated with lower grades of acute GVHD after day±100 [odds ratio (OR), 0.95; 95% confidence interval (CI), 0.87-1.04; P=0.255 (Tregs) and OR, 0.81; 95% CI, 0.70-0.92; P=0.002 (α4β7± Tregs)] and less severe overlap/classic chronic GVHD [OR, 0.91; 95% CI, 0.79-1.04; P=0.158 (Tregs) and OR, 0.93; 95% CI, 0.86-1.01; P=0.071 (α4β7± Tregs)]. Using Cox Proportional Hazard regression (adjusting for donor type and acute GVHD prior to day ±100), increased frequencies of α4β7± Tregs at engraftment continued to be associated with decreased risk of GVHD after day ±100 (hazard ratio, 0.93; 95%CI, 0.88-0.99; P=0.013). Conclusion: Frequency of α4β7± Tregs at engraftment is associated with the incidence and severity of GVHD after day ±100. These data suggest that early lymphocyte subsets and gut associated mucosal immunity are important in determining long-term graft tolerance. Treg subsets at engraftment could be used to risk stratify pts prior to development of GVHD or as an endpoint in future clinical trials examining interventions aimed at increasing Tregs and preventing GVHD. Disclosures: No relevant conflicts of interest to declare.

A Phase II Study Using Post-Transplant Cyclophosphamide (PTC) As Graft Versus Host Disease (GVHD) Prophylaxis in Patients Undergoing HLA Matched Sibling Donor Stem Cell Transplant (SCT) for Severe Aplastic Anemia (SAA)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4199-4199
Author(s):  
Biju George ◽  
Vikram Mathews ◽  
Kavitha M Lakshmi ◽  
Rayaz Ahmed ◽  
Aby Abraham ◽  
...  
Keyword(s):  
Aplastic Anemia ◽  
Immunosuppressive Therapy ◽  
Median Time ◽  
Chronic Gvhd ◽  
Cell Transplant ◽  
Post Transplant ◽  
Sibling Donor ◽  
Gvhd Prophylaxis ◽  
Matched Sibling ◽  
Grade Ii

Abstract Abstract 4199 Between September 2010 and June 2012, 15 patients with SAA underwent HLA identical sibling donor SCT using post transplant cyclophosphamide for GVHD prophylaxis. The conditioning regimen consisted of Inj Fludarabine 30 mg/m2/day from day -7 to -2 and Inj Cyclophosphamide 50 mg/kg IV on days -3 and -2. Total Body irradiation (TBI) 200 cGy as single fraction was added on day -1 from December 2011 because of concern regarding graft failure. GVHD prophylaxis consisted of Inj Cyclophosphamide administered at 50 mg/kg/day IV on day +3 and +4 post SCT. G-CSF mobilized peripheral blood stem cells (PBSC) was the graft source. There were 10 males and 5 females with a median age of 25.9 years (range: 8 – 42). The median time from diagnosis to SCT was 7.5 months (range: 2 – 36). All had 6/6 HLA matched sibling donors except 1 who had a 9/10 matched family donor. The median PBSC cell dose infused was 5.4 × 108 MNC/Kg (range: 2.4 – 8.5) and 9.58 × 106CD34/Kg (range: 5.4 – 17.2). Thirteen patients engrafted (86.6%) with a median time to ANC >0.5 × 109/L of 15.4 days (range: 15–17) and Platelet count >20 × 109 of 16.6 days (range: 12–32). Grade II –IV acute GVHD occurred in 3 patients (23%) at 42, 49 and 68 days post SCT. GVHD was grade II in 2 patients and grade IV in 1 patient. Two responded to a combination of cyclosporine and prednisolone while one patient with grade IV GVHD expired with refractory GVHD at median time of 64 days post SCT. Of the 11 evaluable patients, 4 (36.3%) developed chronic GVHD which was limited in all. Two patients who developed de novo chronic GVHD were managed with prednisolone alone. Overall 7 patients (46.6%) have not required any immunosuppression after SCT while 3 have required immunosuppressive therapy for 114, 127 and 225 days respectively At a median follow up of 11 months (range: 1 – 22), 11 (73.3%) are alive and well including 7 patients who did not require any immunosuppressive therapy following SCT. In conclusion, the use of post transplant cyclophosphamide as GVHD prophylaxis following sibling donor transplant for SAA is associated with low rates of GVHD. What makes it more attractive is the fact that 46% did not require any immunosuppression post SCT. Larger studies are required to understand the utility of this prophylaxis in sibling donor transplants for aplastic anemia. This trial is registered in the Clinical Trials Registry India - CTRI/2010/091/001480. Disclosures: No relevant conflicts of interest to declare.

Tacrolimus/Sirolimus Vs. Tacrolimus/Methotrexate for Graft-Vs.-Host Disease Prophylaxis After HLA-Matched, Related Donor Hematopoietic Stem Cell Transplantation: Results of Blood and Marrow Transplant Clinical Trials Network Trial 0402

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 739-739 ◽  
Author(s):  
Corey Cutler ◽  
Brent R. Logan ◽  
Ryotaro Nakamura ◽  
Laura Johnston ◽  
Sung W. Choi ◽  
...  
Keyword(s):  
Stem Cell ◽  
Research Funding ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Gvhd Prophylaxis ◽  
Graft Vs Host Disease ◽  
Grade Ii ◽  
Related Donor

Abstract Abstract 739 The combination of a calcineurin inhibitor and methotrexate has been the standard of care in graft-vs.-host disease (GVHD) prophylaxis for over 25 years, with resultant rates of grade II-IV acute GVHD between 30–50%. The mTOR inhibitor, sirolimus, has demonstrated promise in a number of Phase II trials as an immunosuppressant used for GVHD prophylaxis. The BMT CTN, sponsored by the NHLBI and NCI, conducted a multicenter, randomized controlled trial comparing the combination of tacrolimus and sirolimus (Tac/Sir) with tacrolimus and methotrexate (Tac/Mtx) as GVHD prophylaxis after matched, related donor (MRD) hematopoietic stem cell transplantation (HSCT). Methods: Eligible patients were between ages 2 – 60 years, and had acute leukemia in remission, myelodysplasia or chronic myeloid leukemia in chronic or accelerated phase. All had adequate organ function, and a 6/6 HLA-A, B, DRB1 matched sibling donor. 304 patients were randomly assigned to either Tac/Sir (n = 151) or Tac/Mtx (n = 153) as GVHD prophylaxis after TBI-based conditioning and MRD HSCT. An intent-to-treat analysis was performed on the primary endpoint of Grade II-IV GVHD-free survival 114 days from randomization. Ten subjects who received busulfan-based conditioning and were previously reported were excluded from analysis. Three subjects who did not undergo HSCT are included in the primary analysis, but not secondary analyses. Results: Treatment groups were well balanced. The median age of participants was 44 years (range 13 – 59) and 83% had acute leukemia. Neutrophil and platelet engraftment were both faster in the Tac/Sir group (14 vs. 16 days, p < 0.001; 16 vs. 19 days, p = 0.03, respectively), but this did not affect the time to first hospital discharge (20 vs. 21 days, p = 0.37). The incidence of grade II-IV and grade III-IV acute GVHD at 100 days were lower in the Tac/Sir group (26 vs. 34%, p = 0.17; 8 vs. 15%, p = 0.05). Day 100 treatment-related mortality was no different between groups (7 vs. 7%, p = 0.43). The primary endpoint of 114-day acute GVHD-free survival was not statistically different between groups (67 vs. 62%, p = 0.38, Figure). The cumulative incidence of relapse at 2 years from transplantation was not different between groups (27 vs. 30%, p = 0.81). The competing-risk cumulative incidence of chronic GVHD was higher in the Tac/Sir arm (54 vs. 43%, p =0.044). Overall toxicities were not different between groups, with two notable exceptions. The peak and average OMAS oral mucositis scores were lower in the Tac/Sir arm (peak 0.70 vs. 0.96, p < 0.001; average 0.31 vs. 0.47, p < 0.001), however, there was an increased rate of the endothelial injury syndromes, veno-occlusive disease (11 vs. 4%, p = 0.03), and thrombotic microangiopathy (5 vs. 1%, p = 0.05) in the Tac/Sir arm. Causes of death were not different between groups. At 2 years from transplantation, disease-free (DFS) and overall survival (OS) were not different between study arms (DFS 53 vs. 53%, p = 0.76; OS 60 vs. 61%, p = 0.44). Conclusions: No difference in 114-day acute GVHD-free survival was noted between treatment arms. Compared with Tac/Mtx in MRD HSCT, Tac/Sir is associated with more rapid engraftment, less severe acute GVHD and oral mucositis, excess chronic GVHD and endothelial injury syndromes, and similar long-term outcomes. Understanding the trade-offs between regimens, Tac/Sir can be used as an alternative to Tac/Mtx in MRD HSCT. Disclosures: Cutler: Pfizer, inc: Research Funding; Astellas, Inc: Consultancy, Research Funding. Off Label Use: Sirolimus - Prevention of GVHD Tacrolimus - Prevention of GVHD. Waller:Outsuka: Research Funding.

A Bortezomib-Based Regimen Offers Excellent Outcomes In Myeloablative HLA-Mismatched and Unrelated Donor Transplantation: Phase II Results

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3335-3335
Author(s):  
John Koreth ◽  
Haesook T. Kim ◽  
Paulina B. Lange ◽  
Bhavjot Bindra ◽  
Philippe Armand ◽  
...  
Keyword(s):  
Stem Cell ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Myeloablative Conditioning ◽  
Upper Gi ◽  
Gvhd Prophylaxis ◽  
Grade Ii ◽  
Grade Iii

Abstract In a phase I/II trial of a novel bortezomib-based regimen for reduced-intensity conditioning (RIC) hematopoietic stem cell transplantation (HSCT) recipients of HLA-mismatched peripheral blood stem cell (PBSC) grafts, we documented low rates of graft-versus-host disease (GVHD) and non-relapse mortality (NRM), with promising survival. In registry analyses, myeloablative conditioning (MAC) HSCT recipients of both HLA-matched (MUD) and 1-locus mismatched donor (MMUD) grafts also have impaired outcomes, with day +100 grade III-IV acute GVHD rates of 28% and 37% respectively, 1-year NRM of 36% and 45% respectively, 1-year progression-free (PFS) of 47% and 38% respectively, and 1-year overall survival (OS) of 52% and 43% respectively. We therefore evaluated a similar bortezomib-based regimen in MAC HSCT recipients lacking 8/8 HLA-matched (-A, -B, -C, -DRB1) related donors. In a prospective single-arm phase II trial, we enrolled patients with hematologic malignancies, aged 18-60 years, receiving MUD, MMUD, or mismatched related donor (MMRD) grafts. Myeloablative conditioning was IV busulfan (130 mg/m2, without PK dose adjustment) and fludarabine (40 mg/m2) once daily for 4 doses (days -7 to -4). T-replete PBSC grafts with ≥ 2x106 CD34+ cells/kg were infused on day 0. GVHD prophylaxis comprised bortezomib (1.3 mg/m2 IV on days +1, +4, +7), methotrexate (15 mg/m2 IV on day +1, 10 mg/m2 on days +3, +6, +11) and tacrolimus from day -3, with a planned taper starting day +100 and complete by day +180. The primary endpoint was day +100 acute GVHD incidence. Secondary endpoints included NRM, relapse, PFS, OS and chronic GVHD at 1 year. The 34 patients (19 male, 15 female), accrued between March 2011 and November 2012, had a median age of 49 years (range, 21-60) and variable diagnoses (17 AML, 6 MDS, 4 NHL, 3 MPD, 2 ALL, 1 CML, 1 MM) and disease risk indices (Low 1, Intermediate 24, High 9). They received 8/8 MUD (n=14), 7/8 MMUD (n=18) or 7/8 MMRD (n=2) PBSC grafts. Mismatches (16 antigen-, 4 allele-level) involved HLA-A (9), -B (1), -C (6) and -DRB1 (4). The median follow up in survivors is 20 months (range, 7.2-25.5). The regimen was feasible and well tolerated. Mucositis was noted in the MAC recipients, but no doses were missed due to toxicity. Excluding 1 patient who died of sepsis prior to engraftment, neutrophil and platelet engraftment was prompt, at a median of 14 (range, 3-33) and 17 (range, 7-54) days respectively. Median day +30 donor chimerism was 99% (range, 90-100). Grade II-IV acute GVHD incidence by day +100 and +180 was 32% and 36% respectively, but only 18% and 21% respectively if upper GI GVHD (which had excellent long term outcomes) was excluded. Grade III-IV acute GVHD incidence by day +100 and +180 was 12%. 2-year cumulative incidence of NRM and relapse was 8.8% and 5.9% respectively. 2-year PFS and OS was 85% and 84% respectively (Figure). 2-year cumulative incidence of extensive chronic GVHD was 57%. For 8/8 MUD vs. 7/8 MMRD/MMUD, grade II-IV acute GVHD by day +180 was 30% vs. 40% (p=0.47) (excluding upper GI GVHD, 16% vs. 25%, p=0.42), and grade III-IV acute GVHD was 7% vs. 15% (p=0.48) respectively.FigureStudy SurvivalFigure. Study Survival In conclusion, bortezomib-based prophylaxis for MAC HSCT recipients of HLA-mismatched and unrelated donor grafts was safe and well-tolerated, with low rates of severe acute GVHD, NRM and relapse, and excellent long-term survival. On preliminary landmark analysis, upper GI GVHD did not appear to impair transplantation outcomes. Bortezomib-based prophylaxis is suitable for prospective randomized evaluation in myeloablative transplantation recipients lacking HLA-matched related donors. Disclosures: Koreth: Millennium pharmaceuticals: Research Funding; Takeda Pharmaceuticals: Consultancy. Off Label Use: Bortezomib for GVHD prophylaxis.

scholarly journals Comparable Outcomes between Unrelated Donor (8/8 or 7/8 matched) and Haploidentical Donor for Allogeneic Stem Cell Transplantation in Adult Patients with Severe Aplastic Anemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4619-4619
Author(s):  
Jee Yon Shin ◽  
Sung-Soo Park ◽  
Gi June Min ◽  
Silvia Park ◽  
Sung-Eun Lee ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Advisory Committees ◽  
Sibling Donor ◽  
Alternative Donor ◽  
Matched Sibling ◽  
Grade Ii

Background Either allogeneic hematopoietic stem cell transplantation (SCT) from HLA-matched sibling donor or immunosuppressive therapy (IST) has been recommended as one of the standard treatments for severe aplastic anemia (SAA). Regarding only 30% of chance finding HLA‐matched sibling donor, SCT from an alternative donor including unrelated (URD) or haplo-identical related donor (HAPLO) is considered to be a treatment option after failure to IST in patients who lack of a HLA-matched sibling donor. The aim of this study was to compare the outcomes of URD SCT and HAPLO SCT for SAA patients. Method Consecutive 152 adult patients with SAA who received first SCT between March 2002 and May 2018 were included: 73 of HLA-well-matched (8/8) URD (WM-URD), 34 of HLA-mismatched URD (MM-URD), and 45 of HAPLO. With the intention to have a follow-up period at least 1 year, data were analyzed at May 2019. A conditioning regimen with total body irradiation (TBI) and cyclophosphamide was used for URD-SCT, whereas that with TBI and fludarabine was administered for HAPLO-SCT (Lee et al, BBMT 2011;17:101, Park et al, BBMT 2017;23:1498, Lee et al, Am J Hematol 2018;93:1368). The combination of tacrolimus and methotrexate were used as graft-versus-host disease (GVHD) prophylaxis. Results The median follow-up was 53.4 (range, 0.2-174.1) months. The median age of URD and HAPLO cohort was 30 (range 18-59) and 34 (range 18-59) years, respectively. Except for one and three patients who failed respective a neutrophil and platelet engraftment, other patients achieved neutrophil and platelet engraftments with median 11 and 15 days for WM-URD, 13 and 16.5 days for MM-URD, and 12 and 14 days for HAPLO, respectively. The five-years overall survival (OS), failure-free survival (FFS), and cumulative incidences (CIs) of graft-failure and transplant-related mortality were similar among three groups: 88.3%, 85.5%, 2.7%, and 11.7% for WM-URD; 81.7%, 81.7%, 0%, and 18.3% for MM-URD, and 86.3%, 84.1%, 6.7%, and 9.2% for HAPLO. The 180-days CI of grade II-IV acute GVHD in WM-URD, MM-URD and HAPLO were 35.6%, 52.9%, and 28.9%, respectively; and moderate to severe chronic GVHD were 28.7%, 38.7% and 11.8% in respective cohort. The CI of grade II-IV acute GVHD and moderate to severe chronic GVHD were significantly higher in MM-URD than those in HAPLO (both, p=0.026). ATG is the only factor affecting both grade II-IV acute GVHD (Hazard ratio 0.511, p=0.01) and moderate to severe chronic GVHD (Hazard ratio 0.378, p=0.003) in multivariate analysis. Other complications including CMV DNAemia, hemorrhagic cystitis, invasive fungal disease, secondary malignancy, and sinusoidal obstruction syndrome were similar among three groups. Survival outcomes of a subgroup of ≥ 2 allele MM-URD (n=16) extracted form MM-URD were inferior that of other donor types (n=136): 75.0% vs. 86.9% (p=0.163) for 5-year OS and 75.0% vs. 84.7% (p=0.272) for 5-year FFS. Conclusion This study shows that there were no significant differences between alternative donor sources in the absence of suitable matched sibling donor. Host/donor features and urgency of transplant should drive physician towards the best choice among alternative donor sources for SAA patients treated with SCT. However, selection of ≥ 2 allele MM-URD should not be recommended due to high incidence of GVHD and inferior outcomes. Figure Disclosures Kim: Celgene: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Hanmi: Consultancy, Honoraria; AGP: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SL VaxiGen: Consultancy, Honoraria; Novartis: Consultancy; Amgen: Honoraria; Chugai: Honoraria; Yuhan: Honoraria; Sanofi-Genzyme: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Handok: Honoraria; Janssen: Honoraria; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; BL & H: Research Funding; Otsuka: Honoraria. Lee:Alexion: Consultancy, Honoraria, Research Funding; Achillion: Research Funding.

Sign in / Sign up

Export Citation Format

Share Document