Impact of total body irradiation‐ vs chemotherapy‐based myeloablative conditioning on outcomes of haploidentical hematopoietic cell transplantation for acute myelogenous leukemia

International audienc

Ibrutinib as a promising treatment for pulmonary complications due to refractory chronic graft versus host disease

Introduction: Despite major improvements in allogeneic hematopoetic stem cell transplantation form matched related/ unrelated donor over last decades, chronic graft-versus-host disease (cGVHD) is still the leading cause of late treatmentrelated deaths among recipients. Ibrutinib is a first class inhibitor of BTK was recently employed in corticosteroid-refractory chronic GVHD with encouraging overall response rates Herein, we share a real-life experience using ibrutinib in the treatment of steroid-refractory cGVHD. Patients and Methods This multicenter retrospective study conducted in 10 different stem cell transplant centers included 44 adult patients diagnosed with steroid-refractory cGVHD. We treated off-label these patients from June 2017 to July 2019 with ibrutinib with a dose of 420 mg. Organ sites affected and cGVHD grading were classified according to the NIH 2014 criteria. Results Patients had undergone both myeloablative and non-myeloablative Allo-SCT for a variety of underlying hematological malignancies. As expected mouth and skin were the most frequently involved organs and 67 % of patients showed evidence of cGVHD in more than two organs. The median Karnofsky Performance Status score was 65%. At a median follow-up of 22.3 months (range 7.1-109 months) after evidence of cGVHD showed, 36 (81.8%) patients were still receiving ibrutinib and 4 (9.1%) had discontinued treatment, because of cGVHD progression. Treatment duration ranged from 2 to 12 months (median 6 months) for all patients. Only three patients had grade 2 muscle spasm, arrhythmia and diarrhea as adverse events and need to reduce the 25% of drug dosage. No several adverse events due to ibrutinib were observed in our cohort. In the all treated population, based on the 2005 NIH cGVHD Consensus Panel response criteria, 45.5% PR and 20.5% CR were achieved. Six patients had progression on manifestations of cGVHD. For the responders, the median time to initial response was 28 days. Nine patients had stable disease under the ibrutinib treatment and still continue receiving. Analysis by organ domain showed similar rates of response in the lung (76.4%) skin (66.7%), and GIS (57.1%). However the response in the liver (54.2%) was lower than the others. Out of 17 patients with bronchiolitis obliterans as a manifestation of cGVHD, we observed an immediate improvement in stability of FEV1 decline that persisted over the study period despite the decreased steroid dosing in 13 patients, 3 patients had stable FEV1 and only 1 patient had reduction in FEV1. Discussion Our study suggests that ibrutinib is a safe and effective agent that reduces steroid requirements and stabilizes lung function in patients with bronchiolitis obliterans as a manifestation of cGVHD. Our study adds to a growing body of evidence for ibrutinib's use in cGVHD. It is important to note that, larger prospective studies are needed to verify and augment our findings.American Society for Transplantation & Cellular TherapyCIBMT

Impact of total body irradiation‐ vs chemotherapy‐based myeloablative conditioning on outcomes of haploidentical hematopoietic cell transplantation for acute myelogenous leukemia

International audienc

Post-transplant cyclophosphamide versus anti-thymocyte globulin for graft-versus-host disease prevention in haploidentical transplantation for adult acute lymphoblastic leukemia

Graft-versus-host disease (GVHD) prophylaxis for unmanipulated haploidentical hematopoietic cell transplantation (haplo-HCT) include post-transplant cyclophosphamide (PTCy) and anti-thymocyte globulin (ATG). Utilizing EBMT registry, we compared ATG versus PTCy based GVHD prophylaxis in adult acute lymphoblastic leukemia (ALL) patients undergoing haplo-HCT. Included were 434 patients; ATG (n=98) and PTCy (n=336). Median follow-up was ~2 years. Baseline characteristics were similar between the groups except that the ATG-group was more likely to have relapsed/refractory ALL (P=0.008), non-TBI conditioning (P<0.001), peripheral blood graft source (P=<0.001) and transplanted at an earlier time-period (median year of HCT 2011 vs. 2015). The 100-day grade II-IV and III-IV acute-GVHD was similar between ATG and PTCy, as was 2-year chronic-GVHD. On multivariate analysis (MVA), leukemia-free survival (LFS) and overall survival (OS) was better with PTCy compared to ATG prophylaxis. Relapse incidence (RI) was lower in the PTCy group (P=0.03), while non-relapse mortality (NRM) was not different. Advanced disease and lower performance score were associated with poorer LFS and OS and advanced disease with inferior GVHD-free/relapse-free survival (GRFS). Peripheral grafts were associated with higher GVHD compared to bone marrow grafts. In ALL patients undergoing unmanipulated haplo-HCT, PTCy for GVHD prevention resulted in lower RI and improved LFS and OS compared to ATG

Outcome of haploidentical versus matched sibling donors in hematopoietic stem cell transplantation for adult patients with acute lymphoblastic leukemia: a study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation

International audienceBackground: Non-T-cell depleted haploidentical hematopoietic stem cell transplantation (HaploSCT) is being increasingly used in acute lymphoblastic leukemia (ALL) with improving patient outcomes. We have recently reported that outcomes of adult patients (pts) with ALL in complete remission (CR) receiving HaploSCT are comparable to unrelated donor transplants. We now compared HaploSCT and matched sibling donor (MSD) transplants in pts with ALL.Aim: To assess transplantation outcomes of HaploSCT and MSD transplants in pts with ALL in CR.Methods: We retrospectively analyzed adult patients (≥ 18 years) with ALL who underwent their first allogeneic stem cell transplantation (alloSCT) in first or second CR between 2012 and 2018, either from a T cell replete Haplo or MSD donor, and whose data were reported to the Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT). Multivariate analysis (MVA) adjusting for differences between the groups was performed using the Cox proportional hazards regression model. Propensity score matching was also performed to reduce confounding effects.Results: The analysis comprised 2304 patients: HaploSCT-413; MSD-1891. Median follow-up was 25 months. Median age was 37 (range 18-75) and 38 (18-76) years in HaploSCT and MSD, respectively. HaploSCT patients were transplanted more recently than those transplanted from MSD (2016 vs 2015, p < 0.0001). A higher rate of HaploSCT was in CR2 (33.4% vs 16.7%, p < 0.0001), respectively, and fewer received myeloablative conditioning (68% vs 83.2%, p < 0.0001). Cytomegalovirus (CMV) seropositivity was lower in HaploSCT patients (22% vs 28%, p = 0.01) and donors (27.1% vs 33%, p < 0.02), and a higher proportion of the HaploSCTs were performed using a bone marrow (BM) graft (46.2% vs 18.6%, p < 0.0001). The 2 groups did not differ with regard to gender, Karnofsky performance status score, ALL phenotype, Philadelphia chromosome (Ph) positivity and pre-alloSCT measurable residual disease (MRD). Graft versus host disease (GVHD) prophylaxis was mainly post-transplant cyclophosphamide (PTCy) based (92.7%) in the HaploSCT setting, while it was mostly pharmacologic in the setting of MSD (18.7% received ATG). Cumulative incidence of engraftment at day 60 was higher in MSD transplants compared to HaploSCT (98.7% vs 96.3%, p = 0.001), respectively. Day 180 incidence of acute (a) GVHD II-IV and III-IV was higher in HaploSCT vs. MSD: 36.3% vs 28.9% (p = 0.002 and 15.2% vs 10.5% (p = 0.005), respectively. Conversely, the 2-year chronic (c) GVHD and extensive cGVHD were 32% vs 38.8% (p = 0.009) and 11.9% vs 19.5% (p = 0.001) in HaploSCT vs MSD, respectively. Main causes of death were leukemia (31.8% vs 45%), infection (33.1% vs 19.7%) and GVHD (16.6% vs 19.7%) for HaploSCT and MSD, respectively. Two-year relapse incidence (RI), non-relapse mortality (NRM), leukemia-free survival (LFS), overall survival (OS) and GVHD-free, relapse-free survival (GRFS) were 26% vs 31.6%, 22.9% vs 13%, 51% vs 55.4%, 58.8% vs 67.4% and 40.6% vs 39% for HaploSCT and MSD, respectively. In the MVA, RI was significantly lower in HaploSCT in comparison with MSD, hazard ratio (HR) = 0.66 (95% CI 0.52-0.83, p = 0.004), while NRM was significantly higher, HR = 1.9 (95% CI 1.43-2.53, p < 0.0001). aGVHD grade II-IV and grade III-IV were higher in HaploSCT than in MSD HR = 1.53 (95% CI 1.23-1.9, p = 0.0002) and HR = 1.54 (95% CI 1.1-2.15, p = 0.011), respectively. Extensive cGVHD was lower in HaploSCT compared with MSD, HR = 0.61 (95% CI 0.43-0.88, p = 0.007), while total cGVHD did not differ significantly, HR = 0.94 (95% CI 0.74-1.18, p = 0.58). LFS, OS and GRFS did not differ significantly between the 2 transplant groups, HR = 0.96 (95% CI 0.81-1.14, p = 0.66); HR = 1.18 (95% CI 0.96-1.43, p = 0.11) and HR = 0.93 (95% CI 0.79-1.09, p = 0.37), respectively. These results were confirmed in a matched-pair analysis.Conclusions: Outcomes of adult patients with ALL in CR receiving alloSCT from haploidentical donors are not significantly different from those receiving transplants from MSD in terms of LFS, OS and GRFS

PTCy versus ATG as graft-versus-host disease prophylaxis in mismatched unrelated stem cell transplantation

There is an increased risk of GVHD and of non-relapse mortality (NRM) after allogeneic stem cell transplantations (alloSCT) when mismatched unrelated donors (MMUD) are used. In Europe, it is standard practice to use rabbit anti-thymocyte globulin (rATG) to reduce the high NRM and GVHD risks after MMUD alloSCT. As an alternative to rATG, post-transplantation Cyclophosphamide (PTCy) is in increasing clinical use. It is currently impossible to give general recommendations regarding preference for one method over another since comparative evidence from larger data sets is lacking. To improve the evidence base, we analyzed the outcome of rATG vs. PTCy prophylaxis in adult patients with hematologic malignancies undergoing first peripheral blood alloSCT from MMUD (9/10 antigen match) between Jan 2018 and June 2021 in the database of the European Society for Blood and Marrow Transplantation (EBMT). We performed multivariate analyses using the Cox proportional-hazards regression model. We included 2123 patients in the final analyses (PTCy, n = 583; rATG, n = 1540). p values and hazard ratios (HR) presented here are multivariate outcomes. Two years after alloSCT we found a lower NRM in the PTCy group of 18% vs. 24.9% in the rATG group; p = 0.028, HR 0.74. Overall survival in the PTCy cohort was higher with 65.7% vs. 55.7% in the rATG cohort; p < 0.001, HR 0.77. Progression-free survival was also better in the PTCy patients with 59.1% vs. 48.8% when using rATG; p = 0.001, 0.78. The incidences of chronic GVHD and acute GVHD were not significantly different between the groups. We found significantly lower NRM as well as higher survival in recipients of peripheral blood alloSCTs from MMUD receiving PTCy as compared to rATG. The results of the current analysis suggest an added value of PTCy as GVHD prophylaxis in MMUD alloSCT.