Ibrutinib added to 10-day decitabine for older patients with AML and higher risk MDS

The treatment of older, unfit patients with acute myeloid leukemia (AML) is challenging. Based on preclinical data of Bruton tyrosine kinase expression/phosphorylation and ibrutinib cytotoxicity in AML blasts, we conducted a randomized phase 2 multicenter study to assess the tolerability and efficacy of the addition of ibrutinib to 10-day decitabine in unfit (ie, Hematopoietic Cell Transplantation Comorbidity Index ≥3) AML patients and higher risk myelodysplasia patients (HOVON135/SAKK30/15 trial). In total, 144 eligible patients were randomly (1:1) assigned to either 10-day decitabine combined with ibrutinib (560 mg; sequentially given, starting the day after the last dose of decitabine) (n = 72) or to 10-day decitabine (n = 72). The addition of ibrutinib was well tolerated, and the number of adverse events was comparable for both arms. In the decitabine plus ibrutinib arm, 41% reached complete remission/complete remission with incomplete hematologic recovery (CR/CRi), the median overall survival (OS) was 11 months, and 2-year OS was 27%; these findings compared with 50% CR/CRi, median OS of 11.5 months, and 2-year OS of 21% for the decitabine group (not significant). Extensive molecular profiling at diagnosis revealed that patients with STAG2, IDH2, and ASXL1 mutations had significantly lower CR/CRi rates, whereas patients with mutations in TP53 had significantly higher CR/CRi rates. Furthermore, multicolor flow cytometry revealed that after 3 cycles of treatment, 28 (49%) of 57 patients with available bone marrow samples had no measurable residual disease. In this limited number of cases, measurable residual disease revealed no apparent impact on event-free survival and OS. In conclusion, the addition of ibrutinib does not improve the therapeutic efficacy of decitabine. This trial was registered at the Netherlands Trial Register (NL5751 [NTR6017]) and has EudraCT number 2015-002855-85

Inferior outcome of addition of the aminopeptidase inhibitor tosedostat to standard intensive treatment for elderly patients with aml and high risk mds

Treatment results of AML in elderly patients are unsatisfactory. We hypothesized that addition of tosedostat, an aminopeptidase inhibitor, to intensive chemotherapy may improve outcome in this population. After establishing a safe dose in a run-in phase of the study in 22 patients, 231 eligible patients with AML above 65 years of age (median 70, range 66–81) were randomly assigned in this open label randomized Phase II study to receive standard chemotherapy (3+7) with or without tosedostat at the selected daily dose of 120 mg (n = 116), days 1–21. In the second cycle, patients received cytarabine 1000 mg/m2 twice daily on days 1-6 with or without tosedostat. CR/CRi rates in the 2 arms were not significantly different (69% (95% C.I. 60–77%) vs 64% (55–73%), respectively). At 24 months, event-free survival (EFS) was 20% for the standard arm versus 12% for the tosedostat arm (Cox-p = 0.01) and overall survival (OS) 33% vs 18% respectively (p = 0.006). Infectious complications accounted for an increased early death rate in the tosedostat arm. Atrial fibrillation w

Outcome of hematopoietic stem cell transplantation is similar for patients with a partial in vitro T-cell-depleted graft compared with a non-T-cell-depleted graft when stratified by the refined disease risk index

Comparisons of hematopoietic stem cell transplantation (HSCT) methods in retrospective studies are often hampered by the heterogeneity of comparison groups. The refined disease risk index (DRI) is a potentially interesting tool to compare HSCT protocols as it is based on the disease type and burden at transplant and stratifies patients into four prognostic groups for overall survival (OS). We included 265 patients with partial T-cell-depleted graft (TDEP) and 163 non-TDEP patients in a retrospective study and compared outcomes following stratification using the refined DRI. The 2-year OS rate for TDEP patients was 81.6, 60.9 and 43.3% for the low-, intermediate- and high-risk groups, respectively (P<0.001). For non-TDEP patients, the 2-year OS rate was 62.9, 48.8, 44.2 and 7.6% for the low-, intermediate-, high- and very-high-risk groups, respectively (P<0.001). There was no significant difference when comparing OS between TDEP and non-TDEP for the low-, intermediate- and high-risk groups, but TDEP patients had less acute GvHD grades II-IV. In conclusion, we confirm that the refined DRI is a valuable tool to compare the outcomes of different HSCT protocols. We demonstrate also that TDEP did not impact on the outcome of HSCT, but it did reduce the incidence of acute GvHD.Bone Marrow Transplantation advance online publication, 7 March 2016; doi:10.1038/bmt.2016.34

How to deal with an unexpected event that could alter the normal activity of cellular therapy? Recommendations of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)

L’épidémie mondiale de SARS-CoV-2 (COVID-19) a rapidement impacté l’ensemble de l’activité de thérapie cellulaire à travers le monde. Non seulement, Cet évènement inattendu était une menace pour les patients ayant déjà reçu une greffe de cellules hématopoïétiques ou une autre thérapie cellulaire telle que les CAR T-cells, mais également, il a été responsable d’une désorganisation des activités de thérapie cellulaire en raison de la dangerosité du virus de du manque de données scientifiques solides quant au mangement des patients et des donneurs. La Société Francophone de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC) a consacré un atelier pour produire des recommandations utiles en cas de survenu d’un tel événement dans le but d’harmoniser les actions de tous les acteurs impliqués pour que l’on puisse faire face collectivement dans le futur aux défis qui pourraient menacer notre activité. Ce travail n’est pas spécifiquement dédié à l’épidémie de SARS-CoV-2, mais cette dernière a été utilisée comme un exemple concret d’un événement inattendu pour construire nos reflétions et recommandations.The SARS-CoV-2 (COVID-19) pandemic has rapidly impacted cell therapy activities across the globe. Not only was this, unexpected event, a threat to patients who had previously received hematopoietic cell transplantation or other cell therapy such as CAR-T cells, but also, it was responsible for a disruption of cell therapy activities due to the danger of the virus and to the lack of solid scientific data on the management of patients and donors. The Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) devoted a workshop to issue useful recommendations in such an unexpected event in order to harmonize the actions of all the actors involved in cellular therapy programs so that we can collectively face, in the future, the challenges that could threaten our patients. This work is not specifically dedicated to the SARS-CoV-2 outbreak, but the latter has been used as a concrete example of an unexpected event to build up our recommendations

Allogeneic Stem Cell Transplantation in Therapy-Related Myelodysplasia after Autologous Transplantation for Lymphoma: A Retrospective Study of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy

peer reviewedTherapy-related myelodysplastic syndrome (t-MDS) after autologous stem cell transplantation (ASCT) is a rare complication with no curative option. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) may be considered for eligible patients and has been understudied in t-MDS. We report 47 consecutive patients with t-MDS after an ASCT who underwent allo-HSCT with a median age of 58 years (range, 30 to 71 years) at transplantation and a median follow-up of 22 months (range, 0.7 to 107). The median overall survival (OS) was 6.9 months (95% confidence interval [CI], 0 to 19 months). OS rates were 45% (29% to 60%) and 30% (15% to 45%) at 1 and 3 years after transplantation, respectively. On univariate analysis, prior therapy for t-MDS before allo-HSCT (P =.02) and mismatched donors (P =.004) were associated with poor OS. Three-year nonrelapse mortality (NRM) and relapse rates were 44% (25% to 63%) and 41% (22% to 61%), respectively. Mismatched donors (P <.001) were associated with higher NRM and a high-risk MDS (P =.008) with a higher relapse risk. On multivariate analysis, HLA mismatch was associated with higher NRM (hazard ratio, 6.21; 95% CI, 1.63 to 23.62; P =.007). In conclusion, our results suggest that one third of the patients who develop t-MDS after an ASCT for lymphoma are cured after an allo-HSCT. The use of mismatched donors with standard graft-versus-host disease prophylaxis should be avoided in such an indication for allo-HSCT. It will be worthwhile to see if the implementation of cyclophosphamide post-transplantation will improve the outcome with mismatched donors. © 2019 American Society for Transplantation and Cellular Therap

Better outcome with haploidentical over HLA-matched related donors in patients with Hodgkin's lymphoma undergoing allogeneic haematopoietic cell transplantation - A study by the Francophone Society of Bone Marrow Transplantation and Cellular Therapy

The question of the best donor type between haploidentical (HAPLO) and matched-related donors (MRD) for patients with advanced HL receiving an allogeneic hematopoietic cell transplantation (allo-HCT) is still debated. Given the lack of data comparing these two types of donor in the setting of non-myeloablative (NMA) or reduced-intensity (RIC) allo-HCT, we performed a multicentre retrospective study using graft-vs.-host disease-free relapse-free survival (GRFS) as our primary endpoint. We analysed the data of 151 consecutive HL patients who underwent NMA or RIC allo-HCT from a HAPLO (N = 61) or MRD (N = 90) between January 2011 and January 2016. GRFS was defined as the probability of being alive without evidence of relapse, grade 3-4 acute GVHD or chronic GVHD. In multivariable analysis, MRD donors were independently associated with lower GRFS compared to HAPLO donors (HR = 2.95, P < 0.001). Disease status at transplant other than CR was also associated with lower GRFS in multivariable analysis (HR = 1.74, P = 0.01). In addition, the administration of ATG was independently linked to higher GRFS (HR = 0.52, P = 0.009). In summary, we observed significantly higher GRFS in HL patients receiving an allo-HCT using the HAPLO PT-Cy platform compared to MRD. © 2017 Macmillan Publishers Ltd., part of Springer Nature