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Purpose: The use of inotuzumab ozogamicin (InO), a conjugated anti-CD22 monoclonal antibody, is becoming a promising frontline treatment for older patients with ALL., Patients and Methods: EWALL-INO is an open-label prospective multicenter phase II trial (ClinicalTrials.gov identifier: NCT03249870). Patients age 55 years and older with newly diagnosed CD22 + Philadelphia chromosome-negative (Ph-) B-cell precursor (BCP) ALL were eligible. After a prephase, a first induction consisting of vincristine, dexamethasone, and three injections of InO (0.8 mg/m 2 day 1, 0.5 mg/m 2 day 8/day 15) was followed by a second induction combining cyclophosphamide, dexamethasone, and two injections of InO (0.5 mg/m 2 day 1/day 8). Responders received up to six cycles of chemotherapy consolidation and 18-month chemotherapy maintenance. Allotransplant was allowed after three consolidations. The primary end point was 1-year overall survival (OS)., Results: Between December 2017 and March 2022, 131 patients (median age 68 years) were included. Three patients died during induction 1 (n = 130), two from multiple organ failure and one from hemorrhage, and none during induction 2 (n = 120). After induction 2, 90% of the patients achieved complete remission (CR) or CR with incomplete platelet recovery (CRp) and 80% had measurable residual disease (MRD2) <10 -4 . Among responders (n = 119), 47 relapsed and 14 died in CR/CRp. One-year OS, relapse-free survival (RFS), and cumulative incidence of relapse (CIR) rates were 73.2%, 66%, and 25%, respectively. High-risk cytogenetics and lower CD22 expression (<70%) were associated with worse OS, while both high-risk cytogenetics and MRD2 ≥10 -4 were associated with lower RFS and higher CIR. The 10 allotransplanted patients had very favorable outcomes (90% 2-year OS/RFS and no relapse). Only one nonfatal sinusoidal obstructive syndrome was documented during the study., Conclusion: Our results support InO's use in first-line regimens for older patients with CD22 + Ph- BCP-ALL.

Purpose: BCR::ABL1 quantification is widely regarded as the standard for monitoring measurable residual disease (MRD) in Philadelphia chromosome-positive (Ph+) ALL. However, recent evidence of BCR::ABL1 multilineage involvement questions the significance of BCR::ABL1 MRD. We aimed to define the prognostic role of MRD as assessed by BCR::ABL1 or lymphoid-specific immunoglobulin/T-cell receptor ( IG/TR ) gene markers., Patients and Methods: We conducted BCR::ABL1 and IG/TR quantification after each treatment cycle in 264 patients treated in the GRAAPH-2014 trial, which used four cycles of reduced-intensity chemotherapy with nilotinib, followed by hematopoietic stem-cell transplantation (HSCT)., Results: Comparing BCR::ABL1 and IG/TR MRD revealed residual BCR::ABL1 -positive non-ALL cells in 98 (43%) of 228 patients, defining multilineage Ph+ ALL. Despite poorer BCR::ABL1 responses, patients with multilineage Ph+ ALL had similar disease-free survival (DFS; hazard ratio [HR], 0.83 [95% CI, 0.49 to 1.41]; P = .50). Although BCR::ABL1 response failed to predict outcomes, IG/TR positivity (≥0.01%) was strongly associated with lower DFS (after cycle 2, HR, 2.49 [95% CI, 1.40 to 4.40]; P = .002; after cycle 4, HR, 4.13 [95% CI, 1.82 to 9.38]; P = .001). In multivariable analysis, both IG/TR positivity after cycle 2 and initial WBC count ≥30 × 10 9 /L predicted poorer DFS, enabling to define a high-risk group having a 4-year DFS of 56.5% compared with 87.6% (HR, 3.72 [95% CI, 1.93 to 7.15]; P < .001). Moreover, allogeneic HSCT significantly improved DFS in the high-risk group (HR, 0.33 [95% CI, 0.18 to 0.60]; P < .001), whereas the standard-risk group had favorable outcomes regardless of allogeneic HSCT., Conclusion: Our findings challenge the significance of BCR::ABL1 monitoring in adult Ph+ ALL and demonstrate the prognostic role of IG/TR MRD. This study provides a framework for using MRD to guide treatment strategies in adults with Ph+ ALL.

Abstract: We hypothesized that fit older patients with acute myeloid leukemia (AML) treated with decitabine (DEC) would report better health-related quality of life (HRQoL) outcomes than those receiving intensive chemotherapy (IC). We conducted a phase 3 randomized trial to compare DEC (10-day schedule) with IC (3+7) in older fit patients with AML. HRQoL was a secondary end point, and it was assessed with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) in conjunction with its elderly module (EORTC QLQ-ELD14). The following scales were a priori selected for defining the primary end point: physical and role functioning, fatigue, pain, and burden of illness. HRQoL was assessed at baseline, at regeneration from cycle 2, and at 6 and 12 months after randomization, and also before allogeneic hematopoietic stem cell transplantation (allo-HSCT) and 100 days after transplantation. Overall, 606 patients underwent randomization. At 2 months, the risk of HRQoL deterioration was lower in the DEC arm than in the 3+7 arm; 76% (95% confidence interval [CI], 69-82) vs 88% (95% CI, 82-93); odds ratio, 0.43 (95% CI, 0.24-0.76; P = .003). No statistically significant HRQoL differences were observed between treatment arms at the long-term evaluation combining assessments at 6 and 12 months. HRQoL deteriorations between baseline and after allo-HSCT were observed in both arms. However, these deteriorations were not clinically meaningful in patients randomized to DEC, whereas this was the case for those in the 3+7 arm, in 4 of 5 primary HRQoL scales. Our HRQoL findings suggest that lower-intensity treatment with DEC may be preferable to current standard IC (3+7) in fit older patients with AML. This trial was registered at www.clinicaltrials.gov as #NCT02172872., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Introduction: Idiopathic Multicentric Castleman Disease (iMCD) is a complex and poorly understood pathophysiological entity, which encompasses a variety of conditions and can mimic or be associated with autoimmune/autoinflammatory diseases, making it challenging to diagnose and treat. Vacuoles, Enzyme E1, X-linked, Autoinflammatory, Somatic (VEXAS) syndrome is an adult-onset autoinflammatory disorder associated with hematological abnormalities and caused by acquired somatic mutations in the ubiquitin-like modifier activating enzyme 1 gene (UBA1) which shares several common clinical and biological signs with iMCD. In this article, we report a patient with VEXAS syndrome initially presenting as iMCD, questioning the link between these two entities., Case Description: We report here a patient initially presenting as iMCD, proved on lymph node histology, which turns out to have a mutation at the splice acceptor site of exon 3 of UBA1 exhibiting VEXAS syndrome with Castleman-like lymph node., Conclusion: This is only the second case of VEXAS syndrome presenting as iMCD. VEXAS syndrome should therefore be considered in the presence of iMCD suspicion, including in cases of compatible histology., (Copyright © 2024 Société française de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.)

In this SFGM-TC registry study, we report the results after stem cell transplantation (HSCT) in 305 myelofibrosis patients, in order to determine potential risk factors associated with outcomes, especially regarding previous treatment with ruxolitinib. A total of 102 patients were transplanted from an HLA-matched-sibling donor (MSD), and 143 patients received ruxolitinib. In contrast with previous studies, our results showed significantly worse outcomes for ruxolitinib patients regarding overall survival (OS) and non-relapse mortality (NRM), especially in the context of unrelated donors (URD). When exploring reasons for potential confounders regarding the ruxolitinib effect, an interaction between the type of donor and the use of ATG was found, therefore subsequent analyses were performed separately for each type of donor. Multivariable analyses did not confirm a significant negative impact of ruxolitinib in transplantation outcomes. In the setting of URD, only age and Fludarabine-Melphalan (FM) conditioning were associated with increased NRM. For MSD, only Karnoksfy <70% was associated with reduced OS. However, a propensity score analysis showed that ruxolitinib had a negative impact on OS but only in non-responding patients, consistent with previous data. To conclude, with all the precautions due to confounders and bias, ruxolitinib itself does not appear to increase mortality after HSCT., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Abstract: We previously demonstrated that a reduced-intensity chemotherapy schedule can safely replace hyper-CVAD (cyclophosphamide-vincristine-doxorubicin [Adriamycin]-dexamethasone) cycle 1 when combined with imatinib in adults with Philadelphia-positive acute lymphoblastic leukemia. In the present randomized GRAAPH-2014 trial, we used nilotinib and addressed the omission of cytarabine (Ara-C) in consolidation. The primary objective was the major molecular response (MMR) rate measured by BCR::ABL1 quantification after cycle 4 (end of consolidation). All patients were eligible for allogeneic stem cell transplant (SCT), whereas those in MMR could receive autologous SCT, followed by 2-year imatinib maintenance in both cases. After the enrollment of 156 of 265 planed patients, the data and safety monitoring board decided to hold the randomization because of an excess of relapse in the investigational arm. Among the 155 evaluable patients, 76 received Ara-C during consolidation (arm A) and 79 did not (arm B). Overall, 133 patients (85%) underwent SCT, 93 allogeneic and 40 autologous. The noninferiority end point regarding MMR was reached with 71.1% (arm A) and 77.2% (arm B) of patients reaching MMR. However, the 4-year cumulative incidence of relapse was higher in arm B compared with arm A (31.3% [95% confidence interval {CI}, 21.1%-41.9%] vs 13.2% [95% CI, 6.7%-21.9%]; P = .017), which translated to a lower relapse-free survival. With a median follow-up of 3.8 years, 4-year overall survival was 79.0% (95% CI, 70.6%-89.3%) in arm A vs 73.4% (95% CI, 63.9%-84.4%) in arm B (P = .35). Despite a noninferior rate of MMR, more relapses were observed when ARA-C was omitted without impact on survival. ClinicalTrials.gov ID, NCT02611492., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Competing Interests: The authors declare no conflict of interest.

The use of post-transplantation cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis is not established after reduced intensity conditioning (RIC) hematopoietic stem cell transplantation (HSCT) from fully matched donors. This was a randomized, open-label, multicenter, phase 2 trial. All patients received a RIC regimen with fludarabine, intravenous busulfan for 2 days (Flu-Bu2), and a peripheral blood stem cell (PBSC) graft from a matched related or 10/10 HLA-matched unrelated donor. Patients were randomly assigned to receive anti-thymocyte globulin (ATG) 5 mg/kg plus standard GVHD prophylaxis or PTCy 50 mg/kg/d at days +3 and +4 plus standard GVHD prophylaxis. The primary endpoint was the composite endpoint of GVHD- and relapse-free survival (GRFS) at 12 months after HSCT. Eighty-nine patients were randomly assigned to receive either PTCy or control prophylaxis with ATG. At 12 months, disease-free survival was 65.9% in the PTCy group and 67.6% in the ATG group (P = 0.99). Cumulative incidence of relapse, non-relapse mortality, and overall survival were also comparable in the two groups. GRFS at 12 months was 54.5% in the PTCy group versus 43.2% in the ATG group (P = 0.27). The median time to neutrophil and platelet count recovery was significantly longer in the PTCy group compared to the ATG group. Except for day +30, where EORTC QLQ-C30 scores were significantly lower in the PTCy compared to the ATG group, the evolution with time was not different between the two groups. Although the primary objective was not met, PTCy is effective for GVHD prophylaxis in patients receiving Flu-Bu2 conditioning with a PBSC graft from a fully matched donor and was well tolerated in term of adverse events and quality of life. This trial was registered at clinicaltrials.gov: NCT02876679., (© 2024. The Author(s).)

Pneumocystis pneumonia (PCP) is a life-threatening complication after allogeneic hematopoietic cell transplantation (allo-HCT). However, allo-HCT procedures have evolved toward older patients, unrelated donors, and reduced-intensity conditioning, possibly modifying the risks. Polymerase chain reaction (PCR), widely used nowadays, is more sensitive than microscopy diagnostic methods. This study aimed to assess the factors associated with PCP in allo-HCT recipients within 2 years of HCT and managed according to current procedures. This multicenter, nested case-control study included PCP cases diagnosed by PCR, cytology, or immunofluorescence on bronchoalveolar lavage fluid between 2016 and 2018. Two controls per case were selected from the ProMISe registry and matched for the center, transplant date, and underlying disease. Fifty-two cases and 104 controls were included among the 5452 patients who underwent allo-HCT in the participating centers. PCP occurred at a median of 11.5 months after transplantation. The mortality rate was 24% on day 30 after the PCP diagnosis and 37% on day 90. The clinical presentation and mortality rates of the 24 patients diagnosed using only PCR were not different from those diagnosed with microscopy methods. Our study demonstrates a substantial incidence of, and mortality from, PCP, after allogeneic HCT despite well-established prophylactic approaches. In our experience, PCP nowadays occurs later after transplant than previously reported, justifying the prolongation of prophylaxis after six months in many cases. Allo-HCT recipients diagnosed with PCR as the only PCP marker should benefit from specific treatment as for other patients., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Whereas the prognosis of adult patients with Philadelphia-negative acute lymphoblastic leukemia (ALL) has greatly improved since the advent of pediatric-inspired regimens, the impact of initial central nervous system (CNS) involvement has not been formerly re-evaluated. We report here the outcome of patients with initial CNS involvement included in the pediatric-inspired prospective randomized GRAALL-2005 study. Between 2006 and 2014, 784 adult patients (aged 18-59 years) with newly diagnosed Philadelphia-negative ALL were included, of whom 55 (7%) had CNS involvement. In CNSpositive patients, overall survival was shorter (median 1.9 years vs. not reached, HR=1.8 [1.3-2.6], P<0.001). While there was no statistical difference in cumulative incidence of relapse between CNS+ and CNS- patients (HR=1.5 [0.9-2.5], P=0.11), non-relapse mortality was significantly higher in those with initial CNS disease (HR=2.1 [1.2-3.5], P=0.01). This increase in toxicity was mostly observed in patients randomized to the high-dose cyclophosphamide arm and in those who received allogeneic stem cell transplantation. Exploratory landmark analyses did not show any association between either cranial irradiation or allogeneic stem cell transplantation and outcome. Despite improved outcome in young adult ALL patients with pediatric-inspired protocols, CNS involvement is associated with a worse outcome mainly due to excess toxicity, without improved outcome with allogeneic SCT.

Background: Many older patients with acute myeloid leukaemia die or cannot undergo allogeneic haematopoietic stem-cell transplantation (HSCT) due to toxicity caused by intensive chemotherapy. We hypothesised that replacing intensive chemotherapy with decitabine monotherapy could improve outcomes., Methods: This open-label, randomised, controlled, phase 3 trial was conducted at 54 hospitals in nine European countries. Patients aged 60 years and older who were newly diagnosed with acute myeloid leukaemia and had not yet been treated were enrolled if they had an Eastern Cooperative Oncology Group performance status of 2 or less and were eligible for intensive chemotherapy. Patients were randomly assigned (1:1) to receive decitabine or standard chemotherapy (known as 3 + 7). For the decitabine group, decitabine (20 mg/m 2 ) was administered for the first 10 days in the first 28-day cycle, followed by 28-day cycles consisting of 5 days or 10 days of decitabine. For the 3 + 7 group, daunorubicin (60 mg/m 2 ) was administered over the first 3 days and cytarabine (200 mg/m 2 ) over the first 7 days, followed by 1-3 additional chemotherapy cycles. Allogeneic HSCT was strongly encouraged. Overall survival in the intention-to-treat population was the primary endpoint. Safety was assessed in all patients who received the allocated treatment. This trial is registered at ClinicalTrials.gov, NCT02172872, and is closed to new participants., Findings: Between Dec 1, 2014, and Aug 20, 2019, 606 patients were randomly assigned to the decitabine (n=303) or 3 + 7 (n=303) group. Following an interim analysis which showed futility, the IDMC recommended on May 22, 2019, that the study continued as planned considering the risks and benefits for the patients participating in the study. The cutoff date for the final analysis presented here was June 30, 2021. At a median follow-up of 4·0 years (IQR 2·9-4·8), 4-year overall survival was 26% (95% CI 21-32) in the decitabine group versus 30% (24-35) in the 3 + 7 group (hazard ratio for death 1·04 [95% CI 0·86-1·26]; p=0·68). Rates of on-protocol allogeneic HSCT were similar between groups (122 [40%] of 303 patients for decitabine and 118 [39%] of 303 patients for 3+7). Rates of grade 3-5 adverse events were 254 (84%) of 302 patients in the decitabine group and 279 (94%) of 298 patients in the 3 + 7 group. The rates of grade 3-5 infections (41% [125 of 302] vs 53% [158 of 298]), oral mucositis (2% [seven of 302] vs 10% [31 of 298]) and diarrhoea (1% [three of 302] vs 8% [24 of 298]) were lower in the decitabine group than in the 3 + 7 group. Treatment-related deaths were reported for 12% (35 of 302) of patients in the decitabine group and 14% (41 of 298) in the 3 + 7 group., Interpretation: 10-day decitabine did not improve overall survival but showed a better safety profile compared with 3 + 7 chemotherapy in older patients with acute myeloid leukaemia eligible for intensive chemotherapy. Decitabine could be considered a better-tolerated and sufficiently efficacious alternative to 3 + 7 induction in fit older patients with acute myeloid leukaemia without favourable genetics., Funding: Janssen Pharmaceuticals., Competing Interests: Declaration of interests MLü received research support to his institution from Janssen and European Organisation for Research and Treatment of Cancer (EORTC); is on the advisory boards for AbbVie, Astex, Janssen-Cilag, Otsuka, and Syros; and is currently working in an ongoing trial with a study drug provided by Cheplapharm. MK received research funding from Merck, Bristol Myers Squibb (BMS), Pierre Fabre, Janssen, and Immunocore. SF received personal funding by BMS and Celgene. AG received a grant for study conduct, and drug supply for Dacogen from Janssen Pharma Educational. JHJ received support for molecular analysis from Janssen and EORTC. FE received personal funding from AbbVie, Incyte, Janssen, Novartis, and Syros. RW received consulting fees from Amgen, BMS, Celgene, Janssen, Kite, Gilead, Novartis, Pfizer, and Sanofi; payment from AbbVie, Amgen, BMS, Celgene, Janssen, Kite, Gilead, Pfizer, and Sanofi; and support for attending meetings or travel from Janssen. HB is secretary of EORTC Leukemia Group; received research funding by the German Jose Carreras Leukemia Foundation and German Research Foundation; and honoraria from AbbVie, BMS, Celgene, Merck, Novartis, and Servier. UD received personal honoraria for participation in a data safety monitoring board from Avencell Europe and data safety monitoring board for an acute myeloid leukaemia CAR-T cell trial from Avencell Europe. FB received payments to his institution from Incyte Biosciences, Takeda, ExCellThera, and MaaT Pharma. SS received funding to his institution from Janssen Pharmaceuticals. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Failure of gastrointestinal acute graft- versus -host disease (GI-aGvHD) to respond to steroid therapy is associated with limited further therapeutic options. We aimed to assess the safety and efficacy of the first-in-human use of the pooled allogeneic faecal microbiota, MaaT013, for the treatment of steroid-refractory GI-aGvHD., Methods: This prospective, international, single-arm, phase 2a study reports clinical outcomes from a 24-patient cohort with grade III-IV, steroid refractory GI-aGvHD treated with the pooled allogeneic faecal microbiota MaaT013. MaaT013 involved pooling faecal matter from 3 to 8 screened donors then transplanting the pooled batches into patients to treat GI-aGVHD. The 24 patients were treated in the HERACLES study (Aug 2018 to Nov 2020) at 26 sites in Europe and an additional 52 patients were treated in a compassionate use/expanded access program (EAP) in France (July 2018 to April 2021). The primary endpoint was GI response at day 28, defined as the proportion of patients with GI-aGvHD who had a complete response (CR) or very good partial response (VGPR). GvHD grading and staging were assessed according to the revised Glucksberg criteria. Adverse events and severe adverse events were monitored for 6 months and 12 months, respectively. The HERACLES study was registered with ClinicalTrials.gov (NCT03359980)., Findings: Compared with single donors, MaaT013 is characterised by higher microbial richness and reduced variability across batches. At day 28 (D28), the GI-overall response rate (ORR) was 38% in the prospective population, including 5 complete responses (CR), 2 very good partial responses (VGPR) and 2 partial responses (PR). In the EAP, the GI-ORR was 58% (17 CR, 9 VGPR and 4 PR). The 12-month overall survival (OS) was 25% in the prospective study and 38% in the EAP. Regarding safety, five infectious complications, including 3 sepsis, could not be excluded from being related to the study procedure in HERACLES. Shotgun sequencing analyses of the identified strains suggest that none were found in MaaT013. In the EAP, 18 pharmacovigilance cases were reported among 52 treated patients, including 11 bacteraemia/sepsis. In HERACLES, we observed in stools from responding patients at D28 a higher microbiota richness and increased levels of beneficial bacteria, in particular butyrate producers, along with increased levels of short-chain fatty acid and bile acids. In contrast, stools from non-responding (NR) patients displayed increased levels of pathogenic pro-inflammatory bacteria along with increased systemic inflammatory parameters., Interpretation: Overall, MaaT013 was safe in this population of highly immunocompromised patients and was associated with responses in some patients with GI-aGvHD and deserves further investigation., Funding: MaaT Pharma., Competing Interests: FM reports honoraria from Therakos/Mallinckrodt, Sanofi and Novartis. TC reports consulting fee from Celgene, Abbvie, Jazz Pharma, Roche, Novartis, Agios and Servier and honoraria from Novartis, Amgen, Astellas, Celgene/BMS and Gilead/Kite. ED report payment for expert testimony from Astellas and support for attending meetings and/or travel from Neovii and Novartis. MJGTV report grants or contracts from MSD, Heel, Biontech and Roche, consulting fees from MaaT Pharma, Tillots, MSD/Merck, Roche and EUMEDICA and payment or honoraria from Merck/MSD, 3M, Ferring, Astellas, Uniklinik Karlsruhe, Uniklinik Köln, Akademie für Infektionsmedizin, Klinikum Essen, Pfizer, Universitätsklinikum Heidelberg, Uniklinik Frankfurt, Landesärztekammer Hessen, Janssen, Intitur Merieux, Forum für medizinische Fortbildung Gmbh, Universitätsklinikum Freiburg, Berliner Dialy Seminar, ADKA, Falk Foundation, St. Johannes Hospital, DiaLog Service, CED Service, Ärztekammer Niedersachsen, St. Josef Hospital, Limbach Gruppe SE, SUMIT OXFORD Ltd. EUMEDICA Kit Kongress, Tillots Pharma, Helios Kliniken, Lahn-Dill-Kliniken, GILEAD and Klinikum Leverkusen. CEB report honoraria from Astellas. EH report grants from Medac, payment for expert testimony from Novartis, participation on Advisory Board of Maat Pharma and Pharmabiome. JD is cofounder and member of the advisory board of MaaT Pharma, report consulting fees from MaaT Pharma, support for attending meetings and/or travel from MaaT Pharma and shares from MaaT Pharma. EPr, CG and EPl are MaaT Pharma employees and have patents as part of company inventor compensation policy MM reports grants and consulting fees from Sanofi, Novartis, and Janssen, honoraria from Sanofi, Novartis, Janssen, and MaaT Pharma, participation on Advisory Board of Janssen and leadership role in The European Group for Blood & Marrow Transplantation. All other authors declare no competing interests., (© 2023 The Author(s).)

Late relapse (LR) after allogeneic hematopoietic stem cell transplantation (AHSCT) for acute leukemia is a rare event (nearly 4.5%) and raises the questions of prognosis and outcome after salvage therapy. We performed a retrospective multicentric study between January 1, 2010, and December 31, 2016, using data from the French national retrospective register ProMISe provided by the SFGM-TC (French Society for Bone Marrow Transplantation and Cellular Therapy). We included patients presenting with LR, defined as a relapse occurring at least 2 years after AHSCT. We used the Cox model to identify prognosis factors associated with LR. During the study period, a total of 7582 AHSCTs were performed in 29 centers, and 33.8% of patients relapsed. Among them, 319 (12.4%) were considered to have LR, representing an incidence of 4.2% for the entire cohort. The full dataset was available for 290 patients, including 250 (86.2%) with acute myeloid leukemia and 40 (13.8%) with acute lymphoid leukemia. The median interval from AHSCT to LR was 38.2 months (interquartile range [IQR], 29.2 to 49.7 months), and 27.2% of the patients had extramedullary involvement at LR (17.2% exclusively and 10% associated with medullary involvement). One-third of the patients had persistent full donor chimerism at LR. Median overall survival (OS) after LR was 19.9 months (IQR, 5.6 to 46.4 months). The most common salvage therapy was induction regimen (55.5%), with complete remission (CR) obtained in 50.7% of cases. Ninety-four patients (38.5%) underwent a second AHSCT, with a median OS of 20.4 months (IQR, 7.1 to 49.1 months). Nonrelapse mortality after second AHSCT was 18.2%. The Cox model identified the following factors as associated with delay of LR: disease status not in first CR at first HSCT (odds ratio [OR], 1.31; 95% confidence interval [CI], 1.04 to 1.64; P = .02) and the use of post-transplantation cyclophosphamide (OR, 2.23; 95% CI, 1.21 to 4.14; P = .01). Chronic GVHD appeared to be a protective factor (OR, .64; 95% CI, .42 to .96; P = .04). The prognosis of LR is better than in early relapse, with a median OS after LR of 19.9 months. Salvage therapy associated with a second AHSCT improves outcome and is feasible, without creating excess toxicity., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

This 16-month-long multicentre retrospective study of 225 allogeneic haematopoietic stem cell transplantation (alloHSCT) recipients with COVID-19 examines risk factors for severity and mortality, describing the successive waves of infections (from March to June 2020 and from August 2020 to June 2021). We confirm the negative role of low respiratory tract disease and immunosuppressive treatment. We highlight significantly lower percentages of severe forms and COVID-19-related mortality during the second wave. Monthly comparative evolution of cases in alloHSCT recipients and in the French population shows a higher number of cases in alloHSCT recipients during the first wave and a decrease from February 2021., (© 2023 British Society for Haematology and John Wiley & Sons Ltd.)

Allogeneic hematopoietic stem cell transplantation remains the best curative option for higher-risk myelodysplastic syndrome. The presence of monosomal karyotype and/or complex karyotype abnormalities predicts inferior survival after allo-SCT in MDS patients. Haploidentical allo-SCT has been increasingly used in acute leukemia (AL) and has similar results as using HLA-matched donors, but data on higher-risk MDS is sparse. We compared outcomes in 266 patients with higher-risk MDS after HLA-matched sibling donor (MSD, n = 79), HLA-matched unrelated donor (MUD, n = 139) and HLA haploidentical donor (HID, n = 48) from 2010 to 2019. Median donor age differed between the three groups (p < 0.001). The overall survival was significantly different between the three groups with a better OS observed in the MUD group (p = 0.014). This observation could be explained by a higher progression-free survival with MUD (p = 0.014). The cumulative incidence of grade 2-4 acute GvHD was significantly higher in the HID group (p = 0.051). However, in multivariable analysis, patients transplanted using an HID had comparable mortality to patients transplanted using a MUD (subdistribution hazard ratio [sHR]: 0.58 [0.32-1.07]; p = 0.080) and a MSD ([sHR]: 0.56 [0.28-1.11]; p = 0.094). MUD do not remain a significant positive predictor of survival, suggesting that beyond the donor-recipient HLA matching, the donor age might impact recipient outcome., (© 2023. The Author(s).)

Background: Empiric antifungal therapy is considered the standard of care for high-risk neutropenic patients with persistent fever. The impact of a preemptive, diagnostic-driven approach based on galactomannan screening and chest computed tomography scan on demand on survival and on the risk of invasive fungal disease (IFD) during the first weeks of high-risk neutropenia is unknown., Methods: Patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) and allogeneic hematopoietic cell transplant recipients were randomly assigned to receive caspofungin empirically (arm A) or preemptively (arm B), while receiving fluconazole 400 mg daily prophylactically. The primary end point of this noninferiority study was overall survival (OS) 42 days after randomization., Results: Of 556 patients recruited, 549 were eligible: 275 in arm A and 274 in arm B. Eighty percent of the patients had AML or MDS requiring high-dose chemotherapy, and 93% of them were in the first induction phase. At day 42, the OS was not inferior in arm B (96.7%; 95% confidence interval [CI], 93.8%-98.3%) when compared with arm A (93.1%; 95% CI, 89.3%-95.5%). The rates of IFDs at day 84 were not significantly different, 7.7% (95% CI, 4.5%-10.8%) in arm B vs 6.6% (95% CI, 3.6%-9.5%) in arm A. The rate of patients who received caspofungin was significantly lower in arm B (27%) than in arm A (63%; P < .001)., Conclusions: The preemptive antifungal strategy was safe for high-risk neutropenic patients given fluconazole as prophylaxis, halving the number of patients receiving antifungals without excess mortality or IFDs. Clinical Trials Registration. NCT01288378; EudraCT 2010-020814-27., Competing Interests: Potential conflicts of interest. J. M. reports consulting fees and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from MSD, Gilead Sciences, and Pfizer, including participation on a data and safety monitoring board or advisory board (DSMB) for MSD, Gilead, and Pfizer. T. L. reports payment for participation on virtual European Society for Blood and Marrow Transplantation meeting. J. P. D. reports consulting fees from F2G and Gilead Sciences, including payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from F2G, Gilead Sciences, and Pfizer, and unpaid leadership or fiduciary role in other board, society, committee, or advocacy group for the European PCR Initiative Foundation. C. R. reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Gilead and Sandoz and support for attending meetings and/or travel for Gilead, MSD, Pfizer, and Sandoz. N. B. reports participation as the chair on a DSMB for the SHORT trial and roles as the president of the Dutch Society of Hematology (unpaid), Treasurer Board member for HOVON (unpaid), chair of the Horizonscan WP Hematology Dutch Healthcare Institute (vacancy fee), and member of the board of supervisors for Matchis (compensation according to Dutch law). D. S. reports grants or contracts from Pfizer, Novartis, BMS, AbbVie, MSD, and Takeda, including consulting fees from Pfizer, Novartis, AbbVie, BMS, Takeda, MSD, Janssen-Cilag, and Astellas; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Pfizer, Novartis, AbbVie, BMS, Takeda, MSD, and Janssen-Cilag; support for attending meetings and/or travel from Pfizer, Novartis, BMS, AbbVie, Takeda, MSD, and Janssen-Cilag; and a leadership or fiduciary role for other board, society, committee, or advocacy groups, paid or unpaid for Belgian College for Reimbursement of Orphan Drugs. F. B. reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AbbVie and Sanofi; support for attending an international meeting from Novartis and Pfizer; and participation on a DSMB or advisory board for some academic studies (no fee) and Maatpharma (paid to institution). W. J. H. reports payment or honoraria for presentations from AbbVie, Amgen, AstraZeneca, Celgene/BMS, Gilead Sciences, and Janssen; support for attending meetings from IPSEN Pharma, Amgen, and Abbvie; and support for attending adboards for Amgen, Astrazeneca, Celgene/BMS, Gilead Sciences Janssen, MSD, and Sanofi-Aventis. B. V. reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Pfizer, Sanofi, and Al Miral; support for attending meetings and/or travel for ViiV; and participation on a DSMB or advisory board for Pfizer. L. D. reports consulting fees from MSD, Pfizer, and Teva; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from MSD, Pfizer, Teva, and Sandoz; support for attending meetings and/or travel from Sandoz; and participation on an advisory board for Pfizer. C. C. L. reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Gilead and Kite and support for attending meetings and/or travel for Gilead and Kite. C. S. P. reports book royalties from Elsevier and Thieme and honoraria for lectures from Canon Medical Systems. R. B. reports consulting fees from Gilead; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Gilead; and support for attending meetings and/or travel for Gilead. P. E. V. reports research grants from ZonMw, Welcome Trust, Eurostars, EORTC, and RIVM; consulting fees from F2G, Gilead Sciences, and Pfizer; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Gilead Sciences and Pfizer. F. L. reports research grants from Merck, Sharpe & Dohme, Gilead, Pfizer, and Novartis and consulting fees (advisory board) from Gilead and Pfizer. P. Y. B. reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Gilead Sciences Switzerland AG and Pfizer PFE Switzerland GmbH and support for Gilead Sciences Switzerland Sarl for TIMM, Trends in Medical Mycology. D. H. reports employment with Merck & Co. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Introduction: Allogeneic hematopoietic stem-cell transplantation (allo-HSCT) remains the best curative option for high-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Unfortunately, it is still associated with a significant risk of relapse due to mechanisms of escape from the control of alloreactive T cells. Repetitive adjuvant donor lymphocyte infusion (DLI), termed prophylactic DLI (proDLI), as an effective strategy in preventing relapse is still debated., Methods: We performed a retrospective multicenter study to evaluate the efficacy of proDLI in allografted AML and MDS. We identified 56 patients treated with proDLI (DLI planned in full chimeras without any sign of disease relapse) and matched them to 167 patients in control group, (DLI performed for mixed chimerism or positive minimal residual disease) based on similar age, initial disease, cytogenetic prognosis, and conditioning intensity., Results: In univariate analysis, the incidence of severe aGVHD at 100 days and incidence of all grades of chronic GVHD 1 year after allo-HSCT were similar in the two groups. We also observed a trend of higher 3-year RI (52.61% [95% confidence interval 25.99-79.23]) in the proDLI group versus the control group (29.31% [20.28-38.34], p = 0.067). However, 3-year overall survival (p = 0.892), progression-free survival (p = 0.239), and nonrelapse mortality (p = 0.343) were similar between the two groups. In multivariate analysis, the only factor influencing overall and progression-free survival was anti-thymocyte globulin administration during the conditioning regimen., Conclusion: The proDLI strategy had an acceptable toxicity profile but did not improve patient outcomes compared to the pre-emptive strategy., (© 2023 S. Karger AG, Basel.)

Relapsed B-cell acute lymphoblastic leukemia (B-ALL) after allogeneic stem cell transplantation (allo-HCT) still represents a major concern with poor outcomes. The aim of this study is to compare the efficacy and safety of blinatumomab and donor lymphocyte infusion (DLI) versus blinatumomab alone in this setting. This is a multicenter retrospective study from centers of SFGM-TC. All transplanted patients who received blinatumomab salvage therapy were included. Patients who received DLI from 1 month before to 100 days after the starting of blinatumomab were included in the blina-DLI group. Seventy-two patients were included. Medium follow-up was 38 months. Fifty received blinatumomab alone and 22 the association blinatumomab-DLI. Two-year overall survival (OS) was 31% in the blinatumomab group and 43% in the blinatumomab-DLI group (p = 0.31). Studying DLI as a time dependent variable, PFS did not significantly differ between the 2 groups (HR:0.7, 95% CI: 0.4-1.5). In multivariate analysis, DLI was not a prognostic factor for OS, progression-free survival and progression/relapse incidence. Adverse events and graft-versus-disease rates were comparable in the 2 groups. In conclusion, adding DLI between 1 month before and 100 days after start of blinatumomab is safe and does not seem to improve outcomes in B-ALL patients who relapsed after allo-HCT., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

The real-world efficacy and safety of gilteritinib was assessed in an ambispective study that included 167 R/R FLT3-mutated AML patients. Among them, 140 received gilteritinib as single agent (cohort B), including 67 previously treated by intensive chemotherapy and midostaurin (cohort C). The main differences in patient characteristics in this study compared to the ADMIRAL trial were ECOG ≥ 2 (83.6% vs. 16.6%), FLT3-TKD mutation (21.0% vs. 8.5%), primary induction failure (15.0% vs. 40.0%) and line of treatment (beyond 2nd in 37.1% vs. 0.0%). The rates of composite complete remission, excluding those that occurred after hematopoietic stem cell transplantation (HSCT), were similar at respectively 25.4% and 27.5% in cohorts B and C. Median overall survival (OS) for these two groups was also similar at respectively 6.4 and 7.8 months. Multivariate analyses for prognostic factors associated with OS identified female gender (HR 1.61), adverse cytogenetic risk (HR 2.52), and allogenic HSCT after gilteritinib (HR 0.13). Although these patients were more heavily pretreated, these real-world data reproduce the results of ADMIRAL and provide new insights into the course of patients previously treated by intensive chemotherapy and midostaurin and beyond the 2nd line of treatment who can benefit from treatment in an outpatient setting., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Purpose: To provide insights into the diagnosis and management of therapy-related myeloid neoplasms (t-MN) following PARP inhibitors (PARPi)., Experimental Design: In a French cancer center, we identified and described the profiles of 13 t-MN diagnosed among 37 patients with ovarian cancer referred to hematology consultation for cytopenia under PARPi. Next, we described these 13 t-MN post-PARPi among 37 t-MN post ovarian cancer according to PARPi exposure. Finally, we described 69 t-MN post-PARPi in a national cohort., Results: From 2016 to 2021, cumulative incidence of t-MN was 3.5% (13/373) among patients with ovarian cancer treated with PARPi. At time of hematologic consultation, patients with t-MN had a longer PARPi exposure (9 vs. 3 months, P = 0.01), lower platelet count (74 vs. 173 G/L, P = 0.0005), and more cytopenias (2 vs. 1, P = 0.0005). Compared with t-MN not exposed to PARPi, patients with t-MN-PARPi had more BRCA1/2 germline mutation (61.5% vs. 0%, P = 0.03) but similar overall survival (OS). In the national cohort, most t-MN post-PARPi had a complex karyotype (61%) associated with a high rate of TP53 mutation (71%). Median OS was 9.6 months (interquartile range, 4-14.6). In multivariate analysis, a longer time between end of PARPi and t-MN (HR, 1.046; P = 0.02), olaparib compared with other PARPi (HR, 5.82; P = 0.003) and acute myeloid leukemia (HR, 2.485; P = 0.01) were associated with shorter OS., Conclusions: In a large series, we described a high incidence of t-MN post-PARPi associated with unfavorable cytogenetic and molecular abnormalities leading to poor OS. Early detection is crucial, particularly in cases of delayed cytopenia., (©2022 American Association for Cancer Research.)

Background: Although recommended in patients with acute myeloblastic leukaemia (AML) after induction chemotherapy, real-life use of antifungal prophylaxis (AFP) is different among centres., Materials and Methods: This is an ancillary study to a randomized trial on intensive induction chemotherapy in AML patients (ALFA-0702/NCT00932412), where AFP with posaconazole was recommended. IFIs were graded by investigators and by central reviewers according to the revised EORTC definitions. Experts conclusions were compared to the investigators' ones., Results: A total of 677 patients were included. Four AFP strategies were reported: Group-1: no AFP (n = 203, 30%), Group-2: posaconazole (n = 241, 36%), Group-3: posaconazole with other AFP (n = 142, 21%), Group-4: other AFP (n = 91, 13%). Experts graded more IFI than investigators: proven/probable IFI, 9.0% (n = 61) versus 6.2% (n = 42). The cumulative incidence at day60 of probable/proven IFI was 13.9% (Group-1); 7.9% (Group-2); 5.6% (Group-3); and 6.6% (Group-4). IFI onset was 26 (19-31) days after induction in Groups 2-3, versus 16 (9-25) days in Group 1 and 20 (12-24) days in Group 4 (P< .001). After a median follow-up of 27.5 months (0.4-73.4), the mortality rate was 38.3%, with 5.4% attributed to IFI. In multivariate analysis, IFI occurrence was an independent risk of death (HR5.63, 95%-CI 2.62-12.08, P< .001). EORTC recommendations were applied in only 57% of patients. In patients without IFI, the rate of AML complete remission was higher., Conclusions: In AML patients, AFP delayed the onset of IFI in addition of decreasing their rate. The frequent misidentification of IFI impacts their appropriate management according to recommendations. hematological remission was more frequent in patients without IFI., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: The present study evaluated the relative survival benefits associated with enasidenib and current standard of care (SoC) therapies for patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) and an isocitrate dehydrogenase 2 (IDH2) mutation who are ineligible for hematopoietic stem cell transplantation (HSCT)., Methods: Propensity score matching (PSM) analysis compared survival outcomes observed with enasidenib 100 mg daily in the phase I/II AG221-C-001 trial and SoC outcomes obtained from a real-world chart review of patients in France., Results: Before matching, enasidenib (n = 195) was associated with numerically improved overall survival (OS) relative to SoC (n = 80; hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.61-1.11). After matching and adjusting for covariates (n = 78 per group), mortality risk was significantly lower with enasidenib than with SoC (HR, 0.67; 95% CI, 0.47-0.97). The median OS was 9.26 months for enasidenib (95% CI, 7.72-13.24) and 4.76 months for SoC (95% CI, 3.81-8.21). Results remained robust across all sensitivity analyses conducted., Conclusions: PSM analyses indicate that enasidenib significantly prolongs survival relative to SoC among patients with R/R AML and an IDH2 mutation who are ineligible for HSCT. Future prospective studies are needed to validate these findings using other data sources and to assess the comparative efficacy of enasidenib for other treatment outcomes., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

To design a simple and reproducible classifier predicting the overall survival (OS) of patients with acute myeloid leukemia (AML) ≥60 years of age treated with 7 + 3, we sequenced 37 genes in 471 patients from the ALFA1200 (Acute Leukemia French Association) study (median age, 68 years). Mutation patterns and OS differed between the 84 patients with poor-risk cytogenetics and the 387 patients with good (n = 13), intermediate (n = 339), or unmeasured (n = 35) cytogenetic risk. TP53 (hazards ratio [HR], 2.49; P = .0003) and KRAS (HR, 3.60; P = .001) mutations independently worsened the OS of patients with poor-risk cytogenetics. In those without poor-risk cytogenetics, NPM1 (HR, 0.57; P = .0004), FLT3 internal tandem duplications with low (HR, 1.85; P = .0005) or high (HR, 3.51; P < 10-4) allelic ratio, DNMT3A (HR, 1.86; P < 10-4), NRAS (HR, 1.54; P = .019), and ASXL1 (HR, 1.89; P = .0003) mutations independently predicted OS. Combining cytogenetic risk and mutations in these 7 genes, 39.1% of patients could be assigned to a "go-go" tier with a 2-year OS of 66.1%, 7.6% to the "no-go" group (2-year OS 2.8%), and 3.3% of to the "slow-go" group (2-year OS of 39.1%; P < 10-5). Across 3 independent validation cohorts, 31.2% to 37.7% and 11.2% to 13.5% of patients were assigned to the go-go and the no-go tiers, respectively, with significant differences in OS between tiers in all 3 trial cohorts (HDF [Hauts-de-France], n = 141, P = .003; and SAL [Study Alliance Leukemia], n = 46; AMLSG [AML Study Group], n = 223, both P < 10-5). The ALFA decision tool is a simple, robust, and discriminant prognostic model for AML patients ≥60 years of age treated with intensive chemotherapy. This model can instruct the design of trials comparing the 7 + 3 standard of care with less intensive regimens., (© 2021 by The American Society of Hematology.)

This multicenter prospective phase 2 trial analyzed disease-free survival (DFS) in myelofibrosis patients receiving ruxolitinib for 6 months before transplantation. Seventy-six patients were recruited. Age-adjusted dynamic international prognostic scoring system was intermediate-1, intermediate-2, and high in 27 (36%), 31 (41%), and 18 (24%) patients. All patients received ruxolitinib from inclusion to conditioning regimen (fludarabine-melphalan) or to progression. A donor was found in 64 patients: 18 HLA-matched sibling donor (MSD), 32 HLA-matched unrelated (UD10/10), and 14 HLA mismatched unrelated donor (UD9/10. Among 64 patients with a donor, 20 (31%) achieved a partial response before transplantation and 59 (92%) could be transplanted after ruxolitinib therapy (18/18 MSD, 30/21 UD10/10, 11/34 UD9/10), of whom 19 (32%) were splenectomized. Overall survival from inclusion was 68% at 12 months. One-year DFS after transplantation was 55%: 83%, 40%, and 34% after MSD, UD10/10 or UD9/10, respectively. Cumulative incidence of grade 2-4 acute graft-versus-host disease (GVHD) was 66% and non-relapse-mortality was 42% at 12 months. Short course of ruxolitinib before transplantation is followed by a high rate of transplantation. With the platform used in this protocol, outcome was much better in patients transplanted with HLA-matched sibling donor as compared to unrelated donor., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Clozapine is mainly used in patients with treatment-resistant schizophrenia and may lead to potentially severe haematologic adverse events, such as agranulocytosis. Whether clozapine might be associated with haematologic malignancies is unknown. We aimed to assess the association between haematologic malignancies and clozapine using Vigibase®, the WHO pharmacovigilance database., Methods: We performed a disproportionality analysis to compute reporting odds-ratio adjusted for age, sex and concurrent reporting of antineoplastic/immunomodulating agents (aROR) for clozapine and structurally related drugs (loxapine, olanzapine and quetiapine) compared with other antipsychotic drugs. Cases were malignant lymphoma and leukaemia reports. Non-cases were all other reports including at least one antipsychotic report., Results: Of the 140 226 clozapine-associated reports, 493 were malignant lymphoma cases, and 275 were leukaemia cases. Clozapine was significantly associated with malignant lymphoma (aROR 9.14, 95% CI 7.75-10.77) and leukaemia (aROR 3.54, 95% CI 2.97-4.22). Patients suffering from those haematologic malignancies were significantly younger in the clozapine treatment group than patients treated with other medicines (p < 0.001). The median time to onset (available for 212 cases) was 5.1 years (IQR 2.2-9.9) for malignant lymphoma and 2.5 years (IQR 0.6-7.4) for leukaemia. The aROR by quartile of dose of clozapine in patients with haematologic malignancies suggested a dose-dependent association., Conclusions: Clozapine was significantly associated with a pharmacovigilance signal of haematologic malignancies. The risk-benefit balance of clozapine should be carefully assessed in patients with risk factors of haematologic malignancies. Clozapine should be used at the lowest effective posology.

The phase 3 ALFA-0701 trial demonstrated improved outcomes with fractionated-dose gemtuzumab ozogamicin (GO) combined with standard chemotherapy vs. standard chemotherapy alone in adults with de novo acute myeloid leukemia (AML). We examined post-transplant outcomes and occurrence of hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) in patients who received hematopoietic stem cell transplantation (HSCT) as follow-up therapy in ALFA-0701. Patients aged 50-70 years were randomized to standard chemotherapy with or without GO (3 mg/m2 on days 1, 4, and 7 of induction and day 1 on each of two consolidation courses). Allogeneic HSCT was recommended for patients in first complete remission with matched (related or unrelated) donor, except those with core-binding factor AML or normal karyotype and either NPM1+/FLT3-ITDwt or CEBPA+ AML. Eighty-five patients (GO: n = 32; control: n = 53) received HSCT in first complete remission or after relapse/primary induction failure. Three patients (GO: n = 2; control: n = 1 [received GO as follow-up therapy]) developed VOD/SOS after HSCT or conditioning. Post-transplant survival, non-relapse mortality, and relapse were not different between arms. Results indicate fractionated-dose GO as part of induction and consolidation chemotherapy for AML does not induce excess post-transplant VOD/SOS or mortality and thus does not preclude the use of HSCT as consolidation treatment.

In patients with isocitrate dehydrogenase (IDH)-mutated acute myeloid leukemia (AML) treated by intensive chemotherapy (IC), prognostic significance of co-occurring genetic alterations and allogeneic hematopoietic stem cell transplantation (HSCT) are of particular interest with the advent of IDH1/2 mutant inhibitors. We retrospectively analyzed 319 patients with newly diagnosed AML (127 with IDH1, 135 with IDH2R140, and 57 with IDH2R172 mutations) treated with IC in 3 Acute Leukemia French Association prospective trials. In each IDH subgroup, we analyzed the prognostic impact of clinical and genetic covariates, and the role of HSCT. In patients with IDH1 mutations, the presence of NPM1 mutations was the only variable predicting improved overall survival (OS) in multivariate analysis (P < .0001). In IDH2R140-mutated AML, normal karyotype (P = .008) and NPM1 mutations (P = .01) predicted better OS. NPM1 mutations were associated with better disease-free survival (DFS; P = .0009), whereas the presence of DNMT3A mutations was associated with shorter DFS (P = .0006). In IDH2R172-mutated AML, platelet count was the only variable retained in the multivariate model for OS (P = .002). Among nonfavorable European LeukemiaNet 2010-eligible patients, 71 (36%) underwent HSCT in first complete remission (CR1) and had longer OS (P = .03) and DFS (P = .02) than nontransplanted patients. Future clinical trials testing frontline IDH inhibitors combined with IC may consider stratification on NPM1 mutational status, the primary prognostic factor in IDH1- or IDH2R140-mutated AML. HSCT improve OS of nonfavorable IDH1/2-mutated AML and should be fully integrated into the treatment strategy., (© 2021 by The American Society of Hematology.)

Allogeneic hematopoietic cell transplantation (alloHCT) is a complex, potentially fatal therapy featuring a myriad of complications. Triggering event(s) of such complications vary significantly, but often a so-called "multi-organ failure" (MOF) is reported as the leading cause of death. The identification of the exact trigger of MOF is critical towards early and disease-specific intervention to improve outcome. We examined data from 202 alloHCT patients reported to have died of MOF from the EBMT registry aiming to determine their exact cause of death focusing on veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) due to its life-threatening, often difficult to capture yet preventable nature. We identified a total of 70 patients (35%) for whom VOD/SOS could be considered as trigger for MOF and leading cause of death, among which 48 (69%) were previously undiagnosed. Multivariate analysis highlighted history of hepatic comorbidity or gentuzumab use and disease status beyond CR1 as the only significant factors predictive of VOD/SOS incidence (OR = 6.6; p = 0.001 and OR = 3.3; p = 0.004 respectively). VOD/SOS-related MOF was widely under-reported, accounting for 27% of deaths attributed to MOF of unknown origin without a previous VOD/SOS diagnosis. Our results suggest most missed cases developed late VOD/SOS beyond 21 days post-alloHCT, highlighting the importance of the newly revised EBMT criteria.

A multistage model instructed by a large dataset (knowledge bank [KB] algorithm) has recently been developed to improve outcome predictions and tailor therapeutic decisions, including hematopoietic stem cell transplantation (HSCT) in acute myeloid leukemia (AML). We assessed the performance of the KB in guiding HSCT decisions in first complete remission (CR1) in 656 AML patients younger than 60 years from the ALFA-0702 trial (NCT00932412). KB predictions of overall survival (OS) were superior to those of European LeukemiaNet (ELN) 2017 risk stratification (C-index, 68.9 vs 63.0). Among patients reaching CR1, HSCT in CR1, as a time-dependent covariate, was detrimental in those with favorable ELN 2017 risk and those with negative NPM1 minimal residual disease (MRD; interaction tests, P = .01 and P = .02, respectively). Using KB simulations of survival at 5 years in a scenario without HSCT in CR1 (KB score), we identified, in a similar time-dependent analysis, a significant interaction between KB score and HSCT, with HSCT in CR1 being detrimental only in patients with a good prognosis based on KB simulations (KB score ≥40; interaction test, P = .01). We could finally integrate ELN 2017, NPM1 MRD, and KB scores to sort 545 CR1 patients into 278 (51.0%) HSCT candidates and 267 (49.0%) chemotherapy-only candidates. In both time-dependent and 6-month landmark analyses, HSCT significantly improved OS in HSCT candidates, whereas it significantly shortened OS in chemotherapy-only candidates. Integrating KB predictions with ELN 2017 and MRD may thus represent a promising approach to optimize HSCT timing in younger AML patients., (© 2021 by The American Society of Hematology.)

Allogeneic stem cell transplantation (allo-SCT) represents the most beneficial treatment for patients with active relapsed/refractory (R/R) hematologic malignancies. Recently, sequential regimens combining debulking chemotherapy followed by reduced-intensity conditioning (RIC) have shown encouraging results for these patients. In this retrospective study, we report the extended results of a sequential regimen of clofarabine, cytosine arabinoside, and RIC in 131 adults with active R/R myeloid disease at transplant. Conditioning consisted of clofarabine (30 mg/m 2 /day) and cytosine arabinoside (1 g/m 2 /day) for 5 days, followed, after a rest of 3 days, by an RIC combining cyclophosphamide (60 mg/kg) for 1 day, iv busulfan (3.2 mg/kg/day) for 2 days, and anti-thymocyte globulin (2.5 mg/kg/day) for 2 days. Between 2007 and 2016, 131 patients (males n = 75, median age: 52.6 years) were identified from the SFGM-TC registry. There were 111 acute myeloid leukemia (AML) patients and 20 cases with myelodysplastic or myeloproliferative syndrome. Status at transplant was known for all but 4 patients and was primary refractory (n = 81) and 1st or 2nd relapse (n = 46). All patients received allo-SCT from a matched donor (sibling n = 64, unrelated n = 67). Engraftment was observed in 105/122 (86%) evaluable cases and 63% of the patients achieved complete remission (CR) after transplant. The 1-year overall survival, disease-free survival, relapse incidence, non-relapse mortality, and graft-versus-host disease-free/relapse-free survival were 39.2%, 28.1%, 41.0%, 30.8%, and 22.2%, respectively. This study confirms that this sequential clofarabine-based regimen provides a high CR rate in this critical population, although relapse remains a matter of concern.

Patients undergoing treatment of acute lymphoblastic leukemia (ALL) are at risk for thrombosis, caused in part by the use of l-asparaginase (L-ASP). Antithrombin (AT) replacement has been suggested to prevent venous thromboembolism (VTE) and thus may increase exposure to ASP. We report herein the results of the prophylactic replacement strategy in the pediatrics-inspired prospective GRAALL-2005 study. Between 2006 and 2014, 784 adult patients with newly diagnosed Philadelphia- ALL were included. The incidence rate of VTE was 16%, with 69% of cases occurring during induction therapy. Most patients received AT supplementation (87%). After excluding patients who did not receive L-ASP or who developed thrombosis before L-ASP, AT supplementation did not have a significant impact on VTE. Administration of fibrinogen concentrates was associated with an increased risk of VTE, whereas transfusion of fresh frozen plasma had no effect. Heparin prophylaxis was associated with an increased risk of VTE. Prophylactic measures were not associated with an increased risk of grade 3 to 4 bleeding complications. The rate of VTE recurrence after L-ASP reintroduction was 3% (1 of 34). In ALL patients receiving L-ASP therapy, the use of fibrinogen concentrates may increase the risk of thrombosis and should be restricted to rare patients with hypofibrinogenemia-induced hemorrhage. VTE developed despite extensive AT supplementation, which suggests the need for additional prophylactic measures. Although this large descriptive study was not powered to demonstrate the efficacy of these prophylactic measures, it provides important insight to guide future trial design. This trial was registered at www.clinicaltrials.gov as #NCT00327678., (© 2020 by The American Society of Hematology.)

The prognostic value of IL7-receptor pathway (IL7Rp) mutations in T-cell acute lymphoblastic leukemia (T-ALL) remains unclear. We performed a comprehensive study of 200 adult patients with T-ALL included in the GRAALL2003/2005 protocols to address the clinical significance of IL7Rp mutations. Next-generation sequencing of the IL7Rp (IL7R/JAK1/JAK3/STAT5B) revealed that IL7Rp mutations were frequent in adult T-ALL (28%) particularly in immature/early T-cell progenitor (ETP)-ALL. They were associated with mutations of NOTCH-pathway, PHF6, and PRC2 components but not with K/NRAS. IL7Rp mutated (IL7Rp mut ) T-ALL were slow-responders, with a high rate of M2/M3 day-8 marrow compared with IL7Rp non-mutated (IL7Rp WT ) T-ALL (p = 0.002) and minimal residual disease positivity at 6-weeks (MRD1) (p = 0.008) but no difference in MRD2 positivity at 12-weeks. Despite this, no adverse prognosis was evidenced when censored for allogeneic hematopoietic stem cell transplantation (HSCT). In time-dependent analysis, HSCT did not benefit IL7Rp mut patients whereas it was of marked benefit to IL7Rp WT cases. IL7Rp-mutations identify a subgroup of slow-responder T-ALLs which benefit from post-induction chemotherapy regimens but not from HSCT. Our data suggest that prior knowledge of the mutation status of IL7Rp may influence HSCT decision and help to guide therapy reduction.

The combination of carmustine, etoposide, cytarabine, and melphalan (BEAM) as conditioning regimen prior to autologous stem-cell transplantation (ASCT) remains the standard of care for patients with mantle cell lymphoma (MCL) who are eligible for transplantation. The replacement of carmustine with bendamustine (BeEAM) was described as a promising alternative in non-Hodgkin lymphoma. The aim of this retrospective study was to compare the BeEAM with the BEAM regimen in MCL patients in the frontline setting. Sixty and 108 patients were included in the BeEAM and the BEAM groups, respectively. At 3 years, progression-free survival (PFS) was significantly higher in the BeEAM than in the BEAM group (84% [73-96] vs. 63% [51-79], p = 0.03). The overall survival was not statistically different between the two groups (p = 0.2). In multivariable analysis, BeEAM regimen remained associated with higher PFS (HR = 0.377, 95% CI, 0.146-0.970; p = 0.043). Subgroup analyses in patients treated with prior rituximab-aracytine induction alone showed that BeEAM improved the PFS compared with BEAM regimen (p = 0.04). Despite the high rate of acute renal failure KDIGO III (32%), treatment-related mortality was not increased with the BeEAM regimen. A prospective randomized trial will be necessary to confirm the beneficial effect of the BeEAM regimen in MCL patients undergoing ASCT.

In this study, we aimed to refine prognostication of older with acute myeloid leukemia (AML) after intensive chemotherapy. Five hundred and nine patients aged 60 years or older (median age, 68 years) were prospectively enrolled in the intensive Acute Leukemia French Association (ALFA)-1200 trial between 2012 and 2016, and 471 patient samples were submitted to multigene analysis. Mutations in any of 8 genes frequently altered in myelodysplastic syndromes (MDS), including ASXL1, SRSF2, STAG2, BCOR, U2AF1, EZH2, SF3B1, and ZRSR2, defined a secondary AML (sAML)-like disease, as reported. Of the samples analyzed, 48% included sAML-like gene mutations. These mutations were associated with a shorter event-free survival, both overall (hazard ratio, 1.46; 95% confidence interval, 1.19-1.79; P < .001) and within the European LeukemiaNet (ELN)-2017 intermediate-risk subgroup (hazard ratio, 1.52; 95% confidence interval, 1.01-2.28; P = .044), which excludes ASXL1-mutated cases by definition. We therefore included patients with intermediate-risk AML carrying sAML-like mutations in a single high-risk patients group together with adverse-risk patients with AML, whereas other intermediate-risk patients were included in a standard-risk group together with favorable-risk patients (high-risk/standard-risk patient ratio, 1.00). Using this 2-class risk assessment, we observed that transplantation prolonged overall survival from remission in patients with high-risk AML only, not in patients with standard-risk AML. Routine analysis of sAML-like gene mutations may thus improve the definition of high-risk older patients with AML, and better identify the half of older patients who clearly derive survival benefit from allogeneic transplantation in first remission. This trial was registered at www.clinicaltrials.gov as #NCT01966497., (© 2020 by The American Society of Hematology.)

Measurable residual disease (MRD) status pre-allogeneic hematopoietic cell transplantation (allo-HCT) has been shown to predict transplant outcomes. We investigated the effect of Anti-Thymocyte Globulin (ATG) on acute myelogenous leukemia (AML) relapse by pretransplant MRD status. AML patients undergoing allo-HCT in first complete remission from either a matched sibling or unrelated donor during the 2006-2017 period were selected. Outcomes of 1509 patients (MRD + , n = 426) were studied. ATG was used in 561 (52%) and 239 (58%) patients within the MRD - and MRD + cohorts, respectively. In MRD - patients, ATG did not affect relapse incidence (RI) (HR = 0.80, p = 0.17), but was associated with reduced incidence of grade II-IV acute GVHD, grade II-IV and chronic GVHD, reduced nonrelapse mortality (HR = 0.66, p = 0.05), improved leukemia-free survival (HR = 0.74, p = 0.02), overall survival (HR = 0.69, p = 0.01), and GVHD-relapse free survival (HR = 0.62, p < 0.01). In MRD + patients, ATG was associated with a lower incidence of chronic GVHD (total, HR 0.56 p = 0.03; extensive, HR 0.40 P = 0.01), without an impact on other allo-HCT outcome parameters, including RI(HR = 1.02, p = 0.92). The use of ATG was associated with reduced risk for GVHD. ATG did not increase RI, even in high-risk AML patients who were MRD + before allo-HCT.

Allogeneic hematopoietic stem cell transplantation is the only potentially curative therapy for acute myeloid leukemia. In the absence of an HLA-matched related or unrelated donor (MRD or MUD), the best alternative donor source remains controversial. Umbilical cord blood and haploidentical donors offer a shorter delay from indication to transplantation. This retrospective multicentre study of a French registry compares overall survival in the 18 months following registration in the absence of a MRD between four types of donors. Between 2012 and 2016, 1302 patients were transplanted using MUD (control, n = 803), mismatched MUD (n = 219), umbilical cord blood (n = 153) and haploidentical (n = 127) donors. Multivariate analyses were conducted for overall survival after registration, after transplant, and transplant-related mortality. After adjustment for variables, the type of donor did not influence any of the three end points. Our results confirmed the significant negative impact of longer time between registration and transplant: HR = 1.04 [1.02-1.06] (p < 0.0001). This indicates a positive correlation between better survival and shorter registration-to-transplantation wait time. In the absence of a sibling donor, the alternative stem cell source does not impact early survival in acute myeloid leukemia patients. The minimization of registration-to-transplantation time should be considered when weighing the alternative donor options.

Acute myeloid leukemia (AML) is a highly heterogeneous disease both in terms of genetic background and response to chemotherapy. Although molecular aberrations are routinely used to stratify AML patients into prognostic subgroups when receiving standard chemotherapy, the predictive value of the genetic background and co-occurring mutations remains to be assessed when using newly approved antileukemic drugs. In the present study, we retrospectively addressed the question of the predictive value of molecular events on the benefit of the addition of gemtuzumab ozogamicin (GO) to standard front-line chemotherapy. Using the more recent European LeukemiaNet (ELN) 2017 risk classification, we confirmed that the benefit of GO was restricted to the favorable (hazard ratio [HR], 0.54, 95% confidence interval [CI], 0.30-0.98) and intermediate (HR, 0.57; 95% CI, 0.33-1.00) risk categories, whereas it did not influence the outcome of patients within the adverse risk subgroup (HR, 0.93; 95% CI, 0.61-1.43). Interestingly, the benefit of GO was significant for patients with activating signaling mutations (HR, 0.43; 95% CI, 0.28-0.65), which correlated with higher CD33 expression levels. These results suggest that molecular aberrations could be critical for future differentially tailored treatments based on integrated genetic profiles that are able to predict the benefit of GO on outcome., (© 2020 by The American Society of Hematology.)

Several approaches have been developed to overcome historical barriers associated with poor outcomes in the setting of HLA-haploidentical allogeneic transplantation (HaploSCT). Here, we examine the outcome of patients with various hematological disorders undergoing HaploSCT with high-dose, post-transplantation cyclophosphamide. We performed a retrospective study on 381 patients from 30 centers between January 2013 and December 2015. At the last follow-up, a total of 1058 infectious episodes were diagnosed, affecting 90.3% of the cohort. Median time to first infection was 13 days for bacterial, 32 days for viral and 20 days for fungal infections. Around 41% of these infections were of bacterial origin and 35% of viral origin, among which 48.8% of patients presented CMV reactivation. Median of GVHD relapse-free survival, progression-free survival and overall survival were 7.1 months, 19.9 months and 33.5 months, respectively. HSCT procedure was the primary or contributing cause of death (55.6%), followed by relapse of the original disease (34.2%). Infections accounted for 45.7% of the HSCT-related deaths. The present multicenter data on a large cohort of patients receiving HaploSCT with PTCy confirmed the feasibility of the procedure with an acceptable incidence of infectious complications, not different as compared to other haploidentical platforms or HLA-matched transplantation.