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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.

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.)

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 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.

Background: Fludarabine/busulfan-based conditioning regimens are widely used to perform allogeneic stem-cell transplantation (allo-SCT) in high-risk non-Hodgkin lymphoma (NHL) patients. The impact of the dose intensity of busulfan on outcomes has not been reported yet., Patients and Methods: This was a retrospective with the aim to compare the outcomes of NHL patients who received before allo-SCT a fludarabine/busulfan conditioning regimen, either of reduced intensity (FB2, 2 days of busulfan at 4 mg/kg/day oral or 3.2 mg/kg/day i.v.) (n = 277) or at a myeloablative reduced-toxicity dose (FB3/FB4, 3 or 4 days of busulfan at 4 mg/kg/day oral or 3.2 mg/kg/day i.v.) (n = 101)., Results: In univariate analysis, the 2-year overall survival (FB2 66.5% versus 60.3%, P = 0.33), lymphoma-free survival (FB2 57.9% versus 49.8%, P = 0.26), and non-relapse mortality (FB2 19% versus 21.1%, P = 0.91) were similar between both groups. Cumulative incidence of grade III-IV acute graft versus host disease (GVHD) (FB2 11.2% versus 18%, P = 0.08), extensive chronic GVHD (FB2: 17.3% versus 10.7%, P = 0.18) and 2-year GVHD free-relapse free survival (FB2: 44.4% versus 42.8%, P = 0.38) were also comparable. In multivariate analysis there was a trend for a worse outcome using FB3/FB4 regimens (overall survival: HR 1.47, 95% CI: 0.96-2.24, P = 0.08; lymphoma-free survival: HR: 1.43, 95% CI: 0.99-2.06, P = 0.05; relapse incidence: HR 1.54; 95% CI: 0.96-2.48, P = 0.07). These results were confirmed using a propensity score-matching strategy., Conclusion: We conclude that reduced toxicity myeloablative conditioning with fludarabine/busulfan does not improve the outcomes compared with reduced-intensity conditioning in adults receiving allo-SCT for NHL., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

This Phase 1/2 study aimed to determine optimal doses of daunorubicin (DNR; mg/m(2)) and cytarabine (mg/m(2)) to be combined with fractionated doses of gemtuzumab ozogamicin (GO, Mylotarg(®); 3 mg/m(2) on day 1, 4, and 7) satisfying safety requirements. Three dose levels of DNR/AraC were investigated namely (45, 100), (60, 100), and (60, 200). Patients included were acute myeloid leukemia in first relapse, aged 50-70 years. Hematological recovery was 31 days for neutrophil and 32 days for platelet counts. A documented infectious episode > Grade 2 occurred in 11/20 patients (55%). None of the 20 patients had signs of veno-occlusive disease. Overall, eleven patients reached complete remission (CR), two CR with incomplete platelets recovery. The results showed that combination of fractionated GO doses with DNR at 60 mg/m(2)/d for 3 days and cytarabine at 200 mg/m(2)/d for 7 days is tolerable and could be further investigated in the front-line therapy., (Copyright © 2011 Wiley Periodicals, Inc.)