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BACKGROUND Many older adults with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) have a relapse despite having a measurable residual disease (MRD)-negative complete remission with combination chemotherapy. The addition of blinatumomab, a bispecific T-cell engager molecule that is approved for the treatment of relapsed, refractory, and MRD-positive BCP-ALL, may have efficacy in patients with MRD-negative remission. METHODS In a phase 3 trial, we randomly assigned patients 30 to 70 years of age with BCRcABLl-negative BCP-ALL (with :: indicating fusion) who had MRD-negative remission (defined as <0.01°/o leukemic cells in bone marrow as assessed on flow cytometry) after induction and intensification chemotherapy to receive four cycles of blinatumomab in addition to four cycles of consolidation chemotherapy or to receive four cycles of consolidation chemotherapy alone. The primary end point was overall survival, and relapse-free survival was a secondary end point. RESULTS The data and safety monitoring committee reviewed the results from the third efficacy interim analysis and recommended that they be reported. Complete remission with or without full count recovery was observed in 395 of 488 enrolled patients (81°/o). Of the 224 patients with MRD-negative status, 112 were assigned to each group. The characteristics of the patients were balanced between the groups. At a median follow-up of 43 months, an advantage was observed in the blinatumomab group as compared with the chemotherapy-only group with regard to overall survival (at 3 years: 85°/o vs. 68%; hazard ratio for death, 0.41; 95% confidence interval [CI], 0.23 to 0.73; P=0.002), and the 3-year relapse-free survival was 80% with blinatumomab and 64% with chemotherapy alone (hazard ratio for relapse or death, 0.53; 95% CI, 0.32 to 0.87). A higher incidence of neuropsychiatrie events was reported in the blinatumomab group than in the chemotherapy-only group. CONCLUSIONS The addition of blinatumomab to consolidation chemotherapy in adult patients in MRD-negative remission from BCP-ALL significantly improved overall survival. [ABSTRACT FROM AUTHOR]

Purpose: Acute lymphoblastic leukemia (ALL) can occur across all age groups, with a strikingly higher cure rate in children compared with adults. However, the pharmacological basis of age-related differences in ALL treatment response remains unclear., Methods: Studying 767 children and 309 adults with newly diagnosed B-cell ALL enrolled on frontline trials at St Jude Children's Research Hospital, MD Anderson Cancer Center, the Alliance for Clinical Trials in Oncology, and the ECOG-ACRIN Cancer Research Group, we determined the ex vivo sensitivity of leukemia cells to 21 drugs. Twenty-three ALL molecular subtypes were identified using RNA sequencing. We systematically characterized the associations between drug response and ALL genomics in children, adolescents and young adults, and elderly adults. We evaluated the effect of age-related gene expression signature on ALL treatment outcomes., Results: Seven ALL drugs (asparaginase, prednisolone, mercaptopurine, dasatinib, nelarabine, daunorubicin, and inotuzumab ozogamicin) showed differential activity between children and adults, of which six were explained by age-related differences in leukemia molecular subtypes. Adolescents and young adults showed similar patterns of drug resistance as older adults, relative to young children. Mercaptopurine exhibited subtype-independent greater sensitivity in children. Transcriptomic profiling uncovered subclusters within CRLF2 -, DUX4 -, and KMT2A -rearranged ALL that were linked to age and cytotoxic drug resistance. In particular, a subset of children had adult-like ALL on the basis of leukemia gene expression patterns across subtypes, despite their chronological age. Resistant to cytotoxic drugs, children with adult-like ALL exhibited poor prognosis in pediatric ALL trials, even after adjusting for age and minimal residual diseases., Conclusion: Our results provide pharmacogenomic insights into age-related disparities in ALL cure rates and identify leukemia prognostic features for treatment individualization across age groups.

Defining genetic factors impacting chemotherapy failure can help to better predict response and identify drug resistance mechanisms. However, there is limited understanding of the contribution of inherited noncoding genetic variation on inter-individual differences in chemotherapy response in childhood acute lymphoblastic leukemia (ALL). Here we map inherited noncoding variants associated with treatment outcome and/or chemotherapeutic drug resistance to ALL cis-regulatory elements and investigate their gene regulatory potential and target gene connectivity using massively parallel reporter assays and three-dimensional chromatin looping assays, respectively. We identify 54 variants with transcriptional effects and high-confidence gene connectivity. Additionally, functional interrogation of the top variant, rs1247117, reveals changes in chromatin accessibility, PU.1 binding affinity and gene expression, and deletion of the genomic interval containing rs1247117 sensitizes cells to vincristine. Together, these data demonstrate that noncoding regulatory variants associated with diverse pharmacological traits harbor significant effects on allele-specific transcriptional activity and impact sensitivity to antileukemic agents., (© 2024. The Author(s).)

Leukemia can arise at various stages of the hematopoietic differentiation hierarchy, but the impact of developmental arrest on drug sensitivity is unclear. Applying network-based analyses to single-cell transcriptomes of human B cells, we define genome-wide signaling circuitry for each B cell differentiation stage. Using this reference, we comprehensively map the developmental states of B cell acute lymphoblastic leukemia (B-ALL), revealing its strong correlation with sensitivity to asparaginase, a commonly used chemotherapeutic agent. Single-cell multi-omics analyses of primary B-ALL blasts reveal marked intra-leukemia heterogeneity in asparaginase response: resistance is linked to pre-pro-B-like cells, with sensitivity associated with the pro-B-like population. By targeting BCL2, a driver within the pre-pro-B-like cell signaling network, we find that venetoclax significantly potentiates asparaginase efficacy in vitro and in vivo. These findings demonstrate a single-cell systems pharmacology framework to predict effective combination therapies based on intra-leukemia heterogeneity in developmental state, with potentially broad applications beyond B-ALL., Competing Interests: Declaration of interests S.E.K. has consulted Servier, Inc. and Jazz Pharmaceuticals. C.M. receives research funding from AbbVie and Pfizer, honoraria from Amgen and Illumina, and royalty payments from Cyrus. C.M. is on an advisory board for Illumina. M.K. receives grants from AbbVie, Allogene, Astra Zeneca, Cellectis, Daiichi, Forty Seven, Genentech, Gilead, MEI Pharma, Precision Bio, Rafael Pharmaceutical, Sanofi, and Stemline-Menarini; personal fees from AbbVie, AstraZeneca, Auxenion, Genentech, Gilead, F. Hoffman-La Roche, Janssen, MEI Pharma, Sellas, and Stemline-Menarini. In addition, M.K. has a patent US 7,795,305 B2 CDDO-compounds and combination therapies with royalties paid to Reata Pharm., a patent Combination Therapy with a mutant IDH1 Inhibitor and a BCL-2 licensed to Eli Lilly, and a patent 62/993,166 combination of a mcl-1 inhibitor and midostaurin, uses and pharmaceutical compositions thereof pending to Novartis. J.J.Y. receives funding from Takeda Pharmaceutical Company and AstraZeneca plc for research unrelated to this work., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)