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Refractory and/or relapsing T-cell acute lymphoblastic leukemia (T-ALL) remains a major therapeutic challenge. The pre-TCR pathway has recently emerged as a therapeutic target via LCK inhibition in this context. However, there is a need for simple and quickly assessable biomarkers to predict sensitivity to LCK inhibitors. Moreover, targeting LCK alone by tyrosine kinase inhibitors, such as Dasatinib, often results in transient clinical responses, emphasizing the need for efficient combination strategies. Here, we assessed pre-TCR alpha chain (pTα) surface expression by flow cytometry in a unique series of 50 adult T-ALL patient-derived xenografts (PDX). We show that cases displaying a cortical phenotype often express high levels of surface pTα (pre-TCR+ T-ALL) and that the latter associates with LCK activation. Furthermore, we show that ectopic interleukin-7 receptor (IL-7R) expression can rescue pre-TCR+ T-ALL from Dasatinib cytotoxicity (5 PDX). We tested whether co-inhibition of pre-TCR and IL-7R signaling pathways could be synergetic in pre-TCR+ IL-7R+ T-ALL (11 PDX). Combination of JAK-inhibitors, Ruxolitinib or Tofacitinib, with Dasatinib elicited strong and specific synergy in IL-7R+ pre-TCR+ T-ALL in vitro, including in the relapse setting (4/28 patient-derived primary samples). Using 3 adult-PDX models, we show that in vivo treatment with this combination significantly delayed leukemic progression and prolonged survival compared to either monotherapy. This preclinical study thus proposes the use of pTα as a biomarker of LCK-inhibitor sensitivity in T-ALL, and suggests that dual targeting of IL-7R and pre-TCR signaling pathways may be a relevant therapeutic strategy in a substantial proportion of adult T-ALL., (Copyright © 2025 American Society of Hematology.)

Not available.

Hodgkin lymphoma (HL) is one of the most common cancers in adolescents and young adults (AYA). Paediatric and adult therapeutic strategies diverge while sharing the common objective: maintaining optimal efficacy with less long-term toxicity. However, few studies have compared the outcome of AYA treated according to one or the other approaches. Among the 148 patients aged 15-25 years, treated at Saint-Louis Hospital for newly diagnosed HL between 2012 and 2018, 71 were treated according to an adult protocol and 77 were treated according to a paediatric one. The 5-year overall survival (OS) and progression-free survival (PFS) were, respectively, 100% and 85%, with no significant difference between treatment groups (85% in paediatric vs. 86% in adult, p = 0.7). Overall, the 5-year PFS was 100% for early favourable stages and 78% for advanced stages. A higher risk of short-term steroid and vincristine-related toxicities was observed in paediatric regimen, whereas a higher risk of late toxicities was expected in adult regimen, due to higher anthracyclines, procarbazine, bleomycin and radiotherapy exposure. These results confirm the excellent outcome of AYA patients with HL, whatever the treatment strategies. They justify a tailor-made therapeutic decision and highlight the importance of managing AYA patients in dedicated units with trained professionals., (© 2025 British Society for Haematology and John Wiley & Sons Ltd.)

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.

In the past decade, there has been considerable progress in the treatment of adults with newly diagnosed B-cell acute lymphoblastic leukaemia. This evolution is the product of a more profound understanding of acute lymphoblastic leukaemia biology, innovations in measurable residual disease quantification that led to precise disease-risk stratification, adoption of contemporary paediatric-inspired regimens, inclusion of tyrosine kinase inhibitors in the treatment of Philadelphia chromosome-positive acute lymphoblastic leukaemia, and the introduction of immunotherapy in the frontline setting. Nevertheless, outcomes of acute lymphoblastic leukaemia in adults are inferior compared with those of children, with excessive rates of treatment failure, and therapy-related morbidity and mortality. Simultaneously, transplant consolidation has continued to be used frequently for high-risk adults with acute lymphoblastic leukaemia in first complete remission. Considering the rapid pace of evolution in acute lymphoblastic leukaemia management, novel trial designs are warranted to accelerate advancements and streamline approaches. Here, we summarise progress in the treatment of adults with newly diagnosed acute lymphoblastic leukaemia, which adds to previously published guidelines by focusing specifically on first-line decisions for B-cell acute lymphoblastic leukaemia and how to best personalise treatment. This Viewpoint also includes experiences with regimens and testing approaches currently available not only in Europe, but also on multiple continents with different practices and resources., Competing Interests: Declaration of interests IA reports research support from AbbVie and MacroGenics and being on advisory boards for Gilead/Kite, Amgen, Jazz, Syndax, Wugen, Takeda, and Pfizer. GJR is a consultant for Agios, Amgen, Amphivena, Astex, Celator, Celgene, Clovis Oncology, CTI BioPharma, Genoptix, Immune Pharmaceuticals, Janssen Pharmaceuticals, Juno, MedImmune, MEI Pharma, Onconova, Pfizer, Roche, and Sunesis; receives research funding from AbbVie, BMS, Teva, and Karyopharm; is an advisory board member or consultant for Novartis, AbbVie, BeiGene, BerGenBio, Arcellx, Jazz Pharmaceuticals, Syros, BMS, Genentech, ImmunoGen, AstraZeneca, Kura, Ryvu, Magenta, and Qihan Zentalis; and has provided research support to Janssen. RB reports participation in meetings and advisory boards (including fees, travel, and accommodations) for Amgen and Incyte. NB reports honorarium from Amgen, Celgene, Jazz Pharmaceuticals, and Pfizer; and has a consulting or advisory role for Amgen, Novartis, Pfizer, and Servier. DJD is a consultant for Amgen, Autolus, Agios, Blueprint, Forty-Seven, Gilead, Incyte, Jazz, Novartis, Pfizer, Servier, and Takeda; has received research funding from AbbVie, Glycomimetics, Novartis, and Blueprint Pharmaceuticals; is on a data safety monitoring board for Daiichi Sankyo and FibroGen; and is a member of Mt Sinai Myeloproliferative Neoplasms Research Consortium. SF reports research support from Amgen and Pfizer; speaker's honorarium from Amgen, Pfizer, Astellas, Jazz, Gilead/Kite, and Novartis; advisory board membership for Amgen, Pfizer, Astellas, Jazz, and Gilead/Kite. NG reports honoraria from Amgen, Pfizer, Kite/Gilead, Jazz Pharmaceuticals, Incyte, Autolus, Clinigen Group, and Servier; research funding from Amgen, Pfizer, Novartis, Servier, Jazz Pharmaceuticals), Incyte, and Clinigen Group. ACL reports consulting or advisory role for Amgen, Pfizer, Sanofi, Kite, and Takeda; research funding from Astellas Pharma, Pharmacyclics, Kite/Gilead, Kadmon, Amgen, Autolus, Talaris; and travel, accommodations, and expenses from Amgen. SML reports honoraria from Astellas, Daiichi Sankyo, Novartis, Marker Therapeutics, AbbVie, Amgen, Bristol-Myers Squibb, Pluristem, Syros, and Agios; and research funding from BioSight (previous funding from Onconova, Celgene, Hoffman LaRoche, and Kura [travel included]). TM reports travel grants from Amgen, Jazz, Pfizer, Bayer, Kyowa Kirin, Celgene/BMS, Kite/Gilead, Janssen, and Takeda; honoraria for advisory board meetings from Kite/Gilead, Amgen, Novartis, Pfizer, Celgene/BMS, Daiichi Sankyo, Atara, Roche, and Janssen; honoraria for lectures from Kite/Gilead, Takeda, Janssen, Roche, Servier, Novartis, Celgene/BMS, Pfizer, and Incyte; and research funding from Janssen, AstraZeneca, and Novartis. JP reports consulting fees from AffyImmune Therapeutics, Amgen, Autolus, Be Biopharma, BeiGene, Bright Pharmaceutical Services, Curocell, Kite, Medpace, Minerva Biotechnologies, Pfizer, Servier, Sobi, Synthekine, and Takeda; honoraria from OncLive, Physician Education Resource, and MJH Life Sciences; serves on scientific advisory board of Allogene Therapeutics and Artiva Biotherapeutics; received institutional research funding from Autolus, Genentech, Fate Therapeutics, Incyte, Servier, and Takeda. ACS reports honoraria from Celgene, Amgen, Pfizer, Novartis, and Jazz Pharmaceuticals; and research funding from Celgene, Amgen, Agios, and Pfizer. BS reports honoraria from Pharmacyclics/Janssen, Spectrum/Acrotech, BeiGene, Gilead Sciences; consulting or advisory role for Adaptive Biotechnologies, Bristol Myers Squibb/Celgene, Novartis, Pfizer, Amgen, Precision Biosciences, Kite, Jazz Pharmaceuticals, Century Therapeutics, Deciphera, Autolus, Lilly, Pepromene; research funding from Incyte, Jazz Pharmaceuticals, Kite/Gilead, and Servier; and travel, accommodations, and expenses from Celgene, Novartis, Pfizer, Janssen, Seattle Genetics, AstraZeneca, Stemline Therapeutics, and Kite. EJ reports research grants and consultancy fees from AbbVie, Adaptive Biotechnologies, Amgen, Ascentage, Autolus, Bristol Myers Squibb, Hikma, Genentech, Jazz, Kite, Novartis, Pfizer, and Takeda., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

This narrative review seeks to summarize chemotherapeutic regimens commonly used for patients with newly diagnosed Philadelphia (Ph) chromosome-negative B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in the frontline setting and to describe the latest clinical research using the bispecific T-cell-engaging immunotherapy blinatumomab in the first-line treatment setting. Current standard-of-care chemotherapeutic backbones for newly diagnosed Ph-negative BCP-ALL are based on the same overarching treatment principle: to reduce disease burden to undetectable levels and maintain lasting remission. The adult treatment landscape has progressively evolved following the adoption of pediatric-inspired regimens. However, these intense regimens are not tolerated by all, and high-risk patients still have inferior outcomes. Therefore, designing more effective and less toxic strategies remains key to further improving efficacy and safety outcomes. Overall, the treatment landscape is evolving in the frontline, and integration of blinatumomab into different standard frontline regimens may improve overall outcomes with a favorable safety profile., Competing Interests: Competing interests EJJ has received research grants from Pfizer, Takeda, Amgen, AbbVie, Novartis, Astex, Adaptive Biotechnologies, and Ascentage and served as a consultant and on advisory boards for Pfizer, Takeda, Amgen, AbbVie, BMS, Novartis, Genentech, Adaptive Biotechnologies, and Ascentage. HMK has received/served as honoraria/advisory board/consulting for AbbVie, Amgen, Amphista, Ascentage, Astellas, Biologix, Curis, Ipsen Biopharmaceuticals, KAHR Medical, Labcorp, Novartis, Pfizer, Shenzhen Target Rx, Stemline, and Takeda and has received research grants from AbbVie, Amgen, Ascentage, BMS, Daiichi-Sankyo, Immunogen, Jazz, and Novartis. NG has received institutional research funding from Amgen, Clinigen, Incyte, Jazz, Novartis, Pfizer, and Servier and received speaker honoraria or fees for advisory board participation from Amgen, AstraZeneca, Autolus, Celgene, Clinigen, Gilead, Incyte Jazz, Novartis, Pfizer, and Servier. BDS has served as a consultant and an educational advisor for Deciphera, Takeda, Kite, Novartis, Beigene, Pfizer, Jazz, BMS, Amgen, Adaptive, Lilly, Autolus, Syndax, Precision Biosciences, and Astra Zeneca; has received grants and served as an investigator for initiated trials for Kite, Jazz, and Servier; and has served on a data safety monitoring committee for Pepromene Bio. SC has served as a consultant and on advisory boards for Amgen, Incyte, Gilead, and AbbVie. JHP has received consulting fees from Affyimmune Therapeutics, Amgen, Autolus, Be Biopharma, Beigene, Bright Pharmaceutical Services, Caribou Biosciences, Curocell, Galapagos, In8Bio, Kite, Medpace, Minerva Biotechnologies, Pfizer, Servier, Sobi, and Takeda; received honoraria from OncLive, Physician Education Resource, and MJH Life Sciences; served on scientific advisory boards of Allogene Therapeutics, Artiva Biotherapeutics and Green Cross Biopharma; and received institutional research funding from Autolus, Genentech, Fate Therapeutics, InCyte, Servier, and Takeda. AWR has no competing interest. LG is an unpaid advisor to Amgen on the development of oncology products in pediatric patients. SF has served as an advisory board member for Amgen, Astellas, Gilead/Kite, Jazz, Pfizer, and Jazz; received speakers’ honoraria from Amgen, BMS, Gilead/Kite, Jazz, Pfizer, and Novartis; and received research funding from Amgen. ACL has received consulting honoraria from Amgen, AbbVie, Actinium, Sanofi, and Takeda, and research funding from Amgen, Autolus, Incyte, Kadmon/Sanofi, Kite/Gilead, Pharmacyclics, and Talaris. JMR has served as a speaker for and received advisory board honoraria from Pfizer, Amgen, Shire, and Ariad; has received research support from and participated in clinical trials with Amgen; and has participated in clinical trials with Pfizer and Ariad. TFM has served on the advisory board for Amgen, Incyte, Gilead, Novartis, and Pfizer. KM, FZ, and KV are employees of and shareholders in Amgen. NB has received personal/consulting fees from Amgen, Gilead Sciences, Novartis, Servier, and Pfizer., (© 2024. The Author(s).)

Inotuzumab ozogamicin (InO) is an antibody-drug conjugate approved for the treatment of relapsed/refractory B-cell acute lymphoblastic leukemia (ALL). Several clinical trials are investigating InO in combination with low-intensity chemotherapy or other anti-ALL-targeted therapies in the salvage and frontline settings, notably in older adults who often cannot tolerate intensive chemotherapy and tend to have higher-risk disease. InO is also increasingly used to bridge patients to hematopoietic stem cell transplantation (HSCT), in sequence with chimeric antigen receptor T-cell therapy, to eliminate measurable residual disease and to prevent post-HSCT relapse. Veno-occlusive disease/sinusoidal obstruction syndrome is a potential complication of InO treatment, particularly when followed by HSCT. Herein, the authors review the historical development and current status of InO, strategies for mitigating the risk of InO-related veno-occlusive disease/sinusoidal obstruction syndrome, and future directions for InO research and clinical use., (© 2024 The Author(s). Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Abstract: We previously reported a better outcome in adult and pediatric T-cell acute lymphoblastic leukemia (T-ALL) harboring NOTCH1 and/or FBXW7 mutations without alterations of K-N-RAS and PTEN genes. Availability of high-throughput next-generation sequencing (NGS) strategies led us to refine the outcome prediction in T-ALL. Targeted whole-exome sequencing of 72 T-ALL-related oncogenes was performed in 198 adults with T-ALLs in first remission from the GRAALL-2003/2005 protocols and 242 pediatric patients with T-ALLs from the FRALLE2000T. This approach enabled the identification of, to our knowledge, the first NGS-based classifier in T-ALL, categorizing low-risk patients as those with N/F, PHF6, or EP300 mutations, excluding N-K-RAS, PI3K pathway (PTEN, PIK3CA, and PIK3R1), TP53, DNMT3A, IDH1/2, and IKZF1 alterations, with a 5-year cumulative incidence of relapse (CIR) estimated at 21%. Conversely, the remaining patients were classified as high risk, exhibiting a 5-year CIR estimated at 47%. We externally validated this stratification in the pediatric cohort. NGS-based classifier was highly prognostic independently of minimal residual disease (MRD) and white blood cell (WBC) counts, in both adult and pediatric cohorts. Integration of the NGS-based classifier into a comprehensive risk-stratification model, including WBC count at diagnosis and MRD at the end of induction, enabled the identification of an adverse-risk subgroup (25%) with a 5-year CIR estimated at 51%, and a favorable-risk group (32%) with a 5-year CIR estimated at 12%. NGS-based stratification combined with WBC and MRD sharpens the prognostic classification in T-ALL and identifies a new subgroup of patients who may benefit from innovative therapeutic approaches. The GRAALL-2003/2005 studies were registered at www.ClinicalTrials.gov as #NCT00222027 and #NCT00327678., (© 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.)

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: Tyrosine kinase inhibitors efficacy in central nervous system (CNS) disease remains uncertain. Ponatinib was studied for CNS distribution in 16 patients with Philadelphia-positive acute lymphoblastic leukemia. Cerebrospinal fluid concentrations fell below the 40 nM threshold, suggesting suboptimal CNS exposure., (© 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.)

Abstract: Given the poor outcome of refractory and relapsing T-cell acute lymphoblastic leukemia (T-ALL), identifying prognostic markers is still challenging. Using single nucleotide polymorphism (SNP) array analysis, we provide a comprehensive analysis of genomic imbalances in a cohort of 317 newly diagnosed patients with T-ALL including 135 children and 182 adults with respect to clinical and biological features and outcomes. SNP array results identified at least 1 somatic genomic imbalance in virtually all patients with T-ALL (∼96%). Del(9)(p21) (∼70%) and UPD(9)p21)/CDKN2A/B (∼28%) were the most frequent genomic imbalances. Unexpectedly del(13)(q14)/RB1/DLEU1 (∼14%) was the second most frequent copy number variant followed by del(6)(q15)/CASP8AP2 (∼11%), del(1)(p33)/SIL-TAL1 (∼11%), del(12)(p13)ETV6/CDKN1B (∼9%), del(18)(p11)/PTPN2 (∼9%), del(1)(p36)/RPL22 (∼9%), and del(17)(q11)/NF1/SUZ12 (∼8%). SNP array also revealed distinct profiles of genomic imbalances according to age, immunophenotype, and oncogenetic subgroups. In particular, adult patients with T-ALL demonstrated a significantly higher incidence of del(1)(p36)/RPL22, and del(13)(q14)/RB1/DLEU1, and lower incidence of del(9)(p21) and UPD(9p21)/CDKN2A/B. We determined a threshold of 15 genomic imbalances to stratify patients into high- and low-risk groups of relapse. Survival analysis also revealed the poor outcome, despite the low number of affected cases, conferred by the presence of chromothripsis (n = 6, ∼2%), del(16)(p13)/CREBBP (n = 15, ∼5%) as well as the newly-identified recurrent gain at 6q27 involving MLLT4 (n = 10, ∼3%). Genomic complexity, del(16)(p13)/CREBBP and gain at 6q27 involving MLLT4, maintained their significance in multivariate analysis for survival outcome. Our study thus demonstrated that whole genome analysis of imbalances provides new insights to refine risk stratification in T-ALL. This trial was registered at www.ClinicalTrials.gov as #NCT00222027 and #NCT00327678, and as #FRALLE 2000T trial., (© 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.)

Relapsed/refractory T-cell acute lymphoblastic leukemia (ALL)/lymphoma (LBL) represent a significant unmet medical need. WU-CART-007 is a CD7-targeting, allogeneic, fratricide-resistant chimeric antigen receptor T cell product generated from healthy donor T cells. WU-CART-007 was evaluated in a phase 1/2 study with a 3 + 3 dose-escalation design followed by cohort expansion in relapsed/refractory T-ALL/LBL. Patients received one infusion of WU-CART-007 after standard or enhanced lymphodepleting chemotherapy. The primary objectives, to characterize safety and assess the composite complete remission rate, were met. Of 26 patients enrolled, 13 received the recommended phase 2 dose (RP2D) of 900 million cells of WU-CART-007 with enhanced lymphodepletion. The most common treatment-related adverse event was cytokine release syndrome (88.5%; 19.2% grade 3-4). Biochemical abnormalities consistent with grade 2 hemophagocytic lymphohistiocytosis were seen in one patient (3.8%). Grade 1 immune effector cell-associated neurotoxicity syndrome events (7.7%) and one grade 2 acute graft-vs-host disease event occurred. Grade 5 events (11.5%) were due to fungal infection and multi-organ failure. The composite complete remission rate was 81.8% among 11/13 patients evaluable for response at the RP2D. WU-CART-007 at the RP2D demonstrated a high response rate in patients with relapsed/refractory T-ALL/LBL and has the potential to provide a new treatment option. ClinicalTrials.gov registration: NCT04984356., Competing Interests: Additional Declarations: Yes there is potential Competing Interest. Financial: Armin Ghobadi: Honorarium from Kite, a Gilead company; consultancy provided for Amgen, Atara, Bristol Myers Squibb, CRISPR therapeutics, Kite, Novartis, and Wugen; research funding from Amgen, Genentech, and Kite. Ibrahim Aldoss: Ad Board and consultant fees from Wugen, Amgen, KITE, Abbvie, Takeda; Research support: MacroGenics, Abbvie Shannon L. Maude: Clinical trial support from Novartis and Wugen; advisory and study steering committees for Novartis and Wugen; patent pending and licensed to Novartis Pharmaceuticals without royalty for PCT/US2017/044425: Combination Therapies of Car and PD-1 Inhibitors. Bhagirathbhai Dholaria: Institutional research funding, no direct payment: Janssen, Angiocrine, Pfizer, Poseida, MEI, Orcabio, Wugen, Allovir, NCI, Atara, Gilead, Molecular templates, BMS, AstraZeneca, Adicet. Consultation/Advisory board: Janssen, Pluri Biotech, BOXER CAPITAL, Ellipsis pharma, Lumanity, Autolus, Acrotech, ADC therapeutics, Gilead, Global health research, GSK, Roche Rawan Faramand: Advisory Board: Kite/Gilead; Autolus; Consultancy: Sanofi;Research Funding: Kite/Gilead; Novartis Andre Baruchel: Servier: symposia, travels; Jazz: advisory boards; Amgen: symposia; Servier: funding for academic clinical research protocol; Astra Zeneca: advisory board paid to institution Nicolas Boissel: Consultant for Novartis, Amgen, Bristol Myers Squibb, and Jazz Pharmaceuticals; and receives honoraria from Novartis, Amgen, Incyte, Servier, Bristol Myers Squibb, Jazz Pharmaceuticals, Celgene, Sanofi, and Pfizer. Brent Wood: Dr. Wood’s institution receives funding for contract laboratory testing from a number of biopharma companies including two that have products whose efficacy is being evaluated in T-ALL. However, there is no interaction between the services provided for each company. Dr. Wood also is a paid consultant on MRD testing for clinical trials for Amgen, but does not involve products for T-ALL. Haley Irons: Employment in Wugen Ben Capoccia: Employment in Wugen Deborah Masters: Employment and shares in Wugen Justo Gonzalez: Wugen employment Tony Wu: Employment and shares in Wugen Maria del Rosario: Employment and shares in Wugen Alexander Hamil: Employment and shares in Wugen Ouiam Bakkacha: Employment and shares in Wugen, MacroGenics stock John Muth: Employment and shares in Wugen Brett Ramsey: Employment and shares in Wugen Eileen McNulty: Employment and shares in Wugen Matthew L. Cooper: Equity, ownership, employment in Wugen Jan Baughman: Consultant to Wugen; MacroGenics stock Jan Davidson-Moncada: Employment and shares in Wugen John F. DiPersio: Consulting: Rivervest, Bluebird Bio, Vertex, HcBiosciences, SPARC; Equity-ownership WUGEN and Magenta; Research support: MacroGenics, Bioline, Incyte. Support: NCI R35 CA210084, Leukemia and Lymphoma Society SCOR Non-Financial: Armin Ghobadi: Wugen founders include members of Washington University physicians that are colleagues of Dr. Ghobadi. Ryan J. Mattison:Vice chair of the Acute Lymphoblastic Leukemia committee for the National Comprehensive Cancer Netork (NCCN) C. Michel Zwaan: Chair of Hem-iSMART study for T-cell ALL with support from Abbvie and Novartis

Acute lymphoblastic leukaemia (ALL) is a haematological malignancy characterized by the uncontrolled proliferation of immature lymphoid cells. Over past decades, significant progress has been made in understanding the biology of ALL, resulting in remarkable improvements in its diagnosis, treatment and monitoring. Since the advent of chemotherapy, ALL has been the platform to test for innovative approaches applicable to cancer in general. For example, the advent of omics medicine has led to a deeper understanding of the molecular and genetic features that underpin ALL. Innovations in genomic profiling techniques have identified specific genetic alterations and mutations that drive ALL, inspiring new therapies. Targeted agents, such as tyrosine kinase inhibitors and immunotherapies, have shown promising results in subgroups of patients while minimizing adverse effects. Furthermore, the development of chimeric antigen receptor T cell therapy represents a breakthrough in ALL treatment, resulting in remarkable responses and potential long-term remissions. Advances are not limited to treatment modalities alone. Measurable residual disease monitoring and ex vivo drug response profiling screening have provided earlier detection of disease relapse and identification of exceptional responders, enabling clinicians to adjust treatment strategies for individual patients. Decades of supportive and prophylactic care have improved the management of treatment-related complications, enhancing the quality of life for patients with ALL., (© 2024. 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.)

Abstract: Working groups of the European LeukemiaNet have published several important consensus guidelines. Acute lymphoblastic leukemia (ALL) has many different clinical and biological subgroups and the knowledge on disease biology and therapeutic options is increasing exponentially. The European Working Group for Adult ALL has therefore summarized the current state of the art and provided comprehensive consensus recommendations for diagnostic approaches, biologic and clinical characterization, prognostic factors, and risk stratification as well as definitions of endpoints and outcomes. Aspects of treatment, management of subgroups and specific situations, aftercare, and supportive care are covered in a separate publication. The present recommendation intends to provide guidance for the initial management of adult patients with ALL and to define principles as a basis for future collaborative research., (© 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.)

Abstract: Experts from the European Leukemia Net (ELN) working group for adult acute lymphoblastic leukemia have identified an unmet need for guidance regarding management of adult acute lymphoblastic leukemia (ALL) from diagnosis to aftercare. The group has previously summarized their recommendations regarding diagnostic approaches, prognostic factors, and assessment of ALL. The current recommendation summarizes clinical management. It covers treatment approaches, including the use of new immunotherapies, application of minimal residual disease for treatment decisions, management of specific subgroups, and challenging treatment situations as well as late effects and supportive care. The recommendation provides guidance for physicians caring for adult patients with ALL which has to be complemented by regional expertise preferably provided by national academic study groups., (© 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.)