bims-hemali 2026-10-18 papers

bims-hemali

Biomed News

on Hematologic malignancies

Issue of 2026–10–18
twenty-two papers selected by
Alexandros Alexandropoulos, Γενικό Νοσοκομείο Αθηνών Λαϊκό

T cells targeting immunoglobulin in myeloma: a way forward?
Venetoclax combined with olverembatinib and prednisone as a frontline therapeutic strategy for Philadelphia chromosome-positive mixed-phenotype acute leukemia.
IFM 2026 Recommendations for First-line Treatment of Newly Diagnosed Multiple Myeloma.
Tyrosine kinase inhibitor use and risk of neurodegenerative disease: A Swedish population-based cohort study.
Targeting the eIF4F translation initiation complex disrupts BCR::ABL1 translation and overcomes drug resistance in CML.
Ponatinib-Blinatumomab or Imatinib-Chemotherapy for Adult Ph-Positive ALL.
Rocbrutinib: First Approval.
Efficacy of Sorafenib Combined with Venetoclax and Azacitidine in Newly Diagnosed FLT3-ITD-Mutant Acute Myeloid Leukemia: Remission Efficacy and Prognostic Influence of Post-Remission Consolidation Therapy.
Molecular Consequences and Targeting of PPM1D Overexpression in Myeloproliferative Neoplasms.
VERIFY: A Phase III Trial of Rusfertide Versus Placebo in Phlebotomy-Dependent Patients With Polycythemia Vera Receiving Standard-of-Care Therapy.
When is 4 Gy enough? Defining dose sufficiency and durable control in indolent B-cell lymphoma.
Flow MRD pre-blinatumomab consolidation, despite subsequent clearance, is associated with inferior survival in Ph+ B-ALL.
Clinical characteristics and outcome of a cohort of CLL patients with BTK T474 gatekeeper mutation.
Supportive Care in Multiple Myeloma: Evidence-Based Recommendations From the Intergroupe Francophone du Myélome (IFM).
Rethinking threats to human survival.
Understanding and clinical approach to early T-cell precursor acute lymphoblastic leukemia.
Teclistamab for ultrahigh-risk multiple myeloma with isolated central nervous system relapse.
CD3-engaging bispecific antibodies convert human regulatory T cells into cytotoxic effectors.
Editorial expression of concern: Hyper-activation of Aurora kinase a-pololike kinase 1-FOXM1 axis promotes chronic myeloid leukemia resistance to tyrosine kinase inhibitors.
Beyond the binding site: PROTAC-mediated protein degradation assists the therapeutic paradigm of hematological malignancies.
Chemotherapy-free Treatment of Ph-Positive ALL.
Combination therapy with nelarabine, pegaspargase, and venetoclax for adult patients with R/R T-cell ALL/LBL.

Blood. 2026 Oct 15. 148(16): 1950-1952

T cells targeting immunoglobulin in myeloma: a way forward?

David E Avigan.

DOI: https://doi.org/10.1182/blood.2026033711
Blood Res. 2026 Oct 13. pii: 65. [Epub ahead of print]61(1):

Venetoclax combined with olverembatinib and prednisone as a frontline therapeutic strategy for Philadelphia chromosome-positive mixed-phenotype acute leukemia.

Xia Li, Yile Zhou, Xiangjie Lin, Hongyan Tong, Jie Jin, Huafeng Wang.

Mixed-phenotype acute leukemia (MPAL) is a rare hematological malignancy with poor prognosis, for which there are currently no standardized therapeutic guidelines. Preclinical and clinical studies have shown that venetoclax and BCR::ABL1 tyrosine kinase inhibitors have synergistic effects on Philadelphia chromosome-positive (Ph +) leukemias. We retrospectively analyzed five patients with de novo Ph + MPAL who received venetoclax, olverembatinib, and prednisone (VOP) therapy. All patients achieved complete remission after the initial induction therapy and tested negative for measurable residual disease. During consolidation therapy, two patients developed severe myelosuppression and died of respiratory failure due to pulmonary infections. The remaining three patients underwent allogeneic hematopoietic stem cell transplantation and maintained durable complete molecular remission. These findings suggest that the VOP regimen may be effective in patients with Ph + MPAL. However, they also underscore the need to optimize venetoclax dosing during consolidation to reduce the risk of life-threatening myelosuppression and infectious complications.

DOI: https://doi.org/10.1007/s44313-026-00180-z
Clin Lymphoma Myeloma Leuk. 2026 Sep 09. pii: S2152-2650(26)03288-X. [Epub ahead of print]

IFM 2026 Recommendations for First-line Treatment of Newly Diagnosed Multiple Myeloma.

Intergroupe Francophone du Myélome (IFM)

  The treatment landscape of newly diagnosed multiple myeloma (NDMM) has changed considerably over the past 5 years. Anti-CD38-VRd quadruplets are now the standard of care for transplant-eligible patients and an important option for transplant-ineligible patients. This review presents unified, evidence-based first-line treatment recommendations from the Intergroupe Francophone du Myélome (IFM), covering transplant-eligible and transplant-ineligible NDMM within a single framework and common methodology. In transplant-eligible patients, daratumumab-VRd and isatuximab-VRd, informed respectively by the PERSEUS and GMMG-HD7 trials, are now the reference induction regimens, followed by autologous stem cell transplantation, optional consolidation, and daratumumab-lenalidomide maintenance. In transplant-ineligible patients, daratumumab-lenalidomide-dexamethasone (DRd), informed by the MAIA trial, remains the treatment backbone: in fit patients, adding bortezomib (isatuximab-VRd or daratumumab-VRd, informed by IMROZ, CEPHEUS, and BENEFIT) could further improve outcomes, while frail patients receive the same backbone without dexamethasone (DR), informed by IFM2017-03. Mathematical modeling projects a median progression-free survival of approximately 205 months with daratumumab-VRd in transplant-eligible patients (PERSEUS model) and approximately 100 months in transplant-ineligible/transplant-deferred patients (CEPHEUS model), approaching for the first time a normal life expectancy for a substantial subset of patients and supporting the emerging concept of functional cure. We discuss the role of measurable residual disease and NGS-based high-risk myeloma definition across both populations, and position these recommendations relative to the 2025 EHA-EMN evidence-based guidelines. Finally, we summarize ongoing trials investigating T-cell-redirecting immunotherapies (CAR-T cells and bispecific antibodies) as replacements for, or additions to, ASCT and maintenance therapy, which may further reshape the first-line treatment paradigm in the coming years.

Keywords:  Functional Cure; MRD; Quadruplet; Transplant

DOI:  https://doi.org/10.1016/j.clml.2026.09.002
Alzheimers Dement. 2026 Oct;22(10): e71916

Tyrosine kinase inhibitor use and risk of neurodegenerative disease: A Swedish population-based cohort study.

Felix Wittström, Enoch Yi-Tung Chen, Iris Blotenberg, Torsten Dahlén.

   INTRODUCTION: Effective disease-modifying therapies remain unavailable for neurodegenerative diseases (NDDs). Tyrosine kinase inhibitors (TKIs) indicated for chronic myeloid leukemia (CML) have been hypothesized to modulate the pathological mechanisms underlying neurodegeneration. Therefore, we aimed to explore the association between initiation of six different TKIs and the subsequent risk of developing NDDs in Swedish nationwide registries (2005-2024).
METHODS: CML patients ≥50 years at diagnosis initiating TKI therapy were identified, alongside five comparators without CML matched on sex, age, and residence at diagnosis. CML cases and comparators were followed from the initiation date of the respective TKI and could contribute follow-up time to multiple TKI cohorts. A composite measure of NDD diagnosis or death due to NDD was the outcome. Hazard ratios (HRs) were estimated using Cox proportional hazards models, with adjustments for calendar year at follow-up initiation, and relevant comorbidities.
RESULTS: A total of 1322 CML cases were included in the study. 1188 initiated imatinib (of which 41 experienced an NDD event), 541 dasatinib (15 events), 390 nilotinib (five events), 174 bosutinib, 71 ponatinib, and 41 asciminib. Adjusted hazard ratios comparing each TKI group to their matched comparator populations were 0.98 (95% confidence interval [CI], 0.71 to 1.36) for imatinib users, 1.18 (95% CI, 0.68 to 2.03) for dasatinib users, and 0.37 (95% CI, 0.15 to 0.90) for nilotinib users. Bosutinib, ponatinib, and asciminib users were too few to conduct comparative analyses.
DISCUSSION: Initiation of nilotinib, but not imatinib or dasatinib, was associated with a significantly lower NDD incidence relative to general population comparators.

Keywords:  chronic myeloid leukemia; cohort study; neurodegenerative disease; pharmacoepidemiology; tyrosine kinase inhibitors

DOI:  https://doi.org/10.1002/alz.71916
Leukemia. 2026 Oct 16.

Targeting the eIF4F translation initiation complex disrupts BCR::ABL1 translation and overcomes drug resistance in CML.

Ryan Yen, Andrew Wu, Min Chen, Lambert Yue, Michael M Lizardo, Christopher S Hughes, Josephine Leung, Yingying Liu, Donna L Forrest, Poul H Sorensen, Steven Pelech, Xiaoyan Jiang.

Chronic myeloid leukemia (CML) is driven by the constitutively active BCR::ABL1 kinase, which promotes uncontrolled cell proliferation. Although protein-tyrosine kinase inhibitors (TKIs) have revolutionized CML treatment, resistance remains a significant barrier to curative therapy, particularly due to BCR::ABL1 mutations and the persistence of leukemia stem cells (LSCs). New treatment strategies that directly inhibit BCR::ABL1 protein expression are needed to achieve more effective therapy. Using a high-content antibody microarray and bioinformatics analyses, we investigated differences in the proteome and phosphorylation landscape of Imatinib (IM)-resistant cells and identified highly activated members of the eukaryotic translation initiation complex (eIF4F), particularly eIF4G1, a core component of eIF4F. These eIF4F complex members are highly expressed and activated in CD34+ CML stem/progenitor cells and in IM-resistant cells. Genetic inhibition of eIF4G1 or pharmacological targeting with the small-molecule inhibitor SBI-756 diminished eIF4F complex assembly, reduced overall translation initiation, reduced BCR::ABL1 expression and key downstream targets, impaired the survival of nonresponder stem/progenitor cells, including BCR::ABL1-T315I mutant cells, and sensitized them to TKIs, with strong synergistic effects in vitro and in a PDX model. These findings underscore the potential of eIF4F complex inhibition as a new therapeutic strategy to overcome TKI resistance in CML and other BCR::ABL1+ malignancies.

DOI: https://doi.org/10.1038/s41375-026-03157-0
N Engl J Med. 2026 Oct 15. 395(15): 1483-1494

Ponatinib-Blinatumomab or Imatinib-Chemotherapy for Adult Ph-Positive ALL.

GIMEMA Investigators

BACKGROUND: The outcome of Philadelphia-positive acute lymphoblastic leukemia (Ph-positive ALL) has greatly improved with the use of tyrosine kinase inhibitors and immunotherapy.
METHODS: In this trial, we randomly assigned adult patients with Ph-positive ALL in a 2:1 ratio to receive ponatinib plus blinatumomab (intervention group) or imatinib plus chemotherapy (control group) as frontline treatment. A crossover to the intervention group was allowed for patients with persistence or reappearance of measurable residual disease in the control group. The primary end point was event-free survival.
RESULTS: A total of 236 patients underwent randomization: 158 to the intervention group and 78 to the control group. The median age of the patients was 55 years (range, 24 to 82). At a median follow-up of 23.7 months, the estimated 24-month event-free survival was 86% in the intervention group and 67% in the control group (P<0.001). Survival with no measurable residual disease was 68% and 42%, respectively. At the end of induction, a complete hematologic response was observed in 94% of the patients in the intervention group and in 79% of those in the control group. After blinatumomab consolidation, a molecular response was observed in 71% and 49% of the patients, respectively. After crossover to the intervention group, 20 of 31 patients (64%) had a molecular response. Overall survival was 90% in the intervention group and 85% in the control group. The cumulative incidence of relapse was 5% and 13%, respectively. As of this report, only 19% of the patients in the intervention group had undergone hematopoietic stem-cell transplantation after having had a first complete hematologic response.
CONCLUSIONS: In this phase 3 trial, a frontline chemotherapy-free targeted and immunotherapeutic approach was superior to the use of imatinib and chemotherapy. (Funded by Associazione Italiana per la Ricerca sul Cancro and others; GIMEMA ALL2820 ClinicalTrials.gov number, NCT04722848.).

DOI: https://doi.org/10.1056/NEJMoa2606208
Drugs. 2026 Oct 15.

Rocbrutinib: First Approval.

Simon Fung.

Rocbrutinib (; LP-168) is a fourth generation Bruton's tyrosine kinase (BTK) inhibitor with both covalent and non-covalent modes of binding, which allow it to inhibit both wildtype as well as mutant variants of BTK. It is being developed by Lupeng Pharmaceuticals primarily as a treatment for patients with B-cell malignancies. Rocbrutinib received its first approval in June 2026 in China for use in adult patients with mantle cell lymphoma (MCL) that is relapsed or refractory to BTK inhibitors, and who have received ≥ 2 systemic therapies (including BTK inhibitors). This article summarizes the milestones in the development of rocbrutinib leading to its first approval in this indication.

DOI: https://doi.org/10.1007/s40265-026-02393-z
J Clin Med. 2026 Sep 29. pii: 7576. [Epub ahead of print]15(19):

Efficacy of Sorafenib Combined with Venetoclax and Azacitidine in Newly Diagnosed FLT3-ITD-Mutant Acute Myeloid Leukemia: Remission Efficacy and Prognostic Influence of Post-Remission Consolidation Therapy.

Qi Chen, Wenbing Duan, Jinsong Jia, Jing Wang, Xiaosu Zhao, Guorui Ruan, Hongxia Shi, Yingjun Chang, Xiaojun Huang, Hao Jiang.

  Background: Mutations of the FLT3 gene, particularly internal tandem duplication (FLT3-ITD), define a biologically aggressive AML subtype with historically poor outcomes. Here we retrospectively assessed the clinical performance and tolerability of sorafenib with venetoclax plus azacitidine (VA) as front-line therapy in patients with newly diagnosed FLT3-ITD-mutated AML. Methods: Forty-five consecutive patients who received sorafenib plus VA induction were retrospectively analyzed. Post-remission therapy comprised sorafenib-based chemotherapy consolidation, continued sorafenib-VA, or allogeneic hematopoietic stem cell transplantation (allo-HSCT) after consolidation therapy according to clinical indication and guidelines. Composite complete remission (CRc), measurable residual disease (MRD), overall survival (OS), and relapse-free survival (RFS) were assessed. Results: The CR/CRi rate was 95.6% (43/45), and the FCM-MRD negativity rate after induction was 90.7%. At a median follow-up of 20.3 months, the 2-year OS and RFS of the entire cohort were 65.3% and 57.3%, respectively. The relapse rate in the patients receiving post-remission allo-HSCT after consolidation therapy was lower. Continued sorafenib-VA achieved a 2-year OS of 57.1% and a 2-year RFS of 64%. Multivariable analysis identified chemotherapy-based post-remission therapy (p = 0.016) and detectable MRD after the second consolidation cycle (p = 0.004) as independent adverse prognostic factors for RFS. No treatment-related mortality occurred. Conclusions: Sorafenib plus VA is a cost-effective, tolerable induction regimen achieving high remission and MRD negativity rates in FLT3-ITD-mutant AML. For transplant-eligible patients, allo-HSCT significantly improves long-term survival; for transplant-ineligible patients, continued sorafenib-VA yields sustained benefit.

Keywords:  FLT3-ITD; acute myeloid leukemia; sorafenib; venetoclax and azacitidine

DOI:  https://doi.org/10.3390/jcm15197576
Blood. 2026 Oct 13. pii: blood.2025030377. [Epub ahead of print]

Molecular Consequences and Targeting of PPM1D Overexpression in Myeloproliferative Neoplasms.

Md Babu Mia, Christoph Schaniel, Cara Clementelli, Sarah Elisabeth Haines, Malgorzata Olszewska, JoAnn Arandela, Sebastian Elghaity-Beckley, Sophie Klingborg, Zinedine Hoque, Ayman Mohammad, Shwetha Hara Sridhar, Brianna Kelly, Xiaoli Wang, Emmanuel Olivier, Alan H Shih, Blake T Langlais, Allison Cote, Noushin Farnoud, Raajit K Rampal, Duke Butterfield, Amylou C Dueck, Min Lu, Kristin G Beaumont, Robert Sebra, John O Mascarenhas, Eirini P Papapetrou, Ronald Hoffman, Bridget K Marcellino.

Phosphatase Mg2+/Mn2+ dependent 1D protein (PPM1D) is a serine threonine phosphatase known to regulate oncogenic pathways. PPM1D mutations are enriched in therapy-related MDS and AML, but the role of PPM1D in myeloproliferative neoplasms (MPN) remains largely unexplored. By sequencing 519 MPN patients, we detected activating PPM1D mutations in 3.1% of them. Importantly, PPM1D was overexpressed in hematopoietic stem and progenitor cells (HSPCs) in most PPM1D wild-type (WT) MPN cases. To elucidate the impact of PPM1D mutations on MPN HSPCs, we generated isogenic JAK2V617F+/PPM1D-WT and JAK2V617F+/PPM1D mutant (MUT) induced pluripotent stem cell (iPSC) lines from a MPN patient. Single-cell RNA-sequencing (scRNA-seq) of iPSC derived HSPCs revealed altered TP53, DNA damage response and cell cycle regulation. scRNA-seq analysis of primary PPM1D-MUT MPN patient mononuclear cells (MNCs) further confirmed upregulation of MYC, mTORC1, OXPHOS, JAK/STAT, and NF-κB pathways and corresponding genes in HSCs. The allosteric PPM1D inhibitor (PPM1Di) GSK2830371 preferentially inhibited colony formation in myelofibrosis (MF) samples. Combination treatment of GSK2830371 with low dose inhibition of HDM2, a negative regulator of p53, significantly improved targeting of JAK2V617F+ HSPCs, while sparing normal HSPCs. Single-cell mutational and protein analysis of a clonally complex MF patient sample treated with this combination strategy revealed reduced mutated clones and increased WT clones by >4-fold. Dual PPM1D and HDM2 targeting also significantly decreased leukemic burden in a xenograft MPN model. These findings support PPM1D as a critical MPN HSPCs regulator and support dual PPM1D/HDM2 inhibition as a treatment strategy for MF patients.

DOI: https://doi.org/10.1182/blood.2025030377
J Clin Oncol. 2026 Oct 13. JCO2600992

VERIFY: A Phase III Trial of Rusfertide Versus Placebo in Phlebotomy-Dependent Patients With Polycythemia Vera Receiving Standard-of-Care Therapy.

VERIFY Investigators

PURPOSE: Polycythemia vera (PV) is a myeloproliferative neoplasm characterized by erythrocytosis. Rusfertide is a subcutaneous, injectable, hepcidin mimetic peptide that suppresses erythrocytosis. The phase III VERIFY trial evaluated the efficacy and safety of rusfertide in phlebotomy-dependent patients with PV and poorly controlled hematocrit.
METHODS: In VERIFY Part 1a (32 weeks), patients requiring frequent phlebotomy were randomly assigned (1:1, double-blind) to receive rusfertide or placebo with or without cytoreductive therapy. The primary efficacy end point was clinical response (absence of phlebotomy eligibility; weeks 20-32). Key secondary end points (baseline to week 32) included mean number of phlebotomies, proportion of patients who maintained hematocrit <45%, and mean change from baseline in patient-reported outcomes (Patient-Reported Outcomes Measurement Information System [PROMIS] Fatigue Short Form 8a [SF-8a] T score and Myelofibrosis Symptom Assessment Form [MFSAF] Total Symptom Score-7 items [TSS7]).
RESULTS: Patients (N = 293) were randomly assigned to rusfertide (n = 147) or placebo (n = 146). Significantly more patients (n = 113, 77%) achieved a clinical response with rusfertide versus placebo (n = 48; 33%; P < .0001). Compared with placebo, rusfertide reduced mean ± standard deviation number of phlebotomies (0.5 ± 1.2 v 1.8 ± 1.5; P < .0001) and was superior in maintaining hematocrit <45% (n = 92 [63%] v n = 21 [14%]; P < .0001). Rusfertide led to a significant improvement in the PROMIS Fatigue SF-8a T-score and MFSAF TSS7 versus placebo (P = .0252 and .0240, respectively). Injection site reactions, anemia, and fatigue were the most common adverse events. No deaths were reported.
CONCLUSION: Rusfertide significantly improved hematocrit control, reduced the need for phlebotomy, and improved patient-reported symptoms versus placebo in phlebotomy-dependent patients with PV who were also receiving standard-of-care therapy.

DOI: https://doi.org/10.1200/JCO-26-00992
Crit Rev Oncol Hematol. 2026 Oct 14. pii: S1040-8428(26)00536-6. [Epub ahead of print]228 105649

When is 4 Gy enough? Defining dose sufficiency and durable control in indolent B-cell lymphoma.

Yun Yang, Hong Zhu, Jun Liu, Bichun Xu, Bing Xiu, Meihua Wang, Judong Luo.

  Ultra-low-dose radiotherapy, most commonly delivered as 4 Gy in two fractions (2 Gy × 2), is an established low-burden approach for radiosensitive indolent B-cell lymphoma. Its use as stand-alone definitive local therapy is constrained by a persistent gap between early tumor regression and durable local control. This review examines when 4 Gy should be considered sufficient by integrating clinical intent, lesion biology, response assessment, immune context, and emerging biomarkers. We distinguish its use as stand-alone local treatment, palliation, response-adapted de-escalation, and immune-integrated strategies. Across these settings, early response indicates radiosensitivity but does not prove lesion sterilization or equivalence to standard-dose radiotherapy. Dose sufficiency depends on durable in-field control, tumor burden, anatomical definition, reassessment reliability, feasibility of salvage, and the consequences of local failure. Immune and cellular combinations may extend the value of 4 Gy beyond local cytoreduction, but the contribution of irradiation should be tested separately from systemic or intratumoral partners. PET response, MRD, ctDNA, and immune correlates may help distinguish transient cytoreduction from durable clearance and local response from patient-level disease control. At present, these biomarkers are better suited to trial design and mechanistic validation than to routine dose selection. Future studies should move beyond response rates and define decision rules that link early response, immune modulation, biomarker dynamics, lesion-level durability, salvageability, and cumulative treatment burden.

Keywords:  4 Gy radiotherapy; Dose sufficiency; Immune integration; Indolent B-cell lymphoma; Response-adapted radiotherapy; Ultra-low-dose radiotherapy

DOI:  https://doi.org/10.1016/j.critrevonc.2026.105649
Blood Adv. 2026 Oct 15. pii: bloodadvances.2026020724. [Epub ahead of print]

Flow MRD pre-blinatumomab consolidation, despite subsequent clearance, is associated with inferior survival in Ph+ B-ALL.

Benjamin F Frost, Yannis K Valtis, Yael Flamand, Emilie W Baxter, Shai Shimony, Jacqueline S Garcia, Martha Wadleigh, Eric S Winer, Virgina O Volpe, Maximilian Stahl, Richard M Stone, Daniel J DeAngelo, Christopher B Hergott, David Nemirovsky, Andriy Derkach, Kuo-Kai Chin, Meira Yisraeli Salman, Leora Boussi, Natalia Tijaro Ovalle, Eytan M Stein, Mark B Geyer, Yanming Zhang, Andrew M Brunner, Hanno Hock, Amir T Fathi, Rupa Narayan, Jae H Park, Marlise R Luskin, Evan C Chen.

Although adults with Philadelphia chromosome-positive (Ph+) B-cell acute lymphoblastic leukemia (B-ALL) may achieve a measurable residual disease-negative (MRD-) complete response (CR) after frontline treatment and blinatumomab (blina) consolidation, survival outcomes are heterogeneous, and known prognostic factors are limited. We conducted a retrospective, multicenter study of 81 adults with Ph+ B-ALL in MRD- (<10-4) CR1 after blina consolidation and stratified them by pre-blina MRD status as determined by multiparametric flow cytometry (flow). Patients who were pre-blina flow MRD- (n = 56) and flow MRD+ (n = 25) had similar baseline characteristics. With a median follow-up of 31.0 months, pre-blina flow MRD- patients had superior disease-free (DFS) and overall survival (OS) on univariate (p = 0.049 and p = 0.045, respectively) and multivariable analyses (HR 0.27, 95% CI 0.08-0.87 and HR 0.17, 95% CI 0.03-0.90, respectively) relative to pre-blina flow MRD+ patients. Inferior DFS was seen with the IKZF1-plus genotype (HR 3.51, 95% CI 1.08-11.44) and extramedullary disease at diagnosis (HR 3.90, 95% CI 1.19-12.73). In exploratory analyses, pre-blina flow MRD+ status remained associated with inferior DFS (p = 0.0005) and OS (p < 0.0001) for patients who did not receive a subsequent hematopoietic cell transplant (HCT) in CR1, but not in patients who did (p = 0.55 and p = 0.99, respectively). In summary, flow MRD+ status before blina consolidation was associated with inferior survival in patients with Ph+ B-ALL in CR1 despite subsequent clearance, and consolidative HCT may reduce this prognostic effect.

DOI: https://doi.org/10.1182/bloodadvances.2026020724
Blood Adv. 2026 Oct 16. pii: bloodadvances.2025019251. [Epub ahead of print]

Clinical characteristics and outcome of a cohort of CLL patients with BTK T474 gatekeeper mutation.

Zulfa Omer, Kerry A Rogers, Max Yano, Jayesh Rai, Joyce Chen, Jennifer A Woyach, Seema A Bhat, Daniel Jones, Michael Rhodes Grever, Erin Hertlein, Sara Elgamal, John C Byrd.

BTK T474 gatekeeper mutations confer resistance to both commercially approved covalent and non-covalent BTK inhibitors (BTKis) in chronic lymphocytic leukemia (CLL), yet their clinical implications remain poorly characterized. While pirtobrutinib was developed to overcome resistance mediated by BTK C481 mutations, its use has been increasingly associated with the emergence of BTK T474, which is associated with resistance to this and commercially available BTKis. We retrospectively analyzed 17 relapsed/refractory CLL patients from two academic centers who acquired BTK T474 mutations on BTKi therapy, integrating paired next-generation sequencing (NGS), cytogenetics, and clinical outcomes. Results showed that this was a heavily pretreated, high-risk cohort; 42% had del(17p) and/or TP53 mutations. T474I was the most common substitution (82%). At first T474 detection, patients were receiving ibrutinib (6/17), acalabrutinib (5/17), pirtobrutinib (5/17), or nemtabrutinib (1/17); median time on the current BTKi at time of mutation detection was 28 months (range, 4-69). Concurrent BTK C481 mutations were present in 14/17 (82%). Median T474 VAF at progression was 13%, and all patients progressed after T474 detection with a median time to progression of 4 months. Non-BTK mutations were frequent (82%), most commonly TP53 and SF3B1. After progression, venetoclax-based therapy produced the longest median progression-free survival (18 months). Median overall survival was 44 months from first documentation of T474 mutation (95% CI, 20-62) and PFS after T474 detection was 6 months. This analysis showed that BTK T474 emergence identifies a high-risk CLL population with rapid progression after detection, underscoring the need for effective post-BTKi strategies.

DOI: https://doi.org/10.1182/bloodadvances.2025019251
Clin Lymphoma Myeloma Leuk. 2026 Sep 14. pii: S2152-2650(26)03294-5. [Epub ahead of print]

Supportive Care in Multiple Myeloma: Evidence-Based Recommendations From the Intergroupe Francophone du Myélome (IFM).

IFM Supportive Care Working Group

  Multiple myeloma (MM) is a largely incurable plasma cell malignancy in which disease- and treatment-related complications substantially impair quality of life and survival, making supportive care a central determinant of outcome. This review presents unified, evidence-based recommendations from the Intergroupe Francophone du Myélome across 7 domains of supportive care and their implications for contemporary practice, including the era of T-cell-redirecting immunotherapy. With the advent of highly effective induction regimens, autologous stem cell transplantation, immunomodulatory drugs, proteasome inhibitors, anti-CD38 monoclonal antibodies, bispecific antibodies (BsAbs), and chimeric antigen receptor T-cell (CAR-T) therapies, the prevention and management of treatment-emergent toxicities and disease-related sequelae have become increasingly complex. Synthesizing a structured review of the literature, international guidelines, and formal expert consensus, we provide practical recommendations for (1) venous thromboembolism prophylaxis, (2) prevention of skeletal-related events with bone-modifying agents, (3) prevention of infectious complications, (4) vaccination, (5) management of MM-related anemia with erythropoiesis-stimulating agents, (6) adapted physical activity, and (7) practical guidance for the management of treatment-emergent peripheral neuropathy, with particular attention to the specific challenges introduced by BsAbs and CAR-T therapy. By consolidating these 7 domains into a single framework applicable across all lines of therapy, from first-line treatment to relapsed/refractory disease, this review offers a pragmatic reference intended to standardize and improve supportive care and, ultimately, patient outcomes and health-related quality of life in MM. Positions that deliberately differ from other international guidelines-notably those of the International Myeloma Working Group-are explicitly identified and justified.

Keywords:  Adapted physical activity; Bone disease; Infection prevention; Thromboprophylaxis; Vaccination

DOI:  https://doi.org/10.1016/j.clml.2026.09.008
Lancet. 2026 Oct 17. pii: S0140-6736(26)01958-6. [Epub ahead of print]408(10564): 1525

Rethinking threats to human survival.

The Lancet.

DOI: https://doi.org/10.1016/S0140-6736(26)01958-6
Blood Res. 2026 Oct 12. pii: 64. [Epub ahead of print]61(1):

Understanding and clinical approach to early T-cell precursor acute lymphoblastic leukemia.

Hee Young Ju.

  Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) is a distinct biological subtype of T-cell acute lymphoblastic leukemia (T-ALL) that was first described in 2009 based on a gene expression profile resembling that of early T-cell precursors in the thymus. ETP-ALL is characterized by an immature immunophenotype featuring positivity for CD7 and cytoplasmic CD3, with co-expression of myeloid/stem cell markers, and absence of CD1a, CD8, with weak or absent CD5 expression. ETP-ALL accounts for 5.5%-17.1% of pediatric and 15.8%-47.3% of adult T-ALL cases. Early studies identified ETP-ALL as a high-risk entity associated with induction failure and poor outcomes. However, subsequent prospective clinical trials demonstrated that outcomes with contemporary intensive chemotherapy were not significantly inferior to those of non-ETP T-ALL, challenging its designation as a uniformly high-risk disease. Recent large-scale genomic studies have identified molecularly defined subtypes that supersede immunophenotypic classifications, including ETP-like, BCL11B-rearranged, and SPI1-rearranged subtypes, with markedly different prognostic implications. Minimal residual disease (MRD) response remains the most robust prognostic indicator for guiding treatment intensification. Allogeneic hematopoietic stem cell transplantation (HSCT) is recommended for patients with persistent MRD positivity after consolidation. For relapsed/refractory disease, novel agents, including daratumumab, venetoclax, and bortezomib, have demonstrated promising activity, with allogeneic HSCT in the second complete remission remaining the treatment goal. This review provides an overview of the definitions, genomic classifications, clinical outcomes, and evolving treatment approaches for ETP-ALL.

Keywords:  Allogeneic HSCT; Daratumumab; ETP-ALL; Early T-cell precursor; Genomic classification; Immunophenotype; MRD; T-cell acute lymphoblastic leukemia; Venetoclax

DOI:  https://doi.org/10.1007/s44313-026-00181-y
Arch Med Sci. 2026 ;22(4): 2518-2521

Teclistamab for ultrahigh-risk multiple myeloma with isolated central nervous system relapse.

Huan Xie, Ran Luo, Dongfeng Zeng.

DOI: https://doi.org/10.5114/aoms/230992
medRxiv. 2026 Sep 29. pii: 2026.09.23.26363285. [Epub ahead of print]

CD3-engaging bispecific antibodies convert human regulatory T cells into cytotoxic effectors.

Julius J Michel, Jan H Frenking, Anna D Metzler, Antonia Schach, Erin W Meermeier, Vera Thiel, Niklas Kehl, Tim R Wagner, Julian Zoller, Sven Cuntz, Cornelius Funk, René Onken, Alanna Kirschner, Stefanie Huhn, Alexander Brobeil, Andreas Trumpp, Mohammad Rahbari, Mathias Heikenwälder, Carsten Müller-Tidow, P Leif Bergsagel, Hartmut Goldschmidt, Hermann Einsele, Leo Rasche, Marta Chesi, Marc S Raab, Niels Weinhold, Mirco J Friedrich.

Bispecific T cell engagers (BTCEs) have transformed the treatment of B cell malignancies, but how they remodel non-conventional T cell circuits in patients, and how they should be ideally combined with existing treatment backbones, remains unclear. Here we show that CD3-engaging BTCEs convert human FOXP3⁺ regulatory T cells (Tregs) into an AP-1-imprinted hybrid cytotoxic state that contributes to tumor clearance. Leveraging longitudinal bone marrow and peripheral blood sampling from patients with newly diagnosed multiple myeloma (NDMM) treated with BTCE-based induction in the phase 2 (GMMG-HD10/DSMM-XX/MajesTEC-5) trial, which achieves uniformly deep, minimal residual disease (MRD)-negative remissions, we integrate single-cell RNA, ATAC and TCR sequencing with functional and metabolic profiling to define the underlying mechanism. BTCE-containing induction drives expansion of cytotoxic CD8⁺ clones and the emergence of a Treg population characterized by GZMA, GNLY and NKG7 expression, enriched cytotoxic gene signatures, and licensed by BATF-AP-1-centered chromatin remodeling. In vitro , BTCE-exposed Tregs acquire bona fide lytic function, killing tumor cells in a target- and dose-dependent manner and undergoing metabolic rewiring towards an effector-like state while retaining canonical Treg lineage markers. Immunomodulatory drugs (IMiDs) do not initiate but quantitatively amplify and qualitatively reshape this BTCE-driven cytotoxic program, providing a mechanistic rationale for BTCE-IMiD combination regimens. Cytotoxic Treg reprogramming is conserved across BTCEs targeting BCMA, GPRC5D, and CD19 and across multiple myeloma, as well as acute lymphoblastic leukemia. These findings reveal unexpected plasticity of human Tregs under synthetic T cell engagement and establish cytotoxic Tregs as active effectors, candidate biomarkers and tractable levers for optimizing T cell-redirecting immunotherapy.
Highlights: Frontline teclistamab (BCMA×CD3) induces deep MRD-negative remissions in newly diagnosed multiple myeloma patients and reshapes the T cell compartment in the phase 2 MajesTEC-5 trial. BTCEs convert FOXP3⁺ Tregs into AP-1-imprinted cytotoxic effector cells in vivo . IMiDs amplify BTCE-driven cytotoxic Treg reprogramming without loss of identity.Cytotoxic reprogramming of Tregs is observed across BTCEs and blood cancers.

DOI: https://doi.org/10.64898/2026.09.23.26363285
J Exp Clin Cancer Res. 2026 10 12. pii: 214. [Epub ahead of print]45(1):

Editorial expression of concern: Hyper-activation of Aurora kinase a-pololike kinase 1-FOXM1 axis promotes chronic myeloid leukemia resistance to tyrosine kinase inhibitors.

M Mancini, S De Santis, C Monaldi, L Bavaro, M Martelli, F Castagnetti, G Gugliotta, G Rosti, M A Santucci, G Martinelli, M Cavo, S Soverini.

DOI: https://doi.org/10.1186/s13046-026-03848-7
Leuk Res. 2026 Oct 08. pii: S0145-2126(26)00180-3. [Epub ahead of print]170 108336

Beyond the binding site: PROTAC-mediated protein degradation assists the therapeutic paradigm of hematological malignancies.

Mahsa Fatahichegeni, Mohammad Amin Ansarian, Yuqi Wang, Tongxin Zhang, Ruimin Liu, Juan Ren, Xiaoning Wang.

  Hematological malignancies represent a growing global health burden, with conventional therapies limited by systemic toxicity and resistance mechanisms. Proteolysis-targeting chimeras (PROTACs) are heterobifunctional molecules that hijack cellular degradation machinery to eliminate, rather than merely inhibit, target proteins, enabling engagement of previously undruggable oncogenic drivers. This review synthesizes PROTAC applications across acute myeloid leukemia, lymphoid malignancies, and multiple myeloma, addressing targets including BRD4, FLT3, BCL-XL, BTK, and epigenetic regulators. Clinical advancement has been notable, with Bruton tyrosine kinase (BTK) degraders achieving response rates exceeding 75% in heavily pretreated patients and progressing to Phase 3 trials, while cereblon-targeting degraders in multiple myeloma represent the most clinically mature application. Mechanistically, PROTACs offer catalytic, substoichiometric activity, elimination of non-catalytic protein functions, and retention of efficacy against certain resistance mutations. Significant challenges persist, however, including poor drug-like properties, limited oral bioavailability, complex ternary-complex optimization, and degrader-specific resistance mechanisms such as E3 ligase loss or impaired proteasomal capacity, necessitating expanded biomarker surveillance frameworks. Emerging innovations, including degrader-antibody conjugates, novel E3 ligase recruiters, and artificial intelligence-driven design, aim to address these limitations. Integration with precision medicine and rational combination strategies positions targeted protein degradation as a potentially transformative approach for addressing longstanding unmet needs in blood cancer therapy, although substantial translational hurdles remain.

Keywords:  BTK degrader; Hematological malignancies; PROTAC; Protein degradation; Targeted therapy

DOI:  https://doi.org/10.1016/j.leukres.2026.108336
N Engl J Med. 2026 Oct 15. 395(15): 1542-1544

Chemotherapy-free Treatment of Ph-Positive ALL.

Adele K Fielding.

DOI: https://doi.org/10.1056/NEJMe2610489
Blood Neoplasia. 2026 Nov;3(4): 100300

Combination therapy with nelarabine, pegaspargase, and venetoclax for adult patients with R/R T-cell ALL/LBL.

Niranjan Khaire, Elias Jabbour, Tapan Kadia, Nicholas Short, Gautam Borthakur, Naveen Pemmaraju, Naval Daver, Abhishek Maiti, Partow Kebriaei, Shilpa Paul, Rebecca Garris, Farhad Ravandi, Hagop Kantarjian, Nitin Jain.

DOI: https://doi.org/10.1016/j.bneo.2026.100300