bims-hemali 2026-02-15 papers

bims-hemali

Biomed News

on Hematologic malignancies

Issue of 2026–02–15
25 papers selected by
Alexandros Alexandropoulos, Γενικό Νοσοκομείο Αθηνών Λαϊκό

Intrinsic cellular resistance to BCR::ABL1 inhibitors.
Follicular lymphoma transformed to classic Hodgkin lymphoma.
A Randomized Phase 2 Study of Ipilimumab, Nivolumab, and Brentuximab Vedotin in Patients with Relapsed Hodgkin Lymphoma.
Penpulimab combined with rituximab, high-dose methotrexate, and cytarabine (Pen-RMA) in newly diagnosed primary central nervous system lymphoma (PCNSL): a phase 2 trial.
MMF unlocks a new path to venetoclax sensitivity in AML.
Efficacy and safety of 50 mg versus 100 mg daily frontline dasatinib therapy in chronic-phase chronic myeloid leukemia: a non-controlled, observational dose-comparative cohort study.
Are CHOP-Plus Really CHOP-Minus Propositions in the Treatment of PTCL? A Comprehensive Assessment of the Strategy.
EZH2 inhibition overcomes immunomodulatory drug resistance in multiple myeloma via a cereblon-dependent pathway.
An old but still good friend: chemoimmunotherapy in HCL.
Tolerability and Outcomes With Serial Cycles of 28 Days of Venetoclax in Newly Diagnosed Patients With Acute Myeloid Leukemia.
First-line Therapy in Newly Diagnosed Multiple Myeloma.
Differential Expression of CD79B, CD19, and PD-L1 in de Novo and Transformed CD20-Negative Large B-Cell Lymphomas.
New Approaches for Measurable Residual Disease Assessment in Multiple Myeloma: Integrating NGS, Mass Spectrometry, and Next-Generation Flow Cytometry to Monitor Treatment Response.
Advances in the pathophysiology and treatment of anaemia in multiple myeloma.
Pivekimab Sunirine in Blastic Plasmacytoid Dendritic Cell Neoplasm.
MRD-2 in the GHSG HD21 trial assessed by a validated circulating tumor DNA sequencing assay.
Differential Prognosis and Transplant Strategies in CBF-AML With RUNX1::RUNX1T1 Versus CBFβ::MYH11 Fusions.
CD138-targeted bispecific protein engager-armed T cells exhibit potent and selective cytotoxicity against multiple myeloma cells.
Obinutuzumab Maintenance in Follicular Lymphoma Is Associated With Better Progression Free Survival and Comparable Toxicity.
Second- and Third-Generation BCR-ABL Tyrosine Kinase Inhibitors and the Risk of Pulmonary Arterial Hypertension: A Prevalent New-User Design.
Targeting PRKCN, an Essential Driver Orchestrating mTOR-IRF4 Axis Independently of Kinase Activity, in Multiple Myeloma.
Tracking MAPK-Dependent CD38 Upregulation by All-Trans Retinoic Acid in Human Leukemia Using 89Zr Immuno-PET.
ASH 2026 Guidelines for Management of Relapsed/Refractory Disease in Adolescents and Young Adults with ALL.
Involvement of Btk in Cardiovascular Disease and Its Therapeutic Targeting.
Conventional Therapy vs HMA or LDAC ± Venetoclax in Older Adults With AML: Systematic Review and Meta-analysis.

Haematologica. 2026 Feb 12.

Intrinsic cellular resistance to BCR::ABL1 inhibitors.

Nataly Cruz-Rodriguez, Yulieth Torres-Llanos, Michael W Deininger.

The clinical implementation of BCR::ABL1 tyrosine kinase inhibitors (TKIs) for the treatment of chronic myeloid leukemia (CML) represents one of the big successes of mechanism-based cancer therapy. In 2025, survival of patients who start TKI therapy while in the chronic phase is approaching that of age-matched controls. Despite this paradigm shift, significant challenges remain. Some patients still develop overt TKI resistance and progress to bast phase, and the majority continue to harbor residual leukemia and require life-long TKI therapy. Growth and survival signals arising from the microenvironment or from within the leukemia cells confer various degrees of resistance to support a spectrum of leukemic activity ranging from overt acute leukemia in blast phase to persistence of minimal residual disease in patients with a deep molecular response. Here we review cell-intrinsic resistance, covering both reactivation of BCR::ABL1 kinase activity and the less welldefined mechanisms underlying BCR::ABL1-independent TKI resistance. We propose that the pathways used by CML to escape TKI effects reflect the potential and the constraints of BCR::ABL1- driven reprogramming of hematopoietic stem and progenitor cells and that the role of BCR::ABL1 functions other than kinase activity may be underappreciated, providing a rationale for the clinical development of BCR::ABL1 degraders.

DOI: https://doi.org/10.3324/haematol.2025.287814
Blood. 2026 Feb 12. 147(7): 800

Follicular lymphoma transformed to classic Hodgkin lymphoma.

Leonard Nsoyori Yenwongfai, Ivo M B Francischetti.

DOI: https://doi.org/10.1182/blood.2025031906
Blood. 2026 Feb 09. pii: blood.2025029546. [Epub ahead of print]

A Randomized Phase 2 Study of Ipilimumab, Nivolumab, and Brentuximab Vedotin in Patients with Relapsed Hodgkin Lymphoma.

Catherine Diefenbach, Opeyemi Jegede, Victoria Wang, Stephen M Ansell, Lale Kostakoglu, Christian Steidl, Yasodha Natkunam, David W Scott, Richard F Ambinder, Kevin A David, Ranjana H Advani, Nancy L Bartlett, Michael J Robertson, Sachdev P Thomas, Jonathon B Cohen, Sami Ibrahimi, Gaurav Goyal, Neha Mehta-Shah, Jennifer Effie Amengual, Christopher Jon Forlenza, Peter D Cole, Fenghai Duan, Kara M Kelly, Brad S Kahl.

The Phase 1/2 Intergroup study E4412 (NCT01896999; ClinicalTrials.gov) investigated checkpoint blockade with nivolumab (Nivo) and ipilimumab (Ipi) in relapsed/refractory (R/R) classic Hodgkin lymphoma (HL) while concurrently targeting CD30+ Hodgkin Reed Sternberg cells with the antibody-drug conjugate brentuximab vedotin (BV). 147 patients ≥12 years were randomized between BV/Nivo and BV/Ipi/Nivo; 132 patients are included in primary efficacy analysis. The primary endpoint, complete response (CR) rate, was 64.7% (52.2, 75.9) for BV/Nivo and 70.3% (57.6, 81.1) for BV/Ipi/Nivo (one-sided p=0.29). The median survival follow-up is 38.0 months (interquartile range 32.6-48.1). Progression-free survival (PFS) did not significantly differ between the two arms (HR=0.78, CI 0.39-1.57, one-sided p=0.24). Treatment-related grade 3+ toxicities in the adult cohort, excluding rash, was similar between both arms (38.5% BV/Nivo and 39.3% BV/Ipi/Nivo); there was higher frequency of grade 3 rash with BV/Ipi/Nivo (24.6%) compared to BV/Nivo (9.2%). We compared PFS by stem cell transplantation (SCT) status in a planned post-hoc comparison; 58 patients received SCT; 36-month PFS (from SCT) was greater than 90% for both arms. Sixty-six patients were alive and progression free after the first scan (disease evaluation) and did not undergo SCT. The 36-month PFS (from first scan) was 73.0% (54.5, 85.0) for BV/Ipi/Nivo compared to 45.8% (26.3, 63.4) for BV/Nivo (HR=0.45, CI 0.19-1.08, one-sided p=0.03). The study did not meet its primary endpoint of superior CR rate for the triplet, but it supports the use of checkpoint-ADC induction prior to auto SCT, and there is an intriguing signal of disease control for patients wishing to defer or avoid SCT for the triplet of BV/Ipi/Nivo.

DOI: https://doi.org/10.1182/blood.2025029546
Blood Cancer J. 2026 Feb 11.

Penpulimab combined with rituximab, high-dose methotrexate, and cytarabine (Pen-RMA) in newly diagnosed primary central nervous system lymphoma (PCNSL): a phase 2 trial.

Hao-Rui Shen, Jia-Zhu Wu, Hua Yin, Kai-Xin Du, Luthuli Sibusiso, Yi-Fan Wu, Wei Hua, Yue Li, Yi-Lin Kong, Xin-Yu Zhang, Rui Gao, Jian-Yong Li, Li Wang, Jin-Hua Liang, Wei Xu.

This clinical trial (NCT05347641) evaluated efficacy and safety of penpulimab combined with rituximab, high-dose methotrexate, and cytarabine (Pen-RMA) in patients with newly diagnosed (ND) primary central nervous system lymphoma (PCNSL). Patients received an induction treatment of six cycles of Pen-RMA every 3 weeks. Patients younger than 60 years who achieved at least partial remission (PR) underwent autologous stem cell transplantation (ASCT), followed by 8 cycles of penpulimab as maintenance therapy. For patients over 60 years or not eligible for ASCT who achieved complete remission (CR) after induction therapy received 8 cycles of penpulimab as maintenance treatment, and those who achieved PR were treated with whole brain radiotherapy (WBRT) combined with 8 cycles of penpulimab. Patients who achieved stable disease (SD) or progressive disease (PD) were withdrawn from this study. The primary endpoint was 2-year progression-free survival (PFS). Between April 2022 and December 2023, twenty-six ND-PCNSL patients were enrolled, and 23 patients were included in the intention-to-treat analysis. The median age was 65 (38‒74) yr. The overall response rate (ORR) and CR rate after the induction therapy were 95.7% and 91.3%, respectively. At a median follow-up of 29.4 months, the median PFS and overall survival (OS) were not reached. 2-year PFS and OS were 70.7% and 75.0%, respectively. The most frequent treatment-related adverse events were leukopenia, anemia, neutropenia, and thrombocytopenia. Grade 3 or worse treatment-related adverse events occurred in 7 (30.4%) of 23 patients. Cerebrospinal fluid (CSF) circulating-tumor DNA (ctDNA) monitoring was performed in 13 patients with imaging CR and 1 with PR after induction treatment. Among them, 8 had CSF ctDNA clearance while 6 were positive. Overall, Pen-RMA regimen demonstrated encouraging antitumor activity with a manageable toxicity in PCNSL.

DOI: https://doi.org/10.1038/s41408-026-01450-w
Blood. 2026 Feb 12. 147(7): 708-709

MMF unlocks a new path to venetoclax sensitivity in AML.

Daisuke Nakada.

DOI: https://doi.org/10.1182/blood.2025032116
BMC Cancer. 2026 Feb 11.

Efficacy and safety of 50 mg versus 100 mg daily frontline dasatinib therapy in chronic-phase chronic myeloid leukemia: a non-controlled, observational dose-comparative cohort study.

Fang Cheng, Fan Wang, Zheng Cui, Qiang Li, Yu Zhu, Weiming Li.



Keywords:  Chromic myeloid leukemia; Dasatinib; Low-dose; Pleural effusions; Standard-dose

DOI:  https://doi.org/10.1186/s12885-026-15719-7
Blood Adv. 2026 Feb 11. pii: bloodadvances.2025018042. [Epub ahead of print]

Are CHOP-Plus Really CHOP-Minus Propositions in the Treatment of PTCL? A Comprehensive Assessment of the Strategy.

Nazaneen Saleh, Owen A O'Connor.

Peripheral T-cell lymphomas (PTCLs) are a rare, heterogeneous subset of non-Hodgkin lymphomas (NHL) that are biologically and clinically distinct from B-cell lymphomas. They are typically resistant to chemotherapy and associated with poor outcomes compared to most B-cell malignancies. Despite this, CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or CHOP-like regimens remain the standard frontline therapy-even though pivotal studies establishing CHOP in NHL included only B-cell patients, with no evidence for PTCL. For decades, efforts to improve outcomes have focused on "CHOP-plus" strategies, adding novel agents to the backbone. Outside of anaplastic large cell lymphoma (ALCL), where brentuximab vedotin has improved survival, this approach has generally failed; in most PTCL subtypes, 5-drug regimens add toxicity without clear benefit. After two decades of disappointing results, this review critically examines the evidence, the limitations of current strategies, and opportunities to rethink future approaches.

DOI: https://doi.org/10.1182/bloodadvances.2025018042
Haematologica. 2026 Feb 12.

EZH2 inhibition overcomes immunomodulatory drug resistance in multiple myeloma via a cereblon-dependent pathway.

Yigen Li, Amy Wilson, Yakinthi Chrisochoidou, Shannon Martin, Sarah Bird, Salomon Morales, Marc Leiro, Zuza Kozik, Nicholas T Crump, Theodoros I Roumeliotis, Jyoti Choudhary, Charlotte Pawlyn.

Immunomodulatory agents (IMiDs) and the next-generation Cereblon (CRBN) E3 ligase modulators (CELMoDs), targeting the IKZF1/IKZF3-IRF4-MYC axis, are effective therapies for multiple myeloma (MM) across all stages of disease. Resistance to treatment can be acquired following exposure, but a subset of patients have primary resistance, with both states necessitating the development of alternative treatment strategies. Enhancer of zeste homolog 2 (EZH2) has been shown to have increased expression at myeloma relapse and higher expression is associated with a shorter progression free survival from diagnosis. EZH2 inhibitors have been studied as a single agent in myeloma and in combination treatments to overcome drug resistance in other malignancies. In this study KMS-11 and RPMI-8226 myeloma cell lines are used as models of primary IMID resistance, demonstrating persistent Interferon regulatory factor 4 (IRF4) expression after IMiDs/CELMoDs exposure without loss of cell viability. The combination of Tazemetostat, an FDA-approved EZH2 inhibitor, with IMiDs/CELMoDs significantly reduces IRF4 expression, induces apoptosis, and leads to synergistic cell death in these resistant cell lines. Further investigations reveal that the synergistic effect of EZH2 inhibition appears specific to IMiDs/CELMoDs, is CRBN-dependent and rescued by IRF4 overexpression. Mechanistically, Tazemetostat appears to reduce IKZF1 binding to the IRF4 promoter and super-enhancer, explaining how the combination with IMiDs/CELMoDs which also have this effect may reach the threshold required to suppress IRF4 expression and ultimately inhibit MM cell growth in resistant cell lines. Our findings highlight a potential strategy for treating MM patients with IMiD resistance.

DOI: https://doi.org/10.3324/haematol.2025.288024
Blood. 2026 Feb 12. 147(7): 705-707

An old but still good friend: chemoimmunotherapy in HCL.

Enrico Tiacci, Alessandro Mancini.

DOI: https://doi.org/10.1182/blood.2025031748
Am J Hematol. 2026 Feb 13.

Tolerability and Outcomes With Serial Cycles of 28 Days of Venetoclax in Newly Diagnosed Patients With Acute Myeloid Leukemia.

Michael K Jones, Jesse Sanchez, Megan Connor, Katherine Julian, Rebecca Rezac, Kelsey Marciano, Jennifer Tobin, Grace Bosma, Diana Abbott, Katelyn Anttila, Connor Sohalski, Ayele Belachew, Christine McMahon, Andrew Kent, Maria Amaya, Mathew G Angelos, Marc Schwartz, Jonathan A Gutman, Daniel A Pollyea.

The standard of care for newly-diagnosed unfit patients with acute myeloid leukemia (AML) is venetoclax (VEN) with azacitidine (AZA). In the phase 3 trial, before remission, AZA was given with 28 days of VEN. This regimen is myelosuppressive; therefore, many decrease VEN duration before and/or after initial response assessment. We report our center's outcomes administering 28 days of VEN preremission, and in most cases, postremission, relying on other strategies to reduce cytopenias. All newly-diagnosed patients with AML treated outside of a clinical trial with VEN/AZA for > 7 days at our center from 2018 to 2024 were reviewed. 134 patients met inclusion criteria; median age was 70 years (interquartile range [IQR] 64-76), 57% male, and 63% had European LeukemiaNet adverse risk AML (85/134). Overall response rate (including complete remission and complete remission with incomplete hematologic recovery) was 87/134 (64.9%). Median cycles completed was 2 (IQR 1-3, range 0-26), with 117 (87%) completing ≥ 1 cycle with a response assessment. Median duration of cycles 1-5 was 42 days. Median overall survival was 381 days. Prior to response assessment, 113/117 (96.6%) received 28 days of VEN. Postresponse, 17/81 (21.0%) had a VEN reduction (in duration or dose). Grade ≥ 3 neutropenia or thrombocytopenia was higher in cycle 1 than in similar studies, without differences in transfusion needs or infectious complications. Hematologic toxicities improved with subsequent cycles. Serial cycles with 28 days of VEN can be administered pre- and postremission with higher early myelosuppression but similar transfusion and infection rates compared to studies of reduced VEN duration.

DOI: https://doi.org/10.1002/ajh.70231
Blood Cancer Discov. 2026 Feb 09. OF1-OF17

First-line Therapy in Newly Diagnosed Multiple Myeloma.

Kevin C Miller, Saad Z Usmani.

First-line multiple myeloma treatment has evolved from melphalan-prednisone to quadruplet regimens incorporating proteasome inhibitors, immunomodulatory drugs, anti-CD38 monoclonal antibodies, and autologous stem cell transplantation, yielding significantly improved survival. This review summarizes current approaches to risk stratification and therapy for newly diagnosed multiple myeloma and highlights the emerging role of measurable residual disease-adaptive strategies. We also discuss recent efforts to integrate chimeric antigen receptor T cells and bispecific antibodies into up-front treatment. As biology-driven strategies advance, select patients may achieve durable treatment-free remissions. Ongoing studies will clarify how to best tailor therapy while balancing efficacy, toxicity, and survivorship toward functional cures.
SIGNIFICANCE: Despite unprecedented advances, multiple myeloma therapy remains largely uniform and emphasizes indefinite treatment. Herein, although summarizing current standard-of-care therapy, we advocate for individualized approaches informed by disease biology, treatment response, and emerging biomarkers. Novel strategies incorporating immunotherapies are paving the way toward treatment-free remissions and functional cures in select patients.

DOI: https://doi.org/10.1158/2643-3230.BCD-25-0384
Hematol Oncol. 2026 Mar;44(2): e70173

Differential Expression of CD79B, CD19, and PD-L1 in de Novo and Transformed CD20-Negative Large B-Cell Lymphomas.

Yuto Kaimi, Yuka Takahashi, Mai Takeuchi, Tetsuro Ochi, Shinichi Makita, Noriko Iwaki, Suguru Fukuhara, Wataru Munakata, Koji Izutsu, Yasushi Yatabe, Akiko Miyagi Maeshima.

  CD20-negative large B-cell lymphomas exhibit aggressive behavior and are ineligible for rituximab-containing therapy. To identify antigens targeted by treatment, we analyzed CD79B and CD19 expression in 108 samples from 75 patients with CD20-negative large B-cell lymphomas using H-score. Diffuse-strong (H-score 300) CD79B and CD19 expression was observed in 51% and 57% of samples, and low/negative (H-score ≤ 100) in 35% and 30%, respectively. CD79B expression was significantly lower in de novo CD20-negative diffuse large B-cell lymphoma (DLBCL) than in CD20-negative DLBCL changed from CD20-positive DLBCL after rituximab-containing therapy and in CD20-negative DLBCL transformed from CD20-positive low-grade B-cell lymphoma after rituximab-containing therapy (H-score ≤ 100 in 79% vs. 27% vs. 10%, p < 0.001). CD19 expression was lower in de novo CD20-negative DLBCL than in transformed DLBCL (H-score ≤ 100 in 43% vs. 3%, p = 0.006). Of 12 patients with plasmablastic lymphoma, CD79B and CD19 were negative in 83% and 66% of cases, respectively. Among 46 CD20-negative large B-cell lymphomas with low CD79B and/or CD19 expression, the tumor proportion score for programmed death-ligand 1 was positive (≥ 1%) in 33% of cases. The combined positive score for programmed death-ligand 1 was positive in 52% of programmed death-ligand 1 tumor proportion score-negative samples. In conclusion, CD79B and CD19 were variably expressed in CD20-negative large B-cell lymphomas, but lower in de novo DLBCL, and especially in plasmablastic lymphoma. Programmed cell death protein 1/programmed death-ligand one inhibitors may represent a treatment option.

Keywords:  CD19; CD79B; PD‐L1; diffuse large B‐cell lymphoma; plasmablastic lymphoma

DOI:  https://doi.org/10.1002/hon.70173
Curr Hematol Malig Rep. 2026 Feb 14. 21(1): 4

New Approaches for Measurable Residual Disease Assessment in Multiple Myeloma: Integrating NGS, Mass Spectrometry, and Next-Generation Flow Cytometry to Monitor Treatment Response.

Bhavesh Mohan Lal, Shaji K Kumar.

   PURPOSE OF REVIEW: Measurable residual disease (MRD) has emerged as the strongest prognostic biomarker in multiple myeloma (MM), providing a deeper assessment of treatment response than conventional serological tests. Sensitive MRD detection is helpful in risk stratification, prognostication, and early relapse prediction and is increasingly being used as an important clinical trial endpoint in MM. Moreover, MRD has emerged as a useful tool in guiding treatment intensity and duration.
RECENT FINDINGS: MRD can be assessed using bone marrow-based, peripheral blood-based, or imaging-based techniques. Bone marrow-based next-generation flow cytometry and next-generation sequencing, with a minimum sensitivity of 10- 5, remain the current standard for MRD testing in MM. However, limitations like the need for frequent bone marrow aspirations and false negative results in patchy marrow involvement or isolated extramedullary disease have accelerated the interest in peripheral blood-based MRD tools. Mass spectrometry-based approaches, including intact protein mass spectrometry (MALDI-TOF assays like 'MASS-FIX' and 'EXENT') and clonotypic peptide mass spectrometry (such as 'EasyM' and 'M-Insight'), have evolved as highly sensitive peripheral blood-based MRD detection tools for relatively non-invasive dynamic MRD monitoring. Newer technologies like droplet digital PCR, circulating tumor cell analysis using enriched flow cytometry, cell-free DNA sequencing, and emerging epigenetic and fragmentomic profiling are in various phases of research and have the potential to revolutionize the way we monitor and treat MM. Finally, numerous active clinical trials worldwide are exploring the role of MRD in guiding treatment and are expected to shed light on the optimal approach to MRD assessments in routine clinical practice.

Keywords:  Mass spectrometry; Measurable residual disease; Multiple myeloma; Next-generation flow cytometry; Next-generation sequencing

DOI:  https://doi.org/10.1007/s11899-026-00771-8
Curr Opin Hematol. 2026 Feb 11.

Advances in the pathophysiology and treatment of anaemia in multiple myeloma.

Nicola Giuliani, Benedetta Dalla Palma, Laura Notarfranchi.

   PURPOSE OF REVIEW: Anaemia is a common sign in multiple myeloma due to multifactorial mechanisms. Apart from the well known factors related to the disease, more recently, the use of several new drugs as the immunotherapeutic ones indicates the emerging role of drug-related mechanisms in the pathophysiology of anaemia in multiple myeloma patients.
RECENT FINDINGS: Anaemia associated with immunomodulatory drugs may result from both direct effect on hematopoietic progenitor cells and indirect one mediated by cytokine modulation within the bone marrow microenvironment. The CD38 expression by erythroid lineage cells, suggests that anti-CD38 antibodies may induce apoptosis or functional inhibition of these progenitors, leading to reductions in erythropoiesis. Recent clinical trials also reported ad high incidence of anaemia in multiple myeloma patients treated either with bispecific antibodies or CAR-T cells.Treatment of anaemia in multiple myeloma patients included the use of red blood cell transfusion and erythropoietin-stimulating agents but recently novel agents were under investigation as the activin receptor fusion proteins.
SUMMARY: The use of the new immunotherapeutic drugs in multiple myeloma patients is associated with an increased incidence of anaemia that should be considered by clinicians particularly in the management of those patients in which coexist other anaemia-related factors.

Keywords:  anaemia; erythropoietin; immunotherapy; multiple myeloma; sotatercept

DOI:  https://doi.org/10.1097/MOH.0000000000000911
J Clin Oncol. 2026 Feb 11. JCO2502083

Pivekimab Sunirine in Blastic Plasmacytoid Dendritic Cell Neoplasm.

Naveen Pemmaraju, Giovanni Marconi, Pau Montesinos, Andrew A Lane, Luca Mazzarella, David A Sallman, Matthew L Ulrickson, Gary J Schiller, Harry P Erba, Eunice S Wang, Roland B Walter, Eric Deconinck, Ahmed Aribi, Ollivier Legrand, Delphine Lebon, Valerio Maisano, Giovanni Martinelli, Daniel J DeAngelo, Enrico Derenzini, Yining Du, Sribalaji Lakshmikanthan, Jalaja Potluri, Hagop M Kantarjian, Naval G Daver.

PURPOSE: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a unique myeloid malignancy with CD123 interleukin-3 receptor-α overexpression and poor prognosis.
METHODS: This phase I/II, open-label, multicenter study evaluated pivekimab sunirine (PVEK), a novel CD123 antibody-drug conjugate, 0.045 mg/kg once every 3 weeks, in adults with frontline (no previous systemic therapy and de novo BPDCN or coexisting hematologic malignancy) or relapsed/refractory BPDCN (ClinicalTrials.gov identifier: NCT03386513) The primary end point in the primary analysis population (PAP; frontline de novo) was composite complete response (CCR; CR+ clinical CR) rate.
RESULTS: Of 84 patients, 33 had frontline BPDCN (22 de novo [20 in PAP]; 11 with previous or concomitant malignancy) and 51 had relapsed/refractory disease. The median (range) age was 72 (63-76) years. In the PAP (n = 20), the CCR rate was 75% (95% CI, 51 to 91; n = 15; median duration: 10.6 [95% CI, 3.8 to not reached] months) and the median overall survival (OS) was 16.6 (95% CI, 7.2 to not reached) months. Eight of these 15 (53%) patients proceeded to stem-cell transplant (SCT). The corresponding rate for relapsed/refractory disease was 14% (95% CI, 6 to 26; n = 7; median duration: 9.2 [95% CI, 2.4 to not reached] months), and the median OS was 5.8 (95% CI, 3.9 to 8.4) months. Adverse events (AEs) included peripheral edema (54%), fatigue (26%), and infusion-related reactions (26%). Grade ≥3 events included neutropenia (16%), thrombocytopenia (14%), and peripheral edema (12%). Serious AEs included pneumonia (6%) and febrile neutropenia (5%). Two on-treatment cases of reversible veno-occlusive disease (VOD) occurred. Of the total 19 patients who proceeded to SCT, VOD was reported in five patients (four with relapsed/refractory BPDCN).
CONCLUSION: PVEK, with convenient dosing, led to high, durable responses, especially in frontline BPDCN, and a manageable safety profile.

DOI: https://doi.org/10.1200/JCO-25-02083
Blood. 2026 Feb 09. pii: blood.2025031089. [Epub ahead of print]

MRD-2 in the GHSG HD21 trial assessed by a validated circulating tumor DNA sequencing assay.

Jan-Michel Heger, Julia Mattlener, Helen Kaul, Justin Ferdinandus, Jessica Schneider, Julia K Schleifenbaum, Gundolf Schneider, Valdete Schaub, Mathias Haenel, Johannes Christian Hellmuth, Judith Dierlamm, Sonja Martin, Stephan Mathas, Julia Meissner, D Michiel Pegtel, Josée M Zijlstra, Anna Ossowski, Kerstin Becker, Michael J Hallek, Bastian von Tresckow, Peter Borchmann, Sven Borchmann.

Beyond cure, major goals in patients with Hodgkin lymphoma (HL) are tailoring treatment to a patient's individual risk for relapse to reduce acute and late toxicities, identifying candidates for early incorporation of novel agents, and making treatment affordable on a global level. Minimal residual disease (MRD) assessment by circulating tumor (ct)DNA sequencing emerged as a promising strategy to achieve these goals; however, previous studies differed in sampling timepoints, assay validation, and definitions for MRD negativity. Here, we applied LymphoVista - a validated ctDNA sequencing assay for genotyping and MRD monitoring in lymphoma - to samples obtained from the GHSG HD21 trial following two cycles of treatment (MRD-2) using a case-cohort-design. Patients with positive MRD-2 were at higher risk for relapse, progression or death compared with MRD-2 negative patients (4-year progression-free survival (PFS): 36.7% vs. 82.2%; HR 5.3, 95%CI 2.0-13.8; p = 0.0008). Following inverse probability weighting accounting for the number of events in the full reference set, patients with positive and negative MRD-2 had 4-year PFS rates of 72.2% vs. 95.3%. By combining MRD-2 with PET-2, patients were stratified into three distinct groups regarding risk of relapse: low (MRD-2 negative and PET-2 negative), intermediate (MRD-2 positive or PET-2 positive), and high (MRD-2 positive and PET-2 positive). In summary, these results suggest that assessment of MRD-2 by LymphoVista allows for early outcome prognostication in patients with HL and could be used as a tool to improve treatment guidance on its own or in conjunction with PET-2.

DOI: https://doi.org/10.1182/blood.2025031089
Am J Hematol. 2026 Feb 14.

Differential Prognosis and Transplant Strategies in CBF-AML With RUNX1::RUNX1T1 Versus CBFβ::MYH11 Fusions.

Jingtao Huang, Huihong Huang, Yunxiang Zhang, Yi Xia, Yuqing Tu, Hao Xu, Yeqian Zhao, Jiayu Huang, Han Yan, Zengkai Pan, Chuanhe Jiang, Luxiang Wang, Zilu Zhang, Xiangqin Weng, YongMei Zhu, Yanmin Zhao, Yang Cao, Jia Chen, Xiaodong Mo, Xiaoxia Hu.

  Core binding factor acute myeloid leukemia (CBF-AML) is defined by t(8;21) or inv. (16), which give rise to the RUNX1::RUNX1T1 and CBFβ::MYH11 fusion genes, respectively. CBF-AML is a favorable-risk AML subtype, yet differences in mutation profiles, measurable residual disease (MRD) response, and relapse risk may warrant tailored treatment approaches. We reviewed adult AML patients treated at five transplant centers across China and identified 825 de novo CBF-AML cases, of which 779 met our eligibility criteria: 536 harbored the RUNX1::RUNX1T1 fusion and 243 the CBFβ::MYH11 fusion. The 3-year overall survival (OS) was 80.6% for RUNX1::RUNX1T1 and 90.2% for CBFβ::MYH11 cases (p = 0.011). Among patients with RUNX1::RUNX1T1, those achieving MRD negativity after two consolidation cycles (PC2) had significantly better OS than nonresponders (86.3% vs. 76.5%, p = 0.008); no difference was observed for CBFβ::MYH11 patients. For RUNX1::RUNX1T1 nonresponders, allogeneic hematopoietic cell transplantation (allo-HCT) in first complete remission (CR1) reduced relapse (CR1-HCT vs. non-CR1-HCT, 8.3% vs. 18.9%; p = 0.024) and improved OS (CR1-HCT vs. non-CR1-HCT vs. chemotherapy, 85.8% vs. 71.4% vs. 64.9%; p < 0.001). In CBFβ::MYH11 patients, deferring allo-HCT until second complete remission (CR2) was associated with comparable outcomes. In RUNX1::RUNX1T1 patients, older age, elevated initial white blood cell count, lower hemoglobin, lower initial fusion transcript load, and the presence of FLT3-ITD or KIT D816/D822 mutations were associated with an increased likelihood of PC2 nonresponse. Based on these variables, we developed a weighted scoring system with good discrimination to identify RUNX1::RUNX1T1 patients at high risk of PC2 nonresponse.

Keywords:  allogeneic hematopoietic cell transplantation; core binding factor acute myeloid leukemia; measurable residual disease

DOI:  https://doi.org/10.1002/ajh.70237
Int Immunopharmacol. 2026 Feb 12. pii: S1567-5769(26)00138-4. [Epub ahead of print]174 116295

CD138-targeted bispecific protein engager-armed T cells exhibit potent and selective cytotoxicity against multiple myeloma cells.

Pucharee Songprakhon, Piriya Luangwattananun, Kornkan Choomee, Nunghathai Sawasdee, Chalermchai Somboonpatarakun, Thaweesak Chieochansin, Sanya Sukpanichnant, Mutita Junking, Seiji Okada, Pa-Thai Yenchitsomanus.

  Multiple myeloma (MM) is a hematologic malignancy that remains incurable, with most patients eventually relapsing or developing resistance to available therapies. Bispecific T cell engagers (BiTEs) have shown promise by redirecting T cells to target and kill tumor cells; however, their clinical application is hindered by a short in vivo half-life, the need for high dosing, and treatment-related toxicities. To address these limitations, bispecific protein engager-armed T cells (BATs) have been developed as a novel cell-based immunotherapy platform that enhances antigen specificity and in vivo persistence. In this study, we evaluated the antitumor efficacy of BATs targeting CD138, a heparan sulfate proteoglycan highly expressed on MM cells and associated with disease progression. BATs were generated by arming T cells with an anti-CD138 × anti-CD3 bispecific protein engager (BiPE), and their antitumor activity was assessed through counting bead technique and flow cytometry. CD138-specific BATs exhibited potent cytotoxicity against CD138-positive MM.1R cells, achieving up to 89.62 ± 2.22% cell lysis after 48 h of co-culture, significantly surpassing the activity of unarmed T cells (33.04 ± 6.57% lysis). Additionally, BATs induced robust expression of interleukin-2 (IL-2) cytokine and cytolytic mediators, including perforin, granzyme A/B, soluble Fas ligand (sFasL), and TNF-α, indicating effective antigen-specific activation. Importantly, pro-inflammatory cytokines such as IL-6, IL-10, and IFN-γ remained at low levels, suggesting a favorable safety profile. These findings support the therapeutic potential of CD138-targeted BATs as a promising and potentially safer cellular immunotherapy for the treatment of MM.

Keywords:  Bispecific protein engager; Bispecific protein engager-armed T cell; CD138; Immunotherapy; Multiple myeloma

DOI:  https://doi.org/10.1016/j.intimp.2026.116295
Eur J Haematol. 2026 Feb 09.

Obinutuzumab Maintenance in Follicular Lymphoma Is Associated With Better Progression Free Survival and Comparable Toxicity.

Renana Robinson, Tamar Berger, Tzippy Shochat, Shlomzion Aumann, Boaz Nachmias, Neta Goldschmidt, Nurit Horesh, Reut Harel, Ariel Aviv, Shai Shimony, Idan Goldberg, Ella Shmerts, Uri Abadi, Pia Raanani, Anat Gafter-Gvili, Ronit Gurion.

   BACKGROUND: The GALLIUM trial showed improved progression-free survival (PFS) with obinutuzumab (O)-based chemoimmunotherapy in first-line treatment of follicular lymphoma (FL), although with increased toxicity compared to rituximab (R). Our previous real-world study found similar toxicity between these protocols during induction.
AIM: To compare real-world toxicity and outcomes of R versus O maintenance therapy in FL patients following first-line chemoimmunotherapy.
METHODS: A multicenter retrospective study included FL patients treated with first-line R- or O-based chemoimmunotherapy. The primary outcome was any infection up to 6 months post-maintenance. Secondary outcomes included other toxicities, PFS, and overall survival (OS).
RESULTS: We analyzed 134 patients (R: 71, O: 63). Baseline characteristics were similar except for higher diabetes and hypertension rates in the R group. The median number of maintenance cycles was comparable. Infections occurred in 56% of patients, with no significant difference (50.7% R vs. 61.9% O, p = 0.21). Grade ≥$$ \ge $$ 3 infections, febrile neutropenia, and treatment discontinuation rates were comparable between groups. Pneumonia and viral infections were less frequent with R versus O (13.8% vs. 28.1%, p = 0.019 and 19% vs. 39%, p = 0.004, respectively), while infusion reactions were higher (8.4% vs. 0%, p = 0.028). After 5.5 years, PFS favored O (19.7% vs. 4.8%, p = 0.028), with similar OS.
CONCLUSIONS: In real-world settings, rituximab- and obinutuzumab-based chemoimmunotherapy with maintenance for FL exhibited a similar toxicity profile, with differences in specific infections. Obinutuzumab had superior PFS and similar OS compared with rituximab therapy, supporting obinutuzumab usage in first-line chemoimmunotherapy, especially in selected young and fit patients.

Keywords:  follicular lymphoma; maintenance therapy; obinutuzumab; rituximab

DOI:  https://doi.org/10.1111/ejh.70136
Circulation. 2026 Feb 12.

Second- and Third-Generation BCR-ABL Tyrosine Kinase Inhibitors and the Risk of Pulmonary Arterial Hypertension: A Prevalent New-User Design.

Clément Jambon-Barbara, Samy Suissa, Sophie Dell'Aniello, Alex Hlavaty, Jean-Luc Cracowski, Marie-Camille Chaumais, Marc Humbert, David Montani, Charles Khouri.

   BACKGROUND: BCR-ABL tyrosine kinase inhibitors (TKIs) have been increasingly linked to pulmonary arterial hypertension (PAH) since 2009, although supporting evidence is limited. Our objective was to evaluate the risk of PAH associated with second- and third-generation BCR-ABL TKIs compared with imatinib in adults.
METHODS: We employed a prevalent new-user design that emulates a randomized trial within the French national health care database population between 2008 and 2024. Thus, subjects initiating a second- and third-generation BCR-ABL TKI were matched on time and propensity score with users of the first-generation BCR-ABL TKI, imatinib. Patients were followed to occurrence of the primary outcome (ie, new onset of PAH), switch to another BCR-ABL TKI, death from any cause, end of registration within the database, or end of the study period, whichever came first. Hazard ratios (HRs) and 95% CIs were estimated using Cox proportional hazards regression models, and incidence rates and corresponding 95% CIs were calculated using the Poisson distribution.
RESULTS: Six thousand six hundred twenty-five dasatinib (age 59.7±15.2 years, 44.0% women), 5205 nilotinib (age 55.4±15.0 years, 44.2% women), 2421 bosutinib (age 63.8±14.2 years, 42.1% women),1358 ponatinib (age 57.3±14.9 years, 46.1% women), and 922 asciminib (age 64.3±13.8 years, 43.7% female) new users were each matched with the maximum of available imatinib users on time-conditional propensity score and on duration of prior imatinib use (prevalent users). Dasatinib use was associated with a 9-fold increased risk of PAH compared with imatinib (1829 versus 43 events per million persons per year; HR=8.89 [95% CI, 5.30-14.92]). Bosutinib and ponatinib were associated with HRs of 10.76 (95% CI, 4.68-24.73) and 7.74 (95% CI, 2.33-25.70) respectively, with most cases occurring in patients previously exposed to dasatinib. Nilotinib and asciminib were not associated with an increased risk of PAH.
CONCLUSION: This study, designed to emulate a randomized trial, suggests that, in French patients with chronic myeloid leukemia treated with BCR-ABL TKIs, dasatinib use is associated with a higher risk of PAH compared with imatinib, while bosutinib and ponatinib exposure may aggravate or trigger a recurrence of PAH in patients with preexisting dasatinib exposure. Whether bosutinib and ponatinib could induce PAH without preexposure to dasatinib remains to be explored.

Keywords:  cohort study; prevalent new-user design; pulmonary arterial hypertension; tyrosine kinase inhibitors

DOI:  https://doi.org/10.1161/CIRCULATIONAHA.125.077764
Adv Sci (Weinh). 2026 Feb 08. e18975

Targeting PRKCN, an Essential Driver Orchestrating mTOR-IRF4 Axis Independently of Kinase Activity, in Multiple Myeloma.

Koukou Tang, Dongpeng Jiang, Peng Ke, Xiaosen Bian, Lili Zhang, Ying Zhang, Tingting Zhu, Weiwei Qu, Wenhui Qi, Yang Xu, Chengcheng Fu, Depei Wu, Jianhong Chu.

  Multiple myeloma (MM) remains incurable, necessitating development of novel therapeutic targets. Deregulated PRKCN is implicated in solid tumors, while its role in MM remains elusive. Here, PRKCN is identified as a super-enhancer-driven gene associated with adverse prognosis in MM. PRKCN is transactivated by NF-κB signaling intrinsically existing or exogenously provoked. Constitutive or inducible knockdown of PRKCN significantly impairs cell growth and tumorigenicity, while overcoming drug resistance. PRKCN harnesses IRF4 to exert its effect, and in turn, IRF4 directly induces PRKCN transcription, establishing a feed-forward IRF4-PRKCN circuit. Furthermore, PRKCN fosters IRF4 expression by activating mTORC1/C2 signaling pathways via physical interaction with mTOR. Surprisingly, PRKCN modulates mTOR-IRF4 axis and cell growth independently of its acknowledged kinase activity yet requiring activation loop phosphorylation. Intriguingly, PRKCN silencing evokes interferon signaling and confers increased sensitivity to interferon. Finally, targeting PRKCN with an orally bioavailable inhibitor suppresses MM cell growth and overcomes drug resistance in vitro, and elicits robust efficacy in cell line-derived xenografts and a patient-derived xenograft, which is connected with the mitigated PRKCN expression and activation loop phosphorylation as well as blunted mTOR-IRF4 axis. Collectively, our study delineates PRKCN function that links aberrant NF-κB signaling and mTOR-IRF4 axis, supporting clinically targeting PRKCN in MM.

Keywords:  IRF4; NF‐κB signaling; mTOR signaling; multiple myeloma; protein kinase

DOI:  https://doi.org/10.1002/advs.202518975
Mol Pharm. 2026 Feb 07.

Tracking MAPK-Dependent CD38 Upregulation by All-Trans Retinoic Acid in Human Leukemia Using 89Zr Immuno-PET.

Mina Kim, Hyun-Jung Koo, Kyung-Ho Jung, Jung Lim Kim, Giro Kim, Hyunjong Lee, Kyung-Han Lee.

  Anti-CD38 antibodies (Abs) are promising immunotherapeutics for hematologic malignancies, but their efficacy in leukemias often requires pharmacologic upregulation of CD38. Immuno-PET provides a noninvasive strategy to evaluate such target modulation in vivo. Cysteine site-specific 89Zr labeling of anti-CD38 Abs was performed using deferoxamine-maleimide. CD38-specific target binding was confirmed in three human myeloma and two leukemia cell lines. Total and surface expressed CD38 levels were assessed by Western blotting and flow cytometry. Immuno-PET imaging and biodistribution studies were conducted in murine leukemia models. All-trans retinoic acid (ATRA) was used to stimulate CD38 expression. Myeloma and MOLT4 leukemia cells showed variable baseline CD38, while HL60 cells exhibited negligible levels. All tumor cells demonstrated 89Zr-OKT10 IgG and 89Zr-daratumumab (Fc-silenced) binding that paralleled surface CD38 expression. ATRA upregulated CD38 in all tested cells, including a marked induction in HL60 cells, all accompanied by corresponding elevations in 89Zr-CD38 Ab binding. On 89Zr-OKT10 IgG PET, MOLT4 tumors showed high uptake that was reduced by 67.9% with unlabeled Ab, but HL60 tumors showed low uptake and high liver accumulation, limiting ATRA assessment. 89Zr-daratumumab produced lower liver uptake and improved MOLT4 and HL60 tumor visualization; ATRA modestly increased MOLT4 tumor uptake and substantially enhanced HL60 tumor uptake from 8.0 ± 1.7 %ID/g to 14.7 ± 3.1 %ID/g (83.8% increase; P < 0.005). Mechanistic studies demonstrated ATRA-induced ERK1/2 activation in HL60 cells that was abolished by the MAPK inhibitor U0126; U0126 also suppressed CD38 induction and 89Zr-CD38 Ab uptakes in all tested tumor cells. Furthermore, U0126 blocked ATRA-induced HL60 tumor 89Zr-daratumumab uptake in vivo. Western blots and immunohistochemistry confirmed ATRA-induced HL60 tumor CD38 elevation, which was partly reversed by U0126. Thus, 89Zr immuno-PET enables noninvasive monitoring of ATRA-driven CD38 upregulation via MAPK signaling and supports its potential utility for optimizing combination strategies in leukemias.

Keywords:  89Zr; CD38; HL60; immuno-PET; leukemia; retinoic acid

DOI:  https://doi.org/10.1021/acs.molpharmaceut.5c01474
Blood Adv. 2026 Feb 11. pii: bloodadvances.2021006479. [Epub ahead of print]

ASH 2026 Guidelines for Management of Relapsed/Refractory Disease in Adolescents and Young Adults with ALL.

Kristen M O'Dwyer, Lena E Winestone, Matthew C Cheung, Lydia Benitez, Barbara Buldini, Peter D Cole, Moussab Damlaj, Bhagirathbhai Dholaria, Ajoy Lawrence Dias, Alexander Dils, Michelle Fritsch, John P Greer, Brandon Hayes-Lattin, Meret Henry, Aaron Jaffe, Omer Jamy, Partow Kebriaei, Ilayna Mehrtens, Nirali N Shah, Lindsay Wilde, Patricia Young, Htun Ja Mai, Ghid Kanaan, Yuliia Sereda, Ian J Saldanha, Ethan M Balk, Sumit Gupta.

BACKGROUND: Adolescents and young adults (AYA) with relapsed or refractory acute lymphoblastic leukemia (ALL) face unique challenges as they experience greater treatment resistance, higher rates of toxicity, and present at a specific life stage with distinct priorities.
OBJECTIVE: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support clinicians, patients, and other health care professionals in their decisions about management of AYAs with relapsed/refractory ALL.
METHODS: ASH formed a multidisciplinary guideline panel including hematologists, AYA psychosocial care specialists, pharmacists, methodologists, and patient representatives with efforts to minimize bias from conflicts of interest. An evidence review team at Brown University supported guideline development, including performing systematic evidence reviews up to November 2023. The panel prioritized clinical questions and outcomes according to importance for clinicians and patients. The panel used Grading of Recommendations Assessment, Development and Evaluation (GRADE), including GRADE Evidence-to-Decision frameworks, to assess evidence and make recommendations, which were subject to public comment.
RESULTS: The panel agreed on eight recommendations and one research-only recommendation, covering remission re-induction and consolidation. They focused on the following treatment modalities: immunotherapy, targeted therapies, allogeneic hematopoietic stem cell transplantation (allo-HSCT), and central nervous system (CNS)-directed therapy.
CONCLUSIONS: Key recommendations include the use of blinatumomab and/or inotuzumab over chemotherapy for re-induction. Additional management of ALL subsets (T-ALL), CNS relapse, and the role of consolidation with allogeneic transplantation are addressed. Future research should evaluate these approaches with special attention to the unique AYA population and should evaluate quality of life outcomes.

DOI: https://doi.org/10.1182/bloodadvances.2021006479
Circulation. 2026 Feb 10. 153(6): 435-456

Involvement of Btk in Cardiovascular Disease and Its Therapeutic Targeting.

Philipp von Hundelshausen, Wolfgang Siess, Rundan Duan, Tonika Bohnert, Brian T Hopkins, Christian Weber.

  Btk (Bruton's tyrosine kinase), a Tec-family kinase initially recognized for its role in B-cell signaling, has emerged as a critical player in thrombosis and cardiovascular disease. Beyond the established therapeutic effects of Btk inhibitors in B-cell malignancies, its expression in platelets, macrophages, and neutrophils implicates Btk in platelet activation, atherothrombosis, and innate immunity. This state-of-the-art review synthesizes the current understanding of Btk's mechanistic contributions to thrombosis and cardiovascular disease, evaluates the evolution of Btk inhibitors (BTKi), and explores their therapeutic potential. Patients with X-linked agammaglobulinemia who lack Btk do not have a bleeding diathesis, indicating that platelet-selective Btk inhibition would be a safe antithrombotic strategy. In platelets, Btk mediates immunoreceptor tyrosine-based activation motif-dependent and -independent signaling, driving atherothrombosis, venous thrombosis, and immunothrombosis without affecting hemostatic platelet functions. In myeloid cells, Btk amplifies inflammation via NLRP3 inflammasome activation and neutrophil extracellular trap formation, linking it to thromboinflammation and atherosclerosis. First-generation BTKi such as ibrutinib demonstrate antithrombotic efficacy but are limited by off-target effects, including bleeding and atrial fibrillation. Second- and third-generation inhibitors (eg, acalabrutinib, zanubrutinib, and pirtobrutinib) show enhanced selectivity, reducing cardiovascular toxicity in patients with B-cell malignancies. Highly selective BTKi (fenebrutinib and remibrutinib) do not show bleeding in clinical trials of various autoimmune disorders, and covalent selective BTKi applied at low dosage are expected to selectively inhibit Btk in platelets without bleeding side effects. Preclinical data and early observations from compassionate use in patients with atypical autoimmune thrombosis highlight the potential of BTKi as selective antithrombotic agents beyond traditional therapies. This review conceptualizes and underscores Btk's pivotal role at immune-thrombosis interfaces in atherothrombosis, advocating for precision medicine approaches and innovative platforms to unlock its full therapeutic potential in cardiovascular disease management.

Keywords:  bleeding; inflammation; platelets; protein-tyrosine kinases; signaling; thrombosis

DOI:  https://doi.org/10.1161/CIRCULATIONAHA.125.076186
Blood Adv. 2026 Feb 11. pii: bloodadvances.2025016877. [Epub ahead of print]

Conventional Therapy vs HMA or LDAC ± Venetoclax in Older Adults With AML: Systematic Review and Meta-analysis.

Sara Ibrahim, Barbara Burgos-Mansilla, Yetiani Roldan, Maria-Jose Oliveros, Gurleen Bhogal, Gonzalo Bravo-Soto, Mobina Bagherianlemraski, Hamed Movahed, Ruvistay Gutierrez-Arias, Francesca Mulazzani, Tanin Khorrami Taj, Seyed Kaveh Hadeiy, Manahil Qureshi, Saifur R Chowdhury, Rachel Couban, Andrew S Artz, Luke Fletcher, Linda Gilberto, Ryan J Mattison, Mikkael A Sekeres, Romina Brignardello-Petersen.

This systematic review summarizes the evidence informing two recommendations from the updated American Society of Hematology (ASH) guidelines for the treatment of newly diagnosed acute myeloid leukemia (AML) in older adults, comparing conventional induction and post-remission therapy versus hypomethylating agents (HMA)- or low-dose cytarabine (LDAC)-based strategies, with or without venetoclax. We searched MEDLINE, Embase, and Cochrane CENTRAL through February 2024, and monitored these databases for new studies throughout November 2024. We included randomized controlled trials (RCTs) and non-randomized studies (NRS). Reviewers screened studies, extracted data, assessed risk of bias, conducted random-effects meta-analyses, and rated certainty of evidence using GRADE. We included 21 studies (3 RCTs, 18 NRS). Compared with HMA- or LDAC-based monotherapy, conventional 7+3-type remission induction therapy may reduce mortality at longest follow-up (RR 0.94; 95% CI, 0.85-1.04; low certainty), increase complete remission rates (OR 1.75; 95% CI, 1.25-2.38; high certainty), and may reduce recurrence at longest follow-up (RR 0.81; 95% CI, 0.64-1.04; low certainty). Conventional therapies probably increase most severe toxicities (moderate certainty). Compared with HMA or LDAC combined with venetoclax, very low certainty evidence suggests that conventional therapy may reduce 1-year mortality (RR 0.72; 95% CI, 0.60-0.87), increase allogeneic transplant rates (RR 2.28; 95% CI, 1.70-3.06), result in no important differences in complete remission or recurrence, and have variable effects on severe toxicities. Conventional therapy may have benefits over HMA or LDAC alone; however, compared to HMA or LDAC plus venetoclax, the evidence remains of very low certainty.

DOI: https://doi.org/10.1182/bloodadvances.2025016877