bims-hemali 2026-07-05 papers

bims-hemali

Biomed News

on Hematologic malignancies

Issue of 2026–07–05
eighteen papers selected by
Alexandros Alexandropoulos, Γενικό Νοσοκομείο Αθηνών Λαϊκό

Low-dose dasatinib in second-line therapy or beyond for the treatment of chronic-phase chronic myeloid leukemia: a real-world cohort study.
Molecular Relapse After a Second Treatment-Free Remission Attempt Following Asciminib in Chronic Myeloid Leukemia: A Case Report.
Favorable tolerability of asciminib versus ATP-competitive tyrosine kinase inhibitors in the ASC4FIRST study of newly diagnosed patients with chronic-phase chronic myeloid leukemia.
Phase I/II Study of Sonrotoclax (BGB-11417) Monotherapy in Patients With Mantle Cell Lymphoma Previously Treated With Anti-CD20 Therapy and a Bruton Tyrosine Kinase Inhibitor.
Metformin: interferon's new dancing partner?
Long-term treatment-free remission in CML after early dasatinib discontinuation due to interstitial pneumonitis.
Zanubrutinib, Obinutuzumab, and Venetoclax in CLL: Long-Term Follow Up, MRD Kinetics, Retreatment, T-Cell Profiling, PKs.
TRANSFORM-1 Phase 3 study: Efficacy and safety of navitoclax plus ruxolitinib in patients with untreated myelofibrosis.
Long-term follow-up of oral decitabine/cedazuridine plus venetoclax for older or unfit patients with newly diagnosed acute myeloid leukemia.
A bone to pick with ferric carboxymaltose.
Vibecotamab for measurable residual disease in acute myeloid leukemia and for myelodysplastic syndromes and chronic myelomonocytic leukemia after hypomethylating agent failure: a phase II study.
Tumor-selective Mcl1 degradation by AUTAC uncouples antitumor efficacy from cardiotoxicity.
Validation of the newly introduced Deauville Score 5a in patients treated for advanced-stage classic Hodgkin Lymphoma.
Src Family Kinase Inhibitors Bosutinib and Dasatinib Enhance ATRA-induced Differentiation of NB4 Leukemia Cells.
Zanubrutinib combined with R-CHOP in previously untreated diffuse large B-cell lymphoma with specific gene alteration: a phase II study.
Circulating CD20-positive extracellular vesicles impair rituximab efficacy and predict outcomes in diffuse large B-cell lymphoma.
Inhibition of PRMT5 sensitizes B-cell non-Hodgkin lymphoma cells to both intrinsic and extrinsic apoptotic cell death.
Design and Synthesis of a Novel Covalent Dihydropteridinone Derivative as a Highly Potent and Orally Bioavailable PLK1 Inhibitor for the Treatment of Chronic Myeloid Leukemia.

Front Pharmacol. 2026 ;17 1734319

Low-dose dasatinib in second-line therapy or beyond for the treatment of chronic-phase chronic myeloid leukemia: a real-world cohort study.

Yilin Chen, Hongxiang Wang, Fang Cheng, Weiming Li.

   Background: Dasatinib is a favorable option for patients with chronic-phase chronic myeloid leukemia (CML-CP) who have an inadequate response, treatment intolerance, or are attempting treatment-free remission (TFR). Dasatinib dose reduction is a strategy to improve tolerability while maintaining efficacy in first-line settings or patients with a stable molecular response. However, whether low-dose dasatinib is safe and effective in second-line or later setting for patients with CML-CP remains unclear.
Methods: We conducted a retrospective analysis of 53 patients with CML-CP who switched to low-dose dasatinib due to inadequate molecular response (n = 37), treatment intolerance (n = 13), or to re-induce a deeper molecular response (n = 3).
Results: Among the 37 patients who had not achieved major molecular response (MMR) before switching, 10 patients (27.0%) attained MMR, 12 patients (32.4%) achieved deep molecular response (DMR/MR4), and 11 patients (29.7%) reached molecular response 4.5 (MR4.5) following low-dose dasatinib therapy. Notably, 81.8% of patients with only baseline MMR improved to MR4 or MR4.5 after switching to low-dose dasatinib. One patient lost MR4 while receiving dasatinib at 50 mg/day and subsequently switched to nilotinib. All three patients who were switched to re-induce deeper molecular responses successfully re-attained MR4.5 after switching to low-dose dasatinib. Adverse events resolved in all 13 patients who switched due to prior TKI intolerance, and no worsening grade 2 or more adverse events were observed.
Conclusion: Our findings suggest that low-dose dasatinib for selected patients with CML-CP in second-line therapy or beyond may be safe and effective under close monitoring. Nevertheless, multicenter prospective clinical trials are needed to validate the efficacy and safety of low-dose dasatinib therapy in second-line treatment settings or beyond in CML.

Keywords:  TKI dose optimization; chronic myeloid leukemia; dasatinib; later-line; molecular response; safety

DOI:  https://doi.org/10.3389/fphar.2026.1734319
Case Rep Hematol. 2026 ;2026 1621284

Molecular Relapse After a Second Treatment-Free Remission Attempt Following Asciminib in Chronic Myeloid Leukemia: A Case Report.

Nobue Sato, Ryo Yoshimaru, Yong-Mei Guo, Hirotaka Nakamura, Kensuke Matsuda, Yosuke Minami, Junichiro Yuda.

  Treatment-free remission (TFR) has become an important therapeutic goal in chronic myeloid leukemia (CML). Although the outcomes of TFR following adenosine triphosphate (ATP)-competitive tyrosine kinase inhibitors (TKIs) have been established, data on TFR after asciminib discontinuation remain limited. In this study, we report the case of a man in his 60s with chronic-phase CML who experienced molecular relapse 8 months after a second TFR attempt following asciminib treatment. The patient was diagnosed with CML approximately 15 years earlier and achieved deep molecular response 4.5 (MR4.5), representing a 4.5-log reduction in BCR::ABL1 transcripts, with first-line imatinib. After the first TFR attempt, major molecular response (MMR) was lost, and ponatinib was initiated but discontinued because of cerebral infarction. Asciminib was subsequently introduced as third-line therapy at a dose of 40 mg twice daily, and BCR::ABL1 transcripts remained undetectable for more than 3 years. Based on the sustained deep molecular response and patient preference, asciminib was discontinued. Eight months after discontinuation, however, loss of MR4.0 (BCR::ABL1 > 0.01% IS) was detected. This threshold was used to guide treatment reinitiation, rather than waiting for loss of MMR as recommended by the ELN guidelines, in the view of the clinical context of a second TFR attempt following prior failure. Imatinib was reintroduced, leading to the reachievement of a deep molecular response. This case underscores the importance of careful patient selection and long-term molecular monitoring following TFR attempts, including those involving novel TKIs such as asciminib.

Keywords:  asciminib; case report; chronic myeloid leukemia; molecular relapse; treatment-free remission; tyrosine kinase inhibitors

DOI:  https://doi.org/10.1155/crh/1621284
Haematologica. 2026 Jul 02.

Favorable tolerability of asciminib versus ATP-competitive tyrosine kinase inhibitors in the ASC4FIRST study of newly diagnosed patients with chronic-phase chronic myeloid leukemia.

Ghayas C Issa, Richard A Larson, Timothy P Hughes, Andreas Hochhaus, Naoto Takahashi, Felice Bombaci, Jianxiang Wang, Dong-Wook Kim, Dennis Dong Hwan Kim, Jiri Mayer, Yeow-Tee Goh, Philipp Le Coutre, Inho Kim, Gabriel Etienne, David Andorsky, Ennan Gu, Yifan Zhang, Tracey McCulloch, Nithya Agrawal, Rajendra Jinwal, Andrea Damon, Islam Sadek, Jorge E Cortes.

Many patients with chronic myeloid leukemia (CML) treated with adenosine triphosphate (ATP)-competitive tyrosine kinase inhibitors (TKIs) experience persistent adverse events (AEs) that negatively impact daily living and the ability to remain on treatment. Asciminib, an allosteric inhibitor of BCR::ABL1, was designed to enhance efficacy and reduce off-target effects vs ATPcompetitive TKIs. The phase 3 randomized ASC4FIRST trial established the overall favorable safety profile of asciminib in patients with newly diagnosed CML in chronic phase (CP). This exploratory post hoc analysis of ASC4FIRST focused specifically on the tolerability of asciminib vs imatinib and asciminib vs second-generation [2G] TKIs. Analyses were conducted within each stratum to account for differences between strata; patients prerandomized to the imatinib stratum were older and had higher cardiovascular risk than those in the 2G stratum. Within both strata, patients receiving asciminib experienced fewer difficult-to-tolerate AEs (such as gastrointestinal toxicity, rash, and pleural effusion) and fewer AEs leading to dose modifications and discontinuations due to nonhematologic and hematologic AEs vs the investigator-selected (IS) TKI comparator, with a shorter median duration of dose modification. Additionally, median onset of AEs leading to dose modification occurred later in patients receiving asciminib vs ISTKIs. The safety and tolerability of asciminib observed in the ASC4FIRST trial demonstrate asciminib's excellent benefit-risk profile as a frontline therapy for a broad range of patients with newly diagnosed CML-CP.

DOI: https://doi.org/10.3324/haematol.2025.300145
J Clin Oncol. 2026 Jul 01. JCO2600550

Phase I/II Study of Sonrotoclax (BGB-11417) Monotherapy in Patients With Mantle Cell Lymphoma Previously Treated With Anti-CD20 Therapy and a Bruton Tyrosine Kinase Inhibitor.

Toby A Eyre, Yuqin Song, Olivier Hermine, Yuerong Shuang, Wojciech Jurczak, João Samuel Farias, Carolina Mahuad, Muhit Özcan, Ron D Jachimowicz, Tianlei Chen, Elena Ivanova, Xiaotong Li, Gabriel Man, Priscille Bourquelot, Remus Vezan, Michael Wang.

PURPOSE: Mantle cell lymphoma (MCL) is a rare and typically aggressive B-cell non-Hodgkin lymphoma characterized by recurrent relapse after short remissions. Sonrotoclax (BGB-11417) is a next-generation B-cell lymphoma 2 inhibitor with greater selectivity and potency than venetoclax, a shorter half-life, and no drug accumulation. Sonrotoclax monotherapy was evaluated in Bruton tyrosine kinase inhibitor-pretreated patients with relapsed/refractory (R/R) MCL.
METHODS: BGB-11417-201 (ClinicalTrials.gov identifier: NCT05471843) is an ongoing global, open-label, phase I/II trial. Sonrotoclax was orally administered once daily with gradual, 4-week ramp-up to 160 mg or 320 mg to mitigate tumor lysis syndrome (TLS). The primary end point was overall response rate by the independent review committee (ORR-IRC) per Lugano classification; secondary end points included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.
RESULTS: Overall, 125 patients were enrolled and assigned to receive sonrotoclax 160 mg (n = 10) or 320 mg (n = 115) target doses once daily. Most patients had advanced disease (stage IV, 78.3%) and were heavily pretreated (median prior therapies, 3). In efficacy-evaluable patients (n = 103), the ORR-IRC was 52.4% (95% CI, 42.4 to 62.4), a statistically significant increase versus the historic control ORR (30%; P < .0001); the complete response rate was 15.5%. Responses were seen across high-risk subgroups, including patients with TP53 mutation (59.1%). With a median study follow-up of 14.2 months, the median DOR-IRC was 15.8 months, and the median PFS-IRC was 6.5 months. Median OS was not reached. The most common all-grade/grade ≥3 treatment-emergent adverse events were neutropenia (35.7%/19.1%), thrombocytopenia (24.3%/9.6%), and anemia (24.3%/7.8%). TLS occurred in 7.0% of patients; all cases resolved without sequelae.
CONCLUSION: Sonrotoclax demonstrated rapid, durable responses and manageable safety in heavily pretreated patients with R/R MCL, including high-risk subgroups, supporting its further clinical evaluation as an oral therapy for R/R MCL.

DOI: https://doi.org/10.1200/JCO-26-00550
Haematologica. 2026 Jul 01. 111(7): 2199-2201

Metformin: interferon's new dancing partner?

Hans C Hasselbalch.

DOI: https://doi.org/10.3324/haematol.2025.300445
Int J Hematol. 2026 Jun 30.

Long-term treatment-free remission in CML after early dasatinib discontinuation due to interstitial pneumonitis.

Makoto Kashimura, Yuki Fujioka, Yong-Mei Guo, Teruko Takahashi, Keiichi Moriya, Naoto Takahashi.

  Achieving treatment-free remission (TFR) in patients with chronic myeloid leukemia (CML) requires several years of tyrosine kinase inhibitor (TKI) therapy and a sustained deep molecular response (DMR). We report an exceptional case of a 54-year-old woman who achieved long-term TFR despite discontinuing dasatinib after only 9 months due to grade 3 interstitial pneumonitis. At the time of discontinuation, the duration of DMR was 128 days. Following cessation, BCR::ABL1 transcript levels transiently rebounded to 0.0729% on the International Scale but subsequently declined spontaneously without resumption of TKI therapy. The patient has remained in TFR for more than 7 years. Immunological analysis revealed clonal expansion of a unique CD56+CD57+CD8dim T-cell population possessing natural killer (NK)-like properties, as confirmed by T-cell receptor gene rearrangement analysis. This specific clone persisted after discontinuation, suggesting a role in the sustained immune surveillance of residual leukemia stem cells. These findings suggest that the quality of immune reconstitution, specifically the induction of innate-like effector T-cell clones, may be a more critical determinant of TFR success than the absolute duration of therapy.

Keywords:  Chronic myeloid leukemia; Dasatinib; Immune surveillance; NK-like T-cell; Treatment-free remission

DOI:  https://doi.org/10.1007/s12185-026-04241-y
Blood Adv. 2026 Jun 30. pii: bloodadvances.2026020221. [Epub ahead of print]

Zanubrutinib, Obinutuzumab, and Venetoclax in CLL: Long-Term Follow Up, MRD Kinetics, Retreatment, T-Cell Profiling, PKs.

Jacob D Soumerai, Meghan C Thompson, Ahmet Dogan, Venkatraman E Seshan, Kelsey Flaherty, Natalie Slupe, Jason Carter, Ephraim Hochberg, Jeffrey A Barnes, Jeremy S Abramson, Ariela Noy, Colette N Owens, M Lia Palomba, Anita Kumar, Lindsey Elizabeth Roeker, Ronald W Takvorian, Zachary D Epstein-Peterson, Mark B Geyer, Gilles A Salles, Robert N Stuver, Philip C Caron, Prioty Islam, Tamanna Haque, Paola Ghione, Raphael E Steiner, Pallawi Torka, Kevin A David, Jennifer K Lue, Paul A Hamlin, Alison J Moskowitz, Lorenzo Falchi, Julie E Haydu, Patrick Connor Johnson, Joanna Mi, Neena Mahajan, Jessica Pendleton, Alyssa Labarre, Maria Chabowska, Morgan Choma, Clare Grieve, Ashlee Joseph, Colleen Dorsey, Jamila Brutus, Rosalba Martignetti, Rachel Nazzaro, Jayne Coyle, Olivia Grace Maas, De Zoysa Meemanage, Elizabeth Simkins, Akshata Kakolu, Cameron Gordan, Eshani Baez, Bernadette Beatty, Athina Apazidis, Michelle Gulotta, Sherry Ratcliff, Jamie Hirata, Mina Shahkarami, Allison P Jacob, Omar Abdel-Wahab, Andrew D Zelenetz.

Triplet regimens induce high rates of undetectable MRD at ≤10-4 (uMRD4) and appear to prolong progression-free survival (PFS) in treatment-naïve (TN) CLL, but the optimal treatment duration to minimize the risk of neutropenia/infections is unknown. In this phase 2 trial, we evaluated zanubrutinib, obinutuzumab, and venetoclax (BOVen) in TN CLL (NCT03824483). Our MRD-driven treatment/retreatment study was designed to optimize treatment duration balancing efficacy against toxicities associated with extended treatment exposure, and evaluate zanubrutinib-venetoclax (Z+V) retreatment. With a median observation time of 69 months and median treatment duration of 10 cycles, 96% achieved blood uMRD4, and 92% achieved uMRD4 in both blood and bone marrow (primary endpoint). BOVen was well-tolerated with low rates of grade 3-4 neutropenia (25%) and infections (9.6%; none grade 5). Median MRD4-free survival was 34.1 months (95% CI 23.1-50.5) and 48-month PFS was 79.7% (95% CI 68.6-92.5). ΔMRD400 (≥400-fold reduction in blood MRD by immunosequencing at 4 months) identified patients with earlier bone marrow uMRD4 (6 vs 12 months, p<0.001), and longer MRD4-free survival (50.5 vs 18.1 months, p<0.001) despite a shorter treatment duration (8 vs 13 mo, p<0.001). This manuscript also reports on the safety/efficacy of Z+V retreatment and describes pharmacokinetic and T-cell profiling studies. In summary, BOVen was well-tolerated and resulted in frequent, early uMRD4 and durable remissions in TN CLL with a short treatment duration (median 10 months). ΔMRD400 is undergoing evaluation for use as a predictive biomarker to guide treatment duration in two prospective trials of venetoclax- and sonrotoclax-based triplets in TN CLL.

DOI: https://doi.org/10.1182/bloodadvances.2026020221
Blood. 2026 Jun 30. pii: blood.2025032360. [Epub ahead of print]

TRANSFORM-1 Phase 3 study: Efficacy and safety of navitoclax plus ruxolitinib in patients with untreated myelofibrosis.

Naveen Pemmaraju, Adam J Mead, Tim C P Somervaille, Francesca Palandri, Steffen Koschmieder, Robert Delage, Jean-Jacques Kiladjian, Christopher B Benton, Srinivas K Tantravahi, Noa Lavi, Su-Peng Yeh, Maria Teresa Gomez Casares, Emanuele Ammatuna, Andrew Bruce McDonald, Sung-Soo Yoon, Keita Kirito, Timothy Devos, Andrew C Perkins, Atanas Radinoff, Omur Gokmen Sevindik, Andrija Bogdanovic, Rastislav Moskal, Jason G Harb, Bryan C Murray, Qi Jiang, Avijeet S Chopra, Elektra J Papadopoulos, Jalaja Potluri, Francesco Passamonti.

The Phase 3 TRANSFORM-1 study (NCT04472598) evaluated ruxolitinib (RUX) in combination with navitoclax (NAV) or placebo (PBO) in Janus-kinase-inhibitor-naïve adults with intermediate-2 or high-risk myelofibrosis and Eastern Cooperative Oncology Group performance status ≤2. Patients were randomized 1:1 to NAV (200 mg/day starting dose or 100 mg escalated to 200 mg/day) or PBO, with RUX dosed per label. The primary endpoint was ≥35% spleen volume reduction (SVR) at Week 24 (SVR35W24). Secondary endpoints included change from baseline in Total Symptom Score (TSS) at Week 24 and SVR35 at any time. A total of 252 patients (NAV+RUX, n=125; PBO+RUX, n=127; median follow-up 20.3 months) were randomized; >80% had intermediate-2 risk and nearly 50% were high-molecular risk (HMR). SVR35W24 was achieved by 63.2% with NAV+RUX versus 31.5% with PBO+RUX (P<0.0001). Mean change in TSS at Week 24 was not significantly different between NAV+RUX and PBO+RUX (-10.2 vs -11.6; P=0.2852). SVR35 at any time was achieved in 76.8% with NAV+RUX versus 44.1% with PBO+RUX (nominal P<0.0001). A ≥20% variant allele frequency reduction (exploratory endpoint) occurred in 58.5% (95% CI: 49.0-67.5) with NAV+RUX and 45.5% (95% CI: 36.4-54.8) with PBO+RUX. NAV+RUX showed higher hematologic toxicity versus PBO+RUX (Grade 3/4 thrombocytopenia: 54.0% vs 19.2%; Grade 3/4 neutropenia: 40.3% vs 8.8%); diarrhea (any grade: 41.9% vs 16.8%) was also more common. Cytopenias were generally manageable and reversible with dose adjustments.

DOI: https://doi.org/10.1182/blood.2025032360
Haematologica. 2026 Jul 02.

Long-term follow-up of oral decitabine/cedazuridine plus venetoclax for older or unfit patients with newly diagnosed acute myeloid leukemia.

Thura Win Htut, Jeannot Kekedjian, Nicholas Short, Alexandre Bazinet, Yesid Alvarado, Alex Bataller, Ghayas Issa, Gautam Borthakur, Abhishek Maiti, Musa Yilmaz, Nitin Jain, Lucia Masarova, Kelly Chien, Jayastu Senapati, Elias Jabbour, Guillermo Montalban-Bravo, Sherry Pierce, Courtney D DiNardo, Tapan Kadia, Naval Daver, Marina Konopleva, Xuelin Huang, Hagop Kantarjian, Guillermo Garcia-Manero, Farhad Ravandi.

Oral decitabine/cedazuridine plus venetoclax offers a fully oral regimen for older or unfit patients with acute myeloid leukemia (AML). We previously reported outcomes from a phase II study; here we present extended follow-up of the frontline cohort. In this single-center phase II study, adults with AML ineligible for intensive induction received oral decitabine/cedazuridine (35 mg/100 mg, days 1-5) plus venetoclax in 28-day cycles. This analysis included newly diagnosed (ND) AML. Endpoints included overall response rate (ORR), overall survival (OS), relapse-free survival (RFS), duration of response (DOR) and safety. Outcomes were compared between de novo and secondary AML. Between March 2021, and January 2026, 68 patients were treated, including 32 de novo and 36 secondary AML; median age was 79 years. The cohort was high risk, with >50% ECOG ≥2, less favorable genomics and 16% prior hypomethylating agents exposure. ORR was 75% in de novo AML and 58% in secondary AML. Among responders, MRD negativity was 58% and 56%. With median follow-up of 32 months, median OS was 12.7 months (95% CI, 9.1-20.3) vs 7.2 months (95% CI, 3.6-29.9) (P = 0.61). Median RFS was 9.2 months vs 11.7 months (P = 0.56). No statistically significant differences were observed in survival, relapse or non-relapse mortality. Oral decitabine/cedazuridine plus venetoclax is an effective oral treatment for older or unfit patients with ND AML. Response rates were higher in de novo AML, while survival outcomes were not statistically significant. These findings highlight the need for improved therapeutic strategies particularly in secondary AML.

DOI: https://doi.org/10.3324/haematol.2026.301126
Blood. 2026 Jul 02. 148(1): 1-2

A bone to pick with ferric carboxymaltose.

Karin E Finberg, Michael Auerbach.

DOI: https://doi.org/10.1182/blood.2026033929
J Hematol Oncol. 2026 Jun 27.

Vibecotamab for measurable residual disease in acute myeloid leukemia and for myelodysplastic syndromes and chronic myelomonocytic leukemia after hypomethylating agent failure: a phase II study.

Nicholas J Short, Alex Bataller, Courtney D DiNardo, Guillermo Montalban-Bravo, Sa A Wang, Wei Wang, Abhishek Maiti, Daniel Nguyen, Maria C Hachem, Timothy M Bi, Ghayas C Issa, Kelly S Chien, Maro Ohanian, Tapan M Kadia, Sanam Loghavi, Omer Karrar, Pavan Bachireddy, Hyunsoo Hwang, Xuelin Huang, Guillermo Garcia-Manero, Farhad Ravandi.

   BACKGROUND: Acute myeloid leukemia (AML) with persistent measurable residual disease (MRD) and relapsed/refractory myelodysplastic syndromes (MDS) are low-blast myeloid diseases for which there are few effective therapeutic options. CD123 represents an attractive target in these diseases. Vibecotamab is a bispecific antibody that binds to CD123 on malignant blasts and to CD3 on T-cells, to recognize and eliminate CD123-positive malignant cells.
METHODS: This single-center phase II study evaluated the efficacy of vibecotamab in patients AML with detectable MRD (AML-MRD cohort) or with MDS or chronic myelomonocytic leukemia (CMML) after hypomethylating agent failure (MDS/CMML cohort). In cycle 1, patients received vibecotamab IV on day 1 (0.43 µg/kg), day 3 (0.75 µg/kg), day 5 (1.1 µg/kg), and days 8, 15 and 22 (1.7 µg/kg). In subsequent cycles, patients received vibecotamab IV on days 1, 8, 15, and 22 (1.7 µg/kg). The primary outcomes were MRD negativity rate (AML-MRD cohort) and overall response (MDS/CMML cohort).
RESULTS: Between May 2022 and April 2025, 48 patients were enrolled (21 AML-MRD cohort, 27 MDS/CMML cohort). The median ages of the AML-MRD and the MDS/CMML cohorts were 70 and 76 years, respectively. In the AML-MRD cohort, the median MRD level by flow cytometry was 0.64% (range, 0.1-3.9%), and in the MDS/CMML, the median bone marrow blast percentage was 7% (range, 3-19%). The AML-MRD clearance rate was 19% (4/21; 95% CI 5-42%), and in the MDS/CMML cohort, the overall response rate was 67% (18/27; 95% CI 46-83%). The median overall survival was 13.1 months (95% CI 8.9-NR) for the AML-MRD cohort and 6.5 months (95% CI 4.2-10.3) for the MDS/CMML cohort. The most frequent adverse event was infusion reaction or cytokine relapse syndrome, which occurred in 29 patients (60%) overall, most of which were grade 1-2.
CONCLUSIONS: Vibecotamab was active in low-blast myeloid diseases, although the durability of responses was modest. Additional studies of CD123-targeting bispecific antibodies, alone or in combination, are warranted for these diseases.
TRIAL REGISTRATION: Clinicaltrials.gov (NCT05285813).

Keywords:  Acute myeloid leukemia; Bispecific antibody; Chronic myelomonocytic leukemia; Clinical trial; Immunotherapy; Measurable residual disease; Myelodysplastic syndromes

DOI:  https://doi.org/10.1186/s13045-026-01825-3
bioRxiv. 2026 Jun 24. pii: 2026.06.18.733247. [Epub ahead of print]

Tumor-selective Mcl1 degradation by AUTAC uncouples antitumor efficacy from cardiotoxicity.

Ahmed M Elshazly, Janakiram R Vangala, Adolfo G Mauro, Fadi N Salloum, Senthil K Radhakrishnan.

Mcl1 is a major driver of therapeutic resistance across hematologic malignancies, but direct Mcl1 inhibition has been limited by on-target cardiotoxicity. Here, building on our development of an Mcl1-targeting autophagy-targeting chimera (AUTAC), we show that AUTAC-mediated degradation creates a tumor-selective therapeutic window that spares the heart. AUTAC induced robust cytotoxicity and Mcl1 degradation in multiple myeloma models, while showing minimal toxicity in cardiac cell lines, primary cardiomyocytes, and murine heart tissue. In vivo , AUTAC reduced tumor Mcl1 without measurably affecting cardiac Mcl1. Mechanistically, this selectivity was associated with lower expression of the p62/SQSTM1, TRAF6, and UBC13 machinery required for AUTAC activity in cardiac cells, together with lower intracellular AUTAC accumulation relative to tumor cells. AUTAC also enhanced the antitumor activity of carfilzomib and venetoclax, including in resistant models, without worsening cardiotoxicity or promoting cardiac Mcl1 loss. Compared with classical Mcl1 inhibitors, AUTAC caused markedly less cardiomyocyte death, mitochondrial depolarization, and apoptotic signaling. These findings identify AUTAC-mediated Mcl1 degradation as a cardiac-sparing strategy to target an otherwise clinically constrained vulnerability and support tumor-selective lysosomal degradation as a path to safer Mcl1-directed therapy.

DOI: https://doi.org/10.64898/2026.06.18.733247
Blood Adv. 2026 Jun 30. pii: bloodadvances.2026019712. [Epub ahead of print]

Validation of the newly introduced Deauville Score 5a in patients treated for advanced-stage classic Hodgkin Lymphoma.

Simon Leiders, Dominic Ufton, Helen Kaul, Jasmin Weindler, Johannes Rosenbrock, Michael Fuchs, Markus Dietlein, Urban Novak, Martin Fehr, Richard Greil, Mark Hertzberg, Josée M Zijlstra, Alexander Fosså, Peter Kamper, Daniel Molin, Peter Borchmann, Carsten Kobe, Justin Ferdinandus.

The Lugano Imaging Committee recently refined the Deauville Score (DS), subdividing DS5 into DS5a (>2x liver uptake without new lesions) and DS5b (new lesions). We investigated whether this improves prognostic discrimination at interim positron emission tomography after two cycles (PET-2) in patients with advanced-stage classical Hodgkin lymphoma (AS-cHL) treated in recent GHSG randomized phase III trials. The primary analysis cohort was HD18 post-amendment standard arms (uniform treatment with six cycles of eBEACOPP); sensitivity cohorts were HD18 intention-to-treat, and HD21 eBEACOPP and BrECADD arms. Progression-free survival (PFS) was analyzed by landmark Cox models starting at PET2. DS5a was infrequent (4-6% across cohorts: 39/639; 67/1745; 33/568; 29/560). In the primary cohort, DS5 vs DS1-3 was associated with inferior PFS (hazard ratio [HR] 3.00, 95% confidence interval [CI] 1.25-7.23) and vs DS1-4 (HR 2.35, 95% CI 1.01-5.50). Across sensitivity cohorts, DS5a remained adverse compared with DS1-4 (HR range 2.57-5.47), while DS4 according to the new definition did not consistently separate from DS1-3, which is likely a result of PET-adapted treatment. Overall survival trends were concordant, but interpretation is limited by few events. To our knowledge, this is the first prognostic validation of the refined DS in prospectively randomized trial populations. The newly introduced DS5a isolates a small high-risk AS-cHL, which further supports risk assessment and adaptation using quantitative biomarkers from PET. HD18 NCT00515554; HD21 NCT02661503.

DOI: https://doi.org/10.1182/bloodadvances.2026019712
Anticancer Res. 2026 Jul;46(7): 3831-3844

Src Family Kinase Inhibitors Bosutinib and Dasatinib Enhance ATRA-induced Differentiation of NB4 Leukemia Cells.

Min-Young Lee, Hee-Jeong Cheong, Seug Yun Yoon, Kyoung Ha Kim, Namsu Lee, Rojin Park, Seong Kyu Park, Jong-Ho Won.

   BACKGROUND/AIM: Acute promyelocytic leukemia (APL) has been treated for decades with all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO), which achieve excellent survival but remain limited by induction mortality, ATO-related toxicities, and relapse in some patients. Src family kinases (SFKs) regulate proliferation and survival of myeloid lineage cells, and SFK inhibition has been reported to enhance retinoic acid (RA)-induced differentiation. We investigated whether clinically available SFK inhibitors can augment ATRA-induced differentiation of APL-derived NB4 cells more effectively than the ATRA plus ATO standard regimen.
MATERIALS AND METHODS: NB4 cells were treated with PP2, bosutinib, or dasatinib with or without ATRA. Differentiation was assessed by CD11b expression using flow cytometry and by nitroblue tetrazolium reduction. SFK phosphorylation and retinoic acid receptor (RAR) target gene expression were evaluated by immunoblotting. Apoptosis was analyzed to distinguish differentiation from cytotoxic effects.
RESULTS: ATRA plus ATO modestly increased CD11b-positive cells (17.4%±1.7), whereas ATRA combined with PP2, bosutinib, or dasatinib yielded 49.5%±5.3, 31.4%±2.1, and 53.2%±2.3 CD11b-positive cells, respectively, all significantly higher than ATRA plus ATO (p<0.05). Enhanced granulocytic differentiation was confirmed by nitroblue tetrazolium reduction and was not accompanied by increased apoptosis. SFK inhibitors reduced SFK phosphorylation and increased RAR target protein expression in parallel with augmented differentiation.
CONCLUSION: Clinically available SFK inhibitors, particularly dasatinib, synergistically enhance ATRA-induced myeloid differentiation of NB4 APL cells and are more effective than the conventional ATRA plus ATO combination in this in vitro model. These findings support further preclinical and clinical evaluation of SFK inhibitor plus ATRA combinations as differentiation-oriented strategies and potential alternatives or complements to ATO-containing regimens in APL.

Keywords:  Src-family kinases; acute promyelocytic leukemia; all-trans-retinoic acid; arsenic trioxide; bosutinib; dasatinib

DOI:  https://doi.org/10.21873/anticanres.18244
Blood Cancer J. 2026 Jul 01.

Zanubrutinib combined with R-CHOP in previously untreated diffuse large B-cell lymphoma with specific gene alteration: a phase II study.

Qunling Zhang, Shiyu Jiang, Ran Wei, Wenhao Zhang, Longlong Bao, Yizhen Liu, Jia Jin, Fangfang Lv, Chuanxu Liu, Xiaojian Liu, Hui Sun, Jiachen Wang, Rong Tao, Xiaoyan Zhou, Junning Cao.

Diffuse large B-cell lymphoma (DLBCL) remains clinically heterogeneous, and outcomes with R-CHOP are suboptimal in patients carrying high-risk genomic alterations such as MYD88, CD79B, NOTCH1, TP53 mutations or MYC rearrangements. Many of these lesions are associated with aberrant BCR signaling, and prior studies in relapsed disease have suggested a degree of sensitivity to BTK inhibitors. These observations provided the rationale for evaluating zanubrutinib in the frontline setting for genomically defined high-risk disease. We conducted a prospective, single-center phase II study in previously untreated DLBCL patients aged 18-75 years with one or more of the above molecular features. To accommodate molecular testing time, patients received one initial cycle of R-CHOP, followed by five cycles of zanubrutinib plus R-CHOP (ZR-CHOP). Response was assessed using Lugano 2014 criteria. Primary endpoint is 3-year PFS; key secondary endpoints include ORR, OS, EFS, and safety. From February 2022 to April 2024, 59 patients were enrolled; 58 were evaluable for efficacy. Molecular subtyping identified 25 MCD-like, 16 A53-like, 3 N1-like, 10 other subtypes, and 4 MYC-rearranged cases. The ORR was 91.4% (53/58), with a CMR rate of 79.3% (46/58). MCD-like patients showed particularly favorable responses, with 84% achieving CMR. After a median follow-up of 30.1 months, the estimated 3-year PFS and OS were 80.3% (95%CI 70.5-91.5%) and 89.1% (95%CI 81.2-97.8%), respectively. MCD-like subgroup showed a 3-year OS of 100%, whereas N1-like had markedly poorer survival (2-year OS 33.3%). AEs occurred in 56/59 patients, mostly grade 1-2. Grade ≥ 3 events occurred in 57.6%, most commonly myelosuppression. No atrial fibrillation or other cardiac toxicities were observed. ZR-CHOP demonstrates encouraging activity and acceptable safety in molecularly selected high-risk DLBCL, particularly in the MCD-like subgroup. (ClinicalTrials.gov number, NCT05290337).

DOI: https://doi.org/10.1038/s41408-026-01553-4
Blood Cancer J. 2026 Jun 27.

Circulating CD20-positive extracellular vesicles impair rituximab efficacy and predict outcomes in diffuse large B-cell lymphoma.

Bon Park, Kyung Ju Ryu, Min Kyu Choi, Sang Eun Yoon, Won Seog Kim, Seok Jin Kim.

Rituximab, an anti-CD20 monoclonal antibody, is a cornerstone of therapy for diffuse large B-cell lymphoma (DLBCL), yet a substantial proportion of patients develop treatment failure. While loss of CD20 expression has been considered a major mechanism of resistance, additional mechanisms limiting effective antibody binding remain incompletely understood. We hypothesized that circulating CD20-positive large extracellular vesicles (EVlarge) act as antigen sinks that sequester rituximab and attenuate its therapeutic activity. Circulating CD20-positive EVlarge were quantified from archived serum samples of newly diagnosed DLBCL patients treated with R-CHOP. The prognostic impact of EVlarge levels was evaluated in a training cohort (n = 26) and an independent validation cohort (n = 90). Functional effects of tumor-derived EVlarge were assessed using OCI-Ly1 and U2932 lymphoma cell models and T cell cytotoxicity assays. Rituximab binding to tumor-derived EVlarge was visualized using light-field 4D microscopy. CD20 positivity was consistently higher in EVlarge than in EVsmall across lymphoma cell lines. Tumor-derived CD20-positive EVlarge enhanced lymphoma cell proliferation and attenuated rituximab-mediated growth inhibition. EVlarge also impaired rituximab-mediated cytotoxicity in T cell co-culture assays. Light-field 4D microscopy demonstrated binding of rituximab to EVlarge near the tumor cell surface with reduced antibody binding to lymphoma cells, supporting an antigen-decoy mechanism. Clinically, high pre-treatment levels of circulating CD20-positive EVlarge were associated with significantly inferior disease-specific and overall survival in both training and validation cohorts and remained independently prognostic after adjustment for International Prognostic Index risk. In conclusion, tumor-derived CD20-positive EVlarge represent a novel mechanism of rituximab resistance by reducing effective antibody exposure and impairing immune-mediated cytotoxicity. Circulating CD20-positive EVlarge provide a biologically informative biomarker that predicts clinical outcomes independently of established prognostic factors and may guide optimization of antibody-based therapy in DLBCL.

DOI: https://doi.org/10.1038/s41408-026-01556-1
Blood Neoplasia. 2026 Aug;3(3): 100249

Inhibition of PRMT5 sensitizes B-cell non-Hodgkin lymphoma cells to both intrinsic and extrinsic apoptotic cell death.

Fen Zhu, Jing Wang, Christine E Ryan, Liam Hackett, Jeremy Zhang, Stephanie Chamberlain, Johnson Ung, Stephen J F Chong, Matthew S Davids.

Protein arginine methyltransferase 5 (PRMT5), a type II arginine methyltransferase, is overexpressed in several aggressive B-cell malignancies and facilitates cancer cell proliferation. JNJ-64619178, a selective small-molecule inhibitor targeting PRMT5, has previously shown promising preclinical activity across a range of hematological malignancies; however, the clinical activity of JNJ-64619178 monotherapy is limited despite strong target engagement. Therefore, we sought to identify rational combination partners for JNJ-64619178 to achieve improved activity in B-cell malignancies. Using dynamic Bcl-2 homology 3 (BH3) profiling, a functional assay to evaluate the net increase in proapoptotic signaling in response to drugs, we found that JNJ-64619178 increased overall proximity to apoptotic cell death (mitochondrial apoptotic priming) and dependence on B-cell leukemia/lymphoma (BCL)-2 for survival (BCL-2 dependence), particularly in diffuse large B cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) cell lines. In other B-cell non-Hodgkin lymphoma (B-NHL) cell lines that are primarily MCL-1 dependent and less BCL-2 dependent, JNJ-64619178 increased mitochondrial apoptotic priming without shifting anti-apoptotic dependence from MCL-1 to BCL-2. Co-targeting PRMT5 and BCL-2 synergistically induced apoptosis in DLBCL and MCL cell lines that displayed at least partial BCL-2 dependence at baseline, but not in less BCL-2-dependent B-NHL cell lines. Interestingly, JNJ-64619178 upregulated death receptor 4 (DR4) and death receptor 5 (DR5) expression on the cell membrane of B-NHL cell lines, thereby sensitizing them, including the less BCL-2-dependent cell lines, to recombinant TRAIL-induced extrinsic apoptotic cell death. These findings highlight a role of PRMT5 in regulating both intrinsic and extrinsic apoptosis and suggest potential combination partners with PRMT5 inhibitors for potential clinical application in B-NHL.

DOI: https://doi.org/10.1016/j.bneo.2026.100249
J Med Chem. 2026 Jun 30.

Design and Synthesis of a Novel Covalent Dihydropteridinone Derivative as a Highly Potent and Orally Bioavailable PLK1 Inhibitor for the Treatment of Chronic Myeloid Leukemia.

Jiaxu Zhou, Zhongtang Li, Xiaojiao Sun, Xiangyu Zhang, Cheng Shi, Xiaowei Chi, Dehua Lu, Weiping Lyu, Siyu Xiu, Tingting Yang, Yanming Chen, Zhongwei Wang, Qi Li, Ruqiu Zheng, Jiarui Du, Yu Lin, Jinghao Yan, Tengfei Li, Liangren Zhang, Zhenming Liu.

Polo-like kinase 1 (PLK1) is a validated cancer therapeutic target, but ATP-competitive PLK1 inhibitors have been limited by dose-limiting toxicities. Here, we designed covalent inhibitors that specifically engage the noncatalytic Cys67 residue of the ATP domain. Rational optimization of the warhead and core scaffold led to B9 as a highly potent lead candidate. B9 exhibited low nanomolar enzymatic inhibition and exceptional cellular potency (IC50 = 0.4 nM in K562 leukemia cells), representing a >150-fold improvement over the reversible reference compound BI2536 (61 nM). B9 also showed favorable overall selectivity against nonrelated kinases. Remarkably, B9 achieved 77.6% oral bioavailability in mice. In an orthotopic K562 leukemia xenograft model, oral administration of B9 significantly suppressed the bioluminescence of leukemia burden and extended survival rates to 100% over 42 days without observable toxicity. These findings underscore the potential of B9 as a safe, orally bioavailable, and highly potent PLK1 inhibitor for preclinical development.

DOI: https://doi.org/10.1021/acs.jmedchem.6c01512