bims-hemali 2026-05-17 papers

bims-hemali

Biomed News

on Hematologic malignancies

Issue of 2026–05–17
29 papers selected by
Alexandros Alexandropoulos, Γενικό Νοσοκομείο Αθηνών Λαϊκό

Circular RNA in chronic myeloid leukemia.
Pruning the Waldenström macroglobulinemia evolutionary tree.
Daratumumab-Bortezomib-Cyclophosphamide-Dexamethasone in Newly Diagnosed Amyloidosis: ANDROMEDA Final Survival Analysis.
One-time treatment to rule them all?
A Comprehensive Review of the Role of Zanubrutinib for Patients with Chronic Lymphocytic Leukemia.
Impaired iron balance and erythrocytosis: a complex relationship.
Long-term safety and efficacy of ponatinib in intolerant chronic myeloid leukemia: subanalysis of the observational study of Iclusig® (ponatinib) treatment in patients with chronic myeloid leukemia in Italy.
Indirect Treatment Comparisons of Lisocabtagene Maraleucel Versus Axicabtagene Ciloleucel and Tisagenlecleucel in Third-Line or Later Relapsed or Refractory Follicular Lymphoma.
Dynamic improvement of the treatment-free remission prognostic score by prolonging MR4 duration in chronic myeloid leukaemia.
Plasmablastic Lymphoma: 2026 Update on Diagnosis, Risk Stratification, and Management.
Timing of Tyrosine Kinase Inhibitor Switching in Chronic Myeloid Leukemia: A Comparative Analysis of Early Versus Late Strategies.
Model-Informed Dosing Strategies for Epcoritamab Monotherapy in Relapsed or Refractory Large B-Cell Lymphoma.
Rilzabrutinib for persistent or chronic immune thrombocytopenia (ITP): a Bruton tyrosine kinase inhibitor that can target multiple pathophysiological pathways.
PSMD1 and myeloma: striking the proteasome from a new angle.
Outcomes Among MM Patients Receiving Early Intervention for MRD Progression Following Autologous Stem Cell Transplantation.
Stuck in traffic: a bispecific antibody-mediated immune re-engagement after allogeneic stem cell transplantation.
A venetoclax-cytarabine-based induction regimen incorporating a translation inhibitor for adult patients with de novo acute myeloid leukemia.
Comprehensive mutational profiling and clinical outcome of adult acute myeloid leukemia patients with NUP98 rearrangement.
Prognostic Value of Combined Baseline FDG PET/CT Radiomic Parameters in Primary Mediastinal B-Cell Lymphoma.
Clinical benefit and predictors of response to momelotinib after ruxolitinib failure: A cooperative real-world study.
Mezigdomide reverses T-cell exhaustion through degradation of IKZF1/IKZF3 and reinvigoration of cytokine production pathways.
Lisaftoclax combined with ixazomib and dexamethasone after CAR-T for maintenance therapy in transplant-ineligible relapsed/refractory ultra-high-risk multiple myeloma: two case reports and literature review.
Modulating CD38 enzymatic activity during antibody-based immunotherapy in multiple myeloma: a basic science perspective.
CD56+/CD38+ Neutrophils: Rapid and Specific Flow Cytometric Signature for Chronic Myeloid Leukemia.
Glofitamab and epcoritamab for large B cell lymphoma: a real-world retrospective UK analysis of efficacy, tolerability, and impact of treatment sequencing.
Hodgkin Reed-Sternberg Cells of Classic Hodgkin Lymphoma: Morphology, Phenotype, Genotype, and Cell of Origin.
From Platelet Toxicity to Precision Targeting: Evolving Strategies to Overcome Thrombocytopenia in BCL-2/BCL-XL Inhibition.
Dermatologic Toxicities Induced by JAK Inhibitors.
Molecular Mechanisms of Resistance to Bispecific Antibodies in Diffuse Large B-Cell Lymphoma.

Blood. 2026 May 14. 147(20): 2285-2286

Circular RNA in chronic myeloid leukemia.

Carlo Gambacorti-Passerini.

DOI: https://doi.org/10.1182/blood.2026033266
Blood. 2026 May 14. 147(20): 2279-2280

Pruning the Waldenström macroglobulinemia evolutionary tree.

Patrick Blaney, Gareth J Morgan.

DOI: https://doi.org/10.1182/blood.2026033492
Blood. 2026 May 12. pii: blood.2025032099. [Epub ahead of print]

Daratumumab-Bortezomib-Cyclophosphamide-Dexamethasone in Newly Diagnosed Amyloidosis: ANDROMEDA Final Survival Analysis.

Efstathios Kastritis, Giovanni Palladini, Monique C Minnema, Ashutosh D Wechalekar, Arnaud Jaccard, Hans C Lee, Vaishali Sanchorawala, Peter Mollee, Jin Lu, Stefan O Schönland, Moshe E Gatt, Kenshi Suzuki, Kihyun Kim, M Teresa Cibeira, Manisha Bhutani, Meral Beksac, Edward N Libby, Jason Valent, Vania Hungria, Michael A Rosenzweig, Naresh Bumma, Antoine Huart, Meletios-Athanasios A Dimopoulos, Divaya Bhutani, Adam Waxman, Stacey Goodman, Jeffrey A Zonder, Selay Lam, Kevin W Song, Timon Hansen, Salomon Manier, Wilfried W H Roeloffzen, Krzysztof Jamroziak, Fiona Kwok, Chihiro Shimazaki, Jin-Seok Kim, Edvan de Queiroz Crusoé, NamPhuong Tran, Jianping Wang, Yuping Chen, Sandra Y Vasey, Jordan M Schecter, Jessica Vermeulen, Raymond Comenzo, Giampaolo Merlini.

In the primary analysis of ANDROMEDA, addition of subcutaneous daratumumab to bortezomib/cyclophosphamide/dexamethasone (D-VCd) significantly improved hematologic complete response (CR) rate versus VCd, establishing D-VCd as the only approved therapy for light-chain (AL) amyloidosis. We present results from the preplanned final analysis. In this phase 3 trial, we randomly assigned 388 patients with newly diagnosed AL amyloidosis to six cycles of VCd alone (control group) or with subcutaneous daratumumab (D-VCd) followed by single-agent daratumumab every 4 weeks for up to 24 total cycles. The primary endpoint was hematologic CR. The updated hematologic CR rate was 59.5% for D-VCd versus 19.2% for VCd (odds ratio, 6.03; 95% confidence interval [CI], 3.80-9.58; P<0.0001). Median time to hematologic CR was shorter with D-VCd (67.5 days [range, 8.0-879.0]) versus VCd (85.0 days [range, 14.0-617.0]). With a median follow-up of 61.4 months, significant improvement was observed with D-VCd versus VCd in major organ deterioration-progression-free survival (hazard ratio, 0.44; 95% CI, 0.31-0.63; P<0.0001) and overall survival (hazard ratio, 0.62; 95% CI, 0.42-0.90; P=0.0121). Cardiac and renal response rates were 2-3 times higher with D-VCd versus VCd. Achieving hematologic or cardiac CR was associated with improved major organ deterioration-progression-free survival and overall survival. Adverse events were consistent with the known safety profiles for VCd and daratumumab. Adding daratumumab to VCd resulted in deeper and more rapid hematologic responses and recovery of organ function, translating to statistically significant improvement in both overall survival and major organ deterioration-progression-free survival in newly diagnosed AL amyloidosis. ClinicalTrials.gov NCT03201965.

DOI: https://doi.org/10.1182/blood.2025032099
Blood. 2026 May 14. 147(20): 2288-2289

One-time treatment to rule them all?

Annkristin Heine.

DOI: https://doi.org/10.1182/blood.2026033165
Oncol Ther. 2026 May 14.

A Comprehensive Review of the Role of Zanubrutinib for Patients with Chronic Lymphocytic Leukemia.

Paolo Ghia, Jennifer R Brown, Mazyar Shadman, Clemens-Martin Wendtner.

  The approval of ibrutinib over a decade ago introduced Bruton tyrosine kinase (BTK) inhibition as a foundational, chemotherapy-free treatment approach for chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). A continuous single-agent BTK inhibitor (BTKi) or a time-limited B cell lymphoma 2 inhibitor (BCL2i)-based regimen plus an anti-CD20 monoclonal antibody or BTKi is now standard of care for CLL/SLL. Although ibrutinib offers durable remission for many patients, its use is limited by side effects associated with inhibition of kinases other than BTK (off-target effects). The second-generation BTKi zanubrutinib was developed to provide sustained BTK inhibition with greater selectivity for BTK in order to improve clinical efficacy and tolerability with minimized off-target effects. The head-to-head ALPINE study of patients with relapsed/refractory (R/R) CLL/SLL demonstrated superior efficacy with zanubrutinib versus ibrutinib, with superior overall response rates and prolonged progression-free survival (PFS), while acalabrutinib demonstrated non-inferior PFS outcomes versus ibrutinib in patients with high-risk R/R CLL/SLL. Data also showed improved safety outcomes with zanubrutinib versus ibrutinib with significantly lower rates of atrial fibrillation/flutter, and infection, and a trend toward lower rates of other adverse events associated with ibrutinib, with the exception of neutropenia. This is reflected in treatment guidelines for CLL, where zanubrutinib and the other approved second-generation BTKi, acalabrutinib, are recommended over ibrutinib owing to their superior safety profiles (particularly reduced cardiotoxicity). In this review, we consider the pharmacologic properties of zanubrutinib that differentiate it from ibrutinib and acalabrutinib, and provide a comprehensive overview of the efficacy and safety data that led to zanubrutinib monotherapy becoming a preferred therapy for a significant subgroup of patients with CLL/SLL. We also highlight trials in CLL/SLL and Richter's transformation with zanubrutinib in targeted therapy combinations that offer the potential for time-limited treatment courses.

Keywords:  Acalabrutinib; Chronic lymphocytic leukemia; Human Bruton tyrosine kinase; Ibrutinib; Small lymphocytic lymphoma; Zanubrutinib

DOI:  https://doi.org/10.1007/s40487-026-00443-w
Blood Cancer J. 2026 May 12.

Impaired iron balance and erythrocytosis: a complex relationship.

Benoît Gendrot, Carole Peyssonnaux, Isabelle Plo, Sophie Vaulont, Guillemette Fouquet.

Erythropoiesis and iron metabolism are closely interconnected, under both physiological and pathological conditions. Polycythemia vera (PV) is a myeloproliferative neoplasm (MPN) caused by a Janus kinase-2 (JAK2) mutation, resulting in uncontrolled red blood cell production and elevated hemoglobin and hematocrit levels. In PV, iron deficiency is common and may be due to several factors, including chronic gastrointestinal bleeding, chronic inflammation, dysregulated hepcidin signaling, and therapeutic phlebotomy. Many patients exhibit low serum ferritin and low to normal hepcidin levels despite erythroid proliferation, suggesting a maladaptive iron-restricted state. This functional iron deficiency may limit erythropoiesis to some extent, but also contributes to burdensome symptoms such as fatigue, cognitive impairment, and restless leg syndrome. Novel therapeutic approaches, including hepcidin mimetics or ferroportin inhibitors, aim to restore iron homeostasis, improving quality of life and potentially reducing the need for cytoreductive therapy (drugs used to treat MPNs by reducing blood cell production) in low-risk PV patients. In secondary forms of erythrocytosis (both congenital and acquired), iron homeostasis has been less often investigated. However, exploring it may be of great interest since in these affections, iron overload could act as a hidden driver of erythrocytosis by stimulating erythroblast proliferation. Hereditary hemochromatosis (HH) is a well-known cause of iron overload. While its association with erythrocytosis has been a subject of interest, it remains incompletely understood. In this review, we will explore the complex relationship between iron (deficiency or overload, including HH) and erythrocytosis (including PV), discussing underlying mechanisms and potential therapeutic applications.

DOI: https://doi.org/10.1038/s41408-026-01516-9
Haematologica. 2026 May 14.

Long-term safety and efficacy of ponatinib in intolerant chronic myeloid leukemia: subanalysis of the observational study of Iclusig® (ponatinib) treatment in patients with chronic myeloid leukemia in Italy.

Massimo Breccia, Alessandra Iurlo, Fabrizio Pane, Anna Rita Scortechini, Antonella Russo Rossi, Marco Santoro, Marco Cerrano, Francesca Lunghi, Alessandro Maggi, Nicola Di Renzo, Valeria Sargentini, Alfonso Piciocchi, Claudia Tringali, Alessandra Malato.

Not available.

DOI: https://doi.org/10.3324/haematol.2026.300586
Adv Ther. 2026 May 15.

Indirect Treatment Comparisons of Lisocabtagene Maraleucel Versus Axicabtagene Ciloleucel and Tisagenlecleucel in Third-Line or Later Relapsed or Refractory Follicular Lymphoma.

Alexander P Boardman, Juan Luis Reguera Ortega, Pearl Wang, Merav Bar, Jinender Kumar, Thalia Farazi, Alejandro Martín García-Sancho, Koji Izutsu.

   INTRODUCTION: No head-to-head clinical trials have compared CD19-directed chimeric antigen receptor (CAR) T cell therapies for treatment of follicular lymphoma (FL). We conducted matching-adjusted indirect comparisons (MAICs) between lisocabtagene maraleucel (liso-cel), axicabtagene ciloleucel (axi-cel), and tisagenlecleucel (tisa-cel), to establish their relative efficacy and safety in patients with third-line or later (3L+) relapsed or refractory (R/R) FL.
METHODS: Sources included individual patient data from TRANSCEND FL (NCT04245839) for liso-cel, summary-level data from ZUMA-5 (NCT03105336) for axi-cel, and summary-level data from ELARA (NCT03568461) for tisa-cel. For each MAIC, TRANSCEND FL patients who met inclusion/exclusion criteria for the comparator study were included. MAICs adjusted for clinically relevant prognostic factors identified a priori to minimize population differences between studies.
RESULTS: After adjustment, liso-cel had a higher complete response (CR) rate than axi-cel (response ratio [RR] 1.24, 95% confidence interval [CI] 1.07‒1.43) and tisa-cel (RR 1.36, 95% CI 1.11‒1.68) and a higher overall response rate (ORR) than tisa-cel (RR 1.12, 95% CI 1.01‒1.24). Estimates numerically favored liso-cel for progression-free survival, duration of response, overall survival, and time to next treatment, though were not statistically significant. Liso-cel demonstrated better safety than axi-cel, with significantly reduced odds ratios (ORs) of grade ≥ 3 cytokine release syndrome (CRS; OR 0.07, 95% CI 0.01‒0.58), tocilizumab use for CRS (OR 0.20, 95% CI 0.09‒0.44), any-grade neurological events (NEs; OR 0.14, 95% CI 0.05‒0.38), and infections (OR 0.42, 95% CI 0.19‒0.93). Liso-cel and tisa-cel had similar safety profiles overall, excluding any-grade NEs, which was significantly lower for liso-cel (OR 0.19, 95% CI 0.08‒0.45).
CONCLUSION: After adjustment for population differences, liso-cel demonstrated a higher CR rate and numerically favorable trends of survival compared to axi-cel and tisa-cel with improved safety compared to axi-cel, and similar safety compared to tisa-cel. These findings underscore liso-cel as a potentially preferred CAR T cell therapy for 3L+ R/R FL. Graphical Abstract available for this article.

Keywords:  Axicabtagene ciloleucel; CAR T cell therapy; ELARA; Follicular lymphoma; Indirect treatment comparison; Lisocabtagene maraleucel; Matching-adjusted indirect comparison; TRANSCEND FL; Tisagenlecleucel; ZUMA-5

DOI:  https://doi.org/10.1007/s12325-026-03596-2
Br J Haematol. 2026 May 11.

Dynamic improvement of the treatment-free remission prognostic score by prolonging MR4 duration in chronic myeloid leukaemia.

Mai Fujita, Hiroshi Ureshino.

DOI: https://doi.org/10.1111/bjh.70558
Am J Hematol. 2026 May 15.

Plasmablastic Lymphoma: 2026 Update on Diagnosis, Risk Stratification, and Management.

Jorge J Castillo, Brady E Beltrán, Jorge A Florindez, Julio C Chavez, Luis Malpica.

DISEASE OVERVIEW: Plasmablastic lymphoma (PBL) is a rare CD20-negative aggressive lymphoma with poor prognosis when treated with standard treatment options. Although PBL is associated with HIV infection and other immunosuppressed states, it can also affect immunocompetent individuals.
DIAGNOSIS: The diagnosis of PBL requires a high clinical suspicion and pathological confirmation. EBV-encoded RNA (EBER) expression and MYC gene rearrangements are frequently detected in the malignant cells. The differential diagnosis includes EBV+ diffuse large B-cell lymphoma (DLBCL), extracavitary primary effusion lymphoma, ALK+ DLBCL, and HHV8+ large B-cell lymphoma, among others.
RISK STRATIFICATION: Age ≥ 60 years, advanced clinical stage, and high International Prognostic Index scores are associated with worse survival.
MANAGEMENT: Combination chemotherapy regimens, such as infusional EPOCH, are recommended. The addition of bortezomib or daratumumab might improve outcomes. B-cell maturation antigen-targeted therapies have shown early efficacy. The participation of patients with PBL in prospective clinical trials is warranted.

DOI: https://doi.org/10.1002/ajh.70373
Clin Lymphoma Myeloma Leuk. 2026 Apr 14. pii: S2152-2650(26)00101-1. [Epub ahead of print]

Timing of Tyrosine Kinase Inhibitor Switching in Chronic Myeloid Leukemia: A Comparative Analysis of Early Versus Late Strategies.

Chidiebube Ugwu, Tarfa Verinumbe, Folajimi Atunde, Ana Chachua, Nneoma Ubah, Muluken Megiso, Angimar Uriepero-Palma, Sam King, Elvis Obomanu, Colton Jones, Gabor Varadi, Alankrita Taneja.

   BACKGROUND: Optimal timing for switching tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) remains uncertain. While early molecular milestones inform treatment decisions, real-world evidence evaluating how the timing of TKI switch influences survival and toxicity is limited.
METHODS: Using the TriNetX US Collaborative Network, we identified adults with CML treated with first-line imatinib, dasatinib, or nilotinib between 2000 and 2022. Patients were categorized as early switchers (≤3 months), late switchers (>12 months), or monotherapy continuers. Propensity score matching (1:1) was performed for three comparisons per TKI: early switching versus monotherapy, late switching versus monotherapy, and early versus late switching. The primary outcome was overall survival; secondary outcomes included hematologic toxicity, cardiovascular events, metabolic complications, and healthcare utilization.
RESULTS: Among 15,967 patients, 3309 (20.7%) underwent TKI switching (776 early, 2,533 late). Early switching was associated with numerically higher mortality without statistical significance (imatinib HR: 1.34; dasatinib HR: 1.15), but significantly higher mortality than late switching in imatinib-treated patients (HR: 2.38). Late switching showed no consistent survival difference across any TKI; imatinib late switchers had increased stroke (HR: 2.09) and pleural effusion (HR: 1.72). Agent-specific complications included heart failure and pleural effusion with imatinib early switching, and anemia, diabetes, and hyperlipidemia with dasatinib early switching.
CONCLUSION: Timing of TKI switching was associated with outcome differences in CML without consistent survival effects. Early switching in imatinib-treated patients carried higher mortality than late switching, suggesting timing reflects underlying disease risk rather than a direct treatment effect. These findings support individualized decision-making incorporating response trajectory, comorbidities, and cumulative toxicity over fixed timepoint thresholds.

Keywords:  CML; Dasatinib; Imatinib; Nilotinib; Real world study; TKI; TKI Switch

DOI:  https://doi.org/10.1016/j.clml.2026.04.001
Clin Pharmacol Ther. 2026 May 15.

Model-Informed Dosing Strategies for Epcoritamab Monotherapy in Relapsed or Refractory Large B-Cell Lymphoma.

Xiaozhi Liao, Tommy Li, Steven Xu, Mohamed-Eslam F Mohamed, Mahipal Sinnollareddy, Manish Gupta, Monica Wielgos-Bonvallet, Andrew J Steele, Mariana Sacchi, Yanguang Cao.

Dose selection is a central challenge in drug development, and direct evaluation of alternative regimens is often ethically difficult. We developed a joint model integrating pharmacokinetics, pharmacodynamics, and Deauville score to evaluate alternative dosing strategies for a CD3 × CD20 bispecific antibody, epcoritamab, as monotherapy in relapsed or refractory (R/R) large B-cell lymphoma (LBCL) after ≥2 lines of systemic therapy. The model was developed using clinical data from 165 patients and simultaneously described plasma epcoritamab concentrations, tumor burden dynamics, and longitudinal Deauville scores. Simulations were conducted in 1,000 virtual patients to evaluate three post-complete response (CR) dosing strategies: continuous, fixed-duration, and stop-at-CR. Responder subgroups were defined based on CR durability, and predictors of patients likely to require continuous treatment were explored. Simulations indicated that continued epcoritamab treatment after CR was associated with higher simulated CR rates over the long term, with simulated 2-year CR rates of 46.4% (continuous), 37.2% (fixed-duration), and 27.0% (stop-at-CR). Exploratory analyses suggested that indicators of residual disease, such as limited early tumor reduction and elevated circulating tumor DNA levels, help identify patients most likely to benefit from continuous treatment. This modeling framework provides a quantitative approach for evaluating alternative dosing strategies for epcoritamab monotherapy in R/R LBCL and supports the potential value of continuous therapy in maintaining long-term CR, as suggested by model-based simulations. However, this study focuses solely on efficacy outcomes; therefore, further validation and incorporation of safety outcomes are needed to fully support clinical decision-making and regimen optimization.

DOI: https://doi.org/10.1002/cpt.70336
Expert Rev Hematol. 2026 May 13. 1-12

Rilzabrutinib for persistent or chronic immune thrombocytopenia (ITP): a Bruton tyrosine kinase inhibitor that can target multiple pathophysiological pathways.

Ahmed Mjali, Sylvain Audia, Yoshitaka Miyakawa, Waleed Ghanima.

   INTRODUCTION: Immune thrombocytopenia (ITP) is characterized by reduced platelet production and platelet destruction. Despite the availability of numerous treatments, many patients develop treatment resistance, experience relapse, or suffer from persistent symptoms such as fatigue, highlighting the need for innovative immune-modulating techniques. This review highlights the chemical properties, clinical efficacy and safety evidence for rilzabrutinib.
AREAS COVERED: Bruton tyrosine kinase (BTK) is a promising therapeutic target in ITP as it is essential for B-cell receptor signaling, Fcγ receptor-mediated platelet clearance, and inflammatory amplification. Rilzabrutinib is a reversible, covalent oral BTK inhibitor developed to treat immune-mediated disorders. It targets several pathogenic immunological pathways. In the phase 2 LUNA 2 trial and the subsequent randomized, placebo-controlled, phase 3 LUNA 3 study, rilzabrutinib was clinically evaluated in patients with persistent or chronic ITP. The treatment resulted in durable platelet responses in extensively pretreated patients, decreased bleeding episodes, and led to significant improvements in patient-reported fatigue. The safety profile was generally good with adverse events considered mild to moderate.
EXPERT OPINION: The approval of rilzabrutinib for persistent and chronic ITP represents an important addition to the therapeutic armamentarium for the disease. The drug's full potential will be further defined in future studies.

Keywords:  Immune thrombocytopenia; bruton tyrosine kinase inhibitor; pathophysiology; platelet; rilzabrutinib

DOI:  https://doi.org/10.1080/17474086.2026.2672113
Blood. 2026 May 14. 147(20): 2282-2283

PSMD1 and myeloma: striking the proteasome from a new angle.

Enrico Milan, Simone Cenci.

DOI: https://doi.org/10.1182/blood.2025033018
Cancer Med. 2026 May;15(5): e71911

Outcomes Among MM Patients Receiving Early Intervention for MRD Progression Following Autologous Stem Cell Transplantation.

Xiaozhe Li, Meilan Chen, Lifen Kuang, Junru Liu, Beihui Huang, Juan Li.

  Minimal residual disease (MRD) testing is essential for evaluating treatment response among multiple myeloma (MM) patients. Many patients experience MRD progression (MRD-P) before they meet the criteria for clinical or biochemical progression (PD), thus raising questions about the timing of treatment. In this retrospective study, the effect of early intervention (EI) on prognosis was investigated among 42 newly diagnosed MM patients who developed MRD-P after initial treatment with autologous stem cell transplantation. In the EI group (n = 9), treatment was modified at the onset of MRD-P; in the PD group (n = 33), treatment was delayed until disease progression occurred. At a median follow-up of 25 months, compared with the PD group, the EI group demonstrated a longer time to progression (median 34.8 months vs. 6.6 months, p = 0.029), superior overall survival (median not reached vs. 41.0 months, p = 0.034), and significantly higher MRD re-negativity rates (median 12.6 months vs. 75.9 months, p < 0.001). Multivariate analysis revealed that early intervention was significantly associated with improved MRD re-negativity (HR = 0.07; p = 0.001). This hypothesis-generating retrospective study demonstrated that early intervention at MRD-P onset was associated with improved survival outcomes and higher rates of MRD re-negativity in this cohort. Despite significant limitations, such as the small sample size, nonrandomized design, and unmeasured confounders, these findings provide preliminary data to inform the design of future prospective randomized trials.

Keywords:  MRD progression; autologous stem cell transplantation (ASCT); early intervention; minimal residual disease (MRD); multiple myeloma (MM)

DOI:  https://doi.org/10.1002/cam4.71911
Haematologica. 2026 May 14.

Stuck in traffic: a bispecific antibody-mediated immune re-engagement after allogeneic stem cell transplantation.

Stephanie Boisclair, Monica Wallin, Sally Ko, Douglas E Gladstone.

Not available.

DOI: https://doi.org/10.3324/haematol.2026.300890
Cancer. 2026 May 15. 132(10): e70432

A venetoclax-cytarabine-based induction regimen incorporating a translation inhibitor for adult patients with de novo acute myeloid leukemia.

Xiao-Hua Luo, Na-Na Tang, Li Wang, Yan Zhu, Lin Liu, Shuang-Nian Xu, Li Yang, Cai-Xia Pei, Qian Zhan, Xin Wang, Jian-Bin Chen.

   BACKGROUND: Translation inhibitors have been shown to accelerate acute myeloid leukemia (AML) cell apoptosis and regulate Akt activity and the Bcl-2 family, suggesting their potential benefit when combined with venetoclax and cytarabine in de novo AML patients.
METHODS: The authors conducted a multicenter, open-label, single-arm study to assess the efficacy and safety of a venetoclax-cytarabine-based induction regimen incorporating a clinically available translation inhibitor in adult patients newly diagnosed with AML in China.
RESULTS: A total of 52 cases (median age, 48.5 years; range, 18-60) were treated, with poor risk in 27% (14 of 52) of patients. The overall response rate was 90% (95% CI, 79-97) after one cycle of the regimen with 46 patients in composite complete remission. With a median follow-up of 816 days (interquartile range, 418-1143), the estimated 1-year overall survival (OS) and event-free survival (EFS) were both 81% (95% CI, 71-92). After induction chemotherapy, patients experienced decreases in CD4+ naive, CD8+ naive, Th2, and CD19+ cells, along with increases in CD4+ TEM, Th1, natural killer cells, and a higher Th1/Th2 ratio in both peripheral blood and bone marrow (BM), whereas BM-specific changes included a decrease in CD8+ naive cells and lower IL-10 levels post-treatment.
CONCLUSION: This venetoclax-cytarabine regimen incorporating a translation inhibitor demonstrated efficacy and was well-tolerated in young adult patients with de novo AML, achieving high complete remission rates and encouraging OS and EFS. The induced immune-cell and cytokine shifts provide deeper insights into integrating translational inhibition with BCL2-targeted therapies and warrant further investigation in randomized controlled trials. This trial was registered at ChiCTR.org.cn as ChiCTR2100048208.

Keywords:  acute myeloid leukemia; immunophenotype; translation inhibitor; venetoclax

DOI:  https://doi.org/10.1002/cncr.70432
Leukemia. 2026 May 12.

Comprehensive mutational profiling and clinical outcome of adult acute myeloid leukemia patients with NUP98 rearrangement.

Benoit Ducourneau, Arnaud Pages, Stéphanie Struski, Matthieu Decamp, Emmanuel Raffoux, Céline Berthon, Laurène Fenwarth, Vincent Marmouset, Cécile Pautas, Thomas Cluzeau, Delphine Lebon, Madalina Uzunov, Patricio Pereyra, Maël Heiblig, Jean-Valère Malfuson, Laure Farnault, Pierre-Yves Dumas, Julia Hieulle, Sarah Bertoli, Sylvain Chantepie, Nathalie Auger, Audrey Bidet, Marie-Joelle Mozziconacci, Augustin Boudry, Isabelle Luquet, Laureen Chat, Romain Loyaux, Lina El-Mur, Emmanuelle Clappier, Claude Gardin, Mathilde Hunault, Stéphane De Botton, Arnaud Pigneux, Dominique Penther, Eric Delabesse, Raphael Itzykson, Claude Preudhomme, Hervé Dombret, Christian Recher, Nicolas Duployez, Jean-Baptiste Micol.

We report a large cohort of 95 adult patients with acute myeloid leukemia (AML) harboring NUP98 rearrangements (NUP98r). Patient characteristics included a young age (median 50 years [IQR 38-64]), 20% of therapy-related AML, a high WBC count (median 52×109/L), normal karyotype in 32%, FLT3-ITD in 48% and WT1 mutations in 34%. NUP98::NSD1 fusion was the most common (54%), and these patients were significantly younger (41 y vs. 61 y), had more de novo AML (94% vs. 64%), higher rates of normal karyotypes (56% vs. 4.5%), FLT3-ITD (76% vs. 18%) and WT1 mutations (50% vs. 16%) than other NUP98r AML. The median overall survival (OS) for the entire cohort was 15.2 months (95% CI, 11.9-20.8) and event-free survival was 5.8 months (2-7.5). Among patients treated intensively (n = 73), age (HR = 2.7), FLT3 inhibitor therapy (HR = 0.45) and hematopoietic stem cell transplant (HR = 0.5) influenced OS in univariate analysis. Compared with NUP98 wild-type (WT) AML, NUP98r patients had a prognosis more similar to that of NUP98 WT ELN adverse patients whether initially classified as intermediate (20.3 months [11.7-30.2]) or adverse (15.7 months [13.5-42.9]). However, treatment with FLT3 inhibitors improved prognosis, with median OS not reached and 5-year OS of 53.3%, approaching that of intermediate-risk patients.

DOI: https://doi.org/10.1038/s41375-026-02973-8
Blood Adv. 2026 May 12. pii: bloodadvances.2026020168. [Epub ahead of print]

Prognostic Value of Combined Baseline FDG PET/CT Radiomic Parameters in Primary Mediastinal B-Cell Lymphoma.

Pierre Decazes, Cedric Rossi, Pierre Sesques, Stéphanie Becker, Mathieu Viennot, Sorina-Dana Mihailescu, François Lemonnier, Eric Durot, Nicolas Gower, Alexandre Willaume, Lucie Obéric, Jérôme Paillassa, Chloe Antier, Loic Renaud, Olivier Tournilhac, Catherine Thieblemont, Caroline Besson, Laure Lebras, Sylvain Choquet, Katell Le Dû, Christophe Bonnet, Sarah Bailly, Gandhi-Laurent Damaj, Kamel Laribi, Nadine Morineau, Roch Houot, Adrien Chauchet, Fabrice Jardin, Hervé Tilly, Elena-Liana Veresezan, Fanny Drieux, Marie Donzel, Alexandra Traverse-Glehen, David Tonnelet, Vincent Camus.

Primary mediastinal B-cell lymphoma (PMBL) is an uncommon aggressive lymphoma with generally favorable outcomes; however, 15-20% of patients develop refractory disease. Reliable baseline prognostic biomarkers remain lacking. We evaluated the prognostic value of radiomic parameters derived from baseline 18F-FDG PET/CT in newly diagnosed PMBL. This post-hoc analysis included 180 treatment-naïve patients from the multicenter LYSA cohort (2007-2017) treated with rituximab plus ACVBP, R-CHOP14, or R-CHOP21. Twelve 3D PET-derived radiomic features were extracted using Oncometer3D. Inter-parameter correlations were assessed using Spearman coefficients. Receiver operating characteristic (ROC) analyses determined optimal cut-offs. Progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan-Meier estimates and Cox regression models. Four clusters of correlated features were identified: activity, tumor burden, massiveness/fragmentation, and dispersion. Among these, total metabolic tumor volume (TMTV), maximal inter-lesion distance (Dmax), and median peripheral centroid distance (medPCD) demonstrated the strongest prognostic associations. TMTV and Dmax were significantly associated with shorter PFS and OS, while medPCD predicted OS. In multivariable analysis adjusted for IPI, bulky disease, B symptoms, and treatment regimen, a composite radiomic score (2-3 high-risk features vs 0-1) independently predicted OS (HR 7.76, 95% CI 1.59-37.74) and showed a strong trend for PFS. The composite score outperformed conventional clinical risk factors. Baseline PET-derived radiomic features capturing tumor burden, spatial dispersion, and compactness provide independent prognostic information in PMBL. A three-parameter radiomic score outperformed conventional risk factors and identified a high-risk subgroup at diagnosis, warranting prospective and external validation before clinical implementation.

DOI: https://doi.org/10.1182/bloodadvances.2026020168
Cancer. 2026 May 15. 132(10): e70457

Clinical benefit and predictors of response to momelotinib after ruxolitinib failure: A cooperative real-world study.

Francesca Palandri, Monia Marchetti, Elena M Elli, Alessandro Isidori, Ilaria Gianesello, Chiara Sartor, Novella Pugliese, Maria Di Perna, Erika Morsia, Susanna Gallo, Federico Itri, Vittorio Montefusco, Elena Crisà, Annalisa Biagi, Eloise Beggiato, Olga Mulas, Giulia Benevolo, Elisabetta Abruzzese, Marco Santoro, Alessandra Iurlo, Elisabetta Calistri, Marco Rossi, Bruno Martino, Mario Tiribelli, Carmen Fava, Arbana Dizdari, Monica Crugnola, Andrea Duminuco, Amedeo Votto, Selene Guerzoni, Giovanni Caocci, Fabrizio Pane, Francesco Lanza, Filippo Branzanti, Alessandra Dedola, Flavia Salvatore, Florian H Heidel, Massimo Breccia, Giuseppe A Palumbo, Andrew T Kuykendall, Alessandro Lucchesi, Sara Galimberti.

   BACKGROUND: Momelotinib, a JAK1/JAK2/ACVR1 inhibitor, is approved for treating myelofibrosis with splenomegaly, symptoms, and moderate-to-severe anemia. Evidence on its real-world effectiveness after ruxolitinib failure is limited.
METHODS: This study retrospectively analyzed 221 patients who received momelotinib after ruxolitinib failure by assessing spleen, symptom, and anemia responses, safety, and survival. Logistic regression analyses identified the responses' predictors.
RESULTS: Before momelotinib initiation, all patients had received ruxolitinib for a median of 31.5 months and discontinued as a result of resistance (29.9%), intolerance (48.0%), or both (22.1%). At baseline, all patients started at full dose; 97.3% presented with cytopenia, 34.8% presented with large splenomegaly, and 43.9% were highly symptomatic. Most patients (74.7%) switched from ruxolitinib stop to momelotinib within 2 months without tapering, whereas 18.1% waited over a year. After a median exposure of 8.2 months, adverse events occurred in 35.7% of patients, which prompted dose reductions or permanent discontinuation in 12.7% and 19.9% of cases, respectively. At 6 months, 30.0% achieved ≥50% spleen length reduction (SR50), with higher responses in those with prior SR50 to ruxolitinib and shorter transition intervals. Symptom and anemia responses occurred in 39.2% and 63.4% of cases, respectively. After a median follow-up of 10.3 months, 11 patients (5.0%) progressed to blast phase, and 37 patients (16.7%) died. Two-year overall and progression-free survival (including death and blast phase transformation) were 60.9% and 59.0%, respectively.
CONCLUSIONS: Momelotinib demonstrated meaningful clinical benefit and acceptable safety in cytopenic patients pretreated with ruxolitinib, which supports its role after ruxolitinib failure.

Keywords:  anemia; cytopenia; momelotinib; myelofibrosis; thrombocytopenia

DOI:  https://doi.org/10.1002/cncr.70457
Blood. 2026 May 12. pii: blood.2025030873. [Epub ahead of print]

Mezigdomide reverses T-cell exhaustion through degradation of IKZF1/IKZF3 and reinvigoration of cytokine production pathways.

Hsiling Chiu, Junfei Zhao, Tara Basavanhally, Chih-Chao Hsu, Michael D Amatangelo, Gaurav Jain, Chad C Bjorklund, Ting-Hsiang Huang, Lucia Y Chen, Thomas A Milne, Sarah Gooding, Samir Parekh, Anita Krithivas Gandhi, Maria Ortiz Estevez, Patrick Ryan Hagner.

T cell exhaustion has been shown to be a key resistance mechanism to efficacy of T cell engagers (TCE) in multiple myeloma (MM). Mezigdomide, a potent cereblon E3 ligase modulator that targets IKZF1 and IKZF3 simultaneously for proteasomal degradation, has been shown to modulate T cell activity in MM patients. We explored the possibility that targeting IKZF1/IKZF3 could address T cell exhaustion and restore functionality. We conducted extensive transcriptomic and epigenetic profiling on ex vivo generated exhausted T cells, using their autologous activated T cells as a comparison. Our study reveals that IKZF1 and IKZF3 are critical regulators contributing to the development and maintenance of T cell exhaustion. They regulate transcription by directly binding to promoters and enhancers, both proximal and distal, thereby altering transcriptional potential. Increased IKZF1 binding to exhaustion genes after multiple T cell stimulations results in enhancement of transcription, while binding to cytokine genes results in transcription repression. Mezigdomide treatment in exhausted T cells results in decreased expression of exhaustion-related markers, increased proinflammatory cytokine expression, and enhanced target cell killing with Alnuctamab, a B-cell maturation antigen (BCMA) targeting TCE. This study provides crucial mechanistic insights into the roles of IKZF1/IKZF3 in T cell exhaustion, supporting the rationale for combining mezigdomide with TCEs to enhance therapeutic outcomes in MM.

DOI: https://doi.org/10.1182/blood.2025030873
Front Oncol. 2026 ;16 1784393

Lisaftoclax combined with ixazomib and dexamethasone after CAR-T for maintenance therapy in transplant-ineligible relapsed/refractory ultra-high-risk multiple myeloma: two case reports and literature review.

Weige Xu, Xue Qiao, Linlin Zhang, Lina Xing, Jingnan Zhang, Xiaonan Guo, Shukai Qiao.

  Multiple myeloma (MM) is an incurable malignancy. The treatment mainly includes induction therapy, minimal residual disease (MRD) clearance therapy, and maintenance therapy. For high-risk/ultra-high-risk (UHR) or relapsed/refractory MM, optimizing the eradication of MRD and sustaining long-term suppression of MRD at low levels are a formidable challenge. Ixazomib (I) is a reversible proteasome inhibitor (PI) that is available orally as the prodrug ixazomib citrate. Lisaftoclax is a novel, potent, selective BCL-2 inhibitor under clinical development for the treatment of patients with hematologic malignancies or solid tumors and has shown clinical antitumor benefit. Herein, we report two patients with relapsed/refractory UHR MM who achieved durable disease control with MRD negativity after receiving ixazomib, lisaftoclax, and dexamethasone (ILD) as maintenance therapy following B Cell Maturity Antigen BCMA-chimeric antigen receptor (CAR)-T cell therapy. Regarding the treatment regimen, all drugs were administered orally: ixazomib 4 mg d1, d8, and d15; lisaftoclax 400 mg d1-d14; and dexamethasone 20 mg d1, d8, and d15. One treatment cycle is defined as 28 days. Treatment will be discontinued in the event of uncontrollable active infection or organ injury. These cases demonstrate that the ILD combination therapy can optimize MRD eradication and sustain long-term MRD suppression, offering a promising therapeutic option for patients with limited treatment choices. Formal evaluations of this regimen in patients with high-risk/ultra-high-risk or relapsed/refractory MM may be meaningful. This study was supported by the China Cancer Foundation (Project No.: CFC2023WJZD003).

Keywords:  CAR-T; dexamethasone; ixazomib; lisaftoclax; maintenance therapy; minimal residual disease; multiple myeloma; ultra-high-risk

DOI:  https://doi.org/10.3389/fonc.2026.1784393
Front Immunol. 2026 ;17 1769281

Modulating CD38 enzymatic activity during antibody-based immunotherapy in multiple myeloma: a basic science perspective.

Alberto L Horenstein, Kristine A Frerichs, Angelo C Faini, Niels W C J van de Donk, Fabio Malavasi.

   Introduction: Multiple myeloma (MM) develops within a profoundly immunosuppressive bone marrow (BM) microenvironment. CD38, a multifunctional ectoenzyme highly expressed on malignant plasma cells, contributes to this niche by degrading nicotinamide adenine dinucleotide (NAD+) into ADPR, which fuels adenosine (ADO) production through CD38/CD203a/CD73 enzymatic pathway. CD38_targeting monoclonal antibodies (mAbs), including daratumumab (DARA) and isatuximab (ISA), exert antitumor activity through direct cytotoxicity and immune modulation; however, resistance to these agents remains a major clinical challenge. Understanding how CD38 enzymatic activity and adenosinergic metabolism evolve during therapy is essential for improving treatment efficacy.
Methods: This study investigates (i) the enzymatic functions of CD38, (ii) the in vitro effects of DARA and ISA on CD38_mediated NAD+ degradation in primary MM cells and a representative MM cell line, and (iii) the in vivo dynamics of ADO and its metabolite inosine (INO) in BM and peripheral blood (PB) plasma from MM patients receiving DARA monotherapy.
Results: In vitro, both DARA and ISA promoted NAD⁺ degradation with accumulation of ADPR. In vivo, ADO concentrations in BM plasma remained consistently in the micromolar range and declined only modestly during treatment, whereas INO progressively increased, leading to a gradual attenuation of the BM -PB gradient. These findings indicate that adenosinergic metabolism remains active during DARA therapy, likely sustained by reduced CD38 expression due to antibody_driven internalization or microvesicle (MV) release, together with adenosine deaminase (ADA) -mediated ADO degradation.
Discussion: Despite CD38_targeted therapy, ADO concentrations in the BM remain well above the activation thresholds of P1 purinergic receptors, suggesting persistent adenosinergic immunosuppression. This sustained ADO production may contribute to a tolerogenic BM niche that promotes immune evasion and therapeutic resistance. These results support the rationale for combining CD38_directed antibodies with agents targeting adenosinergic signaling to enhance antitumor immunity and improve clinical outcomes in MM.

Keywords:  CD38; adenosine; daratumumab; immunosuppression; immunotherapy; inosine; isatuximab; multiple myeloma

DOI:  https://doi.org/10.3389/fimmu.2026.1769281
Mediterr J Hematol Infect Dis. 2026 ;18(1): e2026049

CD56+/CD38+ Neutrophils: Rapid and Specific Flow Cytometric Signature for Chronic Myeloid Leukemia.

Alessandro Laganà, Matteo Breccia, Loredana Elia, Emilia Scalzulli, Maria Laura Bisegna, Claudia Ielo, Sonia Buffolino, Attilio Di Lascio, Concetta Anna Germano, Stefania Intoppa, Maria Laura Milani, Maurizio Martelli, Massimo Breccia, Maria Stefania De Propris.



Keywords:  CD38; CD56; Chronic Myeloid Leukemia (CML); Multiparameter flow cytometry (MFC); Neutrophils

DOI:  https://doi.org/10.4084/MJHID.2026.049
Haematologica. 2026 May 14.

Glofitamab and epcoritamab for large B cell lymphoma: a real-world retrospective UK analysis of efficacy, tolerability, and impact of treatment sequencing.

Wendy Osborne, Euan Haynes, William Wilson, Kushani Ediriwickrema, James Paterson, Tobias Menne, Dima El-Sharkawi, Li Yuan Chan, Sunil Iyengar, Andrew J Davies, Hwai Jing Hiew, Edward Kanfer, David Foldes, Sridhar Chaganti, Henry Crosland, Mary Owen, George Follows, Anna Santarsieri, Sarah Lawless, Matthew Wilson, Pam McKay, Robert Osborn, David Tucker, Cristina M Thiebaud, Christopher P Fox, Harriet Ambrose, Mary Gleeson, Jeff Lam, Angus Broom, Jeffery Smith, Matthew Wells, Laura Oldham, Kim Linton, Lisa Jeffers, Andrea Kuhnl, Graham Collins, Janine Qasim, Nimish Shah, Rory McCulloch, Mahina Baloch, Catherine Cox, David Lewis, Abigail Martin, Kyaw Zin Dino Maw, Jane Norman, Vismay Deshani, Victoria Stables, Gavin Preston, Dominic Culligan, John Willan, Matthew Ahearne, Rishabh Motiwale, Laura Dunning, Joanna Fawcett, Philippa Kelsey, Caroline Besley, Sanne Lugthart, Jack Easton, Sudarshan Gurung, Desmond Ojie, Susanna Mathew, Rebecca Auer, William Townsend.

Glofitamab and epcoritamab are CD3xCD20 bispecific antibodies licensed for relapsed/refractory large B cell lymphoma (RR LBCL), yet real-world data are limited. Data were collected from 332 patients (219 glofitamab, 113 epcoritamab) across 34 UK centres (November 2023-May 2025). This high-risk cohort had median 2 prior lines of treatment; 179 (55%) primary refractory disease; 81 (25%) ECOG ≥2; 152 (50%) prior Chimeric Antigen Receptor T-cell therapy; and 232 (78%) pivotal-trial ineligible. 7 patients died before treatment initiation, 1 patient was yet to start treatment, of 324 treated patients, 28% had cytokine release syndrome (CRS), predominately grade 1/2 (82/90). Overall response rate (ORR) and complete response rate (CRR) were 43% and 24%, respectively, while for trialeligible patients the CRR was 43%. At a median 10.0 months follow-up (IQR 5.3-15.0), median progression-free survival (PFS) was 3.1 months (95% confidence interval [CI], 2.5-4.2), median overall survival (OS) was 6.9 months (95% CI, 4.9-10.8). For patients not completing cycle 2, 6-month OS was 4% (95% CI 1-11%). Median duration of complete response was not reached. Refractoriness to prior line of treatment (HR 2.89, 95% CI 1.73-4.81, p=0.007), elevated LDH (HR 2.62, 95% CI 1.74-3.93. p=0.001), bendamustine exposure within 6 months (HR 1.62, 95% CI 1.14-2.30, p=0.007) and ECOG 1 (HR 2.70, 95% CI 1.52-4.79, p=0.001) or 2 (HR 6.49, 95% CI 3.47-12.01, p.

DOI: https://doi.org/10.3324/haematol.2026.300569
Cancers (Basel). 2026 Apr 30. pii: 1446. [Epub ahead of print]18(9):

Hodgkin Reed-Sternberg Cells of Classic Hodgkin Lymphoma: Morphology, Phenotype, Genotype, and Cell of Origin.

Annunziata Gloghini, Daniele Lorenzini, Chiara Costanza Volpi, Desirè Viola Trupia, Giancarlo Pruneri.

  Classic Hodgkin lymphoma (cHL) is a distinctive B-cell malignancy defined by the presence of scarce but pathobiologically dominant Hodgkin Reed-Sternberg (HRS) cells within an inflammatory tumor microenvironment (TME). Although representing less than 10% of total tumor cellularity, HRS cells shape the TME by recruiting and functionally polarizing immune and stromal elements through cytokine- and chemokine-mediated signaling. Morphologically, HRS cells are large, atypical, often binucleated or multinucleated cells with prominent eosinophilic nucleoli and abundant cytoplasm, giving rise to the classic "owl's eye" appearance. Distinct morphological variants-including lacunar, mummified, mononuclear, and anaplastic forms-contribute to the histopathologic diversity across cHL subtypes such as nodular sclerosis, mixed cellularity, lymphocyte-rich, and lymphocyte-depleted disease. The immunophenotype of HRS cells is equally characteristic, with strong and uniform CD30 expression, frequent CD15 positivity, reduced expression of B-cell markers (CD20, CD79A/B), and partial retention of PAX5, reflecting profound lineage dysregulation. Aberrant expression of activation markers and immune-evasion molecules, including PD-L1 driven by recurrent 9p24.1 amplification, underscores their capacity for immune escape. Genetically, HRS cells display alterations affecting NF-κB, JAK/STAT, and PI3K/AKT pathways, facilitated by somatic mutations, chromosomal gains, and epigenetic remodeling that silence B-cell-defining genes. Despite reprogramming, clonality and somatic hypermutation patterns confirm their origin from germinal center B-cells, even in EBV-associated cases. Collectively, the morphology, phenotype, and genotype of HRS cells reveal a complex pathogenic network in which intrinsic oncogenic pathways and extrinsic TME interactions co-operate to sustain malignant transformation. Understanding these integrated mechanisms provides a biological foundation for current therapeutic strategies.

Keywords:  Hodgkin Reed-Sternberg cells; cell of origin; classic Hodgkin lymphoma; genotype; morphology; phenotype

DOI:  https://doi.org/10.3390/cancers18091446
Health Sci Rep. 2026 May;9 e72506

From Platelet Toxicity to Precision Targeting: Evolving Strategies to Overcome Thrombocytopenia in BCL-2/BCL-XL Inhibition.

Md Mohiuddin.

   Background: Simultaneous blockade of the anti-apoptotic proteins BCL-2 and BCL-XL has been shown to be efficacious in preclinical and clinical trials for tumors that are co-dependent on their survival pathways, although clinical development has been limited owing to dose-limiting thrombocytopenia associated with BCL-XL inhibition.
Discussion: Recent developments have provided strategies that are largely complementary, attempting to separate anti-tumor activity from platelet toxicity: (I) targeted protein degraders (PROTACs) that recruit E3 ligases weakly expressed in platelets to spare platelet BCL-XL, (II) prodrug and formulation strategies that preferentially deliver active drug concentrations to the tumor, (III) dosing and scheduling to leverage catalytic or durable mechanisms of action, and (IV) rational combination regimens that reduce per-agent exposure while retaining or enhancing anti-tumor activity. This perspective will integrate the mechanistic rationale, preclinical support, and emerging clinical evidence supporting these mechanisms and propose the next steps and sequencing for future experimental or clinical directions to explore safe and active dual BCL-2/BCL-XL therapies.
Conclusion: Collectively, these emerging strategies offer an opportunity to develop dual BCL-2/BCL-XL inhibitors with greater anti-tumor activity while minimizing thrombocytopenia and potentially broadening their clinical application.

Keywords:  BCL‐2; BCL‐XL; platelets; thrombocytopenia

DOI:  https://doi.org/10.1002/hsr2.72506
Am J Clin Dermatol. 2026 May 14.

Dermatologic Toxicities Induced by JAK Inhibitors.

Luca Rapparini, Michela Starace, Zoe Apalla, Maha El Barch, Antoine Delpuech, Sarah Baali, Vincent Sibaud.

Janus kinase inhibitors are increasingly used for the treatment of a wide range of dermatologic and non-dermatologic immune-mediated diseases, leading to growing interest in their safety profile, particularly with respect to cutaneous adverse events. This narrative review summarizes current evidence on dermatologic toxicities associated with both systemic and topical Janus kinase inhibitors. The most frequently reported cutaneous adverse event is an acne-like eruption, which shows a clear dose-dependent pattern and typically occurs early after treatment initiation. Cutaneous infections represent another major group of adverse events, with herpes zoster being the most clinically relevant. Less frequently, cutaneous malignancies have been reported, predominantly non-melanoma skin cancers, with a stronger signal observed in hematologic populations and in patients treated with ruxolitinib. Overall, dermatologic adverse events associated with Janus kinase inhibitors are usually manageable and rarely require permanent treatment discontinuation. Increased awareness, early recognition, and appropriate dermatologic management are essential to minimize morbidity and to support long-term treatment adherence across clinical settings.

DOI: https://doi.org/10.1007/s40257-026-01038-x
Cells. 2026 Apr 27. pii: 794. [Epub ahead of print]15(9):

Molecular Mechanisms of Resistance to Bispecific Antibodies in Diffuse Large B-Cell Lymphoma.

Nawar Maher, Bashar Al Deeban, Ndeye Marie Diop, Joelle Assaf, Riccardo Moia, Samir Mouhssine, Gianluca Gaidano.

  CD20 × CD3 bispecific antibodies (BsAbs) have emerged as a meaningful therapeutic option for relapsed or refractory diffuse large B-cell lymphoma (DLBCL), redirecting endogenous T cells against malignant B cells independently of major histocompatibility complex-mediated antigen presentation, and have received regulatory approval after at least two prior lines of therapy. However, a substantial proportion of patients experience primary resistance or early relapse, underscoring the need to characterize the underlying biological mechanisms, which are the focus of this review. Several tumor-intrinsic determinants of resistance have been identified, including CD20 loss driven by MS4A1 mutations, alternative splicing, and gene deletion, as well as genomic reprogramming involving TP53, MYC, and NOTCH1 alterations. T-cell dysfunction represents another critical resistance domain, encompassing inadequate intratumoral cytotoxic CD8+ T-cell infiltration, expansion of immunosuppressive regulatory and follicular helper T cells, progressive exhaustion with upregulation of PD-1, LAG-3, TIM-3, and TIGIT, and impaired T-cell fitness from prior treatment exposure. Microenvironmental barriers, including checkpoint ligand upregulation, PD-L1-enriched extracellular vesicles, spatial exclusion of effector cells from immune-cold germinal center-like niches, hypoxia, and metabolic competition, further reinforce immune escape. Emerging strategies to overcome resistance include epigenetic priming, checkpoint inhibitor combinations, 4-1BB costimulatory approaches, and next-generation multispecific antibody designs.

Keywords:  bispecific antibody; diffuse large B cell lymphoma; drug resistance; immunotherapy; microenvironment

DOI:  https://doi.org/10.3390/cells15090794