bims-hemali 2025-07-20 papers

bims-hemali

Biomed News

on Hematologic malignancies

Issue of 2025–07–20
37 papers selected by
Alexandros Alexandropoulos, Γενικό Νοσοκομείο Αθηνών Λαϊκό

Potential therapeutic targets in chronic myeloid leukemia.
2025 European LeukemiaNet recommendations for the management of chronic myeloid leukemia.
Olutasidenib alone or combined with azacitidine in patients with mutant IDH1 myelodysplastic syndrome.
Effective venetoclax treatment for indolent T-cell lymphoma of the gastrointestinal tract: a case report and literature review.
Real-World Evidence of Treatment-Free Remission Strategies and Outcomes in Chronic Myeloid Leukemia.
Real-world outcomes of patients with aggressive B-cell lymphoma treated with epcoritamab or glofitamab.
Primary Plasma Cell Leukemia: Recent Advances in Molecular Understanding and Treatment Approaches.
Autophosphorylation of oncoprotein TEL-ABL in myeloid and lymphoid cells confers resistance to the allosteric ABL inhibitor asciminib.
Martinostat as a novel HDAC inhibitor to overcome tyrosine kinase inhibitor resistance in chronic myeloid leukemia.
Positron Emission Tomography-Guided Brentuximab Vedotin, Etoposide, Cyclophosphamide, Doxorubicin, Dacarbazine, and Dexamethasone in Older Patients With Advanced-Stage Classic Hodgkin Lymphoma: A Prospective, Multicenter, Single-Arm, Phase II Cohort of the German Hodgkin Study Group HD21 Trial.
Novel insights into the ULK2-FIP200-AMPK-mediated regulation of autophagy and BCR::ABL degradation in chronic myeloid leukemia.
Richter transformation recommendations.
Better Response and Prognosis of Venetoclax Plus Hypomethylating Agents Over Intensive Chemotherapy in Young Adults With Newly Diagnosed ASXL1-Mutated Acute Myeloid Leukemia.
Unusual suspects: a surprise cast in making blood stem cells.
Efficacy of zanubrutinib versus acalabrutinib for relapsed or refractory chronic lymphocytic leukemia (R/R CLL): a matching-adjusted indirect comparison (MAIC).
Rituximab, high-dose methotrexate plus orelabrutinib as induction therapy in newly diagnosed primary central nervous system lymphoma.
First-line Therapy: Time-Limited Venetoclax Doublet Therapy.
The Efficacy of Teclistamab in Multiple Myeloma Patients with Secondary Plasma Cell Leukemia.
Phase I first-in-human dose escalation study of the oral casein kinase 1α and cyclin dependent kinase 7/9 inhibitor BTX A51 in advanced MDS and AML.
Current and future role of carfilzomib-based quadruplet combinations as therapy for newly diagnosed multiple myeloma.
Fertility in patients with advanced-stage classic Hodgkin lymphoma treated with BrECADD versus eBEACOPP: a secondary analysis of the multicentre, randomised, parallel, open-label, phase 3 HD21 trial.
Surface downmodulation of TIM3 safeguards healthy cells but not acute myeloid leukemia from CAR T-cell therapy.
Estimating efficacy of favezelimab plus pembrolizumab relative to pembrolizumab in anti-PD-1-refractory Hodgkin lymphoma.
Molecular and Immunological Determinants of Long-Term Survival in Multiple Myeloma.
The Treatment of Marginal Zone Lymphoma.
Secondary blastoid plasma cell leukemia: can an old dog learn new tricks?
Long term follow-up of patients with AL amyloidosis treated on a phase 1 trial of CAEL-101.
Long-term follow-up of venetoclax monotherapy in previously treated patients with Waldenström macroglobulinemia.
PROTACtion against BCL-xL in post-MPN AML.
Serum Cereblon (CRBN) Levels Predict Long Term Post- Lenalidomide-Dexamethasone Survival in Multiple Myeloma (MM) Patients and Correlate with Disease Characteristics.
Development and validation of a prognostic staging system for primary plasma cell leukemia.
Exploring the origin of the development: totipotent stem cells.
Dual- energy CT versus single-energy CT for estimation of hematocrit and hemoglobin in the brain: an in vivo analysis.
Getting closer to hemophilia gene therapy for all?
IRF4 promotes immune evasion and shapes the tumor microenvironment in Follicular Lymphoma.
Multiorgan Failure Resembling Grade 5 (Fatal) Cytokine Release Syndrome in Patient with Multiple Myeloma Following Carfilzomib Infusion: A Case Report.
IL-16 production is a mechanism of resistance to BTK inhibitors and R-CHOP in lymphomas.

Med Oncol. 2025 Jul 17. 42(8): 344

Potential therapeutic targets in chronic myeloid leukemia.

Manvi Bansal, Malkhey Verma.

  Chronic myeloid leukemia (CML) is driven by the BCR::ABL fusion oncoprotein, caused by a reciprocal translocation between chromosomes no. 9 and 22, leading to the formation of the Philadelphia chromosome having aberrant tyrosine kinase activity. Tyrosine kinase inhibitors (TKIs) revolutionized the CML treatment and helped patients to achieve a higher survival rate. However, TKI resistance, leukemia stem cell (LSC) persistence, and disease relapse highlight the necessity for alternative treatment strategies. Furthermore, oxidative stress pathways are critical in promoting leukemic development and resistance, offering an emerging avenue for targeted intervention. This review explores several promising therapeutic targets in CML, such as suppressor pathways, autophagy modulation, the BCL-2 family proteins, and microRNAs (miRNAs) modulation. Restoring the function of tumor suppressors, such as PTPRG and p53, may complement current therapies since they are essential in regulating cell proliferation and apoptosis. Tumor suppressors offer the potential to enhance apoptosis, while the precise modulation of autophagy, a complex cellular process with context-dependent roles, can regulate cell survival under therapeutic pressure. The BCL-2 family proteins regulate apoptosis by the mitochondrial intrinsic apoptosis pathway, representing a critical target for overcoming apoptotic resistance in CML cells. Meanwhile, miRNAs emerge as potent modulators of oncogenic and apoptotic pathways by acting as tumor suppressors or oncomiRs, presenting an opportunity for advanced treatment. This review also includes gene editing to target oncogenic drivers or correcting mutations and USP inhibition to overcome resistance. Finally, it concludes by emphasizing the importance of combining these diverse therapeutic approaches with ongoing next-generation TKIs and comprehensive and personalized approaches for CML treatment, offering a path toward deeper remissions and ultimately achieving curative outcomes for CML patients.

Keywords:  Apoptosis; BCR::ABL; Chronic myeloid leukemia (CML); Therapeutic targets; Tyrosine kinase inhibitors (TKIs)

DOI:  https://doi.org/10.1007/s12032-025-02895-y
Leukemia. 2025 Jul 11.

2025 European LeukemiaNet recommendations for the management of chronic myeloid leukemia.

Jane F Apperley, Dragana Milojkovic, Nicholas C P Cross, Henrik Hjorth-Hansen, Andreas Hochhaus, Hagop Kantarjian, Jeffrey H Lipton, Hemant Malhotra, Dietger Niederwieser, Jerald Radich, Philippe Rousselot, Susanne Saussele, Charles A Schiffer, Richard Silver, Simona Soverini, Leif Stenke, Anna Turkina, Luis Felipe Casado, Fausto Castagnetti, Francisco Cervantes, Richard E Clark, Jorge Cortes, Michael Deininger, Timothy P Hughes, Jeroen Janssen, Qian Jiang, Dong-Wook Kim, Richard A Larson, Francois X Mahon, Michael Mauro, Jiri Mayer, Franck E Nicolini, Fabrizio Pane, Delphine Rea, Johan Richter, Gianantonio Rosti, Giuseppe Saglio, Rüdiger Hehlmann.

In this 5th version of the European LeukemiaNet guidance for adult patients, there are important changes in several areas of management based on evidence available since 2020, including the World Health Organisation's reclassification of CML as a biphasic disease. Previous advice to switch the tyrosine kinase inhibitor (TKI) on failure of molecular milestones, is modified to better account for individual patient circumstances. Our recommendations are summarized in tables designed to be read in conjunction with the text which offers justification and additional advice. We describe decision-making for first-line treatment, both in available drugs and their initial dosing. Similarly we elaborate on dose reduction rather than drug switching to manage toxicities and discuss treatment sequencing. Data have matured for the outcome of treatment discontinuation and for management of parenting for both men and women. We acknowledge that most patients will remain on treatment for many years and emphasize the needs to minimize side effects, manage co-morbidities and optimize quality of life. Recent advances in allogeneic stem cell transplantation have broadened access to alternative donors, and lessened limitations of age and co-morbidities such that transplant remains a valuable option for patients for whom long-term disease control is not achieved through TKI therapy.

DOI: https://doi.org/10.1038/s41375-025-02664-w
Blood Adv. 2025 Jul 16. pii: bloodadvances.2025016718. [Epub ahead of print]

Olutasidenib alone or combined with azacitidine in patients with mutant IDH1 myelodysplastic syndrome.

Jorge E Cortes, Jay Yang, Gail J Roboz, Shira Naomi Dinner, Eunice S Wang, Andrew H Wei, Hua Tian, Francois di Trapani, Maria R Baer, William B Donnellan, Justin M Watts.

Olutasidenib, a potent, selective, oral small-molecule inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1), is FDA-approved for mIDH1 relapsed/refractory (R/R) acute myeloid leukemia based on results from the pivotal AML cohort of a multi-arm phase 1/2 trial that also enrolled patients with MDS (NCT02719574). We report pooled data evaluating olutasidenib as monotherapy or combined with azacitidine in R/R and treatment-naïve (TN) higher-risk MDS harboring mIDH1. Endpoints included safety, overall response rate (ORR), complete remission (CR) rate, time-to-response (TTR), duration of response (DOR), overall survival (OS), and transfusion-independence. Twenty-two patients (median age 74 years, 59% male) with IPSS-R intermediate- to very high-risk MDS (n=6 monotherapy [4 R/R, 2 TN]; n=16 combination [11 R/R, 5 TN]) were analyzed. The most frequent AEs were fatigue and cytopenias. Differentiation syndrome occurred in 3 patients (14%); 1(5%) grade 3 severity. QT prolongation occurred in 1 patient receiving combination therapy. ORR was 59% (CR: 27%, 6/22; marrow CR: 32%, 7/22) in intent-to-treat (n=22, ITT) and 68% (CR: 32%, 6/19; marrow CR: 37%, 7/19) in response-evaluable (n=19) patients. ORR (ITT population) was 33% (2/6) for monotherapy (3/6 patients received £half the recommended dose) and 69% (11/16) for combination therapy. Median TTR was 2 months (range 1-13), median DOR 14.6 months (95% CI, 5.8-32.8), and median OS 27.2 months (95% CI, 6.9-37). 62% and 67% of patients who were transfusion-dependent at baseline achieved 56-day RBC and platelet transfusion independence, respectively. Olutasidenib with or without azacitidine demonstrated encouraging clinical activity and tolerability in patients with higher-risk mIDH1 MDS. NCT02719574.

DOI: https://doi.org/10.1182/bloodadvances.2025016718
Front Immunol. 2025 ;16 1593343

Effective venetoclax treatment for indolent T-cell lymphoma of the gastrointestinal tract: a case report and literature review.

Ji-Mo Jian, Hong-Yuan Hao, Cheng-Lu Yuan, Shu-Qi Zhang, Zou-Fang Huang, Jun Du.

  Indolent T-cell lymphoma of the gastrointestinal tract (iTCL-GI) is rare, lacking standardized treatments. We report a successful venetoclax treatment in one patient with indolent T-cell lymphoma of the gastrointestinal tract. A 35-year-old male was admitted due to complaints of anemia and hematochezia. He was diagnosed with iTCL-GI according to histopathology and next-generation sequencing (NGS). He received the first cycle of CHOP-E chemotherapy, but he continued to have intermittent blood in stools. After starting oral Bcl-2 inhibitor venetoclax, the results of peripheral hemogram and the body temperature gradually turned normal, with no symptoms of hematochezia occurring again. In addition, colonoscopy showed improved ulcers in the ascending and transverse colon. Routine blood tests returned to normal without adverse effects. Therefore, venetoclax may represent a potential treatment approach for iTCL-GI. This report might provide clues for the future management of similar cases.

Keywords:  B-cell lymphoma 2; gastrointestinal tract; hematochezia; indolent T-cell lymphoma; venetoclax

DOI:  https://doi.org/10.3389/fimmu.2025.1593343
Cancers (Basel). 2025 Jun 26. pii: 2148. [Epub ahead of print]17(13):

Real-World Evidence of Treatment-Free Remission Strategies and Outcomes in Chronic Myeloid Leukemia.

Garrett Bourne, Kendall Diebold, Greg Bascug, Joshua Knapp, Manuel Espinoza-Gutarra, Pankit Vachhani, Kimo Bachiashvili, Sravanti Rangaraju, Razan Mohty, Ravi Bhatia, Omer Jamy.

  Background: Despite the remarkable efficacy of tyrosine kinase inhibitors (TKIs), patients with chronic myeloid leukemia (CML) often face adverse effects, prompting investigations into treatment-free remission (TFR) for patients with sustained deep responses. Methods: Our objective was to assess real-world outcomes of TFR in a single-center cohort of patients in the southeastern U.S., as well as to compare different TKI management strategies (abrupt cessation of a TKI at a standard dose, TKI dose tapering prior to cessation, or upfront TKI dose reduction followed by abrupt cessation before TFR). Results: We queried our CML database of 233 patients and identified 39 patients that aimed for TFR. The median TFR duration was 14.6 months, with 63% actively remaining in TFR with a median follow-up of 21 m. TFR was lost by 54%, 16%, 8%, and 21% of patients in 0-6 m, 6-12 m, 1-2 y, and >2 y, respectively. Among the three TKI management strategies, the safety outcomes were comparable, with no instances of disease progression or CML-related mortality. All patients who lost TFR successfully regained a major molecular response (MMR) upon the resumption of TKIs. In terms of efficacy, 61%, 59%, and 59% of patients who underwent abrupt cessation of standard-dose TKIs, standard-dose tapering, or upfront dose reduction maintained TFR, respectively. Conclusions: Our study highlights the relative safety of pursuing TFR via different TKI treatment strategies in a real-world setting.

Keywords:  CML; TKI strategies; treatment-free remission

DOI:  https://doi.org/10.3390/cancers17132148
Blood. 2025 Jul 15. pii: blood.2025029117. [Epub ahead of print]

Real-world outcomes of patients with aggressive B-cell lymphoma treated with epcoritamab or glofitamab.

Taylor R Brooks, Emily C Zabor, Yohanna Bedelu, Xi Yang, Yasmin H Karimi, Adrienne N Nedved, Yucai Wang, Nikita K Dave, Daniel J Landsburg, Kelsey Baron, Boyu Hu, Daniel Trotier, Priyanka A Pophali, Jordan Miller, Natalie S Grover, Catherine Reinert, Ajay Major, Tenley Schwarz, Krish Patel, Kiarash Salafian, Emily C Ayers, Suchitra Sundaram, Joshua D Brody, Marshall McKenna, Yun Kyoung Ryu Tiger, Megan Sears-Smith, Nilanjan Ghosh, Chelsea Peterson, Cyrus Khan, Sean P Bliven, Mayur Narkhede, Alyssa Gibson, Justin Kline, Javier Munoz, Rodolfo Garza Morales, Carrie Ho, Stephen D Smith, Alex Niu, Francisco J Hernandez-Ilizaliturri, Fadzai Chinyengetere, Sandeep S Dave, Nayef Abdel-Razeq, Muhamad Alhaj Moustafa, Paolo Caimi, Brian T Hill.

Epcoritamab and glofitamab are CD20-directed bispecific antibodies approved in the US for relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL). Limited data exist for patients treated outside of trials. Patients with R/R DLBCL receiving commercial epcoritamab or glofitamab between January 1, 2023 and October 15, 2024 were collected from 21 US institutions. Among 245 patients, 156 received epcoritamab and 89 received glofitamab, 113 were refractory to front-line therapy, 40 had MYC and BCL2 and/or BCL6 rearrangements, 147 received prior chimeric antigen receptor T-cell therapy, and 174 patients would have been ineligible for registrational trials. The overall response rate (ORR) for epcoritamab and glofitamab was 51% (23% complete response, [CR]) and 53% (30% CR), respectively. Median progression-free survival (mPFS) was 2.6 months (95% confidence interval [CI] 2.0 to 3.8 months), and median overall survival (mOS) was 7.8 months (95% CI 6.2 to 11.0 months). The 6-month PFS was 36% (95% CI 30% to 44%) and the 6-month OS was 60% (95% CI 54% to 67%). Both trial ineligibility and undetectable CD20 pre-bispecific portended shorter PFS and OS. Of 17 individuals with paired biopsies, 15 (88.2%) lost CD20 expression after bispecifics with a median time to progression of 3.7 months. This analysis including R/R DLBCL patients shows the ORR to CD3/CD20 BsAbs was comparable to pivotal trials, although PFS and OS were lower. Baseline undetectable levels of CD20 was associated with poor outcomes. These results demonstrate the activity of BsAbs in R/R DLBCL and underscore the importance of target antigen expression.

DOI: https://doi.org/10.1182/blood.2025029117
Int J Mol Sci. 2025 Jun 26. pii: 6166. [Epub ahead of print]26(13):

Primary Plasma Cell Leukemia: Recent Advances in Molecular Understanding and Treatment Approaches.

Ichiro Hanamura, Sivasundaram Karnan, Akinobu Ota, Akiyoshi Takami.

  Primary plasma cell leukemia (pPCL) is a rare and aggressive plasma cell dyscrasia. According to revised diagnostic criteria, pPCL is defined by the presence of ≥5% circulating plasma cells (CPCs) in the peripheral blood of patients with newly diagnosed multiple myeloma (NDMM). pPCL is characterized by a distinct cytogenetic profile, including frequent t(11;14), MAF/MAB translocations, 1q gain, and del(17p). While t(11;14) is generally associated with a favorable prognosis, the coexistence of multiple high-risk cytogenetic abnormalities is linked to poorer outcomes. Tandem autologous hematopoietic stem cell transplantation and novel anti-myeloma agents have improved survival in some patients; however, overall prognosis remains poor, particularly in those ineligible for transplantation. Venetoclax and emerging immunotherapies, such as CAR-T cells and bispecific antibodies, show promise and merit clinical trials focused on pPCL-enriched cohorts. Additionally, recent findings associating even minimal CPCs with adverse outcomes in NDMM support broader inclusion criteria in future trials. A deeper understanding of pPCL's molecular pathology is critical for the development of effective targeted therapies. This article reviews recent advances in the molecular understanding of and treatment strategies for pPCL.

Keywords:  14); CAR-T; bispecific antibodies; circulating plasma cells; plasma cell leukemia; t(11; venetoclax

DOI:  https://doi.org/10.3390/ijms26136166
Sci Signal. 2025 Jul 15. 18(895): eadt5931

Autophosphorylation of oncoprotein TEL-ABL in myeloid and lymphoid cells confers resistance to the allosteric ABL inhibitor asciminib.

Serena Muratcioglu, Christopher A Eide, Chien-Lun Hung, Kent Gorday, Emily Sumpena, Wenqi Zuo, Jay T Groves, Brian J Druker, John Kuriyan.

Chromosomal translocations that fuse ABL1 to BCR or TEL cause human leukemias. In BCR-ABL and TEL-ABL fusion proteins, oligomerization and loss of an autoinhibitory myristoylation site in the SH3 domain of ABL lead to increased ABL tyrosine kinase activity. We assessed the ability of asciminib, an allosteric inhibitor of BCR-ABL that binds to the myristoyl-binding site in the ABL kinase domain, to inhibit these fusion proteins. Although the ABL components of the two fusion proteins have identical sequences, asciminib was much less effective against TEL-ABL than it was against BCR-ABL in cell-growth assays. In contrast, ATP-competitive tyrosine kinase inhibitors, such as imatinib and ponatinib, were equally effective against both fusion proteins. A helix in the ABL kinase domain that closes over bound asciminib was required for the sensitivity of BCR-ABL to the drug but had no effect on that of TEL-ABL, suggesting that the native autoinhibitory mechanism that asciminib engages in BCR-ABL is disrupted in TEL-ABL. Single-molecule microscopy demonstrated that BCR-ABL was mainly dimeric in cells, whereas TEL-ABL formed higher-order oligomers, which promoted trans-autophosphorylation, including of a regulatory phosphorylation site (Tyr89) in the SH3 domain of ABL. Nonphosphorylated TEL-ABL was intrinsically susceptible to inhibition by asciminib, but phosphorylation at Tyr89 disassembled the autoinhibited conformation of ABL, thereby preventing asciminib from binding. Our results demonstrate that phosphorylation determines whether an ABL fusion protein is sensitive to allosteric inhibition.

DOI: https://doi.org/10.1126/scisignal.adt5931
Clin Epigenetics. 2025 Jul 16. 17(1): 125

Martinostat as a novel HDAC inhibitor to overcome tyrosine kinase inhibitor resistance in chronic myeloid leukemia.

Haeun Yang, Vladimir Li, Su Jung Park, Sang Won Cheon, Anne Lorant, Aloran Mazumder, Jin Young Lee, Barbora Orlikova-Boyer, Claudia Cerella, Christo Christov, Gilbert Kirsch, Dag Erlend Olberg, Guy Bormans, Hyoung Jin Kang, Byung Woo Han, Michael Schnekenburger, Marc Diederich.

   BACKGROUND: Chronic myeloid leukemia (CML) remains a therapeutic challenge, particularly in patients who develop resistance to standard tyrosine kinase inhibitors (TKIs) such as imatinib. Here, we present the first demonstration of the potent anti-leukemic activity of the histone deacetylase (HDAC) inhibitor martinostat in both TKI-sensitive and TKI-resistant CML.
METHODS AND RESULTS: Structural and biochemical analyses confirmed the efficient and selective binding of martinostat to HDAC isoenzyme ligand-binding pockets, resulting in histone and tubulin hyperacetylation in both imatinib-sensitive and resistant CML cells, outperforming vorinostat, a clinically used HDAC inhibitor (HDACi). It selectively impaired CML cell proliferation and viability and induced apoptosis across various CML models, including resistant cell models and patient blasts, with minimal toxicity to healthy cells and low developmental toxicity in zebrafish. In addition to its single-agent efficacy, martinostat demonstrated enhanced anticancer effects when combined with imatinib, both in vitro and in vivo, significantly reducing tumor growth in resistant CML xenograft models. Mechanistically, mRNA-seq data showed that martinostat disrupted key survival signaling pathways and amplified apoptotic responses, contributing to its anticancer activity.
CONCLUSIONS: These findings highlight the potential of martinostat as a selective, low-toxicity HDACi that, combined with TKIs, could provide an effective strategy to overcome drug resistance in CML and improve therapeutic outcomes.

Keywords:  Cell death; Chronic myeloid leukemia; Combination treatment; HDAC inhibitors; Imatinib resistance

DOI:  https://doi.org/10.1186/s13148-025-01921-0
J Clin Oncol. 2025 Jul 17. JCO2500439

Positron Emission Tomography-Guided Brentuximab Vedotin, Etoposide, Cyclophosphamide, Doxorubicin, Dacarbazine, and Dexamethasone in Older Patients With Advanced-Stage Classic Hodgkin Lymphoma: A Prospective, Multicenter, Single-Arm, Phase II Cohort of the German Hodgkin Study Group HD21 Trial.

Justin Ferdinandus, Helen Kaul, Alexander Fosså, Andreas Hüttmann, Felix Keil, Yon-Dschun Ko, Felicitas Hitz, Michaela Schwarz, Corinna Trenker, Andrea Kerkhoff, Peter Staib, Kai Wille, Irmgard Dresel, Dennis Hahn, Bernd Hertenstein, Peter Moosmann, Ulrich Mey, Stefan Balabanov, Tasman Armytage, Fernando Roncolato, Johannes C Hellmuth, Mark Hertzberg, Carsten Kobe, Wolfram Klapper, Christian Baues, Hans-Theodor Eich, Stefanie Kreissl, Michael Fuchs, Janina Jablonski, Gundolf Schneider, Hishan Tharmaseelan, Dennis A Eichenauer, Bastian von Tresckow, Peter Borchmann, Paul J Bröckelmann.

PURPOSE: Positron emission tomography (PET)-guided therapy with 4-6 cycles of brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone (BrECADD) is highly effective in younger patients with advanced-stage classic Hodgkin lymphoma (AS-cHL). We report feasibility and efficacy of PET-guided BrECADD as first-line treatment in older patients with AS-cHL.
PATIENTS AND METHODS: Patients with AS-cHL aged 61-75 years were enrolled in a phase II single-arm cohort of the HD21 trial (ClinicalTrials.gov identifier: NCT02661503). Patients with negative PET/computed tomography after 2×BrECADD (PET2) received a total of 4×BrECADD, while PET2-positive patients received 6×BrECADD. The primary end point was the centrally reviewed complete remission (CR) rate after the end of chemotherapy (EOC). Secondary end points included feasibility, adverse events, treatment-related morbidity (TRMB), progression-free survival (PFS), overall survival (OS), and health-related quality of life (HRQoL).
RESULTS: Between June 2020 and April 2023, 85 patients were enrolled, of whom 83 with a median age of 67 years (range, 61-75) were analyzed in the intention-to-treat cohort. Most prevalent ≥grade 3 toxicities included leukopenia (n = 80 [96%]), thrombocytopenia (n = 71 [86%]), anemia (n = 57 [69%]), and febrile neutropenia (n = 46 [55%]). Forty-eight (60%) of 80 patients with centrally reviewed PET2 were scheduled for 4×BrECADD and 32 (40%) for 6×BrECADD. Of these, 71 patients (89%) received the target number of cycles. Sixty-eight patients (82%; 95% CI, 72 to 90) achieved CR at EOC. PFS and OS estimates at 2 years were 91.5% (95% CI, 85 to 98) and 90.8% (95% CI, 84 to 98), respectively. No death was attributed to study treatment. Initially, impaired HRQoL scores improved during follow up and on average reached population reference values.
CONCLUSION: PET-guided BrECADD in older patients is feasible and effective. With a PFS rate on par with that of younger patients, short duration, and limited anthracycline exposure, BrECADD is a valuable treatment option also for older patients with AS-cHL.

DOI: https://doi.org/10.1200/JCO-25-00439
Biochem Biophys Res Commun. 2025 Jul 13. pii: S0006-291X(25)01058-7. [Epub ahead of print]778 152343

Novel insights into the ULK2-FIP200-AMPK-mediated regulation of autophagy and BCR::ABL degradation in chronic myeloid leukemia.

Daisuke Koyama, Naoki Yamamoto, Takaaki Abe, Kengo Suzuki, Yuki Sato, Manabu Suzuki, Naoya Shibayama, Takayuki Ikezoe.

  Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm driven by the BCR::ABL fusion tyrosine kinase. AMP-activated protein kinase (AMPK) plays a pivotal role in regulating cellular energy homeostasis, ensuring an adequate ATP supply for CML cell proliferation. ULK1, a well-known AMPK substrate, is a critical serine/threonine kinase in the autophagy initiation complex. ULK2, a paralog of ULK1, shares approximately 50 % amino acid sequence homology and has been reported to function complementarily with ULK1. However, emerging evidence suggests that ULK2 also has unique functions distinct from those of ULK1. Public RNA sequencing data revealed that ULK2 expression is significantly lower in hematopoietic cells compared to other tissues. To explore the function of ULK2, we performed in vitro assays using 293FT cells, which endogenously express high levels of ULK2. Mass spectrometry analysis demonstrated that ULK2 forms a stable complex with FIP200, which in turn interacts specifically with the AMPK α1 and γ1 subunits. Furthermore, shRNA-mediated knockdown of ULK2 induced AMPK activation and promoted the cytoplasmic accumulation of ULK1 and FIP200, thereby inducing autophagy in CML cells. Although autophagy typically acts as a cytoprotective mechanism, in this context, the autophagy-dependent degradation of BCR::ABL induced cell death. These findings reveal a novel regulatory axis involving ULK2, FIP200, AMPK, and autophagy, suggesting a unique role for ULK2 in CML pathophysiology and offering potential therapeutic insights.

Keywords:  AMPK; Autophagy; Chronic myeloid leukemia; FIP200; ULK2

DOI:  https://doi.org/10.1016/j.bbrc.2025.152343
Blood. 2025 Jul 17. 146(3): 262-263

Richter transformation recommendations.

Birgitta Sander.

DOI: https://doi.org/10.1182/blood.2025029450
Cancer Med. 2025 Jul;14(14): e71037

Better Response and Prognosis of Venetoclax Plus Hypomethylating Agents Over Intensive Chemotherapy in Young Adults With Newly Diagnosed ASXL1-Mutated Acute Myeloid Leukemia.

Yiming Cai, Jingwen Rui, Zhengwen Ding, Judan Xie, Zhou Jin, Jinyan Xiao, Yang Xu.

   BACKGROUND: ASXL1 is one of the most frequently mutated genes in acute myeloid leukemia (AML) and retains adverse-risk status in intensively treated cohorts according to 2022 European Leukemia Net (ELN) risk criteria. The therapeutic and prognostic impacts of hypomethylating agents (HMAs) and venetoclax in young adults with ASXL1-mutated AML is unclear.
METHODS: Eighty-one patients with ASXL1-mutated AML ≤ 60 years old were retrospectively analyzed. The effects of HMAs plus venetoclax on treatment response and its prognostic value were compared with intensive chemotherapy (IC) and HMAs combined with low-intensity chemotherapy.
RESULTS: Intensive chemotherapy independently predicted a worse treatment response (IC vs. HMA + venetoclax, OR = 0.183, 95% CI 0.048-0.693, p = 0.012) and inferior overall survival (OS) (IC vs. HMA + venetoclax, HR = 3.316, 95% CI 1.332-8.255, p = 0.010). After 15 patients with favorable cytogenetics or mutations were excluded, the HMA + venetoclax combination still outweighed IC with respect to treatment response (IC vs. HMA + venetoclax, OR = 0.063, 95% CI 0.012-0.332, p = 0.001) and OS (IC vs. HMA + venetoclax, HR = 3.072, 95% CI 1.216-7.758 p = 0.018) in patients with an adverse risk according to 2022 European Leukemia Net guidelines. Allogeneic hematopoietic stem cell transplantation independently predicted superior OS (HR = 0.234, 95% CI 0.088-0.626, p = 0.004). Additionally, in patients receiving HMAs combined with venetoclax, the G646fs variant of the ASXL1 mutation was associated with a lower complete remission or with an incomplete hematological recovery rate (4/7 vs. 2/19, 42.9% vs. 10.5%, p = 0.026) and worse event-free survival (median, 14.0 months vs. not reach, p = 0.045).
CONCLUSION: HMAs and venetoclax could benefit newly diagnosed younger patients with ASXL1-mutated AML.

Keywords:   ASXL1 ; acute myeloid leukemia; hypomethylating agents; venetoclax

DOI:  https://doi.org/10.1002/cam4.71037
Blood. 2025 Jul 17. 146(3): 265-266

Unusual suspects: a surprise cast in making blood stem cells.

Brandon Hadland.

DOI: https://doi.org/10.1182/blood.2025029369
Ther Adv Med Oncol. 2025 ;17 17588359251340554

Efficacy of zanubrutinib versus acalabrutinib for relapsed or refractory chronic lymphocytic leukemia (R/R CLL): a matching-adjusted indirect comparison (MAIC).

Mazyar Shadman, Jennifer R Brown, Rhys Williams, Leyla Mohseninejad, Keri Yang, Pal Rakonczai, Nicole Lamanna, Sheng Xu, Aileen Cleary Cohen, Susan M O'Brien, Alessandra Tedeschi, Constantine S Tam.

   Background: There are no head-to-head studies comparing the efficacy of the Bruton tyrosine kinase inhibitors, zanubrutinib and acalabrutinib, in relapsed or refractory chronic lymphocytic leukemia (R/R CLL).
Objective: To compare the relative efficacy of zanubrutinib and acalabrutinib in R/R CLL using indirect treatment comparison.
Design: An unanchored matching-adjusted indirect comparison (MAIC) was performed.
Methods: Individual patient-level data from ALPINE (zanubrutinib) were reweighted using prognostic/effect-modifying variables to match aggregate data from ASCEND (acalabrutinib). MAIC outcomes included investigator-assessed progression-free survival (PFS-INV), overall survival (OS), and complete response (CR).
Results: Post-matching, PFS-INV was improved significantly for zanubrutinib versus acalabrutinib (hazard ratio (HR) = 0.68 (95% confidence interval (CI): 0.46-0.99); p = 0.0448) and OS showed a trend toward improvement for zanubrutinib (HR = 0.60; 95% CI: 0.35-1.02, p = 0.0575). CR was significantly higher for zanubrutinib versus acalabrutinib (odds ratio = 2.90 (95% CI: 1.13-7.43); p = 0.0270).
Conclusion: Zanubrutinib was associated with a significant PFS-INV and CR advantage over acalabrutinib, with a trend toward improvement in OS.

Keywords:  Bruton tyrosine kinase inhibitor (BTKi); chronic lymphocytic leukemia; comparative efficacy

DOI:  https://doi.org/10.1177/17588359251340554
Leukemia. 2025 Jul 12.

Rituximab, high-dose methotrexate plus orelabrutinib as induction therapy in newly diagnosed primary central nervous system lymphoma.

Shi-Hua Zhao, Zun-Min Zhu, Tao Yang, Da Gao, Li-Hong Liu, Wei Yang, Xiao-Bo Wang, Yu-Xia Zhao, Meng Li, Yi-Nan Gao, Rong-Jun Ma, Ying Yang, Hui-Ping Li, Li Li, Xiao-Lei Ao, Xiu-Bin Xiao, Chong-Ling Hu, Shun-Zong Yuan, Yao Ding, Xi-Lin Chen, Jian-Xia He, Yao Liu, Wen-Rong Huang.

DOI: https://doi.org/10.1038/s41375-025-02658-8
Hematol Oncol Clin North Am. 2025 Jul 11. pii: S0889-8588(25)00079-6. [Epub ahead of print]

First-line Therapy: Time-Limited Venetoclax Doublet Therapy.

Jennifer Huang, Mazyar Shadman.

  Studies examining venetoclax in combination with anti-CD20 monoclonal antibodies and covalent Bruton tyrosine kinase inhibitors (BTKi) demonstrated a progression-free survival and in some cases overall survival benefit over chemoimmunotherapy. It is currently unclear what is the most optimal combination partner for a B-cell leukemia/lymphoma 2 inhibitor (BCL2i). We are eagerly awaiting results from studies to determine the most effective BCL2i and BTKi combination for the first-line treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma given the development of second-generation drugs.

Keywords:  Chronic lymphocytic leukemia; Doublet therapy; Time-limited therapy; Venetoclax

DOI:  https://doi.org/10.1016/j.hoc.2025.05.007
Blood Adv. 2025 Jul 17. pii: bloodadvances.2025016695. [Epub ahead of print]

The Efficacy of Teclistamab in Multiple Myeloma Patients with Secondary Plasma Cell Leukemia.

Asis Shrestha, Sharmilan Thanendrarajan, Aishee Bag, Binod Dhakal, Maurizio Zangari, Samer Al Hadidi, Frits van Rhee, Anita D'Souza, Nishi Shah, Mansi R Shah, Meera Mohan, Carolina Schinke.

DOI: https://doi.org/10.1182/bloodadvances.2025016695
J Hematol Oncol. 2025 Jul 15. 18(1): 73

Phase I first-in-human dose escalation study of the oral casein kinase 1α and cyclin dependent kinase 7/9 inhibitor BTX A51 in advanced MDS and AML.

Brian J Ball, Wenbin Xiao, Gautam Borthakur, Le Xuan Truong Nguyen, Melissa Valerio, Avanthika Venkatachalam, Guido Marcucci, Anthony S Stein, Dung Luong Thai, David N Cook, Kyle Chan, Sonali Persaud, Ross L Levine, Omar Abdel-Wahab, Yinon Ben-Neriah, Eytan M Stein.

   BACKGROUND: BTX A51, a first-in-class oral small molecule inhibitor of casein kinase 1α (CK1α) and cyclin-dependent kinase (CDK) 7 and 9, induces apoptosis of leukemic cells by activating p53 and inhibiting expression of Mcl1. Here, we report on the results of the phase 1 clinical trial of BTX A51 in patients with relapsed or refractory AML and MDS.
METHODS: Adult patients with R/R AML and high-risk MDS were enrolled into eight potential doses ranging from 1 to 42 mg dosed orally three days/week for 21 or 28 days out of a 28-day cycle. The maximum tolerated dose, recommended phase 2 dose (RP2D), safety, pharmacokinetics (PK), and pharmacodynamics (PD) of BTX A51 were investigated.
RESULTS: Thirty-one patients were enrolled and received treatment with BTX A51. Median age was 75 (range 22- 84) and 55% were male. Most patients (97%) had received prior treatment with venetoclax and hypomethylating agents. The most common treatment-emergent adverse events of any grade were nausea (67%), emesis (63%), hypokalemia (53%), and diarrhea (40%). Two patients experienced hepatic toxicity as DLTs, which resolved upon holding treatment. No treatment-related deaths occurred. The recommended phase 2 dose was 21 mg dosed three days/week for 4 weeks of a 28-day cycle. BTX A51 increased the expression of p53 and reduced the expression of MCL1 and RNA polymerase II phosphorylation in pre- and post-treatment immunocytochemistry studies. Overall, 3 patients (10%) experienced complete remission with incomplete count recovery (CRi). All 3 responding patients had RUNX1 mutations and the CR/CRi rate for RUNX1-mutated patients receiving BTX A51 at efficacious doses (11 mg or higher) was 30%. Ex-vivo studies confirmed higher efficacy of BTX A51 on RUNX1-mutated myeloblasts and demonstrated synergy with azacitidine and venetoclax.
CONCLUSIONS: Although the overall efficacy was modest, this study lays the groundwork for future studies with improved patient selection and combination approaches.
TRIAL REGISTRATION: NCT04872166.

Keywords:  AML; Casein kinase 1α; Cyclin-dependent kinase 7/9; MDS; Refractory; Relapsed; Targeted therapy

DOI:  https://doi.org/10.1186/s13045-025-01724-z
Hemasphere. 2025 Jul;9(7): e70178

Current and future role of carfilzomib-based quadruplet combinations as therapy for newly diagnosed multiple myeloma.

Ola Landgren, Noa Biran, Elizabeth K O'Donnell, Joseph Mikhael, Katja C Weisel, Annemiek Broijl, Saad Z Usmani, Philippe Moreau, Francesca M Gay, Roberto Mina, Paula Rodríguez-Otero, Andrzej J Jakubowiak, Benjamin A Derman.

The treatment of newly diagnosed multiple myeloma (NDMM) has advanced rapidly in recent years, with the standard of care (SOC) now including not only triplet combinations of proteasome inhibitors (PIs), immunomodulatory agents, and steroids but also quadruplet combinations that add the anti-CD38 monoclonal antibodies isatuximab (Isa) or daratumumab (D) to a triplet backbone. In addition to the widely used bortezomib-lenalidomide-dexamethasone (VRd) combination, an alternative triplet option that can be considered is the combination of the second-generation PI carfilzomib (K) with lenalidomide-dexamethasone (KRd). In patients with transplant-eligible NDMM, US treatment guidelines have included the KRd triplet as a recommended regimen and the quadruplet combinations of either Isa-KRd or D-KRd as additional options. However, currently, KRd does not have regulatory approval for use in the NDMM population. This review describes the current evidence for using KRd as a backbone of therapy in frontline treatment regimens for patients with NDMM. In addition to multiple studies that have examined the KRd triplet in this population, several clinical trials have been investigating anti-CD38-KRd quadruplets. The data reported from these various trials are revealing deep and durable responses with Isa-KRd and D-KRd, including minimal residual disease negativity. Importantly, these benefits have also been demonstrated in high-risk NDMM populations. KRd-based combinations may represent a suitable alternative to VRd for some patients. This article discusses measures that may help to establish KRd-based quadruplets as an additional SOC in this setting, including proper patient selection, steps to mitigate safety concerns, and the establishment of optimal dosing schedules.

DOI: https://doi.org/10.1002/hem3.70178
Lancet Oncol. 2025 Jul 10. pii: S1470-2045(25)00262-1. [Epub ahead of print]

Fertility in patients with advanced-stage classic Hodgkin lymphoma treated with BrECADD versus eBEACOPP: a secondary analysis of the multicentre, randomised, parallel, open-label, phase 3 HD21 trial.

Justin Ferdinandus, Gundolf Schneider, Alden Moccia, Richard Greil, Mark Hertzberg, Valdete Schaub, Andreas Hüttmann, Felix Keil, Judith Dierlamm, Mathias Hänel, Urban Novak, Julia Meissner, Johannes Christian Hellmuth, Stephan Mathas, Josée M Zijlstra, Alexander Fosså, Andreas Viardot, Bernd Hertenstein, Sonja Martin, Pratyush Giri, Peter Kamper, Daniel Molin, Janina Jablonski, Carla Damaschin, Anne Sophie Robertz, Johannes Rosenbrock, Michael Fuchs, Peter Borchmann, Karolin Behringer.

BACKGROUND: BrECADD (brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone) has shown higher efficacy and better acute tolerability than eBEACOPP (escalated doses of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) in newly diagnosed, advanced-stage classic Hodgkin lymphoma. In this secondary analysis of the HD21 trial, we aimed to compare gonadal function recovery and fertility outcomes between these two regimens.
METHODS: In the multicentre, parallel, open-label, phase 3 HD21 trial, conducted across 233 trial sites in nine countries, patients aged 18-60 years with newly diagnosed, advanced-stage classic Hodgkin lymphoma and an Eastern Cooperative Oncology Group performance status of 0-2 were randomly assigned (1:1) to receive 4-6 cycles of eBEACOPP or BrECADD, guided by interim response. Patients and investigators were not masked to treatment assignment. Primary outcomes were progression-free survival and treatment-related morbidity (reported elsewhere). Here we report an unplanned analysis of fertility outcomes. Fertility outcomes included gonadal function recovery (via follicle-stimulating hormone [FSH] concentrations), concentrations of anti-Müllerian hormone (AMH; women only) and inhibin B (men only), frequencies of pregnancies, and incidence of parenthood. Gonadal function recovery, AMH, and inhibin B were assessed in the patients of childbearing potential (POCBP) cohort, which included women younger than 40 years and men younger than 50 years without baseline gonadal dysfunction. Pregnancy and parenthood analyses also included patients with baseline gonadal dysfunction. The HD21 trial was registered at ClinicalTrials.gov (NCT02661503) and is ongoing but closed to enrolment.
FINDINGS: Between July 22, 2016, and Aug 27, 2020, 1183 POCBP were enrolled (592 in the eBEACOPP group, 591 in the BrECADD group; 692 men, 491 women). FSH measurements were available for 767 patients (420 men and 347 women). Median follow-up was 49·6 months (IQR 39·7-58·4). BrECADD was associated with significantly higher 4-year gonadal function recovery rates compared with eBEACOPP (95·3% [95% CI 92·0-98·8] in the BrECADD group vs 73·3% [66·9-80·4] in the eBEACOPP group, HR 1·69 [95% CI 1·34-2·14] in women; 85·6% [80·8-90·8] vs 39·7% [33·6-46·9], HR 3·28 [2·51-4·30] in men). AMH and inhibin B concentrations were generally higher in the BrECADD group compared with the eBEACOPP group. A total of 92 pregnancies were reported among female patients, and 36 among partners of male patients. These led to 108 reported childbirths in 99 patients (59 in the BrECADD group and 40 in the eBEACOPP group). After therapy, 5-year incidence of parenthood was significantly higher in men (9·3% [95% CI 6·0-14·5] vs 3·3% [1·7-6·5], p=0·014), but not significantly higher in women (19·3% [13·7-27·3] vs 17·1% [11·9-24·6], p=0·53) with BrECADD versus eBEACOPP.
INTERPRETATION: Compared with eBEACOPP, BrECADD led to significantly better gonadal function recovery, as well as higher parenthood rates (significantly so in men). These findings support BrECADD as preferred first-line therapy, especially for patients wishing to preserve fertility.
FUNDING: Takeda Oncology.

DOI: https://doi.org/10.1016/S1470-2045(25)00262-1
Hemasphere. 2025 Jul;9(7): e70155

Surface downmodulation of TIM3 safeguards healthy cells but not acute myeloid leukemia from CAR T-cell therapy.

Jort J van der Schans, Paresh Vishwasrao, Renée Poels, Morgan Antti, Ziyu Wang, Marjolein Quik, Jennemiek van Arkel, Tom Reuvekamp, Niels W C J van de Donk, Maria Themeli, Gert J Ossenkoppele, Arjan A van de Loosdrecht, Rebecca Richards, Tuna Mutis.

T-cell immunoglobulin and mucin-domain containing-3 (TIM3), generally known as an immune checkpoint receptor, is expressed on leukemic stem and progenitor cells (LSPCs) in acute myeloid leukemia (AML), and has an active role in LSC self-renewal. Therefore, TIM3 has been suggested as a potential target for AML treatment. Hence, we explored the feasibility of targeting TIM3 with chimeric antigen receptor (CAR) T-cells. Despite the expression of TIM3 on activated T-cells, TIM3 CAR T-cells were successfully generated from different healthy individuals with excellent in vitro expansion without signs of fratricide and sustained central-memory phenotype with minimal expression of exhaustion-related markers, including complete loss of TIM3 expression. TIM3 loss also did not affect effector functions since TIM3 CAR T-cells efficiently lysed TIM3+ leukemic cell lines, produced Th1-predominant cytokines, successfully inhibited the colony-forming of TIM3+ AML-derived LSPCs, and showed excellent AML tumor control in xenogeneic mouse models. Notably, TIM3 CAR T-cells did not affect healthy hematopoietic progenitor cells and healthy mature hematopoietic cells that express TIM3 at moderate levels, suggesting an optimal therapeutic window for the treatment of AML.

DOI: https://doi.org/10.1002/hem3.70155
Blood Adv. 2025 Jul 16. pii: bloodadvances.2024014654. [Epub ahead of print]

Estimating efficacy of favezelimab plus pembrolizumab relative to pembrolizumab in anti-PD-1-refractory Hodgkin lymphoma.

Philippe Armand, Pier Luigi Zinzani, John M Timmerman, Nathalie A Johnson, David Lavie, Kannan Thiagarajan, Brian Topp, Pallavi M Pillai, Alex F Herrera.

Favezelimab plus pembrolizumab had promising efficacy in anti-PD-1-refractory classical Hodgkin lymphoma in MK-4280-003; however, the contribution of favezelimab was unclear. Here, we assessed the relative contribution of favezelimab by comparison with data from participants treated with only pembrolizumab beyond progression in KEYNOTE-087. Participants in MK-4280-003 had received ≥2 doses of anti-PD-1 therapy and progressed <12 weeks of last dose. Participants eligible from KEYNOTE-087 had received >2 doses of pembrolizumab beyond progression and progressed <12 weeks of last dose. Participants received pembrolizumab 200 mg plus favezelimab 200 mg or 800 mg or pembrolizumab 200 mg intravenously every 3 weeks. Change in target lesion size and response per International Working Group 2007 criteria were assessed. Baseline tumor size was reset at first progression for KEYNOTE-087. A bootstrapping method compared change in target lesion size between groups. Twenty-seven participants from MK-4280-003 and 81 from KEYNOTE-087 were included. Objective response rates were 37% (95% CI, 15-51) for favezelimab plus pembrolizumab and 2% (95% CI, 0-6) for pembrolizumab alone. A clinically meaningful reduction (≥50%) in target lesion size was observed in 13 (48%) vs 4 (5%) participants, respectively. Mean change from baseline in target lesion size was -49% and -0.4%. In the bootstrapping analysis, 99.4% of samples showed greater decrease in tumor burden with favezelimab plus pembrolizumab. Favezelimab plus pembrolizumab had a higher response rate and greater reduction in tumor burden vs pembrolizumab alone in anti-PD-1-refractory classical Hodgkin lymphoma, suggesting favezelimab contributed substantially to efficacy in MK-4280-003. NCT03598608, NCT02453594.

DOI: https://doi.org/10.1182/bloodadvances.2024014654
Blood Adv. 2025 Jul 17. pii: bloodadvances.2025016829. [Epub ahead of print]

Molecular and Immunological Determinants of Long-Term Survival in Multiple Myeloma.

Khanmi Kasomva, Kritika Yadav, Siegfried Janz, Binod Dhakal, Sridhar Rao.

Long-term survival (LTS) in multiple myeloma (MM), defined as survival of ≥10 years post-diagnosis following a single line of therapy, is an increasingly observed outcome due to significant therapeutic advancements. The introduction of proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies, autologous stem cell transplantation (ASCT), and novel immunotherapies has transformed MM treatment. Importantly, only a subset of patients achieves long-term, durable disease control, suggesting that both myeloma-intrinsic and immune-mediated mechanisms play critical roles. Therapeutic advancements, including chimeric antigen receptor T-cell (CAR-T) therapy and bispecific antibodies, have primarily benefited standard-risk patients. Beyond therapeutic interventions, LTS appears to be driven by distinct features of the immune bone marrow environment (IBME), where enhanced T cell function, increased NK cell cytotoxicity, and reduced immunosuppressive myeloid populations contribute to disease control. Understanding these immune adaptations in LTS MM provides a foundation for developing next-generation treatment strategies. Future research integrating genomic and immune profiling, along with IBME modulation, will be critical in shifting MM treatment paradigms from disease management to sustained remission and functional cures.

DOI: https://doi.org/10.1182/bloodadvances.2025016829
Blood. 2025 Jul 15. pii: blood.2024028269. [Epub ahead of print]

The Treatment of Marginal Zone Lymphoma.

Juan Pablo Alderuccio, Ariela Noy.

The treatment landscape of B-cell non-Hodgkin lymphomas is rapidly evolving. However, few advances have occurred in marginal zone lymphoma (MZL) with a single FDA-approved agent impacting the treatment landscape. Multiple factors are associated with this slower pace of progress, with a lower MZL incidence representing a significant factor. Pivotal randomized indolent lymphoma clinical trials analyzed MZL subsets without the appropriate power to capture differences between treatment arms. Furthermore, the current Lugano Classification may not fully capture the presentation or treatment responses of some subtypes, preventing access to clinical trials and limiting an efficacy assessment across the disease spectrum. Thus, current MZL treatment is largely informed by single-arm studies with relatively empiric treatment sequencing among available agents. While frontline strategies in early- and advanced-stage MZL can achieve prolonged disease control, few options exist in the relapsed/refractory setting capable of achieving similar results. Emerging data demonstrate the encouraging efficacy of CD3xCD20 bispecific antibodies and antibody-drug conjugates in achieving deep responses, as well as the potential of circulating tumor DNA in risk stratification and molecular response monitoring. Compounding all these considerations, it is essential to recognize MZL as a heterogeneous group of diseases characterized by unique biology, clinical presentation, treatment response, toxicity, and survival. Nonetheless, a common characteristic across MZL subtypes is their general indolent disease course, emphasizing the need to incorporate patient-centered assessment in clinical trials to better inform the decision-making process.

DOI: https://doi.org/10.1182/blood.2024028269
Blood. 2025 Jul 17. 146(3): 396

Secondary blastoid plasma cell leukemia: can an old dog learn new tricks?

Jinjun Cheng, Jiehao Zhou.

DOI: https://doi.org/10.1182/blood.2025029282
Blood Adv. 2025 Jul 17. pii: bloodadvances.2025016731. [Epub ahead of print]

Long term follow-up of patients with AL amyloidosis treated on a phase 1 trial of CAEL-101.

Michael Sang Hughes, Samuel S Pan, Rajshekhar Chakraborty, Jayant Raikhelkar, Mathew S Maurer, Markus Y Mapara, Andrew Eisenberger, Suzanne Lentzsch, Divaya Bhutani.

DOI: https://doi.org/10.1182/bloodadvances.2025016731
Blood Adv. 2025 Jul 17. pii: bloodadvances.2025016890. [Epub ahead of print]

Long-term follow-up of venetoclax monotherapy in previously treated patients with Waldenström macroglobulinemia.

Jorge J Castillo, Alberto Guijosa, John N Allan, Tanya Siddiqi, Ranjana H Advani, Catherine Flynn, Kirsten E Meid, Nina Budano, Julia Nguyen, Andres Ramirez-Gamero, Nicholas Tsakmaklis, Zachary R Hunter, Christopher J Patterson, Steven P Treon, Shayna Sarosiek.

Venetoclax is highly active in previously treated Waldenström macroglobulinemia (WM). However, data on long-term durability and retreatment with venetoclax remain limited. Herein, we present an update of a prospective clinical trial of finite-duration venetoclax on 32 previously treated patients with WM. With a median follow-up of 81 months, twenty-three patients (72%) had disease progression, 17 (53%) began a new treatment, and 3 (9%) had died. The median progression-free survival (PFS) was 36 months, and the median treatment-free survival (TFS) was 43 months. PFS and TFS were superior in patients who attained at least a partial response to therapy. CXCR4 mutations or previous BTK inhibitor exposure did not impact these outcomes. Of the 17 patients who started a new therapy after completion of venetoclax therapy, nine were retreated with venetoclax alone or in combination (three attained a very good partial response, four a partial response, one had stable disease, and one did not respond). No BCL2 G101V mutations were detected in 52 CD19-selected bone marrow samples from 27 patients during treatment. Venetoclax induces durable responses in WM, allowing for retreatment in patients who progressed after completing therapy without the emergence of BCL2 G101V mutations. Clinical Trial Information: NCT02677324.

DOI: https://doi.org/10.1182/bloodadvances.2025016890
Blood. 2025 Jul 17. 146(3): 266-267

PROTACtion against BCL-xL in post-MPN AML.

Nicole S Arellano, Shannon E Elf.

DOI: https://doi.org/10.1182/blood.2025029273
Int J Mol Sci. 2025 Jun 30. pii: 6341. [Epub ahead of print]26(13):

Serum Cereblon (CRBN) Levels Predict Long Term Post- Lenalidomide-Dexamethasone Survival in Multiple Myeloma (MM) Patients and Correlate with Disease Characteristics.

Annita-Ioanna Gkioka, Alexandros Gkiokas, Mavra Papadatou-Gigante, Alexandros Alexandropoulos, Thomai-Marina Tryfou, Aspasia Koudouna, Vasiliki Bartzi, Marie-Christine Kyrtsonis.

  Serum cereblon (CRBN) has been proposed as a target protein for immunomodulatory drugs (IMiDs). IMiDs are one of the backbone treatment options in multiple myeloma (MM), rendering CRBN an intriguing candidate for use as a biomarker in clinical settings. Ninety-two (92) MM patients, mostly relapsed/refractory and a few at diagnosis, were included in the study, from lenalidomide-dexamethasone (LD) initiation until last follow-up or death. Median CRBN at LD initiation (N = 68) treatment was 247 pg/mL (range, 0-9760 pg/mL), at the time of best response (BR) status (N = 59) 142.5 pg/mL (range, 0-9940 pg/mL) and in patients with relapse/refractory MM to LD regimen (N = 54) 298 pg/mL (range, 0-9840 pg/mL). CRBN in healthy individuals was almost undetectable and significantly lower compared to the CRBN at LD initiation (p = 0.003), at BR to LD (p = 0.012) and at relapse to LD (p = 0.002). CRBN was significantly lower at BR in contrast to LD initiation and relapse to LD (p = 0.04, p = 0.028). High levels of CRBN at treatment initiation correlated with early relapse to LD (≤12 months) (p = 0.03). Seven-year survival was improved in patients with CRBN levels below median measured at the time of LD initiation (p = 0.013) as well as at BR (p = 0.032). CRBN was associated with treatment response and is predictive of survival after LD.

Keywords:  CRBN; immunomodulatory drugs; lenalidomide; multiple myeloma; prognosis; response biomarkers; serum cereblon

DOI:  https://doi.org/10.3390/ijms26136341
J Hematol Oncol. 2025 Jul 15. 18(1): 72

Development and validation of a prognostic staging system for primary plasma cell leukemia.

Mengru Tian, Gang An, Weijun Fu, Wenqiang Yan, Lu Li, Chunyan Sun, Zhenyu Li, Lijuan Chen, Aijun Liao, Guangxun Gao, Xiaoqi Qin, Mengyao Li, Chunrui Li, Hua Xue, Li Gao, Yi Wang, Aili He, Fan Zhou, Dongmei Guo, Yujun Dong, Zhihong Fang, Xiaoxia Chu, Jianqing Mi, Chengcheng Fu, Hui Zeng, Shuling Hou, Xiaotao Wang, Hua Wang, Yongqiang Wei, Xinyue Liang, Xingcheng Yi, Yue Sun, Lugui Qiu, Yun Dai, Fengyan Jin.

   BACKGROUND: The existing risk models for multiple myeloma (MM) are suboptimal for the stratification of patients with primary plasma cell leukemia (pPCL), a rare and peculiar MM. In this study, we aimed to develop a staging system for pPCL defined as the presence of ≥ 5% circulating plasma cells (CPC) according to the new diagnostic criteria, utilizing one of the largest series of patients with pPCL.
METHODS: This multicenter retrospective study included 340 patients with pPCL (the training cohort) from 25 centers nationwide in China. The prognostic impact of baseline characteristics and cytogenetic abnormalities was evaluated. Univariate and multivariate analyses were conducted to identify variables predicting overall survival (OS) to develop a staging system. Its performance was then validated in an independent cohort (n = 80). Genome-wide DNA and RNA sequencing were performed to explore the molecular basis for inter-stage clinical heterogeneity.
RESULTS: Del(17p), t(4;14), and t(14;16), but not 1q+, were verified as high-risk cytogenetic abnormalities (HRCAs) of pPCL. HRCA, elevated LDH, and thrombocytopenia had the highest impact on OS and were used to create a simple algorithm, stratifying patients with pPCL into stages I, II, and III, with median OS of 54.1, 24.0, and 5.4 months (II vs. I: HR, 1.986; 95% CI, 1.034-3.814; P = 0.0394; III vs. II: HR, 3.206; 95% CI, 1.757-5.852; P = 0.0001) in the training cohort and 62.1, 31.6, and 21.8 months (II vs. I: HR, 2.013; 95% CI, 0.954-4.251; P = 0.0664; III vs. II: HR, 2.694; 95% CI, 1.136-6.392; P = 0.0245) in the independent validation cohort. The accuracy (c-index 0.711) was higher than other models. Moreover, patients with different stages had highly diverse genomic and transcriptomic aberrations.
CONCLUSIONS: We propose a pPCL-specific staging system based on LDH, thrombocytopenia, and cytogenetic abnormalities, which warrants further validation, particularly in a prospective setting.

Keywords:  Biological heterogeneity; High-risk cytogenetics; Overall survival; Primary plasma cell leukemia; Staging system

DOI:  https://doi.org/10.1186/s13045-025-01723-0
Curr Opin Genet Dev. 2025 Jul 10. pii: S0959-437X(25)00069-3. [Epub ahead of print]94 102377

Exploring the origin of the development: totipotent stem cells.

Shiyu Li, Hui Shen, Bing Peng, Peng Du.

As the origin of the development, a fertilized egg owns the ability to generate a whole new organism, including both embryonic and extraembryonic tissues, representing the highest developmental potency, totipotency. For more than 40 years, pluripotent stem cells, with differentiation potential weaker than that of totipotent cells, have been easily derived from inner cell mass and maintained in vitro. Until now, capturing totipotent stem cells is still challenging. Recently, the stable culture of mouse and human totipotent blastomere-like cells was achieved for the first time using spliceosomal repression. Subsequently, other methods, particularly epigenetic manipulation, have also succeeded in culturing mouse totipotent stem cells. These advancements provide an excellent system for studying early embryonic development and offer new possibilities for regenerative medicine. However, the in vitro culture of totipotent stem cells has only been recently realized, and much further exploration is needed in this field. This review aims to compare different totipotent stem cells and discuss their potential applications in regenerative medicine and disease modeling.

DOI: https://doi.org/10.1016/j.gde.2025.102377
Neuroradiology. 2025 Jul 14.

Dual- energy CT versus single-energy CT for estimation of hematocrit and hemoglobin in the brain: an in vivo analysis.

Richard Dagher, Megan C Jacobsen, Satvik Vasireddy, Rick R Layman, Dong-Eog Kim, Max Wintermark, Dawid Schellingerhout.

   PURPOSE: Hematocrit (Hct) and hemoglobin (HB) levels in blood are known to be correlated with vascular attenuation values on single-energy computed tomography (SECT). Dual-energy computed tomography (DECT) is likely to have even better correlations than SECT, given its richer information content, but this remains unproven clinically. We compare and contrast DECT and SECT correlations between attenuation in the superior sagittal sinus (SSS) to patient Hct/HB levels, and explore the use of iodine/water decomposition maps for the same purpose.
METHODS: Brain SECT and DECT were acquired contemporaneously in 83 patients and attenuation was measured in the SSS on SECT, monoenergetic DECT images (40 to 140 keV in 5 keV increments) and DECT material decomposition images (water and iodine). Hct/HB values were from complete blood counts (CBC) within 30 days of imaging. Linear regressions were performed to Hct/HB using the measured attenuations as explanatory variables.
RESULTS: Hct and HB were strongly mutually correlated (r = 0.964). Hct/HB were moderately correlated (r = 0.493/0.458) with SSS attenuation on SECT, and moderately to strongly correlated for DECT (Pearson's r ranging 0.331-0.656) over a range of monoenergetic levels (40 to 140 keV). Above 60 keV, DECT monoenergetic images were better correlated to Hct/HB than SECT, with correlation maximized at 95 keV (r = 0.656, p < 0.001). Material decomposition water images had moderate correlation (r = 0.51), improving to strong correlation (r = 0.659) for a two-variable water and iodine regression, similar to the monoenergetic results.
CONCLUSION: DECT has better correlations to Hct/HB than SECT for all monoenergetic energies above 60 keV, with best correlations at 95 keV.

Keywords:  Brain; Dual-energy CT; Hematocrit; Hemoglobin; Single-energy CT

DOI:  https://doi.org/10.1007/s00234-025-03700-3
Blood Adv. 2025 Jul 22. 9(14): 3629-3630

Getting closer to hemophilia gene therapy for all?

Ulrike M Reiss.

DOI: https://doi.org/10.1182/bloodadvances.2025016642
Blood Cancer Discov. 2025 Jul 16.

IRF4 promotes immune evasion and shapes the tumor microenvironment in Follicular Lymphoma.

Surendra Dasari, Kerstin Wenzl, Geoffrey M Nelson, Emmanuel Contreras Guzman, Zhiquan Wang, Loic Chartier, Zhi-Zhang Yang, Jose C Villasboas, Joshua Olson, Prithviraj Mukherjee, Vaishali Bhardwaj, Xinyi Tang, Brianna J Negaard, Johannes L Zakrzewski, Rebecca L King, Sarah Huet, Bruno Tesson, Matthew J Maurer, Franck Morschhauser, Grzegorz S Nowakowski, Karen L Adelman, Harinder Singh, Laura Pasqualucci, Mark Shlomchik, Anne J Novak, Stephen M Ansell, Patrizia Mondello.

Twenty percent of follicular lymphoma (FL) patients relapse early with poor outcomes; however, the molecular mechanisms underlying this aggressive behavior are unknown. Using a multi-omics approach, we show that FL patients with elevated IRF4 expression (IRF4hi) have increased transformation risk, dysregulated immune signaling, and a suppressive tumor microenvironment. Loss- and gain-of-function experiments in IRF4hi lymphoma cells, along with chromatin profiling, demonstrate that IRF4 impairs their interaction with T cells by repressing antigen presentation and co-receptor gene modules, while promoting the expression of cytokines that antagonize TFH and Treg functions. Additionally, IRF4 rewires tumor metabolism which restricts glucose availability to immune cells. Silencing of IRF4 inhibits tumor cell growth and restores immune surveillance mechanisms, thus representing a promising target for therapy. Our data suggest that IRF4hi lymphoma cells co-opt a developmental mechanism used to exit the germinal center response in promoting a more aggressive cancer via engagement of multiple immune-evasive mechanisms.

DOI: https://doi.org/10.1158/2643-3230.BCD-24-0223
J Clin Med. 2025 Jul 03. pii: 4723. [Epub ahead of print]14(13):

Multiorgan Failure Resembling Grade 5 (Fatal) Cytokine Release Syndrome in Patient with Multiple Myeloma Following Carfilzomib Infusion: A Case Report.

Strahinja Gligorevic, Nebojsa Brezic, Joshua Jagodzinski, Andjela Radulovic, Aleksandar Peranovic, Igor Dumic.

  Background: Cytokine release syndrome (CRS) is a life-threatening systemic inflammatory condition marked by excessive cytokine production, leading to multi-organ dysfunction. It is commonly associated with T-cell-engaging therapies such as chimeric antigen receptor (CAR) T cells, T-cell receptor bispecific molecules, and monoclonal antibodies. Carfilzomib, a proteasome inhibitor, is known to cause a range of adverse effects, primarily hematologic and cardiovascular. However, multiorgan failure grade 5 (fatal), resembling CRS has not been previously reported in association with Carfilzomib. Case Report: A 74-year-old male with relapsed multiple myeloma developed grade 5 multiorgan failure 60 min after the third dose of Carfilzomib, resulting in death within 24 h of symptom onset. The patient tolerated the first doses of Carfilzomib well with only fever and headache developing post infusion. Before the second dose, the patient developed worsening pancytopenia, prompting the discontinuation of Lenalidomide. After the second Carfilzomib infusion, he experienced fever and transient encephalopathy, which resolved with acetaminophen, corticosteroids, and supportive care. However, following the third dose, he rapidly deteriorated-developing fever, tachycardia, hypotension, hypoxia, and encephalopathy. Despite aggressive management with intravenous fluids, broad-spectrum antibiotics, corticosteroids, and tocilizumab, the patient progressed to refractory shock and multi-organ failure, culminating in death within 24 h. A comprehensive infectious workup was negative, ruling out sepsis and suggesting possible Carfilzomib-induced CRS. Conclusion: Grade 5 multiorgan failure with signs and symptoms similar with CRS following Carfilzomib administration is a rare but potentially fatal adverse drug reaction. Further research is needed to better define the risk factors and optimal management strategies for Carfilzomib-induced multiorgan failure and possible CRS.

Keywords:  carfilzomib; cytokine release syndrome; multiorgan failure; multiple myeloma; shock

DOI:  https://doi.org/10.3390/jcm14134723
bioRxiv. 2025 May 10. pii: 2025.05.07.652612. [Epub ahead of print]

IL-16 production is a mechanism of resistance to BTK inhibitors and R-CHOP in lymphomas.

Alberto J Arribas, Francesca Guidetti, Eleonora Cannas, Luciano Cascione, Sara Napoli, Giulio Sartori, Federica Fuzio, Emma Pesenti, Chiara Tarantelli, Filippo Spriano, Antonella Zucchetto, Francesca M Rossi, Alessio Bruscaggin, Andrea Rinaldi, Manuel Castro de Moura, Sandra Jovic, Andrea Raimondi, Roberta Bordone Pittau, Lodovico Terzi di Bergamo, Xiaofei Ye, Anastasios Stathis, Yaacov Ben-David, Qiang Pan-Hammarström, Federico Simonetta, Georg Stussi, Emanuele Zucca, Valter Gattei, Jennifer R Brown, Manel Esteller, Davide Rossi, Francesco Bertoni.

Introducing Bruton's tyrosine kinase (BTK) inhibitors has significantly improved outcomes for patients with B-cell malignancies and autoimmune disorders. However, resistance, either primary or acquired, remains a major clinical challenge. To better understand the underlying resistance mechanisms to BTK inhibitors, we established an ibrutinib-resistant model from a patient-derived splenic marginal zone lymphoma (MZL) cell line (VL51) through prolonged drug exposure. Resistant cells exhibited a 15-fold increase in ibrutinib's IC50, along with distinct morphological changes, mitochondrial activation, and cross-resistance to covalent, non-covalent BTK inhibitors and BTK degraders. Integrated transcriptomic, epigenomic, and proteomic analyses identified overexpression and secretion of IL-16 as a key feature of resistance, driven by chromatin remodeling and activation of the FLI1 transcription factor. IL-16 conferred ibrutinib resistance via CD9-mediated activation of the NF-κB and AKT signaling pathways and was found to be elevated in the serum of ibrutinib-refractory CLL patients. Functional studies showed that targeting the IL-16/CD9 axis using neutralizing antibodies or CD9-binding peptides restored sensitivity to BTK inhibitors and R-CHOP chemotherapy in MZL, mantle cell lymphoma, and diffuse large B-cell lymphoma models. These findings reveal a novel, targetable resistance mechanism with potential therapeutic implications for overcoming BTK inhibitor resistance in B-cell lymphomas.

DOI: https://doi.org/10.1101/2025.05.07.652612