bims-hemali 2025-11-16 papers

bims-hemali

Biomed News

on Hematologic malignancies

Issue of 2025–11–16
25 papers selected by
Alexandros Alexandropoulos, Γενικό Νοσοκομείο Αθηνών Λαϊκό

Successful fatherhood of males with tyrosine kinase inhibitor-resistant chronic myeloid leukemia taking olverembatinib.
Venetoclax plus decitabine, cytarabine, aclarubicin, and G-CSF in adults with newly diagnosed acute myeloid leukemia: A multicenter, retrospective study.
Natural Products Targeting BCR-ABL: A Plant-Based Approach to Chronic Myeloid Leukemia Treatment.
Teclistamab Dosing Strategies in Relapsed/Refractory Myeloma: A Real-World Comparison of Weekly and Biweekly Versus Fixed Intervals.
Venetoclax Plus Blinatumoma as First Line Therapy for Newly Diagnosed Ph-Negative B-Cell Acute Lymphoblastic Leukemia.
Olutasidenib for mutated IDH1 acute myeloid leukemia: final five-year results from the phase 2 pivotal cohort.
Epcoritamab Plus Gemcitabine and Oxaliplatin Versus Rituximab Plus Gemcitabine and Oxaliplatin in Transplant-Ineligible Relapsed/Refractory Diffuse Large B-Cell Lymphoma: A Match-Adjusted Comparative Analysis.
Dose-Attenuated-Polatuzumab Vedotine plus CHP vs. Dose-Attenuated -R-CHOP in Patients Aged ≥ 80 Years with Diffuse Large B-Cell Lymphoma: A Retrospective, Propensity Score-Matched Analysis Stratified by Simplified Frailty Score.
Refitting fitness in CLL.
Converging approaches in the frontline treatment of mantle cell lymphoma.
P3-GemOx as a novel immunochemotherapy candidate in NK/T-cell lymphoma management.
Treatment Cessation in Chronic Myeloid Leukemia: Evidence and Uncertainties.
Optimizing the use of melflufen (melphalan flufenamide) in relapsed or refractory multiple myeloma: recommendations for clinical practice.
Saga of MCL1 inhibitors in multiple myeloma.
Hijack the HiJAKer: rethinking therapy for JAK2-mutant MPN.
Sustained remission with PD-1 and BTK inhibitors maintenance after chimeric antigen receptor T-cell therapy in CNS lymphoma.
Efficacy and safety of ropeginterferon alfa-2b in the treatment of polycythemia vera: a systematic review with single arm meta-analysis.
Acalabrutinib May Offer a New Therapeutic Approach for Consolidation and Maintenance of Primary CNS Lymphoma with Expression of MYD88 and CD79B Gene Variants: A Case Report and Literature Review of Primary CNS Lymphoma in the BTKi Era.
Smoldering multiple myeloma in the United States: A population-based analysis.
Potential therapeutic GSK-3β inhibitor 9-ING-41 is active in combination with venetoclax in double-hit lymphoma (DHL).
First in human phase 1 study of DT2216, a selective BCL-xL degrader, in patients with relapsed/refractory solid malignancies.
Novel Agents and Immunotherapies for Primary Diffuse Large B-Cell Lymphoma of the Central Nervous System: Innovating for Impact in a Disease With Unmet Needs.
Mantle cell lymphoma with KMT2A rearrangement.
Venetoclax combined with cladribine, idarubicin, cytarabine (CLIA-VEN) results in higher remission rates over conventional 7 + 3 chemotherapy without increased toxicity in newly diagnosed acute myeloid leukaemia.
Chronic myeloid leukemia with atypical transcript e8a2: a case report and literature review.

Ann Hematol. 2025 Nov 14.

Successful fatherhood of males with tyrosine kinase inhibitor-resistant chronic myeloid leukemia taking olverembatinib.

Lu Yu, Qian Jiang.

  As life expectancy in patients with chronic myeloid leukemia (CML) approaches that of the general population, fertility preservation has become a critical quality-of-life consideration, especially for younger patients. Although third-generation (3G) tyrosine kinase inhibitors (TKIs), such as olverembatinib, demonstrate potent efficacy against TKI-resistant disease, their reproductive safety profiles remain largely undefined. We report two TKI-resistant male patients who achieved sustained deep molecular responses with olverembatinib and who subsequently conceived healthy offspring with their partners. These cases provide clinical evidence that olverembatinib exposure does not preclude normal male fertility or healthy offspring, emphasizing the need for systematic reproductive safety data on 3G TKIs.

Keywords:  Chronic myeloid leukemia; Fatherhood; Olverembatinib; Tyrosine kinase inhibitor-resistant

DOI:  https://doi.org/10.1007/s00277-025-06722-2
Int J Cancer. 2025 Nov 14.

Venetoclax plus decitabine, cytarabine, aclarubicin, and G-CSF in adults with newly diagnosed acute myeloid leukemia: A multicenter, retrospective study.

Ying Zhang, Kun Yang, Yong Guo, Jin Rao, Feng Wang, Yunfan Yang, Zhongqing Zou, Kai Shen, Chunyan Liang, Hongwei Wu, Chenlu Yang, Wenjiao Tang, Yantao Ling, Yiwen Du, Jirui Tang, Mei Wang, Duanzhong Zhang, Xiaoling Yu, Qi Chen, Yanqiu Xiong, Xu He, Yuchen Zhan, Hongbin Ma, Yuping Gong.

  This multicenter, retrospective study evaluated the efficacy and safety of the venetoclax plus decitabine, cytarabine, aclarubicin, and granulocyte colony-stimulating factor (VD-CAG) regimen in newly diagnosed acute myeloid leukemia (ND-AML) patients aged 18-60. The analysis included, but was not limited to, the composite complete response (CRc) rate, measurable residual disease (MRD) negativity rate, overall survival (OS), event-free survival (EFS), and safety. A total of 107 adult patients with AML were included in the study, conducted between March 1, 2022, and December 31, 2024. The median age was 49 years (range: 18-60 years), with a male-to-female ratio of 44:63. The CRc rate after one cycle of the VD-CAG regimen was 86.9% (95% CI 79-92.7; 93 of 107 patients) in the entire cohort. 73 (79%) of 93 patients who reached CRc had undetectable MRD. Grade 3 or worse adverse events included neutropenia in 107 (100%) of 107 patients, thrombocytopenia in 107 (100%), anemia in 107 (100%), febrile neutropenia in 57 (53%), pneumonia in 10 (9.3%), sepsis in five (4.7%), and tumor lysis syndrome in three (2.8%). No treatment-related deaths occurred. With a median follow-up of 8.8 months (range: 1-33.5 months), the median EFS and OS are not reached. The estimated 12-month OS was 90% (95% CI 90-95) and 12-month EFS was 79% (95% CI 69-87). The VD-CAG regimen represents an effective induction therapy for young ND-AML. It leads to high rates of CRc and MRD-negative remissions, along with encouraging OS and EFS across prognostic subgroups.

Keywords:  CAG; acute myeloid leukemia; decitabine; induction treatment; venetoclax

DOI:  https://doi.org/10.1002/ijc.70239
Molecules. 2025 Oct 22. pii: 4160. [Epub ahead of print]30(21):

Natural Products Targeting BCR-ABL: A Plant-Based Approach to Chronic Myeloid Leukemia Treatment.

Louisa Pechlivani, Alexandros Giannakis, Chrissa Sioka, Georgios A Alexiou, Athanassios P Kyritsis.

  The BCR-ABL fusion oncoprotein, a constitutively active tyrosine kinase, plays a central role in the pathogenesis of chronic myeloid leukemia (CML). While tyrosine kinase inhibitors (TKIs) have transformed CML treatment, issues such as drug resistance, particularly involving mutations like T315I, and adverse effects underscore the need for alternative or complementary therapeutic strategies. Natural products derived from plants have long served as a reservoir for anticancer agents, offering structural diversity and multi-targeted bioactivity. Notably, many plant-based compounds exhibit anticancer effects with comparatively lower toxicity and fewer side effects than synthetic TKIs, making them attractive candidates for safer long-term use. This review explores the recent advances in plant-based natural compounds that directly or indirectly inhibit BCR-ABL kinase activity and its downstream signaling pathways. Key compounds are discussed with respect to their mechanisms of action, structure-activity relationships, and potential to overcome TKI resistance. Several of these compounds directly target BCR-ABL or promote its degradation, while others inhibit downstream effectors such as STAT5 and PI3K/Akt, leading to apoptosis and growth inhibition of leukemic cells. The synergistic potential of these natural products with existing TKIs and their promise to target drug-resistant CML cells further highlight their translational value. By integrating insights from molecular pharmacology, medicinal chemistry, and leukemia biology, this review supports the continued investigation of plant-derived agents as novel or adjunctive therapies against BCR-ABL-driven leukemias.

Keywords:  BCR-ABL inhibition; chronic myeloid leukemia; natural products; plant-derived compounds; tyrosine kinase inhibitor resistance

DOI:  https://doi.org/10.3390/molecules30214160
Cancers (Basel). 2025 Nov 05. pii: 3569. [Epub ahead of print]17(21):

Teclistamab Dosing Strategies in Relapsed/Refractory Myeloma: A Real-World Comparison of Weekly and Biweekly Versus Fixed Intervals.

Jordan Snyder, Shebli Atrash, Barry Paul, Abdullah Mohammad Khan, Alma Habib, Hira Shaikh, Christopher Strouse, Omar Alkharabsheh, Anita Mazloom, Nausheen Ahmed, Zahra Mahmoudjafari, Muhammad Umair Mushtaq, Anas Zayad, Joseph McGuirk, Yun Kyoung Tiger, Mansi R Shah, Al-Ola Abdallah.

  Background/Objectives: Teclistamab is a bispecific antibody targeting BCMA and CD3, approved for relapsed/refractory multiple myeloma. It is administered continuously until progression or intolerance; however, prolonged use may increase infections and treatment burden. This study compares continuous versus fixed-duration teclistamab to determine whether treatment discontinuation after response is feasible without compromising outcomes. Methods: A multicenter retrospective study was conducted on adults with relapsed/refractory multiple myeloma treated with teclistamab between August 2022 and May 2024. Patients received step-up dosing followed by weekly administration. Those who achieved ≥VGPR and discontinued therapy due to deep response, toxicity, or preference were assigned to the fixed-duration group. Outcomes included response rates, progression-free survival (PFS), overall survival (OS), and adverse events. Results: Eighty-eight patients were included (continuous: n = 72; fixed: n = 16). The fixed group had higher complete response rates (69% vs. 44%) and shorter median time to best response (1 vs. 2 months). Median PFS was 16 months for continuous dosing versus 13 months for fixed-duration. Twelve-month PFS was similar (65% vs. 66%). Twelve-month OS was 83% vs. 81% in the continuous and fixed groups, respectively. Cytokine release syndrome and neurotoxicity rates were similar. Infections were more frequent and severe in the fixed cohort (75% any grade; 69% grade ≥ 3). Conclusions: Fixed-duration teclistamab after deep response appears feasible in appropriately selected patients, with comparable early survival outcomes to continuous treatment. Prospective studies are needed to define selection criteria, immune recovery markers, and optimal discontinuation timing.

Keywords:  dosing strategies; relapsed/refractory multiple myeloma; teclistamab

DOI:  https://doi.org/10.3390/cancers17213569
Blood Lymphat Cancer. 2025 ;15 193-202

Venetoclax Plus Blinatumoma as First Line Therapy for Newly Diagnosed Ph-Negative B-Cell Acute Lymphoblastic Leukemia.

Yutian Lei, Xiaoli Zhao, Huijun Huang, Limin Duan, Ji Xu, Kourong Miao, Huihui Zhao, Chun Qiao, Ming Hong, Sixuan Qian, Lei Fan, Yu Zhu.

   Purpose: This study evaluated the efficacy and safety of a 14-day blinatumomab-venetoclax (BV) regimen as induction therapy for newly diagnosed Ph-negative B-cell acute lymphoblastic leukemia (B-ALL), focusing on rapid remission and tolerability in unfit patients.
Patients and Methods: Thirteen patients received venetoclax (100 mg on day 1, 200 mg on day 2, 300 mg on day 3, and 400 mg from days 4 to 14) with blinatumomab (9 to 28 ug/day) for 14 days. Bone marrow assessments were performed at days 14-21. Primary endpoints were complete remission (CR) rate, minimal residual disease (MRD) negativity by flow cytometry, and adverse events.
Results: The CR rate after one cycle of BV regimen was 92.3% (12/13), and all patients achieved MRD-negativity; 91.7% (11/12) achieved MRD clearance by day 21. Grade 1-2 cytokine release syndrome occurred in 46.2% (6/13; 1 grade 3). Hematologic toxicity included grade 3-4 neutropenia (92.3%) and thrombocytopenia (46.2%), with only 30.8% febrile neutropenia. All AEs resolved rapidly with supportive care, allowing therapy to continue without interruption. At median follow-up of 283 days, 1-year relapse-free survival rate and overall survival rate were 60.6% and 83.3%.
Conclusion: The 14-day BV regimen induced rapid deep remission (91.7% MRD-negative by day 21) with manageable toxicity in Ph-negative B-ALL. Synergistic T-cell activation by venetoclax may explain enhanced efficacy.

Keywords:  Ph-negative B-cell acute lymphoblastic leukemia; blinatumomab; venetoclax

DOI:  https://doi.org/10.2147/BLCTT.S556608
J Hematol Oncol. 2025 Nov 14. 18(1): 102

Olutasidenib for mutated IDH1 acute myeloid leukemia: final five-year results from the phase 2 pivotal cohort.

Jorge Cortes, Antonio Curti, Pierre Fenaux, Brian A Jonas, Jürgen Krauter, Pau Montesinos, Christian Récher, David C Taussig, Eunice S Wang, Justin Watts, Andrew Wei, Karen Wl Yee, Hua Tian, Aaron Sheppard, Christophe Marzac, Stephane de Botton.

   BACKGROUND: Olutasidenib is an oral, selective inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1), FDA-approved for relapsed/refractory (R/R) acute myeloid leukemia (AML) based on a registrational, phase 2, open-label, multicenter trial.
METHODS: Results from the pre-planned interim analysis were previously published (data cut-off [DCO]: June 2021). In this final-follow up analysis, we report an additional 2 years of efficacy and safety data (DCO: June 2023).
RESULTS: At study completion, the overall population included 153 patients (median age, 71 years); 66% had received ≥ 2 prior treatment regimens, and 39% with a hypomethylating agent. Among the 147 efficacy-evaluable patients, 51 achieved complete remission (CR) or CR with partial hematologic recovery (CRh), resulting in a CR/CRh rate of 35% (P < 0.001; 95% CI, 27-43), with 32% of responders achieving CR. The median time to CR/CRh was 1.9 months (range, 0.9-5.6 months). Among responders, 33% achieved CR/CRh within 2-4 months and 12% required ≥ 4 months. The overall response rate (ORR) was 48% (n = 71; 95% CI, 40-56.7). Median duration of CR/CRh was 25.3 months (95% CI, 13.5-not reached), and median overall survival (OS) was 11.5 months (95% CI, 8.3-15.5). Patients with 1-2 prior regimens had a higher CR/CRh rate (41%) and longer median OS (13 months) than those with ≥ 3 prior regimens (CR/CRh: 24%; median OS: 8.9 months). CR/CRh rates were higher among patients with R132C (42%) and R132L/G/S mutations (33%) compared with those harboring R132H mutations (17%). Response rates decreased with increasing numbers of co-mutations. Few new adverse events (AEs) and no treatment discontinuations due to AEs occurred beyond Year 3.
CONCLUSION: These 5-year data support the durable efficacy and manageable safety profile of olutasidenib in R/R mIDH1 AML, including heavily pretreated patients. Findings highlight the potential role of olutasidenib in earlier lines of treatment, and support sustaining therapy for at least 6 months to allow for a clinical response. Further research is warranted to optimize treatment sequencing and patient selection.
TRIAL REGISTRATION: NCT02719574.

Keywords:  Mutant IDH1 inhibitor; Olutasidenib; Relapsed/refractory AML; Targeted therapy

DOI:  https://doi.org/10.1186/s13045-025-01751-w
Clin Lymphoma Myeloma Leuk. 2025 Oct 13. pii: S2152-2650(25)04247-8. [Epub ahead of print]

Epcoritamab Plus Gemcitabine and Oxaliplatin Versus Rituximab Plus Gemcitabine and Oxaliplatin in Transplant-Ineligible Relapsed/Refractory Diffuse Large B-Cell Lymphoma: A Match-Adjusted Comparative Analysis.

Javier Munoz, Allison Rosenthal, Andrew Ip, Justin M Darrah, Tongsheng Wang, Guihua Zhang, Alex Mutebi, Tychell Branchcomb, Zhijie Ding, Anindit Chhibber, Fernando Rivas Navarro, Malene Risum, Mohammad Atiya, Samantha Brodkin, Anthony Wang, Abualbishr Alshreef, Diala Harb, Mariana Sacchi, Daniela Hoehn, Yasmin H Karimi.

   BACKGROUND: This indirect treatment comparison evaluated epcoritamab plus gemcitabine and oxaliplatin (Epcor+GemOx) versus rituximab (R)-GemOx in patients with transplant-ineligible relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL).
METHODS: Individual patient data (IPD) for Epcor+GemOx from EPCORE NHL-2 Arm 5 (NCT04663347) were compared with clinical practice data for patients treated with R-GemOx using 2 methodologies: a matching-adjusted indirect comparison (MAIC) using published aggregate data from clinical sites in France (Cazelles et al. Lymphoma. 2021;62:2161) and inverse probability of treatment weighting (IPTW) using IPD from the US-based COTA database (COTA Healthcare). Outcomes included objective response rate (ORR), complete response (CR) rate, progression-free survival (PFS), and overall survival (OS).
RESULTS: In the MAIC, after adjustment, Epcor+GemOx versus R-GemOx had significantly higher ORR (86.8% vs 38.3%; relative risk [RR], 2.27 [95% confidence interval (CI), 1.76-2.93]; P < .0001) and CR rate (71.2% vs 32.7%; RR, 2.18 [95% CI, 1.61-2.96]; P < .0001). Median PFS was 26.7 versus 4.8 months (hazard ratio [HR], 0.38 [95% CI, 0.22-0.67]; P < .001); median OS was not reached with Epcor+GemOx versus 10.0 months with R-GemOx (HR, 0.54 [95% CI, 0.29-1.00]; P = .05). In the IPTW, Epcor+GemOx versus R-GemOx had significantly higher ORR (88.5% vs 35.6%; RR, 2.48 [95% CI, 1.80-3.43]; P < .0001), CR rate (63.9% vs 10.2%; RR, 6.25 [95% CI, 3.08-12.68]; P < .0001), median PFS (11.2 vs 2.4 months; HR, 0.23 [95% CI, 0.15-0.36]; P < .001), and median OS (21.6 vs 8.3 months; HR, 0.47 [95% CI, 0.30-0.74]; P = .002).
CONCLUSION: Epcor+GemOx provides significantly greater response rates and survival outcomes compared with R-GemOx in patients with transplant-ineligible R/R DLBCL.

Keywords:  Bispecific antibody; Indirect treatment comparison; Non-Hodgkin lymphoma; Overall survival; Response rate

DOI:  https://doi.org/10.1016/j.clml.2025.10.010
Mediterr J Hematol Infect Dis. 2025 ;17(1): e2025070

Dose-Attenuated-Polatuzumab Vedotine plus CHP vs. Dose-Attenuated -R-CHOP in Patients Aged ≥ 80 Years with Diffuse Large B-Cell Lymphoma: A Retrospective, Propensity Score-Matched Analysis Stratified by Simplified Frailty Score.

Shuku Sato, Emi Sawazaki, Shun Tsunoda, Wataru Kamata, Tomiteru Togano, Yotaro Tamai.

   Background: Polatuzumab vedotin combined with rituximab, cyclophosphamide, doxorubicin, and prednisolone (PRCHP) is a new standard first-line therapy; however, patients aged >80 years were excluded from the POLARIX trial. This single-center, retrospective study evaluated the efficacy and safety of dose-attenuated PRCHP compared with those of dose-attenuated RCHOP in very elderly patients.
Methods: A total of 63 participants aged 80 years or older were treated with PRCHP, and 76 were treated with RCHOP. Propensity score matching (PSM) was performed to adjust for baseline differences in Ann Arbor stage, international prognosis index, and frailty score.
Results: After a 1:1 PSM matching, 59 patient pairs were selected (median age: 84 years). Patients were classified as fit (n= 9, 15%), unfit (n= 21, 36%), or frail (n= 29, 49%) based on their frailty scores. The overall response rate, complete response rate, overall survival, and progression-free survival (PFS) at 12 months were comparable between the dose-attenuated PRCHP and RCHOP groups. In patients with frailty, the 12-month PFS was comparable (50.9% vs. 53.7%); however, in non-frail patients, the PFS was higher in the dose-attenuated PRCHP group than that in the RCHOP group (80.8% vs. 60.1%, p=0.04). Safety profile of grade 3/4 adverse events was similar for both groups; however, peripheral neuropathy was prominent in the RCHOP group (p=0.06).
Conclusion: Despite limitations-including the retrospective design, single-center setting, small sample size, and heterogeneous dose modifications-this study suggests that dose-attenuated PRCHP offers comparable efficacy and safety to dose-attenuated RCHOP in patients aged >80 years. PFS may be prolonged in non-frail patients receiving PRCHP, with a potentially lower risk of peripheral neuropathy.

Keywords:  Mini-PRCHP; Pola-R-CHOP; older individuals; survival outcome

DOI:  https://doi.org/10.4084/MJHID.2025.070
Blood. 2025 Nov 13. 146(20): 2374-2375

Refitting fitness in CLL.

Danielle M Brander.

DOI: https://doi.org/10.1182/blood.2025030837
Clin Adv Hematol Oncol. 2025 Nov;23(8): 497-507

Converging approaches in the frontline treatment of mantle cell lymphoma.

Dilan A Patel, Brad S Kahl.

Mantle cell lymphoma is a biologically and clinically heterogeneous subtype of non-Hodgkin lymphoma that affects predominantly older patients. The disease remains incurable with modern therapies. The integration of first- and now second-generation Bruton tyrosine kinase inhibitors (BTKis) into earlier-line settings appears to improve outcomes. Remaining questions in the field relate to the need for chemotherapy and the choice and duration of maintenance therapy, given its cost and infectious complications. In this review, we highlight clinical data showing BTKis targeting genetic vulnerabilities within mantle cell lymphoma cells. We then assess the integration of these agents into the first-line setting for all patients with newly diagnosed disease. Special consideration is given to patients with TP53-mutated disease, for which non-chemotherapy approaches are preferred.
Front Med (Lausanne). 2025 ;12 1666601

P3-GemOx as a novel immunochemotherapy candidate in NK/T-cell lymphoma management.

Yuyang Zhang, Haiming Kou, Zhipeng Cheng, Xuan Lu, Yu Hu, Liang V Tang.

   Introduction: Natural killer/T-cell lymphoma (NKTL) is a rare disease that shows suboptimal responses to existing therapies. This study reports the efficacy of the P3-GemOx regimen compared to the traditional PP-GemOx regimen in advanced NKTL.
Methods: Eleven patients received the P3-GemOx regimen [mitoxantrone hydrochloride liposome (Plm60) combined with PP-GemOx (anti-PD-1 antibody, pegaspargase, gemcitabine, and oxaliplatin)] every 3-4 weeks, with a median of 3 cycles (range: 1-4). Another eleven patients received the PP-GemOx regimen every 3-4 weeks, with a median of 4 cycles (range: 2-6). Treatment response was assessed using 18F-FDG-PET with CT or MRI.
Results: All patients treated with P3-GemOx responded, with nine achieving complete remission (CR) and two partial remission (PR), yielding an overall response rate (ORR) of 100%. Seven of these patients underwent hematopoietic stem cell transplantation (HSCT). In the PP-GemOx group, the ORR was 63.6%, and no patients underwent HSCT. All adverse events were manageable and resolved.
Discussion: The P3-GemOx regimen demonstrates superior efficacy over the PP-GemOx regimen in advanced NKTL.

Keywords:  NK/T-cell lymphoma; hematopoietic stem cell transplantation; immunochemotherapy; prognosis; retrospective studies

DOI:  https://doi.org/10.3389/fmed.2025.1666601
Hematol Oncol. 2025 Nov;43(6): e70155

Treatment Cessation in Chronic Myeloid Leukemia: Evidence and Uncertainties.

Jiří Mayer.

  Testing to discontinue imatinib already started some years after the advent of this new CML therapy. Since that time, despite many trials and studies in this field, there are still significant gaps, and many fundamental questions remain unanswered. Probably the most intriguing is the persistence of minimal residual disease, which does not lead to disease recurrence in all patients. Nevertheless, today's understanding enables TKI to be safely discontinued in eligible patients outside clinical trials. Notwithstanding, TKI cessation still has to be considered and indicated with caution, taking into account several important viewpoints, like: (i) why stop the therapy in a particular patient, and are all the eligible patients willing to cease the treatment? (ii) Will all the TKI-related side effects relieve upon stopping? (iii) are there any side effects after discontinuing treatment? This review covers extensively all aspects of treatment cessation, like history, theoretical background, eligible patients, monitoring after treatment discontinuation, trigger for retreatment, therapy restart, predictive factors for successful therapy cessation, immunological aspects, potential complications of TKI withdrawal, late molecular relapses, blast crisis development, kinetics of preexisting TKI-related side effects and laboratory values, and quality of life upon treatment cessation. The art of treatment cessation is to select the best candidate based on many diverse facts and information, and follow the patient in the most rational way with smartly anticipating the potential risks and side effects.

Keywords:  chronic myeloid leukemia; treatment cessation; treatment‐free remission; withdrawal syndrome

DOI:  https://doi.org/10.1002/hon.70155
Ann Hematol. 2025 Nov 10.

Optimizing the use of melflufen (melphalan flufenamide) in relapsed or refractory multiple myeloma: recommendations for clinical practice.

Heinz Ludwig, Elias K Mai, Marion Högner, Manfred Welslau, Johannes M Waldschmidt.

  In this report, a panel of multiple myeloma experts assesses the role of melflufen (melphalan flufenamide) in the treatment of patients with relapsed or refractory multiple myeloma (RRMM). Based on available data, recommendations for administration of melflufen, management of adverse events and optimal patient selection are given. Melflufen, a first-in-class peptide-drug conjugate, is approved in the European Union and the United Kingdom in combination with dexamethasone for the treatment of adult patients with multiple myeloma (MM) who have received at least three prior lines of therapies and whose disease is refractory to at least one proteasome inhibitor, one immunomodulatory agent, and one anti-CD38 monoclonal antibody, and who have demonstrated disease progression on or after the last therapy. For patients with a prior autologous stem cell transplantation, the time to progression should be at least three years from transplantation. Melflufen has demonstrated sustained and durable responses in single-arm and randomized trials. The recommended starting is 40 mg intravenously every 28 days in combination with dexamethasone. Adverse events are mainly dose-related haematological toxicities and infections, which are manageable according to standard guidelines. Melflufen is recommended in patients with no prior high-dose melphalan therapy or in those with a long treatment-free interval after such treatment (> 36 months). In high-risk patients, including patients with del(17p) and TP53 gene mutations, melflufen may be considered as a treatment option, especially if patients have not previously been treated with high-dose melphalan.

Keywords:  Melflufen; Melphalan flufenamide; Multiple myeloma; Relapsed or refractory

DOI:  https://doi.org/10.1007/s00277-025-06659-6
Biochem Pharmacol. 2025 Nov 07. pii: S0006-2952(25)00797-X. [Epub ahead of print]243(Pt 2): 117532

Saga of MCL1 inhibitors in multiple myeloma.

Emily Nelson, Sandesh P Telang, Tulin Budak-Alpdogan, Subash C Jonnalagadda, Sandeep K Srivastava, Manoj K Pandey.

Myeloid cell leukemia 1 (MCL1) is an anti-apoptotic protein within the B-cell lymphoma 2(Bcl-2) family that is aberrantly overexpressed in many cancers such as Multiple Myeloma (MM). The protein is a key contributor to MM relapses, and effectively inhibiting MCL1 is a solution to overcoming drug resistance. Since MCL1 was identified in 1993, significant progress has been made in investigating the protein's role in cancer development and the benefits of inhibition. After years of research, in 2008 AbbVie developed the first small molecule inhibitor, A-1210477, with an indole-2-carboxylic acid core that targeted MCL1's BH3 binding groove selectively and had low affinity for Bcl-2 and Bcl-xL. Following this, there was a surge in the development of novel MCL1 inhibitors, which are still being produced today. In 2016, the first MCL1 SMI, AMG 176, advanced to a phase 1 clinical trial for relapsed/refractory (R/R) MM patients and was sponsored by Amgen (NCT02675452). Spanning 8 years, this trial is the longest to date among all studies investigating MCL1 inhibition in patients with R/R MM. Six novel MCL1 inhibitors have been evaluated in clinical trials for R/R MM patients, sponsored by six different pharmaceutical companies. Adverse side effects and particularly cardiotoxicity present a significant barrier to the widespread clinical use of MCL1 inhibitors. This review explores the history and progress of MCL1 inhibition in MM through highlighting molecular methods of inhibition, early and current preclinical small molecule inhibitors, and past and present MCL1 inhibitor clinical trials for R/R MM.

DOI: https://doi.org/10.1016/j.bcp.2025.117532
Blood. 2025 Nov 13. 146(20): 2377-2378

Hijack the HiJAKer: rethinking therapy for JAK2-mutant MPN.

Martin Zenke, Steffen Koschmieder.

DOI: https://doi.org/10.1182/blood.2025030551
Cancer Immunol Immunother. 2025 Nov 12. 74(12): 372

Sustained remission with PD-1 and BTK inhibitors maintenance after chimeric antigen receptor T-cell therapy in CNS lymphoma.

Lingzi Yu, Nana Ping, Rui Zou, Qian Zhu, Junhong Li, Xiao Zhang, Fan Xia, Jiajie He, Jiajie Tu, Danqing Kong, Depei Wu, Zhengming Jin, Changju Qu.

   BACKGROUND: Chimeric antigen receptor T-cell (CAR-T) therapy is gradually reshaping the treatment paradigm for patients with central nervous system lymphoma (CNSL). However, the duration of remission (DOR) has remained the major challenge in existing studies. This study aimed to provide real-world long-term follow-up data on CAR-T therapy in CNSL patients and primarily investigate the impact of maintenance therapy on prolonging DOR.
METHODS: This study evaluated the efficacy and safety of CAR-T therapy in 22 patients with CNSL, including 5 with primary CNSL and 17 with secondary CNSL (2025004, retrospectively registered). Maintenance therapy with programmed cell death protein-1 inhibitor (PD-1i) and Bruton's tyrosine kinase inhibitor (BTKi) was initiated in responding patients, while subgroup analysis comparing maintenance versus non-maintenance was restricted to those who achieved complete remission after CAR-T therapy.
RESULTS: The best overall remission rate was 90.9%, with the best complete remission rate of 68.2%. With a median follow-up of 20.7 months (range, 3.1-88.9 months), the estimated 2-year progression-free survival and overall survival rates were 59.1% and 71.6%, respectively. No patient suffered severe immune effector cell-associated neurotoxicity syndrome, and only 3 patients experienced severe cytokine release syndrome. Patients who underwent PD-1i and BTKi maintenance achieved a 2-year DOR rate of 100%, which was significantly superior to those without maintenance therapy (Log-rank, P = 0.04).
CONCLUSION: Our findings suggested the promising efficacy and manageable toxicities of CAR-T therapy in patients with CNSL. This study preliminarily proposed the concept that maintenance therapy may improve the DOR after CAR-T therapy.

Keywords:  Bruton’s tyrosine kinase inhibitor; Central nervous system lymphoma; Chimeric antigen receptor T-cell therapy; Duration of remission; Programmed cell death protein-1 inhibitor

DOI:  https://doi.org/10.1007/s00262-025-04236-4
Ann Hematol. 2025 Nov 15.

Efficacy and safety of ropeginterferon alfa-2b in the treatment of polycythemia vera: a systematic review with single arm meta-analysis.

Eman Ayman Nada, Mohamed Abdelhalim Elfagieh, Fares Abdelsalam, Asmaa Ahmed Elrashedy, Fatima A Idres, Abdelrahman Shata, Ali M Othman, Hasan Mohammad Masoum Hamoud, Radwa Mohamed Awadalla, Israa Ahmed Qutob, Belal Mohamed Hamed.

Polycythemia vera (PV) is a myeloproliferative neoplasm characterized by increased red blood cell production, with high risk of venous and arterial thrombosis. Mutations in the JAK2 gene, particularly JAK2 V617F, play a central role in its pathogenesis. Ropeginterferon alfa-2b is a novel long-acting interferon showing promise in managing PV through hematologic and molecular control.This study aimed to evaluate the efficacy and safety of Ropeginterferon alfa-2b in patients with PV based on a systematic review and meta-analysis of available clinical trials.A systematic search was conducted across PubMed, Cochrane Library, Web of Science, Google Scholar, and Scopus on May 8, 2025. Randomized controlled trials (RCTs) assessing Ropeginterferon alfa-2b in PV were included. The PRISMA guidelines were followed, and the protocol was registered in PROSPERO (CRD420251051466). Quality assessment was performed using RoB 2.0 and ROBINS-I tools. A random-effects model was applied using R software.Eight studies involving 761 patients were included and only six studies included in single arm meta-analysis with 328 patients. The pooled proportion of complete hematological response at 12 months was 0.63 (95% CI [0.51-0.73]), with high heterogeneity. Reductions in JAK2 V617F allele burden were significant (MD: 26.57, 95% CI [13.49-39.65]). Molecular response was achieved in 25% (95% CI [0.04-0.70]) of patients. The most common adverse events were elevated liver enzymes (AST: 0.28; ALT: 0.32), influenza-like illness (0.11), and anemia (0.09), with unresolved heterogeneity in all outcomes.Ropeginterferon alfa-2b shows promising efficacy in achieving hematological and molecular responses in patients with PV. However, notable heterogeneity and safety concerns, particularly liver-related adverse effects, warrant further investigation in large-scale trials.

DOI: https://doi.org/10.1007/s00277-025-06701-7
Int J Mol Sci. 2025 Oct 29. pii: 10521. [Epub ahead of print]26(21):

Acalabrutinib May Offer a New Therapeutic Approach for Consolidation and Maintenance of Primary CNS Lymphoma with Expression of MYD88 and CD79B Gene Variants: A Case Report and Literature Review of Primary CNS Lymphoma in the BTKi Era.

Eleanor Allison, Ashlea Campbell, Anne-Marie Watson, Brendan Beaton.

  We present the case of a patient with primary CNS lymphoma (PCNSL), with MYD88 and CD79B gene variants, who was unable to complete standard induction and consolidation treatment due to toxicity and co-morbidities after three cycles of MATRix. Although he had responded to truncated induction, acalabrutinib, the BTK inhibitor, was used in an attempt to consolidate and maintain his response. He has an ongoing remission at 18 months of follow-up. Following the case presentation, we provide a review of PCNSL, the evolution of therapy, and how BTK inhibitors are now emerging treatments incorporated into the salvage of relapsed and refractory disease and into first-line treatment in some clinical trials. This is the first reported case in the literature of acalabrutinib use for consolidation and maintenance of PCNSL. We hope this can support clinical trial design for BTKi use in this setting in the future.

Keywords:  BTK inhibitor; CD79B variant; MYD88 variant; primary CNS lymphoma

DOI:  https://doi.org/10.3390/ijms262110521
Blood Adv. 2025 Nov 10. pii: bloodadvances.2025017817. [Epub ahead of print]

Smoldering multiple myeloma in the United States: A population-based analysis.

Shi-Yi Wang, Rong Wang, Martin Schoen, John H Huber, Eric Feuer, Jennifer Ruhl, Natalia Neparidze, Xiaomei Ma, Amy J Davidoff, Su-Hsin Chang.

DOI: https://doi.org/10.1182/bloodadvances.2025017817
Cancer Biol Ther. 2025 Dec 31. 26(1): 2581831

Potential therapeutic GSK-3β inhibitor 9-ING-41 is active in combination with venetoclax in double-hit lymphoma (DHL).

Haohao Lei, Yunxia Zhang, Haiqing Zheng, Pengcheng Shi, Xiaolei Wei, Xutao Guo.

   BACKGROUND: Double-hit lymphoma (DHL) exhibits aggressive behavior due to dysregulated proliferation and resistance to apoptosis. Current therapies, including R-CHOP, show limited efficacy, necessitating novel strategies. 9-ING-41, a novel ATP-competitive small-molecule inhibitor that targets glycogen synthase kinase-3β (GSK-3β), has emerged as a promising therapeutic agent because of its ability to disrupt oncogenic signaling pathways associated with tumor progression and treatment resistance. However, the antitumor effects of 9-ING-41 in DHL remain unclear.
MATERIALS AND METHODS: DHL cell lines (Karpas-422 and SuDHL2) were treated with venetoclax and 9-ING-41, either alone or in combination. Cell viability in cytotoxicity assays was assessed using the CCK-8 assay, while apoptosis and cell cycle changes were analyzed via flow cytometry. Western blotting was employed to evaluate alterations in the levels of GSK-3β and WNT/β-catenin pathway proteins following treatment.
RESULTS: In preclinical studies utilizing DHL cell models, the single agent 9-ING-41 demonstrated robust biological activity through inducing significant G1/S phase cell cycle arrest and triggering apoptosis. When coadministered with venetoclax, a clinically approved BCL-2 inhibitor, the combination exhibited marked synergistic cytotoxicity in DHL cells, achieving superior inhibitory effects compared to either agent alone. The combined treatment enhanced cell cycle arrest, significantly reducing the number of S-phase cells and reinforcing G0/G1 arrest. Further mechanistic studies revealed that the combination modulated key proteins in the GSK-3 pathway and downstream WNT/β-catenin pathway, revealing a potential synergistic mechanism.
CONCLUSION: The demonstrated single-agent efficacy and combination synergy with venetoclax support the potential of 9-ING-41 as a novel therapeutic strategy for DHL. These findings provide a proof-of-concept that may serve as a basis for future preclinical investigations in DHL.

Keywords:  9-ING-41; Glycogen synthase kinase-3; apoptosis; cell cycle arrest; double-hit lymphoma

DOI:  https://doi.org/10.1080/15384047.2025.2581831
J Hematol Oncol. 2025 Nov 12. 18(1): 98

First in human phase 1 study of DT2216, a selective BCL-xL degrader, in patients with relapsed/refractory solid malignancies.

Daruka Mahadevan, Minal Barve, Devalingam Mahalingam, Jay Parekh, Michael Kurman, James Strauss, Larry Tremaine, Robert Hromas, Joshua Sills, John McCulloch, John Harkey, Stacy Suberg, Lisa Zimmerman, Guangrong Zheng, Daohong Zhou.

BACKGROUND: Small molecule inhibition of BCL-XL with navitoclax resulted in on-target dose-limiting thrombocytopenia. DT2216 was more effective than navitoclax and reduced platelet toxicity in preclinical models by selectively degrading BCL-XL via the VHL E3 ligase, which is minimally expressed in platelets.
METHODS: A dose escalation study using a 3 + 3 design with doses ranging from 0.04 to 0.4 mg/kg IV twice weekly (BIW) was performed. Eligible subjects had solid tumors of any histology that had progressed on standard treatment and had measurable tumor by RECIST v1.1. Tumor assessment was performed at 8-week intervals. BCL-XL levels were measured in peripheral leukocytes by western blotting.
RESULTS: Twenty patients were enrolled, with a median age of 60.5 year; 60% were female. Only one dose-limiting toxicity was observed, grade 4 thrombocytopenia that resolved within 48 h. Stable disease, observed in 20% of the patients. The lowest platelet count in the first cycle ranged from 24,000 to 297,000. In all cases, the platelet count recovered to > 50,000 within 4 days and > 75,000 within 1 week. There were no episodes of bleeding or treatment emergent adverse events leading to death. The median overall survival was 7.9 months. The plasma AUC of DT2216 was dose proportional with no dose accumulation. Patients receiving 0.4 mg/kg DT2216 demonstrated rapid and sustained degradation of BCL-XL.
CONCLUSIONS: Based on the rapid recovery of transient thrombocytopenia that occurred only in the first cycle and the degradation of BCL-XL in peripheral leukocytes, the RP2D of DT2216 is 0.4 mg/kg IV BIW. (NCT04886622).

DOI: https://doi.org/10.1186/s13045-025-01753-8
J Hematol. 2025 Oct;14(5): 241-252

Novel Agents and Immunotherapies for Primary Diffuse Large B-Cell Lymphoma of the Central Nervous System: Innovating for Impact in a Disease With Unmet Needs.

Tatyana Gavrilova.

  Primary diffuse large B-cell lymphoma of the central nervous system (CNS-DLBCL), the most prevalent subtype of primary CNS lymphoma (PCNSL), is a highly aggressive extranodal non-Hodgkin lymphoma (NHL) that arises in the brain, spinal cord, leptomeninges, and orbits. Systemic methotrexate-based chemoimmunotherapy regimens, followed by consolidative autologous stem cell transplantation (ASCT), are the standard treatments for newly diagnosed PCNSL. A considerable number of patients with PCNSL, however, are medically frail and possess multiple comorbidities, which render them unsuitable for these intensive treatments. Furthermore, a substantial proportion of those who undergo treatment still face the challenge of disease recurrence. There is no universally accepted treatment for relapsed disease, particularly for patients who are unable to tolerate systemic chemotherapy, and participation in clinical trials is encouraged. There is a notable treatment gap in PCNSL, underscoring an urgent need to investigate novel agents and immunotherapies that could potentially offer superior tolerability and efficacy profiles. Emerging therapies could play a pivotal role in expanding the therapeutic landscape and addressing the limitations inherent in current treatments. This review examines the oncogenesis of PCNSL, highlighting its reliance on chronic active B-cell receptor (BCR) and nuclear factor-kappa B (NF-κB) signaling pathways, mechanisms of immune evasion, and characteristics of its immunosuppressive tumor microenvironment (TME), which have facilitated the exploration of methotrexate-free targeted therapies for this disease.

Keywords:  BTK inhibitors; Immunomodulatory drugs; Immunotherapy; Primary CNS lymphoma

DOI:  https://doi.org/10.14740/jh2095
Blood. 2025 Nov 13. 146(20): 2491

Mantle cell lymphoma with KMT2A rearrangement.

Shimin Hu, Guilin Tang.

DOI: https://doi.org/10.1182/blood.2025030135
Br J Haematol. 2025 Nov 12.

Venetoclax combined with cladribine, idarubicin, cytarabine (CLIA-VEN) results in higher remission rates over conventional 7 + 3 chemotherapy without increased toxicity in newly diagnosed acute myeloid leukaemia.

Benjamin J Lee, Shawn P Griffin, Jean Doh, Anthony Quach, Yujiao Sun, Piyatida Chumnumsiriwath, Stefan O Ciurea, Jorge Ramos-Perez, Polina Bellman, Deepa Jeyakumar, Piyanuch Kongtim, Kiran Naqvi.

  Induction chemotherapy in fit de novo acute myeloid leukaemia (AML) patients has historically combined an anthracycline with standard-dose cytarabine ('7 + 3') despite complete response (CR) rates of 50%-70%. In May 2023, our institution adopted the utilization of cladribine, cytarabine, idarubicin and venetoclax (CLIA-VEN) for intensive remission-induction therapy. In this retrospective study, outcomes of newly diagnosed adult AML patients who were consecutively treated with CLIA-VEN (n = 20; 2023-2025) were compared to a historical cohort that received 7 + 3 (n = 42; 2016-2023). The median interquartile range [IQR] age was 54 [42-63] years, 54% were male and 58% had European LeukemiaNet (ELN) 2022 adverse-risk disease. CLIA-VEN was associated with a higher cumulative incidence of composite CR (CCR) (90% vs. 54.8%; p = 0.002) and minimal residual disease (MRD)-negative CCR (93.8% vs. 40.9%; p < 0.001) at 28 days. Any grade ≥ 2 end-organ toxicity (45% vs. 59.5%; p = 0.28) and early mortality (0% vs. 16.7%; p = 0.09) were not increased with CLIA-VEN. Utilizing propensity score guided inverse probability treatment weighting to balance baseline demographics, receipt of CLIA-VEN was associated with improved overall survival (p = 0.002). Acknowledging the limitations of a retrospective single-centre study, our data suggest that CLIA-VEN has higher efficacy without increasing toxicity and the potential to prolong survival compared to the current standard of care in de novo AML patients.

Keywords:  CLIA; MRD; acute myeloid leukaemia; venetoclax; ‘7 + 3’

DOI:  https://doi.org/10.1111/bjh.70253
Int J Hematol. 2025 Nov 15.

Chronic myeloid leukemia with atypical transcript e8a2: a case report and literature review.

Xikun Liu, Jirui Zhong, Man Luo, Xuekui Gu, Jiduo Liu, Zenghui Liu, Jing He, Yaohe Li.

  Chronic myeloid leukemia (CML) is characterized by the BCR::ABL1 fusion gene, resulting from Philadelphia (Ph) chromosome rearrangements that generate abnormal t (9; 22)(q34;q11) translocations. The most common fusion variants are e13a2 and e14a2. We diagnosed a case of CML with the rare e8a2 fusion variant using real-time quantitative PCR and sequencing. Although the e8a2 variant is increasingly reported in CML, comprehensive retrospective analyses remain scarce. Through a systematic review of published e8a2 BCR::ABL1 cases, we summarized the classification, treatment outcomes, and prognostic characteristics associated with this rare genotype. This analysis aims to provide additional evidence to facilitate improved diagnosis and therapeutic strategies for e8a2-positive CML patients.

Keywords:   BCR::ABL1 ; Chronic myeloid leukemia; E8a2; Philadelphia; Tyrosine kinase inhibitors

DOI:  https://doi.org/10.1007/s12185-025-04088-9