bims-hemali Biomed News
on Hematologic malignancies
Issue of 2026–06–21
twenty-two papers selected by
Alexandros Alexandropoulos, Γενικό Νοσοκομείο Αθηνών Λαϊκό
  1. Low-Dose Vemurafenib Plus Rituximab in Front-Line and Relapsed or Refractory Hairy Cell Leukemia: The Scripps Regimen.
  2. Talquetamab-Daratumumab in Relapsed or Refractory Myeloma.
  3. Treatment-Free Remission and Immune Profiling after Frontline Second-Generation TKI Therapy in CML.
  4. Glofitamab Induces Complete Responses in Relapsed and Refractory Primary Central Nervous System Lymphoma.
  5. Ropeginterferon alfa-2b-njft treatment in essential thrombocythemia across different driver mutations: results from a North American, single-arm, multicentre study (EXCEED-ET).
  6. Comprehensive molecular characterization of treatment-free remission and molecular relapse in chronic myeloid leukemia patients: the EURO-SKI Biomarker Study.
  7. BTKi orelabrutinib improved the outcome of newly-diagnosed PCNS-LBCL by alleviating MyD88L265P-induced PIM1 stability.
  8. Selinexor in combination with azacitidine or ruxolitinib in myelodysplastic/myeloproliferative neoplasm overlap syndromes: A multicenter prospective study.
  9. Combined treatment of zingerone and nilotinib induces cytotoxicity and reverses nilotinib resistance in chronic myeloid leukemia cells via inhibition of the PI3K signaling.
  10. Phase 3 PERSPECTIVE study: Ibrutinib with rituximab for initial treatment of patients with follicular lymphoma.
  11. Final analysis of phase 2 clinical trial of ruxolitinib and azacitidine combination therapy in patients with myelodysplastic syndrome/myeloproliferative neoplasms.
  12. Mezigdomide, carfilzomib, and dexamethasone versus carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma (SUCCESSOR-2): a phase 3, open-label, randomised controlled trial.
  13. Outcomes of Adolescents and Young Adults with AML Treated on Pediatric vs Adult Protocols.
  14. Liposomal mitoxantrone plus tislelizumab in patients with relapsed or refractory extranodal natural killer/T-cell lymphoma: a phase 1b/2 trial.
  15. Systemic Mastocytosis in Adults: 2026 Update on Diagnosis, Risk Stratification and Management.
  16. Second-line bosutinib for chronic phase chronic myeloid leukemia after imatinib: final, 10-year results of a phase I/II study.
  17. Association between CD79B expression and polatuzumab vedotin efficacy, and therapy-induced changes in CD79B expression in diffuse large B-cell lymphoma.
  18. Anti-CD19 CAR-T in transformed indolent lymphoma versus de novo large B-cell lymphoma: a meta-analysis of 5,006 patients.
  19. Outcomes of CAR T-Cell Therapy in transformed indolent Non-Hodgkin Lymphomas and de novo DLBCL: A comparative analysis from the Italian CAR T-SIE study.
  20. EHA Guidelines on management of chronic lymphocytic leukemia and Richter transformation.
  21. The 10-year RELEVANCE trial analysis.
  22. Venetoclax and hypomethylating agents synergize to increase cell death and metabolic remodeling in acute B-lymphoblastic leukemia cells.
  1. Blood Adv. 2026 Jun 16. pii: bloodadvances.2025019243. [Epub ahead of print]
    Low-Dose Vemurafenib Plus Rituximab in Front-Line and Relapsed or Refractory Hairy Cell Leukemia: The Scripps Regimen.
    David J Hermel, Alan Saven.
      Purine nucleoside analogues are highly effective in the treatment of hairy cell leukemia (HCL) but are associated with myelosuppression and immunosuppression. Targeted therapy with the BRAF inhibitor vemurafenib in combination with the anti-CD20 antibody rituximab has shown marked efficacy, but traditional dosing of vemurafenib (960 mg twice daily) requires frequent dose reductions. We conducted a prospective observational study of low-dose vemurafenib (240 mg twice daily orally for 8 weeks) plus rituximab (375 mg/m² intravenously every 2 weeks for 14 weeks, 8 total doses) in adults with treatment-naïve or relapsed/refractory HCL. Fifteen patients were enrolled. All achieved complete hematologic recovery, with normalization of thrombocytopenia (>100 ×10³/µL) and neutropenia (>1.0 ×10³/µL) by a median of 15 and 29 days, respectively. The overall response rate was 87%, including 11 complete responses (73%; 95% CI, 48-89%) and 2 partial responses, with 8 patients (53%; 95% CI: 27-79%) achieving MRD negativity at 6 months. Front-line patients (n=7) had 6 CRs (86%; 95% CI: 42-100%) and 4 were MRD-negative (57%; 95% CI: 18-90%), while relapsed/refractory patients (n=8; median of 1 prior therapy) had 5 CRs (63%; 95% CI: 24-91%) and 4 were MRD-negative (50%; 95% CI: 16-84%). At a median follow-up of 18 months, one patient progressed at 20 months; median progression-free survival was not reached. No grade 3-4 toxicities or deaths occurred. Low-dose vemurafenib combined with rituximab induced rapid hematologic recovery, and favorable tolerability in patients with both untreated and relapsed/refractory HCL. NCT05388123.
    DOI:  https://doi.org/10.1182/bloodadvances.2025019243
  2. N Engl J Med. 2026 Jun 13.
    Talquetamab-Daratumumab in Relapsed or Refractory Myeloma.
    MonumenTAL-3 Investigators
       BACKGROUND: Talquetamab, a bispecific antibody targeting GPRC5D and CD3, has led to durable responses in patients with heavily pretreated relapsed or refractory multiple myeloma in phase 1-2 trials, with a limited effect on normal B cells.
    METHODS: In a phase 3 trial, we randomly assigned patients with relapsed or refractory multiple myeloma who had previously received at least one line of therapy to receive talquetamab plus daratumumab and pomalidomide (Tal-DP), talquetamab plus daratumumab (Tal-D), or daratumumab plus pomalidomide and dexamethasone (DPd). The primary end point was progression-free survival as assessed by an independent review committee. Key secondary end points were overall response, complete response or better (complete or stringent complete response), measurable residual disease-negative complete response, and overall survival.
    RESULTS: A total of 287, 287, and 290 patients were assigned to the Tal-DP, Tal-D, and DPd groups, respectively. At the interim analysis (median follow-up, 24.6 months), progression-free survival was significantly longer with Tal-DP and Tal-D than with DPd (24-month estimate, 81.3% and 77.6% vs. 51.2%; hazard ratio for disease progression or death, Tal-DP vs. DPd, 0.28 [95% confidence interval {CI}, 0.20 to 0.40], and Tal-D vs. DPd, 0.33 [95% CI, 0.24 to 0.46]; P<0.001 for both comparisons). The overall response was higher with Tal-DP and Tal-D than with DPd (88.2% and 88.5% vs. 77.6%), as was complete response or better (71.1% and 69.0% vs. 34.5%) and measurable residual disease-negative complete response (52.3% and 46.3% vs. 15.9%) (P<0.001 for all comparisons). Overall survival at 24 months was 89.2% with Tal-DP, 87.9% with Tal-D, and 79.1% with DPd (hazard ratio for death, Tal-DP vs. DPd, 0.47 [95% CI, 0.30 to 0.73], and Tal-D vs. DPd, 0.51 [95% CI, 0.33 to 0.78]). Serious adverse events occurred in 63.0%, 52.6%, and 53.7% of the patients in the Tal-DP, Tal-D, and DPd groups, respectively; fatal adverse events occurred in 1.8%, 4.0%, and 4.6%.
    CONCLUSIONS: Among patients with relapsed or refractory multiple myeloma who had previously received at least one line of therapy, both Tal-DP and Tal-D led to significantly longer progression-free survival than DPd. (Funded by Johnson & Johnson; MonumenTAL-3 ClinicalTrials.gov number, NCT05455320.).
    DOI:  https://doi.org/10.1056/NEJMoa2604657
  3. Blood Adv. 2026 Jun 18. pii: bloodadvances.2026020915. [Epub ahead of print]
    Treatment-Free Remission and Immune Profiling after Frontline Second-Generation TKI Therapy in CML.
    Naoto Takahashi, Yosuke Minami, Yuki Fujioka, Shigeki Ohtake, Yoshiko Atsuta, Mio Kurata, Takaaki Ono, Shinya Sato, Shingo Yano, Katsumichi Fujimaki, Takeshi Maeda, Yukiyasu Ozawa, Emiko Sakaida, Takeshi Kondo, Masahide Yamamoto, Noriyoshi Iriyama, Toshihiro Miyamoto, Hitoshi Kiyoi, Yasushi Miyazaki, Itaru Matsumura.
      Treatment-free remission (TFR) is a major therapeutic goal in chronic myeloid leukemia (CML). This study analyzed 5-year follow-up data and immune profiling from two independent phase 2 trials, JALSG N-STOP216 (nilotinib [NIL], n=51) and D-STOP216 (dasatinib [DAS], n=49), involving patients who discontinued frontline 2G-TKIs after sustaining deep molecular response (DMR) for ≥2 years. Both trials successfully met their primary endpoints, with 12-month TFR rates of 76.5% and 55.1% in the NIL and DAS trials, respectively. No disease progression was observed, confirming the safety of this strategy. The 5-year treatment-free survival (TFS) rates were 68.6% and 50.9% for NIL and DAS patients, respectively. While recurrent cases in both cohorts rapidly regained a molecular response, NIL-treated patients showed a more gradual molecular recurrence and a persistent gap between TFS and event-free survival, suggesting relatively stable immune surveillance. Comparative immune profiling, although exploratory, suggested an "immune paradox" in the DAS cohort, characterized by expansion of effector memory T cells and mature CD57+ CD56dim NK cells alongside depletion of the "immune reservoir" of naïve and central memory cells. In the D-STOP trial, the retreatment group showed higher levels effector Tregs and exhausted CD4+ T cells than the TFR group. Furthermore, elevated pre-discontinuation IL-1β and IL-6 levels were associated with molecular relapse. These findings suggest that 2G-TKI-specific off-target effects influence TFR sustainability by modulating the immune microenvironment and the CD4+ helper cell status. JALSG N-STOP216 (UMIN000024984); JALSG D-STOP216 (UMIN000024985).
    DOI:  https://doi.org/10.1182/bloodadvances.2026020915
  4. Hematol Oncol. 2026 Jul;44(4): e70211
    Glofitamab Induces Complete Responses in Relapsed and Refractory Primary Central Nervous System Lymphoma.
    Coen J Lap, James Di Palma-Grisi, Andrew Ip, Joseph L Roswarski.
      Although most patients with primary central nervous system lymphoma (PCNSL) respond to treatment with high-dose methotrexate-containing regimens, over 50% relapse and 15% is refractory to treatment. The prognosis of these patients is poor, and limited treatment options exist. This report describes two patients with PCNSL who both progressed after several lines of therapy and who obtained a rapid and complete response after treatment with the bispecific antibody glofitamab. Both tolerated the treatment well without signs of cytokine release syndrome or immune-effector cell-mediated neurotoxicity syndrome. The observed responses highlight that glofitamab is a promising therapeutic option for patients with R/R PCNSL.
    Keywords:  CNS lymphoma; PCNSL; bispecific; glofitamab; refractory; relapsed
    DOI:  https://doi.org/10.1002/hon.70211
  5. Lancet Reg Health Am. 2026 Sep;61 101529
    Ropeginterferon alfa-2b-njft treatment in essential thrombocythemia across different driver mutations: results from a North American, single-arm, multicentre study (EXCEED-ET).
    Brandi N Reeves, Firas El Chaer, Lynda Foltz, Tsewang Tashi, Ghaith Abu-Zeinah, Albert Qin, Jennifer Lucas, Anna B Halpern, Dawn Maze, Hana Safah, Casey L O'Connell, Swati Goel, Lindsay Rein, Bruno Fang, Joan How, Sunil Babu, Zhuoyan Li, Sonia Cerquozzi, Stephen T Oh, Anthony M Hunter, Nikolai Podoltsev, Pankit Vachhani, Julia M Cunningham, Christopher Hillis, Prithviraj Bose, Abdulraheem Yacoub, John Mascarenhas, Oleh Zagrijtschuk, Henry Castro, Ruben A Mesa, Lucia Masarova.
       Background: Ropeginterferon alfa-2b-njft (ropeg), a mono-PEGylated interferon-α, showed efficacy and safety in patients with hydroxyurea-intolerant/resistant essential thrombocythemia (ET) in the phase 3 SURPASS-ET largely conducted in Asia. Here we report the results from the EXCEED-ET study, which evaluated ropeg in both treatment-naïve and hydroxyurea pre-treated ET in North America.
    Methods: The single-arm, multicentre, phase 2b trial EXCEED-ET was conducted at 28 centers in the United States and Canada. Patients with ET enrolled were required to have a platelet count >450 × 109/L at screening. Patients were eligible regardless of prior cytoreductive therapy status and included both treatment-naïve and hydroxyurea-pretreated patients. Ropeg was subcutaneously administered in an accelerated titration schedule at 250 μg at Week 0, 350 μg at Week 2, and 500 μg from Week 4 and beyond. The primary endpoint was durable, modified European LeukemiaNet (ELN) response at both Months 10 and 13 (ClinicalTrials.gov identifier: NCT05482971).
    Findings: Between January 17, 2023, and May 15, 2025, 106 patients were screened and 91 were enrolled. At baseline, participant median age was 57 years (range, 22-84) with 57/91 (62.6%) being female and 71/91 (78.0%) being White. Among 91 patients enrolled, durable modified ELN response rate was 60.2% (95% CI, 49.0-71.4). The median time to hematologic response was only 8.4 weeks (95% CI: 8.1-11.9). Splenomegaly and symptom improvement or non progression occurred in 90/91 (98.9%) and 71/91 (78.0%), respectively. Seven of 91 (7.7%) patients with palpable spleen at baseline and all had an improvement in disease-related signs. The rates of molecular response for driver mutations at Month 13 as defined by ELN2009 criteria were 35.0% (7/20) for patients with JAK2V617F, 16.0% (4/25) for CALR, and 25.0% (2/8) for MPL mutations. One (1/1) TP53 mutation-positive patient showed a complete molecular response. Thrombosis and progression occurred in 3.4% (3/91) and 1.1% (1/91), respectively. Most treatment-emergent adverse events were mild, including fatigue (60%) and reversible transaminase elevations (58%). There was no grade 5 TEAE and one (1.1%) grade 4 TEAE (hepatitis toxic) which recovered without sequelae. Grade ≥3 TEAEs occurred in 27.5% (25/91) of the participants, most commonly with alanine aminotransferase and aspartate aminotransferase increases (4.4%; 4/91), neutrophil count decrease (4.4%; 4/91), fatigue (3.3%; 3/91) and lymphocyte count decrease (3.3%; 3/91). Treatment-related serious adverse events occurred in 5.5% (5/91) of patients. Pneumonia was the most common SAE, occurring in 2/91 (2.2%) patients. Ropeg-related discontinuations occurred in 9/91 (9.9%) patients.
    Interpretation: Ropeg showed efficacy and substantial molecular responses with good overall tolerability across a broad ET population.
    Funding: PharmaEssentia.
    Keywords:  Essential thrombocythemia; Northern American; Pre-treated; Ropeginterferon alfa-2b-njft; Treatment-naïve
    DOI:  https://doi.org/10.1016/j.lana.2026.101529
  6. Leukemia. 2026 Jun 18.
    Comprehensive molecular characterization of treatment-free remission and molecular relapse in chronic myeloid leukemia patients: the EURO-SKI Biomarker Study.
    S Rinaldetti, M Chepeleva, A Hedblom, C Sticht, M Muciek, P Panayiotidis, J Richter, U Olsson-Strömberg, D Nowak, V Nowak, P Ljungman, N von Bubnoff, K Lotfi, L Stenke, T H Brümmendorf, H Hjorth-Hansen, T Gedde-Dahl, W Majeed, A Burchert, P V Nazarov, E Felde, I Tarnopolscaia, C Hoelting, A Fabarius, W-K Hofmann, F-X Mahon, S Saussele, M Pfirrmann.
      The European Stop Kinase Inhibitors (EURO-SKI) trial was launched to investigate the discontinuation of tyrosine kinase inhibitors (TKIs) in patients with chronic myeloid leukemia (CML). The molecular mechanisms underlying sustained treatment-free remission (TFR) and loss of TFR, are still poorly understood. To address this, we performed whole transcriptome gene expression analyses coupled with NanoString nCounter-based absolute gene quantification. Gene expression was assessed in peripheral blood leukocytes from 240 CML patients on the final day of TKI intake (training sample: n = 122, validation sample: n = 118) as well as from 10 healthy controls. To identify TKI-specific mechanisms, transcriptomic data from an external dataset of 96 TKI-naïve CML patients was incorporated into our analyses. TFR patients showed an activation of GATA1, KLF1 and MYBL1 regulons characteristic for erythroid progenitor cells. TFR patients maintain persistent communication between innate (natural killer and dendritic cells) and adaptive immunity (e.g., CD8+, CD4+, and γδ T lymphocytes), mirroring patterns observed in healthy controls. This intercellular communication is disrupted in patients with loss of TFR. Furthermore, we identified an FLT3 threshold that distinguished two patient groups with significantly different probabilities of TFR loss. Leveraging mechanisms that reestablish or reinforce the communication between innate and adaptive immunity could be pivotal in achieving durable TFR.
    DOI:  https://doi.org/10.1038/s41375-026-03001-5
  7. J Hematol Oncol. 2026 Jun 17. pii: 42. [Epub ahead of print]19(1):
    BTKi orelabrutinib improved the outcome of newly-diagnosed PCNS-LBCL by alleviating MyD88L265P-induced PIM1 stability.
    Yan Yuan, Bo Dai, Haoshu Zhong, Jiajun Zheng, Zhen Fan, Di Chen, Qian Wang, Hao Wu, Yuan Li, Ping Zhu, Tianling Ding, Shu Wang, Kunpeng Wu, Yu Zhang, Zhenhua Wang, Rui Feng, Fengping Zhu, Kang Zheng, Zhiyong Qin, Bojie Yang, Hong Chen, Xiaolei Lin, Yu Yao, Dongxiao Zhuang, Zhifeng Shi, Ying Mao, Tong Chen.
      Primary central nervous system large B-cell lymphoma (PCNS-LBCL) exhibits the worst prognosis among all extranodal LBCLs, with the enriched genetic mutations in MyD88L265P, CD79B and PIM1. However, the upfront incorporation of targeted therapies remains an unmet need in newly diagnosed (ND) patients. In this study, we found that in the presence of MyD88L265P context, B-cell receptor downstream bruton's tyrosine kinase (BTK) was significantly overexpressed, which subsequently enhanced the stability of PIM1 oncoprotein. To evaluate the intracranial delivery of BTK inhibitor(BTKi), patient-derived PCNS-LBCL xenografted mice models were treated with highly-selective BTKi orelabrutinib, either monotherapeutically or in combining with methotrexate. Interestingly, orelabrutinib showed excellent efficiency crossing BBB with the functional BTK blockade and promoted PIM1 degradation, providing the molecular basis of incorporating BTKi into PCNS-LBCL therapy. Thus, we determined the efficacy and toxicity of orelabrutinib in combination with high-dose methotrexate in a prospective dose-escalating cohort and real-world practice. The patients being treated with orelabrutinib-included ORMD regimen showed better response and more prolonged survival compared to those with RMD regimen. We further investigated the genetic mutations of PCNS-LBCL across tumor tissue, cerebrospinal fluid (CSF) and plasma. The mutations in CSF circulating tumor DNA (ctDNA) rather than plasma-ctDNA were more consistent to those in tumor tissue, indicating that CSF-ctDNA is a useful tool for monitoring PCNS-LBCL. In summary, our data provided the molecular rationale as well as clinical evidences that incorporation of BTKi into frontline induction therapy is a promising strategy for ND PCNS-LBCL.
    Keywords:   MyD88 L265P ; Bruton’s tyrosine kinase inhibitor; CSF-circulating tumor DNA.; Orelabrutinib; PIM1; Primary CNS large B-cell lymphoma
    DOI:  https://doi.org/10.1186/s13045-026-01812-8
  8. Cancer. 2026 Jul 01. 132(13): e70459
    Selinexor in combination with azacitidine or ruxolitinib in myelodysplastic/myeloproliferative neoplasm overlap syndromes: A multicenter prospective study.
    Xijuan Lin, Ziwei Liu, Chen Yang, Junling Zhuang, Na Wei, Tingting Cui, Wenqi Zheng, Fang Ye, Xiaoqing Ding, Miao Chen, Bing Han.
       BACKGROUND: Therapeutic strategies for myelodysplastic syndrome/myeloproliferative neoplasms (MDS/MPNs) remain suboptimal. Selinexor, an oral selective inhibitor of exportin 1, represents a mechanism-based therapeutic approach. Preclinical and clinical evidence indicated synergistic antileukemic effects when selinexor was combined with hypomethylating agents or janus kinase inhibitors.
    METHODS: A prospective, single-arm trial was conducted to evaluate selinexor plus either azacitidine (for MDS-dominant features) or ruxolitinib (for MPN-dominant features) in patients with MDS/MPN. The primary end point was the overall response rate at 6 months, which was assessed according to 2015 International Working Group criteria. Secondary end points included safety, progression, and survival.
    RESULTS: Twenty patients were enrolled (four with MDS-dominant features, 16 with MPN-dominant features). The median age was 66 years in the MDS group and 62.5 years in the MPN group. The overall response rate was 60% (12 of 20 patients; 95% confidence interval [CI], 36.1%-80.5%) overall, 75% (three of four patients; 95% CI, 31.1%-95.4%) in the MDS group, and 56.3% (nine of 16 patients; 95% CI, 33.2%-76.9%) in the MPN group. In the MDS group, clinical benefits included improvements in the total symptom score, erythroid response, platelet response, and spleen response (one in each of four patients; 25% for each response). In the MPN group, partial responses occurred in two of 16 patients (12.5%), and partial bone marrow responses occurred in three of 16 (18.8%), with additional benefits including spleen response (five of 16; 31.3%), total symptom score improvement (two of 16; 12.5%), erythroid response (two of 16; 12.5%), and platelet response (one of 16; 6.3%). Adverse events occurred in 14 patients (70%). Three patients experienced grade 3 or greater events, including two disease-related fatalities. After a median follow-up of 6 months (range, 2-15 months), one patient's disease transformed to acute myeloid leukemia.
    CONCLUSIONS: Selinexor combined with azacitidine or ruxolitinib showed encouraging efficacy with a manageable safety profile in patients with MDS/MPN.
    Keywords:  azacitidine; efficacy; myelodysplastic syndrome/myeloproliferative neoplasms; ruxolitinib; selinexor
    DOI:  https://doi.org/10.1002/cncr.70459
  9. Toxicol Mech Methods. 2026 Jun 17. 1-12
    Combined treatment of zingerone and nilotinib induces cytotoxicity and reverses nilotinib resistance in chronic myeloid leukemia cells via inhibition of the PI3K signaling.
    Chong Chen, Fang Wang, Suludefu.
       INTRODUCTION: Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of chronic myeloid leukemia (CML) treatment; however, TKI resistance remains a persistent challenge. This study investigates the effects of zingerone on CML cell growth and nilotinib resistance.
    METHODS: K562 and LAMA84 cells were treated with zingerone (5-100 μM) or nilotinib (1-50 nM), and cytotoxicity was assessed using Cell Counting Kit-8 assay. Nilotinib-resistant cells (K562R, LAMA84R) were generated through gradual exposure to increasing nilotinib concentrations (1-10 nM) over six months. Subsequently, cells were treated with 10 μM zingerone and/or 5 nM nilotinib. Cell survival and apoptosis were measured by Trypan blue staining and flow cytometry. Protein levels of Bcr-Abl, apoptotic markers, and PI3K pathway components were analyzed by Western blotting.
    RESULTS: Zingerone, nilotinib, and their combination reduced parental CML cell survival and increased apoptosis. Resistant cells showed no significant response to nilotinib alone, confirming acquired resistance. However, the addition of zingerone markedly reduced survival and increased apoptosis in these resistant cells. The combination of zingerone and nilotinib increased levels of cleaved PARP, cleaved caspase-3, -9, and -8, while decreasing Bcl-2. Zingerone alone or in combination with nilotinib also reduced phosphorylation of PI3K, AKT, and mTOR in resistant cells.
    CONCLUSION: Zingerone enhances the inhibitory effects of nilotinib on CML cell survival and overcomes nilotinib resistance by suppressing the PI3K pathway.
    Keywords:  Apoptosis; Chronic myeloid leukemia cells; Nilotinib; PI3K; Zingerone
    DOI:  https://doi.org/10.1080/15376516.2026.2691543
  10. Hemasphere. 2026 Jun;10(6): e70400
    Phase 3 PERSPECTIVE study: Ibrutinib with rituximab for initial treatment of patients with follicular lymphoma.
    David Belada, Faithlore P Gardner, Ana C de Oliveira, Juan-Manuel Sancho, Elza Lomaia, David Wright, Mehmet Turgut, Elena Martynova, Zsolt Lázár, Bertrand Anz, Ming-Chung Wang, Wojciech Legiec, Stephen Opat, Junvie Pailden, Hillary M Peltier, Emerenziana Marturano, James P Dean, Ian W Flinn.
      We report primary analysis results from the Phase 3 PERSPECTIVE study comparing ibrutinib + rituximab versus placebo + rituximab in patients with previously untreated follicular lymphoma requiring treatment per Groupe d'Etude des Lymphomes Folliculaires criteria who were ineligible for chemoimmunotherapy due to age and/or comorbidities. The primary endpoint was investigator-assessed progression-free survival (PFS). Patients were randomly assigned 3:1 to receive ibrutinib (560 mg) or placebo once daily until progression, together with rituximab 375 mg/m2 weekly for 4 weeks, then every 8 weeks for 12 cycles. Overall, 445 patients were assigned to receive ibrutinib + rituximab (n = 334) or placebo + rituximab (n = 111). With a median follow-up of 53.7 months, PFS was significantly improved with ibrutinib + rituximab versus placebo + rituximab (hazard ratio, 0.713 [95% CI, 0.532-0.955]; P = 0.0231; median 42.0 vs. 32.8 months), as was overall response rate (81% vs. 68%; rate ratio, 1.190 [95% CI, 1.039-1.364]; P = 0.004). Complete response rates also favored ibrutinib + rituximab (31% vs. 26%). Overall survival (OS) was immature and not significantly different between arms (hazard ratio 1.121 [95% CI, 0.771-1.631]; P = 0.5485). Grade ≥3 adverse events occurred in 78% versus 57% of patients with ibrutinib + rituximab versus placebo + rituximab, most commonly neutropenia (16% vs. 7%), pneumonia (9% vs. 5%), hypertension (8% vs. 5%), COVID-19 (6% vs. 2%), COVID-19 pneumonia (6% vs. 3%), and diarrhea (6% vs. 2%). In patients with previously untreated follicular lymphoma, adding ibrutinib to rituximab significantly improved PFS and response rates but did not improve OS. This trial was registered at www.clinicaltrials.gov, NCT02947347.
    DOI:  https://doi.org/10.1002/hem3.70400
  11. J Hematol Oncol. 2026 Jun 16.
    Final analysis of phase 2 clinical trial of ruxolitinib and azacitidine combination therapy in patients with myelodysplastic syndrome/myeloproliferative neoplasms.
    Sankalp Arora, Jayastu Senapati, Indraneel Deshmukh, Prithviraj Bose, Lucia Masarova, Sanam Loghavi, Xuemei Wang, Graciela Nogueras-Gonzalez, Guillermo Montalban-Bravo, Gautam Borthakur, Courtney D DiNardo, Tapan Kadia, Lingsha Zhou, Dyana Saenz, Habiba Halim, Yesid Alvarado, Maro Ohanian, Koichi Takahashi, Nicholas J Short, Elias Jabbour, Farhad Ravandi, Guillermo Garcia-Manero, Naveen Pemmaraju, Naval G Daver.
       BACKGROUND: Myelodysplastic syndrome and myeloproliferative neoplasm (MDS/MPN) overlap syndromes are characterized by the presence of features of both MDS and MPN and have a poor prognosis. We conducted a phase 2 clinical trial evaluating the combination of Azacitidine (AZA) and Ruxolitinib (RUX) in MDS/MPN, with interim analysis showing an objective response rate of 57%. Herein, we report the final analysis from this clinical trial, including long-term survival data.
    METHODS: This was an open-label phase 2 clinical trial including adult patients in 2 diagnostic arms: myelofibrosis (arm 1) and MDS/MPN (arm 2). This manuscript reports outcomes of MDS/MPN patients. RUX 5-20 mg twice daily (per RUX label) was administered in 28-day cycles, and AZA 25 mg/m2 on days 1-5 was added starting cycle 4. Primary endpoint was objective response rate per the 2015 International Consortium Proposal (ICP) MDS/MPN response criteria.
    RESULTS: From 5/2013 to 8/2022, 52 patients were treated with a median age of 68 years (range, 39-82). Disease subtypes were MDS/MPN-Unclassifiable in 24 patients (46%), chronic myelomonocytic leukemia in 23 patients (44%), and atypical chronic myeloid leukemia in 5 patients (10%). Majority of patients (n = 40, 77%) had intermediate-2/high-risk disease by Dynamic International Prognosis Scoring System criteria. Objective responses were attained in 30 patients (58%), with a median duration of response of 13.6 months (95% CI: 6.4-41.1). After a median follow up of 88.5 months, 13 (25%) patients are alive, with median overall survival (OS) of 26.7 months (95% CI: 16.5-52.7), 5-year OS 33%. Median OS in MDS/MPN-U and CMML was 52.7 months (5-year OS 46%) and 17.5 months (5-year OS 27%), respectively. Twelve patients (23%) underwent allogeneic stem cell transplantation; with median OS not reached, 5-year OS 51%. Transformation to acute myeloid leukemia occurred in 13 patients (25%). The most common grade 3-5 adverse events (AEs) regardless of attribution were anemia (31, 60%), thrombocytopenia (27, 52%) and pneumonia (17, 33%). AE-related treatment discontinuation occurred in only 3 patients (6%).
    CONCLUSIONS: AZA-RUX therapy led to durable responses and encouraging OS in MDS/MPN with a manageable safety profile.
    TRIAL REGISTRATION: NCT01787487, (clinicaltrials.gov, date: 2/6/2013).
    DOI:  https://doi.org/10.1186/s13045-026-01813-7
  12. Lancet. 2026 Jun 14. pii: S0140-6736(26)01088-3. [Epub ahead of print]
    Mezigdomide, carfilzomib, and dexamethasone versus carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma (SUCCESSOR-2): a phase 3, open-label, randomised controlled trial.
    SUCCESSOR-2 Trial Investigators
       BACKGROUND: A growing number of patients with multiple myeloma are anti-CD38 antibody-exposed and lenalidomide-exposed at first relapse, subsequently limiting their treatment options. Mezigdomide, a potent cereblon E3 ligase modulator, induces maximal, rapid Ikaros and Aiolos degradation, resulting in enhanced myeloma cell cytotoxicity and immune stimulation versus immunomodulatory drugs. The SUCCESSOR-2 trial evaluates the efficacy and safety of mezigdomide in combination with carfilzomib and dexamethasone versus carfilzomib plus dexamethasone.
    METHODS: This phase 3, open-label, randomised controlled trial was conducted at 160 hospital-based sites in 26 countries using a two-stage, inferentially seamless design. Eligible adult patients had measurable multiple myeloma, had received at least one previous regimen (including anti-CD38 antibodies and lenalidomide) on which they had achieved minimal response or better, and documented disease progression during or after their most recent treatment. Interactive response technology was used to randomly assign patients, stratified by age (≤70 years or >70 years), number of previous lines of therapy (≤2 or >2), and International Staging System stage (I, II, or III). Patients received oral mezigdomide (days 1-21 of each 28-day cycle) plus intravenous carfilzomib (56 mg/m2 weekly) and oral or intravenous dexamethasone (40 mg weekly) or carfilzomib (56 mg/m2 twice weekly or 70 mg/m2 weekly) and dexamethasone (20 mg twice weekly or 40 mg weekly). In stage 1, mezigdomide dosing across three levels was optimised. In stage 2, patients were randomly assigned to the selected mezigdomide dose (1·0 mg) plus carfilzomib and dexamethasone or carfilzomib-dexamethasone alone. The primary endpoint was progression-free survival (PFS) evaluated in patients who received 1·0 mg mezigdomide plus carfilzomib and dexamethasone or carfilzomib-dexamethasone alone across both study stages. No imputation was planned for missing efficacy endpoint values or missing safety evaluations. The trial is registered with ClinicalTrials.gov (NCT05552976) and EUClinicalTrials.eu (EUCT number 2022-500861-29-00). The trial is active but not recruiting.
    FINDINGS: Between Feb 3, 2023, and Nov 28, 2025, 762 patients were assessed for eligibility, of which 606 patients were enrolled and 479 were included in the analyses (288 patients in the mezigdomide-carfilzomib-dexamethasone group and 191 patients in the carfilzomib-dexamethasone group). 252 (53%) patients were male, 411 (86%) were anti-CD38 antibody-refractory, and 363 (76%) were lenalidomide-refractory, with a median of two previous lines of therapy (IQR 2-4). At 10·6 months median follow-up, mezigdomide-carfilzomib-dexamethasone significantly improved PFS compared with carfilzomib-dexamethasone (median 18·0 months vs 8·3 months; hazard ratio 0·48 [95% CI 0·36-0·63]; p<0·0001). Grade 3 or 4 adverse events were observed in 241 (84%) patients receiving mezigdomide-carfilzomib-dexamethasone versus 105 (56%) patients receiving carfilzomib-dexamethasone, including neutropenia (176 [61%] vs 17 [9%]) and infections (98 [34%] vs 29 [16%]). Eight (3%; 95% CI 1-5) and one (1%; 95% CI 0-3) treatment-related grade 5 adverse events were reported with mezigdomide-carfilzomib-dexamethasone and with carfilzomib-dexamethasone, respectively (rate difference 2%; 95% CI -1 to 5). Deaths occurred in 62 (22%) patients in the mezigdomide-carfilzomib-dexamethasone group and 51 (27%) patients in the carfilzomib-dexamethasone group, mainly due to disease progression.
    INTERPRETATION: Mezigdomide-carfilzomib-dexamethasone provided a significant PFS benefit compared with carfilzomib-dexamethasone alone, with higher rates of grade 3 or 4 adverse events, including infections, which were mostly manageable with standard clinical practice and supportive care. These findings support mezigdomide-carfilzomib-dexamethasone as a clinically meaningful treatment option as early as first relapse in predominantly triple-class-exposed, anti-CD38 antibody-refractory and lenalidomide-refractory patients, a growing population with substantial unmet need.
    FUNDING: Bristol Myers Squibb.
    DOI:  https://doi.org/10.1016/S0140-6736(26)01088-3
  13. Blood Adv. 2026 Jun 18. pii: bloodadvances.2026020372. [Epub ahead of print]
    Outcomes of Adolescents and Young Adults with AML Treated on Pediatric vs Adult Protocols.
    Baher Krayem, Jeetayu Biswas, Andriy Derkach, Michael Rafizadeh, Jenna R Ciervo, Christopher A Famulare, Omar Abdel-Wahab, Neerav N Shukla, Tanya Trippett, Christopher Jon Forlenza, Kavitha Ramaswamy, Martin S Tallman, Mark B Geyer, Maria Luisa Sulis, Eytan M Stein.
      Adolescents and young adults (AYA) with acute myeloid leukemia (AML) represent a biologically and clinically distinct population managed across pediatric and adult oncology services, with no established optimal treatment paradigm. In this single-center retrospective study, we analyzed 81 AYA patients aged 14-29 years with newly diagnosed AML treated at Memorial Sloan Kettering Cancer Center between 2010 and 2025. Patients were stratified by treating service, European LeukemiaNet (ELN) 2022 risk category, and induction regimen. Pediatric patients received two cycles of cytarabine, daunorubicin, and etoposide (ADE)-based induction, while adult patients received one cycle of cytarabine plus daunorubicin (7+3) induction-three of whom required 7+3 reinduction-followed by risk-adapted consolidation including allogeneic hematopoietic stem cell transplantation. Composite complete response rates were similar between adult and pediatric cohorts (79% vs. 78%), as were rates of MRD negativity by multicolor flow cytometry among responders (63% vs. 55%). Despite comparable depth of response, five-year overall survival favored adult-service patients in both the full cohort (77.9% vs. 56.7%) and the ELN 2022 intermediate-adverse risk subgroup (62.7% vs. 47.9%), while relapse-free survival was nearly identical. On multivariable analysis, ELN 2022 risk retained independent prognostic significance, whereas treatment protocol did not. These findings demonstrate that pediatric-style and adult AML regimens achieve comparable remission depth in AYA patients. The survival advantage observed with adult protocols challenges the assumption that further cytotoxic intensification improves outcomes in this population.
    DOI:  https://doi.org/10.1182/bloodadvances.2026020372
  14. Nat Commun. 2026 Jun 15.
    Liposomal mitoxantrone plus tislelizumab in patients with relapsed or refractory extranodal natural killer/T-cell lymphoma: a phase 1b/2 trial.
    Qihua Zou, Shenrui Bai, Liang Wang, Hongyan Tong, Dongfeng Zeng, Ying Zhao, Yuerong Shuang, Xiaobo Wang, Xiuhua Sun, Zhenya Hong, Zhigang Peng, Yu Yang, Runhui Zheng, Huiqiang Huang, Jianbo Liu, Chunmei Yang, Xi Li, Xin Gao, Hao Xu, Daoguang Chen, Xiaojie Fang, Man Nie, Jinni Wang, Xinna Gao, Jingjing Ye, Wei Zhang, Jianzhen Shen, Rong Tao, Hong Cen, Yuchen Zhang, Jun Cai, Yi Xia, Qingqing Cai.
      Treatment options for relapsed or refractory extranodal natural killer/T-cell lymphoma (R/R ENKTL) remain limited. In this phase 1b/2 trial (NCT05464433), we evaluated the safety and efficacy of liposomal mitoxantrone (Lipo-MIT) plus anti-PD-1 tislelizumab in this setting. During dose escalation, patients received Lipo-MIT (16 or 20 mg/m2) plus tislelizumab using a 3 + 3 design, followed by dose expansion at the recommended phase 2 dose (RP2D). The primary endpoint of the dose-escalation phase was dose-limiting toxicities (DLTs), which were assessed to determine the RP2D. The primary efficacy endpoint of the dose-expansion phase was the best complete response (CR) rate. Between July 23 2022 and November 28 2024, 40 patients received study treatment (dose-escalation, n = 6; dose-expansion, n = 34). No DLTs were observed and the RP2D of Lipo-MIT was 20 mg/m2. The prespecified primary efficacy endpoint was met, with a CR rate of 53% (21/40; one-sided 95% lower confidence bound, 38%). The median progression-free survival (secondary endpoint) was 8.2 months (95% confidence interval, 6.1-not estimable) after a median follow-up of 15.3 months. The most common grade ≥ 3 adverse events were leukopenia (53%), neutropenia (40%), and febrile neutropenia (18%). In conclusion, Lipo-MIT plus tislelizumab showed promising anti-tumor activity with an acceptable safety profile in R/R ENKTL.
    DOI:  https://doi.org/10.1038/s41467-026-74483-1
  15. Am J Hematol. 2026 Jun 17.
    Systemic Mastocytosis in Adults: 2026 Update on Diagnosis, Risk Stratification and Management.
    Animesh Pardanani.
       OVERVIEW: Systemic mastocytosis (SM) results from clonal proliferation of mast cells (MC) in extra-cutaneous organs.
    DIAGNOSIS: The major criterion is the presence of multifocal MC clusters in the bone marrow and/or extracutaneous organs. Minor diagnostic criteria include elevated serum tryptase level, MC CD25/CD2/CD30 expression, and the presence of activating KIT mutations.
    RISK STRATIFICATION: Establishing SM subtype as per the International Consensus Classification/World Health Organization classification systems is an important first step. Patients either have indolent/smoldering SM (ISM/SSM) or advanced SM, including aggressive SM (ASM), SM with associated myeloid neoplasm (SM-AMN), or mast cell leukemia. Identification of poor-risk mutations (i.e., ASXL1, RUNX1, SRSF2, NRAS) further refines the risk stratification. Several risk models are available to help assign prognosis in SM patients.
    MANAGEMENT: Treatment goals for ISM patients are primarily directed towards anaphylaxis prevention/symptom control/osteoporosis treatment. Patients with advanced SM frequently need MC cytoreductive therapy to reverse disease-related organ dysfunction. Tyrosine kinase inhibitors (TKI) (midostaurin, avapritinib) have changed the treatment landscape in SM. While deep biochemical, histological, and molecular responses have been documented with avapritinib treatment, its efficacy as monotherapy against a multimutated AMN disease component in SM-AMN patients remains unclear. Cladribine continues to have a role for MC debulking, whereas interferon-α has a diminishing role in the TKI era. Treatment of SM-AMN primarily targets the AMN component, particularly if an aggressive disease such as acute leukemia is present. Allogeneic stem cell transplant has a role in such patients. Imatinib has a therapeutic role only in the rare patient with an imatinib-sensitive KIT mutation.
    DOI:  https://doi.org/10.1002/ajh.70395
  16. Haematologica. 2026 Jun 18.
    Second-line bosutinib for chronic phase chronic myeloid leukemia after imatinib: final, 10-year results of a phase I/II study.
    Carlo Gambacorti-Passerini, Tim H Brümmendorf, Dong-Wook Kim, Yeow Tee Goh, Iryna Dyagil, Katia Pagnano, Arpad Batai, Anna G Turkina, Eric Leip, Simon Purcell, Jocelyn Leone, Andrea Viqueira, Jorge E Cortes.
      This is the final ≥10-year report of a phase I/II study and its extension study of second-line bosutinib for chronic phase chronic myeloid leukemia (CP-CML), representing the longest follow-up to date of any tyrosine kinase inhibitor after imatinib failure (n=284). Median (range) follow-up and treatment duration were 53.7 (0.5-171.6) and 25.6 (0.2-170.5) months, respectively. At the start of year 11, 19.4% of patients were receiving bosutinib; 13.4% were receiving bosutinib at study completion. The most common reasons for treatment discontinuation were lack of efficacy (disease progression/unsatisfactory response; 26.8%) and adverse events (26.1%). Cumulative rates of complete cytogenetic response, major molecular response, and MR4 were 49.6%, 42.1%, and 37.1%, respectively. Kaplan-Meier probabilities of maintaining response at year 11 were 58.3%, 56.1%, and 55.7%, respectively. At year 11, cumulative incidence of on-treatment disease progression/death was 24.6%; 15 (5.3%) patients had ontreatment transformations to accelerated/blast phase (one after year 5). The Kaplan-Meier overall survival rate was 70.5%; 55 (19.4%) patients died on study (15 after year 5). At the start of year 11, 29/55 (52.7%) patients still on bosutinib were receiving ≥500 mg once daily. Thirteen patients had adverse events leading to discontinuation in year 6 or later. No new safety signals emerged. After ≥10 years, bosutinib demonstrated durable efficacy and acceptable safety as second-line treatment for CP-CML.
    DOI:  https://doi.org/10.3324/haematol.2025.300221
  17. Virchows Arch. 2026 Jun 16.
    Association between CD79B expression and polatuzumab vedotin efficacy, and therapy-induced changes in CD79B expression in diffuse large B-cell lymphoma.
    Yuto Kaimi, Yuka Takahashi, Mai Takeuchi, Yuta Ito, Shinichi Makita, Noriko Iwaki, Suguru Fukuhara, Wataru Munakata, Koji Izutsu, Yasushi Yatabe, Akiko Miyagi Maeshima.
      Polatuzumab vedotin (PV), a CD79B-directed antibody-drug conjugate, is approved for treating diffuse large B-cell lymphoma (DLBCL). However, the clinical relevance of CD79B expression and the frequency of loss or decrease after PV-containing therapy remain unclear. We evaluated immunohistochemical CD79B expression using H-score (0-300) in 91 patients with DLBCL before PV-containing therapy and assessed post-treatment changes. Low CD79B expression was observed in 15 (16%) patients, including one case with no expression. Relapsed/refractory (R/R) DLBCL occurred more frequently in cases transformed from low-grade B-cell lymphoma than in de novo DLBCL (23% vs. 2%, P = 0.009), as well as in CD10-positive (25% vs. 49%, P = 0.033) and MUM1-negative (71% vs. 46%, P = 0.028) cases. R/R DLBCL also tended to occur more frequently in CD20-negative DLBCL than CD20-positive DLBCL (2% vs. 13%, P = 0.099). CD79B expression level was not associated with R/R DLBCL incidence. Among 15 patients with DLBCL with low CD79B expression, 60% achieved and maintained complete response after PV-containing therapy. Among 24 patients with recurrent tumor biopsies, 13% showed loss of/decreased CD79B expression. In conclusion, immunohistochemical CD79B expression was not significantly associated with PV-containing therapy efficacy, which remained effective even in DLBCL with low CD79B expression.
    Keywords:  CD79B; Diffuse large B-cell lymphoma; Polatuzumab vedotin; Relapsed/refractory
    DOI:  https://doi.org/10.1007/s00428-026-04619-7
  18. Blood Adv. 2026 Jun 18. pii: bloodadvances.2025019087. [Epub ahead of print]
    Anti-CD19 CAR-T in transformed indolent lymphoma versus de novo large B-cell lymphoma: a meta-analysis of 5,006 patients.
    Min-Yue Zhang, Ke-Jie Lu, Xiao-Qing Zhu, Li-Jing Shen, Juan Du.
      
    DOI:  https://doi.org/10.1182/bloodadvances.2025019087
  19. Eur J Cancer. 2026 Jun 13. pii: S0959-8049(26)00660-X. [Epub ahead of print]244 116879
    Outcomes of CAR T-Cell Therapy in transformed indolent Non-Hodgkin Lymphomas and de novo DLBCL: A comparative analysis from the Italian CAR T-SIE study.
    Nicole Fabbri, Beatrice Casadei, Annalisa Chiappella, Federico Stella, Livia Donzelli, Eugenio Galli, Marcello Riva, Massimo Martino, Anna Maria Barbui, Maurizio Musso, Mirko Farina, Piera Angelillo, Ilaria Cutini, Armando Santoro, Federica Cavallo, Paolo Rivela, Alessia Castellino, Mauro Krampera, Giuseppe Petruzzellis, Giovanni Grillo, Lisa Argnani, Francesca Bonifazi, Paolo Corradini, Pier Luigi Zinzani.
       BACKGROUND: Transformed indolent non-Hodgkin lymphoma (TiNHL) generally has poorer outcomes than de novo diffuse large B-cell lymphoma (dnDLBCL). Although anti-CD19 CAR T-cell therapy is standard for relapsed/refractory (R/R) large B-cell lymphoma (LBCL), its prognostic role across histologies remains unclear.
    METHODS: We conducted a multicenter, retrospective/prospective observational study comparing R/R TiNHL and R/R dnDLBCL patients treated with commercial CAR T-cell therapy and enrolled in the Italian CART-SIE study.
    FINDINGS: Among 438 patients, 107 had TiNHL (96 transformed follicular lymphoma [tFL], 11 transformed marginal zone lymphoma [tMZL]) and 331 had dnDLBCL. Baseline characteristics were comparable. TiNHL patients showed superior overall (83% vs 69%) and complete response rates (62% vs 53%) (both p < 0·01), with better 2-year progression-free survival (PFS: 44% vs 31%) and overall survival (OS: 61% vs 48%) (both p < 0·01). CAR-HEMATOTOX score predicted worse outcomes (PFS HR=2·10; OS HR=3·57). No significant differences were found between tFL and tMZL. Two-year relapse/progression incidence was lower in TiNHL (28% vs 47%, p < 0·01), with similar non-relapse mortality (11% vs 4%, p = 0·12). Safety profiles, including cytokine release syndrome and ICANS rates, were comparable.
    CONCLUSION: TiNHL patients receiving CAR T-cell therapy achieved better outcomes than dnDLBCL patients, with comparable safety, supporting its use as a standard treatment in TiNHL.
    Keywords:  CAR T-Cell Therapy; De novo DLBCL; Transformed Indolent Non-Hodgkin Lymphomas
    DOI:  https://doi.org/10.1016/j.ejca.2026.116879
  20. Hemasphere. 2026 Jun;10(6): e70403
    EHA Guidelines on management of chronic lymphocytic leukemia and Richter transformation.
    Barbara Eichhorst, Paolo Ghia, Francesc Bosch, Ruth Clifford, Michael Gregor, Romain Guieze, Arnon P Kater, Carsten U Niemann, Sarka Pospisilova, Tadeusz Robak, Anna Schuh, Kostas Stamatopoulos, Tamar Tadmor, Nick York.
      Previous editions of the European guidelines for the management of chronic lymphocytic leukemia (CLL) were developed by experts in CLL under the auspices of the European Society for Medical Oncology (ESMO). These previous editions have served as a reference text for many physicians caring for patients with CLL. The current, 2026 edition, represents the new, updated guidelines that, for the first time (and in agreement with ESMO), were written on behalf of the European Hematology Association (EHA), which will be solely responsible for subsequent editions, published annually to keep pace of the fast-moving field of CLL research and clinical applications. The new guidelines support approaching the management of CLL in a more holistic fashion, from the initial diagnosis (including active surveillance) to treatment need, with particular emphasis on the interplay between disease- and patient-specific criteria for decision-making, to the latest stage of possible Richter transformation, which is now specifically mentioned in the title of the guidelines. These new recommendations are the result of a consensus reached among medical experts from several European countries and, for the first time, have involved patient advocacy representatives, which is in line with EHA standard operating procedures for clinical practice guideline development. Updates in terms of treatment options include the recently European Medicines Agency-approved, time-limited combination therapy acalabrutinib and venetoclax ± obinutuzumab as first-line treatment, and continuous pirtobrutinib for patients exposed to covalent Bruton's tyrosine kinase inhibitors in the relapsed/refractory setting.
    DOI:  https://doi.org/10.1002/hem3.70403
  21. Blood. 2026 Jun 18. 147(25): 3124
    The 10-year RELEVANCE trial analysis.
      
    DOI:  https://doi.org/10.1182/blood.2026034593
  22. Mol Metab. 2026 Jun 17. pii: S2212-8778(26)00086-4. [Epub ahead of print] 102402
    Venetoclax and hypomethylating agents synergize to increase cell death and metabolic remodeling in acute B-lymphoblastic leukemia cells.
    Patricia Maass, Sandra Lange, Felix Wittig, Nares Trakooljul, Frieder Hadlich, Anett Sekora, Christian Schmidt, Hugo Murua Escobar, Klaus Wimmers, Burkhard Hinz, Christian Junghanss, Anna Richter.
      Overexpression of anti-apoptotic protein BCL-2 and hypermethylation are hallmarks of acute lymphoblastic leukemia (ALL) and can be pharmacologically addressed by venetoclax (VEN) and hypomethylating agents (HMA) such as azacytidine (AZA) or decitabine (DEC). Combined VEN and HMA application was recently successfully implemented into the clinical treatment regimen of acute myeloid leukemia but has so far not been investigated in ALL. We therefore analyzed the anti-leukemic potential of VEN+HMA in four ALL cell lines and identified potential modes of synergy to overcome mono-drug-induced resistance. All substances influenced cell proliferation and induced apoptosis in a subset of the tested cell lines. Investigating potential ways of synergy, combined VEN and HMA application resulted in significantly reduced metabolic activity in all investigated cell lines. In contrast, no synergistic effects were observed regarding the BCL-2 protein and methyltransferase expression or global methylation. Single cell RNAseq of a patient-derived xenograft model revealed that VEN interferes with both main energy supply routes, oxidative phosphorylation as well as glycolysis, to impede the cells' metabolism and mitochondrial activity. The addition of HMA, especially DEC, further increased anti-metabolic effects, leading to a strong reduction of basal and maximal respiration, ATP production and proton leakage. AZA-induced metabolic suppression as well as overall anti-leukemic activity alone and in combination with VEN was generally weaker compared to DEC. Altogether, we herein demonstrate that combined VEN and HMA application acts synergistically and significantly reduces the leukemic burden in ALL cell lines via impairment of tumor cell metabolism and mitochondrial function.
    DOI:  https://doi.org/10.1016/j.molmet.2026.102402
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