bims-hemali Biomed News
on Hematologic malignancies
Issue of 2026–06–28
twelve papers selected by
Alexandros Alexandropoulos, Γενικό Νοσοκομείο Αθηνών Λαϊκό
  1. Four Decades of Molecular Innovation in Chronic Myeloid Leukemia: From Antisense Targeting to Treatment-Free Remission.
  2. Optimizing Flumatinib Therapy in Chinese Chronic-Phase Chronic Myeloid Leukemia Based on Therapeutic Drug Monitoring.
  3. Asciminib Provides Better Efficacy and Favorable Safety and Tolerability Against Investigator-Selected Tyrosine Kinase Inhibitors in East Asian Patients With Newly Diagnosed Chronic Myeloid Leukemia: Results From a Subgroup Analysis of the Pivotal ASC4FIRST Study.
  4. Immunological mechanisms and therapeutic advances in chronic myeloid leukemia.
  5. Meta-analysis of survival by phased-variant ctDNA and PET response in large B-cell lymphoma.
  6. Teclistamab-based induction treatment in transplant-eligible, newly diagnosed multiple myeloma: a phase 2 trial.
  7. Renoir phase III Rituximab-Lenalidomide vs Rituximab as Maintenance Treatment in Relapsed/Refractory Follicular Lymphoma.
  8. Loss of miR-146a-5p contributes to ibrutinib resistance in mantle cell lymphoma.
  9. SAVE, Safe Accelerated Venetoclax Escalation: A phase Ib study of obinutuzumab plus venetoclax with daily ramp-up in CLL.
  10. Iron in HSCs: too much of a good thing.
  11. CD49d: beyond a prognostic marker in CLL.
  12. Phase I study of oral azacitidine plus salvage chemotherapy in relapsed/refractory diffuse large B-cell lymphoma.
  1. Cancers (Basel). 2026 Jun 12. pii: 1922. [Epub ahead of print]18(12):
    Four Decades of Molecular Innovation in Chronic Myeloid Leukemia: From Antisense Targeting to Treatment-Free Remission.
    Maria Stefania De Propris, Alessandro Laganà, Massimo Breccia, Paolo De Fabritiis.
      Chronic myeloid leukemia (CML) represents a paradigm of targeted therapy, driven by the BCR::ABL1 fusion kinase. Over the past four decades, therapeutic strategies have evolved from early molecular targeting approaches and interferon-α to tyrosine kinase inhibitors (TKIs), dramatically improving survival and transforming CML into a largely controllable disease. To provide a comprehensive overview of this evolution, we conducted a narrative literature search across the PubMed and Embase databases, selecting peer-reviewed articles, international guidelines, and landmark clinical trials based on their historical and clinical relevance. Through this expert-driven synthesis, focusing on key milestones in CML therapy, including antisense strategies, interferon-based treatment, first-, second-, and third-generation TKIs, and the development of allosteric inhibitors, this paper analyzes current management strategies, treatment-free remission (TFR), and emerging therapies. The introduction of imatinib established proof of principle for oncogene-targeted therapy, leading to sustained survival improvements. Second- and third-generation TKIs further enhanced response depth and addressed resistance, including the T315I mutation. More recently, the development of the allosteric inhibitor asciminib introduced a novel mechanism of action and expanded therapeutic options for pretreated patients. Furthermore, the achievement of deep molecular responses has enabled TFR in approximately 40-60% of selected patients, redefining treatment goals toward functional cure. Emerging agents, including next-generation ATP-competitive and allosteric inhibitors, are showing promising activity in resistant disease and may further improve outcomes. Thus, CML represents a unique model of translational oncology, demonstrating how mechanistic insight can drive therapeutic innovation. Future strategies will focus on increasing TFR rates, overcoming resistance, targeting leukemic stem cells, and improving global access to therapy and monitoring, with the ultimate aim of achieving functional cure in the majority of patients.
    Keywords:  BCR::ABL1 oncogene; chronic myeloid leukemia (CML); treatment-free remission; tyrosine kinase inhibitors (TKIs)
    DOI:  https://doi.org/10.3390/cancers18121922
  2. Drug Des Devel Ther. 2026 ;20 612207
    Optimizing Flumatinib Therapy in Chinese Chronic-Phase Chronic Myeloid Leukemia Based on Therapeutic Drug Monitoring.
    Fang Cheng, Fan Wang, Zheng Cui, Qiang Li, Xin Liu, Weiming Li.
       Background: The quantitative exposure-response-toxicity relationships for flumatinib have yet to be established in chronic-phase chronic myeloid leukemia (CML-CP) patients.
    Methods: We investigated associations between steady-state flumatinib plasma concentrations and clinical efficacy/adverse events in CML-CP patients.
    Results: Flumatinib exposure exhibited dose-dependent pharmacokinetics. In first-line patients, responders achieving major molecular response (MMR) exhibited significantly higher Cmax_2h (2-hour post-dose concentration) than non-responders (Non-MMR) (127.75±60.40 vs. 58.29±30.47 ng/mL; p<0.001). Similarly, deep molecular response (DMR) responders showed higher Cmax_2h than Non-DMR patients (134.63±66.45 vs. 88.87±47.89 ng/mL; p<0.001). Receiver operating characteristic analysis identified an optimal Cmax_2h threshold of >87.75 ng/mL for MMR (AUC=0.87, 95% CI: 0.78-0.96) and >132.0 ng/mL for DMR (AUC=0.79, 95% CI: 0.68-0.89). In the later-line, the effective treatment group also achieved substantially higher mean Cmax_2h than the failure group (133.75±39.02 vs 88.69±65.07 ng/mL; p<0.01). Furthermore, the results identified an association between diarrhea and a Cmin (trough concentration)>49 ng/mL, as well as between nausea and vomiting and a Cmax_2h>126.5 ng/mL.
    Conclusion: Flumatinib demonstrates exposure-efficacy-toxicity relationships in Chinese patients with CML-CP. These exploratory findings suggest potential concentration thresholds that may inform future therapeutic drug monitoring strategies, pending prospective validation.
    Keywords:  chromic myeloid leukemia; exposure-efficacy; exposure-toxicity; flumatinib; therapeutic drug monitoring
    DOI:  https://doi.org/10.2147/DDDT.S612207
  3. Cancer Med. 2026 Jun;15(6): e72019
    Asciminib Provides Better Efficacy and Favorable Safety and Tolerability Against Investigator-Selected Tyrosine Kinase Inhibitors in East Asian Patients With Newly Diagnosed Chronic Myeloid Leukemia: Results From a Subgroup Analysis of the Pivotal ASC4FIRST Study.
    Naoto Takahashi, Dong-Wook Kim, Inho Kim, Xin Du, Sung-Eun Lee, Yu Hu, Yoshikane Kikushige, Qian Jiang, Yi Wang, Suning Chen, Huanling Zhu, Tatsunori Goto, Akihiro Tomita, Michiko Ichii, Hirohisa Nakamae, Lei Liu, Beini Liu, Kamel Malek, Tong Zhu, Shengyuan Wu, Jianxiang Wang.
      ASC4FIRST (ClinicalTrials.gov NCT04971226) is a pivotal phase 3 clinical trial comparing the efficacy and safety of asciminib vs. standard of care (SoC) tyrosine kinase inhibitors (TKIs) in newly diagnosed patients with chronic myeloid leukemia in chronic phase (CML-CP). The study demonstrated superior efficacy and a favorable safety profile for asciminib vs. all current SoC TKIs; this subgroup analysis involved 138 patients from East Asian sites enrolled in ASC4FIRST. Patients were randomized to receive either asciminib or investigator-selected TKIs (IS-TKIs: imatinib, bosutinib, dasatinib, or nilotinib) following stratification by risk category and prerandomization-selected TKI (imatinib or second-generation TKI). Consistent with non-East Asian patients, asciminib showed better efficacy in East Asian patients, with a major molecular response (MMR) rate at Week 48 and Week 96 of 64.9% and 77.0% compared to 45.3% and 57.8% for all IS-TKIs combined, respectively (common treatment difference: 19.5% and 20.0%, respectively). Similar results were obtained for patients with imatinib as the prerandomization-selected TKI (MMR rate at Week 48 and Week 96: 67.9% and 78.6% for asciminib compared to 30.8% and 46.2% for imatinib, respectively; common treatment difference: 36.5% and 32.7%, respectively). Asciminib also showed a favorable safety profile in East Asian patients, with lower rates of Grade ≥ 3 adverse events (AEs) and AEs leading to discontinuation compared to IS-TKIs (41.9% vs. 54.0% and 2.7% vs. 9.5%, respectively), consistent with the results from non-East Asian patients. These findings support the use of asciminib as a first-line treatment option for East Asian and non-East Asian patients with CML-CP.
    Keywords:  asciminib; chronic myeloid leukemia; frontline; imatinib; second generation; tyrosine kinase inhibitor
    DOI:  https://doi.org/10.1002/cam4.72019
  4. Leukemia. 2026 Jun 25.
    Immunological mechanisms and therapeutic advances in chronic myeloid leukemia.
    Tiffany K Ybarra, Ryan S Sathianathen, Rohaum Hamidi, Nobuko Hijiya, Neil P Shah, Kathleen M Sakamoto.
      Chronic myeloid leukemia (CML) is defined by the reciprocal translocation between chromosomes 9 and 22 [t(9;22)], resulting in the constitutively active BCR::ABL1 fusion oncogene in hematopoietic stem cells (HSC). CML is mostly diagnosed in older adults. However, it can also occur in children, adolescents, and young adults. Therapeutic strategies for chronic phase-CML (CML-CP) have drastically improved overall survival and disease relapse, including the development of small molecular tyrosine kinase inhibitors (TKI). However, therapeutic approaches in CML still face challenges and potential downfalls, including resistance, intolerance, persistence of leukemic cells (LCs) that risk the progression to blast phase-CML (CML-BP), and other challenges in effectiveness. Furthermore, standardized treatment by pediatric oncologists follows guidelines designed for adult CML patients and does not consider differences in host or disease biology in pediatric patients. Although some patients can achieve treatment-free remission (TFR), most patients require lifelong TKI therapy. Thus, an attractive goal in CML, particularly in children with CML, who may need several decades of TKI treatment, is to identify and target immunoregulatory pathways and restoration of immune surveillance mechanisms to promote strong immune responses and TFR success. In this review, we discuss the immunological mechanisms that contribute to the development, progression and control of CML, including supporting evidence of currently approved or investigated therapeutic approaches.
    DOI:  https://doi.org/10.1038/s41375-026-03006-0
  5. Blood Adv. 2026 Jun 24. pii: bloodadvances.2026020988. [Epub ahead of print]
    Meta-analysis of survival by phased-variant ctDNA and PET response in large B-cell lymphoma.
    Max J Gordon, Hyoyoung Choo-Wosoba, Gonca Ozcan, Rahul Lakhotia, Elizabeth Hill, Christopher Melani, Wyndham H Wilson.
      Positron emission tomography (PET) is used to assess response in large B cell lymphoma (LBCL) but 20% to 30% of responding patients will relapse. Circulating tumor DNA detected by phased-variants is a highly sensitive means of identifying measurable residual disease (MRD) which may improve PET response assessment. We conducted a meta-analysis of end of treatment MRD and PET in LBCL treated with curative intent frontline therapy. Three studies and 367 patients were included. In the pooled analysis, the hazard ratio (HR) for progression-free survival (PFS) in undetectable vs. detectable MRD was 14.02 (95% CI, 7.35 - 26.74) and 5.09 (95% CI, 3.29 - 7.88) in PET complete metabolic response (CMR) vs. no CMR (p=0.01 for group difference). Two-year PFS rates were 95.7% (95%, CI 89.7% - 98.3%) with undetectable MRD and CMR, 91.3% (95% CI, 84.5% - 95.3%) in undetectable MRD and no CMR, 40.2% (95% CI, 20.9% - 63.2%) in detectable MRD and CMR and 23.4% (95% CI, 11.7% - 41.3%) in detectable MRD and no CMR (p<0.0001 for group differences). Phased-variant detected MRD provides clinically meaningful prognostic information when assessed at end of frontline curative intent chemoimmunotherapy in patients with LBCL independent of PET response assessment.
    DOI:  https://doi.org/10.1182/bloodadvances.2026020988
  6. Nat Med. 2026 Jun 25.
    Teclistamab-based induction treatment in transplant-eligible, newly diagnosed multiple myeloma: a phase 2 trial.
    GMMG-HD10/DSMM-XX (MajesTEC-5) investigators
      Advancements in frontline therapies have substantially improved outcomes in newly diagnosed multiple myeloma (NDMM); however, many patients will not achieve deep responses and will relapse. Teclistamab, a BCMA×CD3 bispecific antibody, in combination with daratumumab, has demonstrated strong efficacy in relapsed/refractory multiple myeloma versus standard of care as early as first relapse. This ongoing phase 2 GMMG-HD10/DSMM-XX (MajesTEC-5) study evaluates teclistamab-based regimens in transplant-eligible NDMM. In this prespecified pooled analysis of three cohorts, 49 patients received teclistamab/daratumumab/lenalidomide (Tec-DR; arms A and A1) or Tec-DR with bortezomib (Tec-DVR; arm B). Primary endpoints were incidence and severity of adverse events (AEs) and serious AEs; secondary endpoints included overall response rate (ORR), minimal residual disease (MRD) negativity and MRD-negative complete response (CR). The current analysis spans the induction and autologous stem cell transplantation phases until the premaintenance timepoint. Grade 3 or 4 treatment-emergent AEs (TEAEs) occurred in 91.8% (45/49); most were hematologic (lymphopenia (59.2%; 29/49), neutropenia (59.2%; 29/49) and leukopenia (18.4%; 9/49)). No grade 5 TEAEs were reported. Serious AEs occurred in 55.1% (27/49); pyrexia (12.2% (6/49)) was most common. Any-grade and grade 3 or 4 infections occurred in 81.6% (40/49) and 36.7% (18/49), respectively, the most common grade 3 or 4 infections being COVID-19 and pneumonia (6.1% (3/49) each). Cytokine release syndrome occurred in 67.3% (33/49); all were grade 1 or 2, all resolved and none led to discontinuation of any study treatment. No treatment-related immune effector cell-associated neurotoxicity syndrome (ICANS) events occurred. Across arms, the MRD-negative CR rate was 91.8% (45/49) by the premaintenance timepoint; the MRD negativity rate was 100% in evaluable samples at postinduction cycle 3 (1 × 10-5 (46/46)), cycle 6 (1 × 10-5 (46/46) and 1 × 10-6 (46/46)) and premaintenance (1 × 10-5 (40/40)); the ORR was 100% (49/49). Total median stem cell yield was 8.1 × 106 per kg. Data support the feasibility of Tec-D(V)R induction in transplant-eligible NDMM, with a consistent safety profile compared with individual regimen components and notable early MRD negativity rates. ClinicalTrials.gov identifier: NCT05695508 .
    DOI:  https://doi.org/10.1038/s41591-026-04471-x
  7. Blood Adv. 2026 Jun 25. pii: bloodadvances.2025018732. [Epub ahead of print]
    Renoir phase III Rituximab-Lenalidomide vs Rituximab as Maintenance Treatment in Relapsed/Refractory Follicular Lymphoma.
    Barbara Botto, Carola Boccomini, Andrea Evangelista, Vittorio Ruggero Zilioli, Antonella Anastasia, Federica Cavallo, Francesco Merli, Manuela Zanni, Monica Tani, Annalisa Chiarenza, Anna Marina Liberati, Annarita Conconi, Chiara Rusconi, Alessia Bari, Ilaria Del Giudice, Gianluca Gaidano, Michele Spina, Nilla Maschio, Claudia Castellino, Delia Rota-Scalabrini, Benedetta Puccini, Annalisa Arcari, Sara Bigliardi, Giorgia Maria Elena Matta, Benedetta Bianchi, Donato Mannina, Dario Marino, Piero Galieni, Fabrizio Ciambelli, Gerardo Musuraca, Cristina Muzi, Chiara Bottelli, Elisa Genuardi, Erika Meli, Simone Ferrero, Stefano Luminari, Marco Ladetto, Giovannino Ciccone, Umberto Vitolo.
      Maintenance treatment in elderly patients with relapsed or refractory (R/R) follicular lymphoma (FL) remains an area of investigation. RENOIR was a multicenter, phase III, open-label randomized trial conducted by the Fondazione Italiana Linfomi (FIL) in elderly patients with R/R FL after one or two prior therapies. Patients achieving partial or complete response (PR/CR) after 4-6 cycles of standard rituximab-based chemotherapy were randomized 1:1 to maintenance with rituximab alone (R, standard arm) or rituximab plus lenalidomide (R2, experimental arm). The primary endpoint was 2-year progression-free survival (PFS) from randomization with an expected HR =0.5. A total of 152 patients (median age 71 years) were enrolled. After induction, 129 (85%) achieved an overall response (CR 58%) and were randomized to R (n=65) or R2 (n=64). At a median follow-up of 68 months, the 2-year PFS was 73% in the R2 arm and 64% in the R arm (HR 0.73, 95% CI 0.46-1.16, p=.183). An unplanned hypothesis- generating subgroup analysis showed a greater 2-year PFS benefit with R2 in patients aged <70y (HR=0.35): R2 96% vs R 69%. Two-year overall survival (OS) rates were similar (R2 80% vs R 89%; HR 1.12). Grade 3/4 adverse events were more frequent in R2, mainly neutropenia and gastrointestinal disorders. In conclusion, the primary endpoint of the study was not met and R2 maintenance did not significantly improve 2-year PFS in elderly patients with R/R FL, though a numerically benefit was observed. R2 showed a more favorable benefit/risk profile in patients <70 years whereas in older patients careful consideration of individual tolerability is warranted. Trial registration: RENOIR study (NCT02390869) clinicaltrial.gov.
    DOI:  https://doi.org/10.1182/bloodadvances.2025018732
  8. Blood Adv. 2026 Jun 23. pii: bloodadvances.2025016640. [Epub ahead of print]
    Loss of miR-146a-5p contributes to ibrutinib resistance in mantle cell lymphoma.
    Olga Kersy, Nir Cohen, Mali Salmon-Divon, Pavel Klener, Katarina Mekin, Tal Zvida, Maria Gomes Silva, Filipa Moita, Jose M Cabecadas, Marek Trněný, May Basood, Martin Dreyling, Benjamin Heath Durham, Omar Abdel-Wahab, Ofer Shpilberg, Oshrat Hershkovitz-Rokah.
      Resistance to Bruton's tyrosine kinase (BTK) inhibition represents a major clinical challenge in mantle cell lymphoma (MCL). While ibrutinib suppresses B-cell receptor signaling, patients eventually relapse, underscoring the need to elucidate non-genetic resistance mechanisms. MicroRNAs (miRNAs) are key post-transcriptional regulators of gene expression, yet their contribution to ibrutinib resistance in MCL remains incompletely defined. To this end, we established three ibrutinib-resistant MCL cell line models through prolonged drug exposure and performed integrated miRNA and transcriptome profiling. Resistant cells exhibited a distinct miRNA signature characterized by downregulation of miRNAs targeting the MAPK-ERK and PI3K-AKT survival pathways, resulting in pathway hyperactivation. These findings were validated in patient-derived xenografts and clinical biopsy samples from ibrutinib-resistant patients. Pharmacological inhibition of these pathways effectively suppressed pathway activation, reduced mitochondrial activity, and induced apoptosis in resistant cells, with enhanced efficacy observed upon dual pathway targeting. Among deregulated miRNAs, miR-146a-5p was consistently reduced in resistant cell lines, PDX models, and patient samples. Restoration of miR-146a-5p expression resensitized resistant cells to ibrutinib. Promoter hypermethylation of miR-146a provides a potential epigenetic mechanism underlying its repression. Overall, these data identify miRNA-mediated activation of MAPK and PI3K signaling as epigenetic driver of ibrutinib resistance in MCL and support rational combination strategies to overcome therapeutic failure.
    DOI:  https://doi.org/10.1182/bloodadvances.2025016640
  9. Blood Adv. 2026 Jun 23. pii: bloodadvances.2026020392. [Epub ahead of print]
    SAVE, Safe Accelerated Venetoclax Escalation: A phase Ib study of obinutuzumab plus venetoclax with daily ramp-up in CLL.
    Jennifer L Crombie, Inhye E Ahn, Yue Ren, Svitlana Tyekucheva, Celeste Carey, Mari Kniezewski, Samantha Normilus, Shantal Solomon, Josie Montegaard, Austin I Kim, Reid W Merryman, Philippe Armand, David C Fisher, Jennifer R Brown, Matthew S Davids.
      While venetoclax (VEN)-based regimens are highly effective for patients with chronic lymphocytic leukemia (CLL), initiation is complex, due to the requirement of a 5-week dose ramp-up used to mitigate the risk of tumor lysis syndrome (TLS). We report the results of the first prospective study of VEN initiation using an accelerated inpatient dose ramp-up in CLL. Forty patients were treated, including 15 (37.5%) with relapsed or refractory disease and 13 (32.5%) with medium (27.5%, n=11) or high (5%, n=2) TLS risk at enrollment. All except one (97.5%) received obinutuzumab in combination with VEN. All patients completed an accelerated daily VEN ramp-up from 20 mg to 400 mg in the inpatient setting. None had clinical TLS. One (2.5%) patient with Bruton tyrosine kinase inhibitor-refractory CLL and high TLS risk developed laboratory TLS after the 200 mg dose of VEN, which normalized within a day with a 1-day dose hold and supportive care. The median inpatient time was 7 days. In intent-to-treat analyses of efficacy at 3 months, the overall response rate was 78.0%. Our data support the feasibility of accelerated VEN ramp-up in select patients in experienced centers and warrant further exploration of this approach in broader clinical settings. NCT04843904.
    DOI:  https://doi.org/10.1182/bloodadvances.2026020392
  10. Blood. 2026 Jun 25. 147(26): 3131-3132
    Iron in HSCs: too much of a good thing.
    Massiel Chavez Stolla.
      
    DOI:  https://doi.org/10.1182/blood.2026033923
  11. Blood. 2026 Jun 25. 147(26): 3126-3127
    CD49d: beyond a prognostic marker in CLL.
    Phuong-Hien Nguyen.
      
    DOI:  https://doi.org/10.1182/blood.2026033672
  12. Ann Hematol. 2026 Jun 22.
    Phase I study of oral azacitidine plus salvage chemotherapy in relapsed/refractory diffuse large B-cell lymphoma.
    Brian Hess, Nina D Wagner-Johnston, Lindsey Hendrickson, James A Davis, Elizabeth Hill, Anshu Giri, Kent Armeson, Maria V Revuelta, Shanta Salzer, Robin Klingenberg, Leandro Cerchietti.
      Salvage chemotherapy and autologous stem cell transplantation (ASCT) offer the opportunity to cure eligible patients with relapsed diffuse large B-cell lymphoma (DLBCL). Epigenetic alterations such as aberrant DNA methylation patterns have been linked to chemotherapy resistance in DLBCL. Oral Azacitadine (AZA) is a hypomethylating agent that inhibits DNA methyltransferase and has provided evidence of chemotherapy sensitization in DLBCL. In this phase I trial the safety and feasibility of two dose levels of AZA were investigated in combination with standard cytotoxic chemotherapy rituximab, ifosfamide, carboplatin, and etoposide (R-ICE) in relapsed DLBCL patients who were candidates for ASCT.
    Keywords:  Dlbcl; Epigenetics; Lymphoma
    DOI:  https://doi.org/10.1007/s00277-026-07125-7
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