bims-hemali Biomed News
on Hematologic malignancies
Issue of 2025–09–07
23 papers selected by
Alexandros Alexandropoulos, Γενικό Νοσοκομείο Αθηνών Λαϊκό



  1. Clin Lymphoma Myeloma Leuk. 2025 Aug 06. pii: S2152-2650(25)00261-7. [Epub ahead of print]
      Philadelphia chromosome-positive chronic myeloid leukemia (CML) during pregnancy is rare, with an annual incidence of 1 per 100,000 pregnancies. Managing CML in pregnancy is challenging due to concerns about the teratogenicity of the BCR::ABL1 tyrosine kinase inhibitors (TKIs). While some pregnant patients with chronic-phase CML may be managed with close monitoring and no therapy, others, particularly those diagnosed in the first trimester, may require treatment to prevent disease progression and maternal complications. Imatinib has been associated with an increased risk of congenital malformations when used in the first trimester; however, growing evidence support its safety later in the second and third trimesters. Similar to imatinib, nilotinib has limited placental transfer with no congenital malformations reported to date in women who received it later in pregnancy. Dasatinib, however, is contraindicated due to its high association with congenital abnormalities and hydrops fetalis. Ponatinib exposure has been linked to a higher incidence of Hirschsprung's disease and should be avoided in pregnancy. Although no congenital malformations have been reported with bosutinib or asciminib, data remains limited, and their use is not recommended. Interferon-α is a safer alternative during pregnancy but is slower in achieving cytoreduction, and less effective compared to TKIs. Hydroxyurea, while not teratogenic, may increase the risk of miscarriage and low birth weight. If a male patient is receiving TKI therapy, the female partner can safely become pregnant without an increased risk for the fetus. Shared decision-making and thorough counseling on the risks and benefits of different treatment options are essential. This review examines the potential fetotoxicity of CML therapies, focusing on TKIs and alternative treatments for pregnant women.
    Keywords:  BCR::ABL1; CML-CP; Conceive; Fetus; Pregnant
    DOI:  https://doi.org/10.1016/j.clml.2025.07.017
  2. Int J Clin Oncol. 2025 Sep 02.
       BACKGROUND: Patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL) face a poor prognosis in the absence of effective treatment options. Ibrutinib plus venetoclax demonstrated high response rates and a tolerable safety profile in the primary analysis of the Phase 2, M20-075 study (NCT04477486) in Japanese patients with R/R MCL. We report updated efficacy and safety from this study with longer follow-up.
    METHODS: Patients received 560 mg ibrutinib and 400 mg venetoclax (5-week ramp-up to 400 mg) once daily for up to 104 weeks followed by ibrutinib monotherapy. Primary endpoint was Independent Review Committee-assessed complete response (CR) rate. Secondary endpoints included overall response rate (ORR), duration of response (DOR), undetectable minimal residual disease (uMRD) in patients achieving CR, progression-free survival (PFS), overall survival (OS), and safety.
    RESULTS: After a median follow-up of 37.2 months, 13 patients had received ibrutinib plus venetoclax, 8 (62%) remained on ibrutinib monotherapy, and 9 (69%) completed 24 months of venetoclax. ORR was 83% (10/12 [per-protocol population]; all CR); median DOR was not reached. All 6 patients positive for MRD at baseline who achieved CR had uMRD. Median PFS and OS were not reached. Most frequent Grade ≥ 3 treatment-emergent adverse events (TEAEs) were neutropenia (46%) and leukopenia (23%); one TEAE leading to treatment discontinuation was squamous cell carcinoma unrelated to treatment. There were no cases of tumor lysis syndrome or TEAEs leading to death.
    CONCLUSION: Long-term follow-up of ibrutinib plus venetoclax showed prolonged efficacy and a well-tolerated safety profile in Japanese patients with R/R MCL.
    Keywords:  Ibrutinib; Mantle cell lymphoma; Relapsed/refractory; Venetoclax
    DOI:  https://doi.org/10.1007/s10147-025-02865-4
  3. Blood. 2025 Sep 02. pii: blood.2025030259. [Epub ahead of print]
      Genomic profiling in chronic-phase chronic myeloid leukemia (CP-CML) patients demonstrated somatic variants in blood cancer-related genes (CGVs) and rearrangements associated with the formation of the Philadelphia-chromosome (Ph-associated rearrangements) at diagnosis, collectively termed additional genetic abnormalities (AGA). AGAs had a negative impact on failure-free survival and molecular response in imatinib-treated patients. We investigated whether treatment with more potent therapies could overcome the negative impact of AGAs at diagnosis. Targeted RNA-based next generation sequencing (NGS) was performed on diagnostic samples of 315 patients consecutively enrolled in four clinical trials of frontline potent tyrosine kinase inhibitors (TKIs) in CP-CML. AGAs were present in 34% of patients at diagnosis, including 20% with CGVs and 18% with Ph-associated rearrangements (4% had both). While the negative impact of Ph-associated rearrangements was overcome by more potent inhibitors, patients with CGVs continued to have inferior outcomes. This was largely attributable to patients with ASXL1 variants, observed in 7% overall. Comparing patients with ASXL1 variants to ASXL1 wildtype: 12-month major molecular response 55% versus 83% (P=0.001); 2-year failure-free survival 61% versus 91% (P<0.001); and notably, development of treatment emergent BCR::ABL1 kinase domain mutations at 2 years, 35% versus 1% (P<0.001). In multivariable models, CGVs and ASXL1 variants were predictors of each of these outcomes. Treatment with frontline potent TKIs overcame the negative impact of Ph-associated rearrangements observed with frontline imatinib. However, inferior outcomes were still associated with the presence of CGVs. The acquisition of TKI-resistant BCR::ABL1 mutations was almost exclusively associated with mutated ASXL1 at diagnosis.
    DOI:  https://doi.org/10.1182/blood.2025030259
  4. Bull Cancer. 2025 Sep 03. pii: S0007-4551(25)00338-8. [Epub ahead of print]
      Molecular biologists play an important role in therapeutic decisions in the context of Chronic Myelogenous Leukemia (CML). Before treatment, it is mandatory to identify the BCR::ABL1 fusion and any prognostic cytogenetic abnormalities that may be present. During treatment, regular assessment of measurable residual disease (MRD) is essential to objectively evaluate the optimal response and identify situations of resistance to treatment. Monitoring of MRD is also required when considering treatment discontinuations. In cases of resistance, identifying mutations that confer resistance to tyrosine kinase inhibitors is essential for adapting the treatment. The Group of Molecular Biologists of Hematologic Malignancies (GBMHM) and the France Intergroup of Chronic Myeloid Leukemia (Fi-LMC) convened a panel of experts to critically review methods used for molecular diagnostics and follow-up of patients with CML, define best practices applicable in this context and formulate recommendations.
    Keywords:  BCR::ABL1; CML; Chronic myeloid leukemia; Diagnostic moléculaire; Leucémie myéloïde chronique; Maladie résiduelle mesurable; Measurable residual disease; Molecular diagnostics; Mutations de résistance; Mutations of resistance
    DOI:  https://doi.org/10.1016/j.bulcan.2025.05.017
  5. Expert Opin Pharmacother. 2025 Sep 04. 1-18
       INTRODUCTION: There have been recent major advances in the management and treatment of mantle cell lymphoma (MCL). This uncommon subtype of mature B-cell lymphoma has a heterogeneous clinical course, including a spectrum of indolent and aggressive disease. While historically regarded as an incurable disease with a poor long-term prognosis, recent developments have improved outcomes.
    AREAS COVERED: The incorporation of targeted treatments, such as covalent Bruton's tyrosine kinase inhibitors (cBTKi), with or without chemo-immunotherapy in the upfront treatment setting is supported by recent clinical trials indicating encouraging efficacy and safety. Measurable residual disease (MRD) testing is emerging as a potent tool in guiding treatment decision and improving outcomes while minimizing toxicities. Therapies utilized in relapsed/refractory disease, such as BCL2 inhibitors as well as immune-leveraging therapies, including T-cell engaging antibodies and chimeric antigen receptor (CAR) T-cells therapy, are being evaluated in upfront settings.
    EXPERT OPINION: This review will discuss recent advances in the upfront management of this challenging disease as well as a suggested treatment algorithm considering both availability and unavailability of first-line cBTKi. The incorporation of cBTKi to chemo-immunotherapy regimens appears effective and safe. However, patients with high-risk disease may require novel therapeutic approaches due to suboptimal outcomes with chemo-immunotherapy.
    Keywords:  BTK inhibitor; Mantle cell lymphoma; expert opinion; frontline management; newly diagnosed; recent advances; review; treatment-naïve
    DOI:  https://doi.org/10.1080/14656566.2025.2556138
  6. Cancer Innov. 2025 Oct;4(5): e70024
       Background: Chronic myeloid leukemia (CML) is a clonal malignancy propelled by the BCR::ABL1 fusion gene originating from the Philadelphia chromosome. This gene activates ABL tyrosine kinase, which enhances the survival of leukemic cells. Although tyrosine kinase inhibitors (TKIs) have significantly advanced the treatment of CML, resistance to these inhibitors presents a substantial hurdle. Consequently, novel therapeutic strategies targeting resistance mechanisms independent of BCR::ABL1 are urgently needed.
    Methods: This study investigated the potential impact of combining WEE1 inhibitors, particularly MK-1775, with vitamin K2 (VK2) in treating CML. To analyze differentially expressed and spliced transcripts in CML, we examined mRNA profiles from peripheral blood mononuclear cells of five patients with CML (during chronic and blast phases) and five healthy controls. The samples were analyzed using deep sequencing. Differential expression analyses were performed using RaNA-Seq and Heatmapper, the latter of which was designed for complex data set visualizations.
    Results: WEE1 controls the G2/M checkpoint to prevent early mitosis, and blocking it increases the cytotoxicity of agents that damage deoxyribonucleic acid, especially in cancers lacking p53. VK2, a micronutrient, exerts anticancer effects against various malignancies. Gene expression studies have indicated that PKMYT1 expression is elevated in CML but not WEE1 cells. MK-1775 successfully halted the growth of both standard and TKI-resistant CML cell lines by triggering apoptosis via caspase 3/7 activation. VK2 reduced the viability of CML cells and increased cytotoxicity. A combined regimen of MK-1775 and VK2 markedly decreased colony growth, disrupted mitochondrial membrane potential, and increased death in CML cells, including those resistant to TKIs.
    Conclusions: The results suggest that a combination of MK-1775 and VK2 represents a potentially effective treatment strategy for CML, especially in drug-resistant cases.
    Keywords:  WEE1 inhibitor; chronic myeloid leukemia; vitamin K2
    DOI:  https://doi.org/10.1002/cai2.70024
  7. Leuk Lymphoma. 2025 Sep 01. 1-8
      Hairy cell leukemia (HCL) is a rare, indolent lymphoproliferative disorder that is highly responsive to purine analog therapy. While agents such as cladribine and pentostatin remain standard front-line therapies, their long-term toxicities-particularly myelosuppression and immune dysfunction-have led to growing interest in chemotherapy-free agents. Recent advances in molecular characterization of HCL, including the near-universal presence of BRAF V600E mutations, have led to an era of targeted therapeutics for the treatment of this disease. In this review, we summarize existing and emerging treatment strategies for HCL, including BRAF and MEK inhibitors, Bruton tyrosine kinase (BTK) inhibitors, anti-CD20 monoclonal antibodies, and venetoclax. These approaches offer therapeutic promise for patients with relapsed/refractory disease and for those ineligible to receive traditional chemotherapy. These regimens also result in high rates of minimal residual disease (MRD) negativity, potentially bringing us closer to the cure for HCL.
    Keywords:  Targeted therapy; braf inhibitor; cladribine; hairy cell leukemia; precision oncology; rituximab
    DOI:  https://doi.org/10.1080/10428194.2025.2548373
  8. Br J Haematol. 2025 Aug 30.
      The therapeutic landscape of follicular lymphoma (FL) is undergoing a transformative shift driven by the advent of novel chemo-free strategies that challenge the traditional chemo-oriented paradigms; this shift offers promising alternatives for both newly diagnosed and relapsed or refractory (RR) patients. Available data support a full chemo-free approach starting from second-line therapy, with rituximab-lenalidomide (R2) or tafasitamab-R2, whereas bispecific antibodies (bsAbs), Bruton's tyrosine kinase (BTK) inhibitors and chimeric antigen receptor (CAR) T-cell therapies are available options after second relapse. In the near future, bsAbs, mainly in combination with lenalidomide, will likely be employed as first- or second-line therapy, potentially fully replacing immunochemotherapy, whereas CAR T-cell therapy will play a role in selected high-risk patients. Given the different toxicity profiles of chemo-free options, refined prognostic scores are awaited so as to properly allocate patients to the most appropriate therapy with the best trade-off between efficacy and safety.
    Keywords:  chemo‐free therapies; follicular lymphoma; immunotherapy
    DOI:  https://doi.org/10.1111/bjh.70126
  9. J Hematol. 2025 Aug;14(4): 193-201
      Recent studies show that the B-cell lymphoma 2 (BCL-2) inhibitor venetoclax is a promising therapeutic drug for acute lymphoblastic leukemia (ALL), especially in high-risk subtypes including early T-cell precursor (ETP)-ALL, Philadelphia chromosome (Ph)-like B-cell ALL, and KMT2A-rearranged leukemia. The preclinical and early-phase clinical research shows that venetoclax-based combinations can increase apoptosis and improve response rates when used with chemotherapy or hypomethylating agents. The main challenge to venetoclax efficacy remains the resistance mechanisms that primarily involve myeloid cell leukemia-1 (MCL-1) and BCL-extra large (XL). This review provides an overview of the current state of venetoclax in ALL by discussing its mechanistic basis and clinical trial results as well as safety data and strategies to overcome resistance and enhance venetoclax-based treatments.
    Keywords:  Acute lymphoblastic leukemia; Apoptosis resistance; B-cell ALL; BCL-2 inhibition; Combination therapy; T-cell ALL; Targeted therapy; Venetoclax
    DOI:  https://doi.org/10.14740/jh2092
  10. Proc Natl Acad Sci U S A. 2025 Sep 09. 122(36): e2426935122
      Chronic lymphocytic leukemia (CLL) remains incurable despite treatment advances, and a major challenge is that biomarkers that predict response and resistance to current therapies are lacking. We report that activated and proliferating malignant CLL B cells in circulation express PD-1, a protein normally expressed in T cells. PD-1 expression is absent in circulating B cells from healthy controls and nonmalignant B cells from patients with CLL. Circulating PD-1+ CLL cells are found in all treatment naïve patients, regardless of immunoglobulin heavy-chain variable region gene mutation status or cytogenetic abnormalities. PD-1+ CLL cells are transcriptionally distinct compared to PD-1- CLL cells and upregulate genes associated with cell activation, proliferation, and B cell receptor (BCR) and toll-like receptor (TLR) signaling. Indeed, ex vivo stimulation of the BCR and TLR9 readily increased PD-1 expression in CLL cells from treatment-naïve patients within 24 h, an effect that was blocked by Bruton's tyrosine kinase inhibitors (BTKi). More importantly, patients initiating BTKi therapy experienced profound reductions in circulating PD-1+ CLL cell numbers within 1 mo, which is in line with reduction in Ki-67+ CLL cells. Elevated percentages of circulating PD-1+ CLL cells also preceded a clinical diagnosis of disease progression in patients receiving BTKi. Thus, our findings indicate that PD-1 expression is a potential biomarker to identify proliferating CLL cells in vivo and will be useful to predict response and resistance to BTKi. In addition, eliminating PD-1+ CLL cells with depleting anti-PD-1 monospecific or bispecific antibodies should be explored as a potential therapeutic strategy.
    Keywords:  BTK inhibitors; PD-1; biomarker; chronic lymphocytic leukemia
    DOI:  https://doi.org/10.1073/pnas.2426935122
  11. Leuk Lymphoma. 2025 Aug 28. 1-16
      Peripheral T-cell lymphomas (PTCL) comprise a heterogeneous group of 15 different neoplasms in adults. In Europe and North America, PTCL not otherwise specified (PTCL NOS), nodal T follicular helper lymphoma, angioimmunoblastic type (nTFHL-AI), and anaplastic large cell lymphoma (ALCL) either anaplastic lymphoma kinase (ALK) positive (+) or negative (-) are the most prevalent PTCLs. Relapsed or refractory disease (R/R) is common in PTCL and its management is challenging. Despite response rates and prognoses being disease specific, the outcome of R/R PTCL is dismal except for R/R ALK+ ALCL. Populations in R/R PTCL studies have mostly been heterogeneous and encompassing several entities. While there are many treatment options for R/R PTCL such as salvage chemotherapy, autologous or allogeneic stem cell transplant, epigenetic drugs, monoclonal antibodies, and small molecules, responses are limited and few are curative. Here we review the management of R/R PTCL, focusing on ALCL, nTFHL, and PTCL NOS.
    Keywords:  PTCL; Peripheral T-cell lymphoma; relapsed/refractory disease; review; stem cell transplant
    DOI:  https://doi.org/10.1080/10428194.2025.2545927
  12. Blood Cancer Discov. 2025 Sep 03.
      Menin inhibitors are targeted therapies for the treatment of genetically defined subsets of acute leukemia. The menin inhibitor revumenib is currently approved for relapsed or refractory leukemia with rearrangement of lysine methyltransferase 2 A (KMT2A). However, multiple other menin inhibitors are currently in clinical development aimed at targeting additional subsets such as nucleophosmin 1 (NPM1) mutations which form up to 30% of acute myeloid leukemia. As observed with other targeted therapies for cancer, on-target resistance mutations emerged in advanced cases following monotherapy. Therefore, combination strategies incorporating menin inhibitors are needed to improve durability and depth of remission.
    DOI:  https://doi.org/10.1158/2643-3230.BCD-24-0212
  13. Blood Adv. 2025 Aug 28. pii: bloodadvances.2025018034. [Epub ahead of print]
      
    DOI:  https://doi.org/10.1182/bloodadvances.2025018034