bims-hemali Biomed News
on Hematologic malignancies
Issue of 2025–04–13
sixteen papers selected by
Alexandros Alexandropoulos, Γενικό Νοσοκομείο Αθηνών Λαϊκό
  1. Venetoclax-based treatment combinations in relapsed/refractory multiple myeloma: practice patterns and impact of secondary cytogenetic abnormalities on outcomes.
  2. SMAC mimetics in action in chronic myeloid leukemia.
  3. Tyrosine kinase inhibitors modulate the expression of peroxiredoxins 1 and 2 in chronic myeloid leukemia cells.
  4. Allogeneic NK cells with a bispecific innate cell engager in refractory relapsed lymphoma: a phase 1 trial.
  5. A phase 1 trial of fully human BCMA CAR-T therapy for relapsed/refractory multiple myeloma with 5-year follow-up.
  6. Asciminib in combination with imatinib, nilotinib, or dasatinib in patients with chronic myeloid leukemia in chronic or accelerated phase: phase 1 study final results.
  7. Case Report: Decitabine and venetoclax sequentially followed by FLAG-Ida and venetoclax with immediate allogeneic stem cell transplantation in newly diagnosed acute myeloid leukemia with chromosome 3 inversion/MECOM rearrangement.
  8. Clinical applicability of the ELN2020 criteria for tyrosine kinase inhibitor discontinuation in chronic myeloid leukemia: insights from a multicenter retrospective study in real-world practice.
  9. Olverembatinib in chronic myeloid leukemia-Review of historical development, current status, and future research.
  10. Optimal MRD-based end point to support response-adapted treatment cessation in newly diagnosed multiple myeloma.
  11. Doubling down: the new deal in the clinical management of double-refractory chronic lymphocytic leukaemia.
  12. Molecular response with asciminib 20 mg QD in a patient intolerant to multiple TKIs.
  13. Asciminib monotherapy in patients with chronic myeloid leukemia in chronic phase without BCR::ABL1T315I treated with at least 2 prior TKIs: Phase 1 final results.
  14. Synergistic effect of asciminib with reduced doses of ponatinib in human Ph + myeloid leukemia with the T315M mutation.
  15. Novel drug combinations for newly diagnosed multiple myeloma: how can we improve on current regimens?
  16. Advancing MRD Detection in Multiple Myeloma: Technologies, Applications, and Future Perspectives.
  1. Blood Cancer J. 2025 Apr 04. 15(1): 57
    Venetoclax-based treatment combinations in relapsed/refractory multiple myeloma: practice patterns and impact of secondary cytogenetic abnormalities on outcomes.
    Abiola Bolarinwa, Madhu Nagaraj, Saurabh Zanwar, Nadine Abdallah, P Leif Bergsagel, Moritz Binder, Francis Buadi, Saurabh Chhabra, Joselle Cook, David Dingli, Angela Dispenzieri, Morie A Gertz, Wilson Gonsalves, Suzanne Hayman, Prashant Kapoor, Taxiarchis Kourelis, Nelson Leung, Yi Lin, Eli Muchtar, Ricardo Parrondo, Vivek Roy, Taimur Sher, Mustaqeem Siddiqui, Rahma Warsame, Amie Fonder, Miriam Hobbs, Yi Lisa Hwa, Michelle Rogers, Udit Yadav, J Erin Wiedmeier-Nutor, Linda B Baughn, S Vincent Rajkumar, Rafael Fonseca, Sikander Ailawadhi, Shaji Kumar.
      Venetoclax (Ven), a BCL-2 inhibitor, has demonstrated efficacy in patients with relapsed/refractory multiple myeloma (RRMM) harboring a t(11;14) and/or elevated BCL-2 expression. However, data from clinical trial remain inconclusive. This retrospective study evaluated the efficacy and safety of Ven-based therapies in 232 MM patients without concurrent AL amyloidosis treated at Mayo Clinic sites between Jan 2015 and Dec 2023. The median age was 62 years, with a median of 3 prior lines of therapy. Among the cohort, 82% had t(11;14), and elevated BCL-2 expression was identified in 17 of 18 non-t(11;14) patients tested. Ven combinations included Ven-Dex (VenD; 48.3%), Proteasome Inhibitor-Ven (30.2%), and Daratumumab-Ven (19%) with other combinations making up the rest. The overall response rate was 57%; 64% for t(11;14) patients and 26% for non-t(11;14) patients. Median progression-free survival (PFS) was 9.4 months overall; 11.8 months for t(11;14) patients and 2.9 months for those without (p < 0.001). Among t(11;14) patients, the presence of del(17p) or 1q gain/amplification significantly reduced PFS to 7.7 months. Venetoclax-based regimens remain an important option for t(11;14) patients, but efficacy is limited in patients without a t(11;14). The presence of secondary high-risk cytogenetics imparts an inferior PFS.
    DOI:  https://doi.org/10.1038/s41408-025-01264-2
  2. Blood. 2025 Apr 10. 145(15): 1596-1597
    SMAC mimetics in action in chronic myeloid leukemia.
    Ali G Turhan.
      
    DOI:  https://doi.org/10.1182/blood.2024027994
  3. Leuk Res Rep. 2025 ;23 100508
    Tyrosine kinase inhibitors modulate the expression of peroxiredoxins 1 and 2 in chronic myeloid leukemia cells.
    Hiroshi Kazama, Yan-Hua Wang, Junji Tanaka.
      Chronic myeloid leukemia (CML) is characterized by the presence of the BCR::ABL1 fusion protein with active tyrosine kinase activity. The BCR::ABL1 fusion protein induces the production of reactive oxygen species (ROS). DNA damage caused by ROS is involved in the mechanism of CML progression. Antioxidant systems include peroxiredoxins (PRDXs), which play various roles in hematological malignancies. Although tyrosine kinase inhibitors (TKIs) are known to affect ROS production, their effects on the expression of the antioxidants PRDX1 and PRDX2 remain unclear; thus, we aimed to evaluate the effects of TKIs on the expression of these PRDXs and ROS levels in CML cells. We found that TKIs, such as imatinib, nilotinib, and dasatinib, increased the gene expression of PRDX2 in K562 cells; however, only dasatinib increased the cytoplasmic protein expression of PRDX2. Additionally, while TKIs reduced the gene expression of PRDX1 in contrast to that of PRDX2, dasatinib increased the cytoplasmic protein expression of PRDX1. This discrepancy was linked to post-translational regulation through SUMOylation in cooperation with dasatinib. Our results suggest that the antioxidants PRDX1 and PRDX2 could serve as potential targets for TKIs in the treatment of CML.
    Keywords:  Chronic myeloid leukemia; Dasatinib; Peroxiredoxin 1; Peroxiredoxin 2; Tyrosine kinase inhibitors
    DOI:  https://doi.org/10.1016/j.lrr.2025.100508
  4. Nat Med. 2025 Apr 04.
    Allogeneic NK cells with a bispecific innate cell engager in refractory relapsed lymphoma: a phase 1 trial.
    Yago Nieto, Pinaki Banerjee, Indreshpal Kaur, Rafet Basar, Ye Li, May Daher, Hind Rafei, Lucila N Kerbauy, Mecit Kaplan, David Marin, Lori Griffin, Melissa Barnett, Roland Bassett, Nadima Uprety, Rejeena Shrestha, Francia Reyes Silva, Sanjida Islam, Christina Ganesh, Zephanie Borneo, Jeremy Ramdial, Alejandro Ramirez, Chitra Hosing, Amin Alousi, Uday Popat, Muzaffar Qazilbash, Sairah Ahmed, Swaminathan Iyer, Tania P Sainz, Francisco Vega, Natalie W Fowlkes, Karenza Alexis, Michael Emig, Andreas Harstrick, Andre Overesch, Elizabeth J Shpall, Katayoun Rezvani.
      Outcomes of patients with CD30-positive (CD30+) lymphomas have improved with the advent of brentuximab vedotin (BV) and, in Hodgkin lymphoma, anti-PD1 checkpoint inhibitors (CPI). However, there is a need for new therapies for patients with tumors refractory to both BV and CPI, who face dismal outcomes. AFM13-a CD30/CD16A bispecific antibody-activates natural killer (NK) cells to kill CD30+ cells. Here we studied cord-blood-derived cytokine-preactivated and expanded NK cells precomplexed with AFM13 (AFM13-NK) in patients with CD30+ lymphoma refractory to BV and CPI. The primary endpoint of this phase 1 trial was to establish the safety and recommended phase 2 dose of AFM13-NK followed by intravenous AFM13 infusions. Secondary endpoints included the overall response rate and complete response (CR) rate, event-free survival and overall survival, and persistence of infused AFM13-NK cells. This is the final analysis of this trial; 42 heavily pretreated patients received 2 to 4 cycles of lymphodepletion followed by AFM13-NK cell infusion at 3 dose levels (106, 107 and 108 kg-1) and 3 weekly AFM13 infusions. No cytokine release syndrome, neurotoxicity or graft-versus-host disease was observed. The highest NK dose was established as the recommended phase 2 dose. Donor NK cells peaked in blood 1 day postinfusion, persisted up to 3 weeks and trafficked to tumor sites. The overall response and CR rates were 92.9% and 66.7%, respectively. At a median follow-up of 20 months, the 2-year event-free and overall survival rates were 26.2% and 76.2%, respectively. Eleven patients (6 with and 5 without consolidation) remained in CR at 14-40 months. This therapy showed encouraging preliminary safety and efficacy. ClinicalTrials.gov Identifier: NCT04074746 .
    DOI:  https://doi.org/10.1038/s41591-025-03640-8
  5. Blood. 2025 Apr 08. pii: blood.2024027681. [Epub ahead of print]
    A phase 1 trial of fully human BCMA CAR-T therapy for relapsed/refractory multiple myeloma with 5-year follow-up.
    Sherilyn A Tuazon, Andrew J Portuguese, Margot J Pont, Andrew J Cowan, Gabriel O Cole, Blythe D Sather, Xiaoling Song, Sushma Thomas, Brent L Wood, Michelle Lee Blake, Melissa G Works, Mazyar Shadman, Emily C Liang, Qian Wu, Jenna M Voutsinas, Ted A Gooley, Cameron J Turtle, Brian G Till, David G Coffey, David G Maloney, Stanley R Riddell, Damian J Green.
      FCARH143, an autologous BCMA-targeted CAR-T therapy which incorporates a fully human BCMA-specific scFv and 4-1BB costimulatory domain, was evaluated in a phase 1 trial (NCT03338972) for relapsed/refractory multiple myeloma (RRMM). Patients were stratified by bone marrow (BM) plasma cell involvement (10-30% or >30%) and received lymphodepleting chemotherapy followed by escalating CAR-T cell doses (50×106 to 450×106). The primary endpoint was safety; secondary endpoints were overall response rate (ORR), duration of response (DOR), and progression-free survival (PFS). Among 28 enrolled patients, all underwent leukapheresis and successful CAR-T manufacturing, though three (11%) did not proceed to infusion. The 25 treated patients (median age 64 years) had a median of eight prior therapies, 80% were triple-class refractory, and 44% had extramedullary disease (EMD). Cytokine release syndrome (CRS) occurred in 84% (8% grade 3-4, no grade 5), and neurotoxicity in 24% (12% grade 3, no grade 4-5). No treatment-related deaths occurred. At a median follow-up of 67.3 months, treated patients had an ORR of 100%, including a stringent complete response in 64%. Median PFS and overall survival (OS) were 15.5 and 32.1 months, respectively. In an intention-to-treat analysis (median follow-up 69.6 months), the ORR was 89.3%, and OS was 30.2 months. FCARH143 demonstrated potent anti-myeloma activity with a 100% response rate and manageable toxicity, independent of disease burden or cytogenetic risk. Further evaluation in high-risk RRMM is warranted.
    DOI:  https://doi.org/10.1182/blood.2024027681
  6. Leukemia. 2025 Apr 09.
    Asciminib in combination with imatinib, nilotinib, or dasatinib in patients with chronic myeloid leukemia in chronic or accelerated phase: phase 1 study final results.
    Jorge E Cortes, Fabian Lang, Delphine Rea, Andreas Hochhaus, Massimo Breccia, Yeow Tee Goh, Michael C Heinrich, Timothy P Hughes, Jeroen J W M Janssen, Philipp le Coutre, Hironobu Minami, Koji Sasaki, Daniel J DeAngelo, Gessami Sanchez-Olle, Nathalie Pognan, Meng Cao, Matthias Hoch, Michael J Mauro.
      Data from in vitro and animal studies suggest that asciminib, the first BCR::ABL1 inhibitor that Specifically Targets the ABL Myristoyl Pocket (STAMP), synergizes with adenosine triphosphate (ATP)-competitive tyrosine kinase inhibitors (TKIs) to prevent emergence of and overcome resistance. Combination therapy may provide new treatment options for patients with chronic myeloid leukemia (CML) with suboptimal responses to ATP-competitive TKI monotherapy. Preliminary analysis of asciminib combined with nilotinib, imatinib, or dasatinib in a phase 1 dose-escalation study suggested promising efficacy and safety for patients with CML in chronic phase or accelerated phase treated with prior ATP-competitive TKIs; herein, we present final results from the 3 combination therapy arms. Asciminib, in combination with ATP-competitive TKIs, demonstrated rapid efficacy offset by a decreased tolerability compared with asciminib monotherapy. Based on these safety, tolerability, and preliminary efficacy results, asciminib 40 mg twice daily (BID) plus nilotinib 300 mg BID, asciminib 40 or 60 mg once daily (QD) plus imatinib 400 mg QD, and asciminib 80 mg QD plus dasatinib 100 mg QD were identified as recommended doses for expansion. The maximum tolerated dose was reached at asciminib 60 mg QD plus imatinib 400 mg QD and was not reached with asciminib plus nilotinib or dasatinib.
    DOI:  https://doi.org/10.1038/s41375-025-02592-9
  7. Front Oncol. 2025 ;15 1530852
    Case Report: Decitabine and venetoclax sequentially followed by FLAG-Ida and venetoclax with immediate allogeneic stem cell transplantation in newly diagnosed acute myeloid leukemia with chromosome 3 inversion/MECOM rearrangement.
    Andrius Žučenka, Milvydė Tamutytė.
      The prognosis of MECOMr AML is poor, with a 5-year overall survival (OS) rate of less than 10%. This is mostly attributable to the low efficacy of all available therapies and high relapse rates even after allogeneic stem cell transplantation (alloSCT), which remains the only curative approach. We report upfront sequential alloSCT with venetoclax-based preconditioning as a safe and effective treatment for two newly diagnosed and fit MECOMr AML patients. The sequential alloSCT regimen consisted of triple therapy: preconditioning with decitabine and venetoclax on days 1-5 followed by FLAG-Ida and venetoclax on days 6-10. One or 3 days after preconditioning, the patients underwent busulfan-based myeloablative conditioning and HLA haploidentical or matched related donor stem cell infusion. One month after alloSCT, timely engraftment and complete remission were achieved. At the last follow-up, both patients were in good health and in MRD-negative complete remissions after 11 and 17 months after alloSCT, respectively. The safety and efficacy of upfront sequential alloSCT indicate the need to evaluate this approach for adverse risk of AML in clinical trials.
    Keywords:  FLAG-Ida; MECOM (MDS1 and EV1 complex locus); PubChem CID: 49846579); acute myeloid leukaemia (AML); allogeneic stem cell transplantation; hypomethylating agents; inv(3)(q21q26.2); venetoclax (ABT-199
    DOI:  https://doi.org/10.3389/fonc.2025.1530852
  8. Leuk Res. 2025 Apr 04. pii: S0145-2126(25)00049-9. [Epub ahead of print]152 107689
    Clinical applicability of the ELN2020 criteria for tyrosine kinase inhibitor discontinuation in chronic myeloid leukemia: insights from a multicenter retrospective study in real-world practice.
    Yuto Hibino, Shin Fujisawa, Katsumichi Fujimaki, Maki Hagihara, Hiroyuki Fujita, Masatsugu Tanaka, Kosuke Takayama, Takaaki Takeda, Ayako Matsumura, Taisei Suzuki, Yoshimi Ishii, Yuki Nakajima, Takuya Miyazaki, Hideaki Nakajima.
      The prognosis of chronic myeloid leukemia has significantly improved with the introduction of tyrosine kinase inhibitors (TKIs). However, indefinite TKI treatment can lead to adverse effects and high costs. Recent studies have suggested that treatment-free remission (TFR) is achievable in patients with a deep molecular response (DMR). The present multicenter, retrospective observational study conducted in Japan evaluated the applicability of the European LeukemiaNet (ELN) 2020 TKI discontinuation criteria, which recommend TKI therapy of ≥ 5 years with sustained MR4 for ≥ 3 years or MR4.5 for ≥ 2 years. A total of 100 patients who discontinued TKI therapy were analyzed, with 70 meeting the ELN2020 criteria. The overall 12-month TFR rate was 71.9 %. Univariate analysis showed that both the duration of DMR and TKI therapy were significantly associated with TFR, with hazard ratios (HR) of 0.305 and 0.450, respectively. Only DMR duration remained significant (HR 0.362) in multivariate analysis. Patients who lost MMR after TKI discontinuation rapidly re-achieved molecular response upon TKI resumption. The most common reason for TKI discontinuation was elective cessation, followed by adverse events, among which pleural effusion due to dasatinib was the most frequent. The results of this study, the first to assess the ELN2020 criteria in a Japanese cohort, suggest that the criteria are applicable in real-world clinical practice.
    Keywords:  Chronic myeloid leukemia; Deep molecular response; Treatment-free remission; Tyrosine kinase inhibitor
    DOI:  https://doi.org/10.1016/j.leukres.2025.107689
  9. Cancer. 2025 Apr 15. 131(8): e35832
    Olverembatinib in chronic myeloid leukemia-Review of historical development, current status, and future research.
    Hagop Kantarjian, Yifan Zhai, Vivian G Oehler, Omer Jamy, Paul B Koller, Fadi G Haddad, Koji Sasaki, Elias J Jabbour.
      Once considered an incurable disease with a poor prognosis (median survival, 3-6 years), chronic myeloid leukemia (CML) is now managed with a diverse clinical armamentarium that includes BCR::ABL1 tyrosine kinase inhibitors (TKIs), which have largely normalized life expectancy in most patients in the chronic phase of the disease (CML-CP). Clinical challenges remain, including ABL1 mutation-driven treatment resistance (under the selection pressures exerted by TKIs), as well as treatment intolerance, which can involve potentially serious arterial occlusive events. Olverembatinib is a third-generation TKI approved in China for TKI-resistant CML-CP and accelerated-phase CML with the T135I mutation, as well as for CML-CP resistant to or intolerant of first- and/or second-generation TKIs. Olverembatinib exhibits a broad coverage of ABL1 mutants, including the gatekeeper T315I variant and compound mutations. In preclinical models, olverembatinib inhibited multiple downstream protein kinases, which has potentially opened avenues for future management of other malignancies, including acute myeloid and lymphoid leukemias, gastrointestinal tumors, and others. The pharmacokinetic profile of olverembatinib is compatible with alternate-day dosing. In clinical trials, olverembatinib exerted potent antileukemic effects in heavily pretreated patients with CML, including those with ponatinib or asciminib resistance or intolerance, and was well tolerated. Future studies include the phase 3 registrational POLARIS-1 (NCT06051409; in patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia), POLARIS-2 (NCT06423911; in patients with CML with or without the T315I mutation), and POLARIS-3 (NCT06640361; in patients with succinate dehydrogenase-deficient gastrointestinal stromal tumors) clinical trials.
    Keywords:  chronic myeloid leukemia; efficacy; safety; third‐generation; tyrosine kinase inhibitor
    DOI:  https://doi.org/10.1002/cncr.35832
  10. Blood. 2025 Apr 07. pii: blood.2024027674. [Epub ahead of print]
    Optimal MRD-based end point to support response-adapted treatment cessation in newly diagnosed multiple myeloma.
    Smith Giri, Binod Dhakal, Natalie S Callander, Eva Medvedova, Kelly Godby, Bhagirathbhai Dholaria, Susan Bal, Gayathri Ravi, Saurabh Chhabra, Rebecca Silbermann, Luciano J Costa.
      The therapeutic success of first line quadruplet (QUAD) induction therapy and autologous stem cell transplantation (ASCT) has reinvigorated an interest in fixed-duration therapy, yet optimal short-term efficacy endpoint for treatment cessation is unknown. Using data from a phase II clinical trial and a prospective institutional database, we tested the predictive performance of 5 short-term efficacy endpoints among 221 patients who received QUAD+ASCT followed by treatment cessation if minimal residual disease (MRD by next generation sequencing) negative for two consecutive timepoints. Efficacy endpoints tested were IMWG-defined stringent complete response (sCR), MRD<10-5 (single datapoint), MRD<10-6, sustained MRD (S-MRD, two consecutive assessments at least 1 year apart) <10-5and S-MRD<10-6. We built five parallel Cox regression models for each efficacy endpoint with progression free survival (PFS) as the outcome. Best fitting models were determined using Akaike's information criterion (AIC) and Heagerty & Zheng C-index. The best fitting model (AIC 417.2, C-stat 0.757) was based on S-MRD<10-5 (HR=0.23, 95% C.I. 0.11-0.47). Similar results were seen for predicting risk of progression/MRD resurgence among 121 patients undergoing MRD-guided treatment cessation. S-MRD<10-5 is the best predictor of PFS and yields best predictive models for risk of MRD resurgence or progression in the setting of fixed duration therapy. NCT03224507.
    DOI:  https://doi.org/10.1182/blood.2024027674
  11. Blood. 2025 Apr 10. pii: blood.2024024893. [Epub ahead of print]
    Doubling down: the new deal in the clinical management of double-refractory chronic lymphocytic leukaemia.
    Brian T Grainger, Philip A Thompson, Chan Y Cheah.
      Targeted therapy with covalent Bruton tyrosine kinase inhibitors (cBTKi) and/or the B-cell lymphoma 2 (BCL-2) inhibitor venetoclax is now well-established in the first-line management of chronic lymphocytic leukemia (CLL). However, patients with 'double refractory' disease due to the acquired resistance to both drug classes represent an increasing clinical challenge for whom few well-tolerated and effective treatment options currently exist. The highly selective, non-covalent BTKi pirtobrutinib and CD19-directed chimeric antigen receptor T-cell therapy lisocabtagene maraleucel have both recently gained FDA approval for use in patients with CLL which has progressed following ≥2 prior lines, including a cBTKi and a BCL-2i. Additionally, novel BTK-directed therapies and T-cell engaging bispecific antibodies have achieved promising responses in pre-treated CLL in early phase clinical trials. Here, we review the mechanisms responsible for resistance to cBTKi and venetoclax in CLL, appraise recent evidence supporting the use of each of the novel and emerging agent classes and then suggest innovative treatment strategies incorporating these in patients with double-refractory disease, remaining cognizant of the variability of access to novel therapies and clinical trials.
    DOI:  https://doi.org/10.1182/blood.2024024893
  12. Ann Hematol. 2025 Apr 07.
    Molecular response with asciminib 20 mg QD in a patient intolerant to multiple TKIs.
    Ruth Stuckey, Laura Navarrete Bullón, Asunción Borrero Borrego, Violeta Vidal Ballester, Carlos Rodríguez-Medina, Alejandro Morales Curbelo, Leslie González Pinedo, Melissa Torres Ochando, Alvaro Veiga Vaz, María Del Mar Perera, Cristina Bilbao-Sieyro, Juan Francisco López Rodríguez, Adrián Segura-Díaz, María Teresa Gómez-Casares.
      This case highlights a young CML patient who achieved a major molecular response (MMR) after just four months with a subtherapeutic dose of asciminib. The patient could not tolerate full-dose asciminib, or the full dose of two previous tyrosine kinase inhibitors (TKI) due to myelotoxicity, but blood counts recovered rapidly upon TKI suspension and reduced dosing enabled sustained treatment. This is the second reported case of the use of 20 mg QD asciminib, four times below the recommended dose, and the first to demonstrate efficacy at this dose. The study emphasizes asciminib's potential for overcoming treatment challenges associated with multi-resistant/intolerant CML patients.
    Keywords:  Asciminib; Cytopenia; Subtherapeutic dosing; Tyrosine kinase inhibitors (TKIs)
    DOI:  https://doi.org/10.1007/s00277-025-06339-5
  13. Leukemia. 2025 Apr 09.
    Asciminib monotherapy in patients with chronic myeloid leukemia in chronic phase without BCR::ABL1T315I treated with at least 2 prior TKIs: Phase 1 final results.
    Andreas Hochhaus, Dong-Wook Kim, Jorge E Cortes, Koji Sasaki, Michael J Mauro, Timothy P Hughes, Massimo Breccia, Moshe Talpaz, Hironobu Minami, Yeow Tee Goh, Daniel J DeAngelo, Fabian Lang, Oliver Ottmann, Michael C Heinrich, Valle Gomez Garcia de Soria, Philipp le Coutre, Gessami Sanchez-Olle, Meng Cao, Nathalie Pognan, Shruti Kapoor, Matthias Hoch, Delphine Rea.
      Asciminib is the first approved BCR::ABL1 inhibitor that Specifically Targets the ABL Myristoyl Pocket (STAMP). The present final analysis of the phase 1, open-label, nonrandomized trial (NCT02081378) assessed the long-term safety, tolerability, and antileukemic activity of asciminib in 115 patients with chronic myeloid leukemia in chronic phase without the BCR::ABL1T315I mutation who received asciminib 10-200 mg twice daily (BID) or 80-200 mg once daily (cutoff: March 14, 2023). Median exposure duration was 5.9 (range, 0-8.4) years; 60.9% of patients continued receiving asciminib through post-trial access. Grade ≥3 adverse events (AEs) occurred in 88 patients (76.5%). AEs led to treatment discontinuation, dose adjustment/interruption, or additional therapy in 15 (13.0%), 74 (64.3%), and 106 (92.2%) patients, respectively. Most first-ever AEs, particularly hematologic AEs, presented within the first year and no new safety signals emerged. Of 56 patients who achieved major molecular response, 50 maintained the response by cutoff; the Kaplan-Meier-estimated probability of maintaining this response for ≥432 weeks ( ≈ 8.3 years) was 88% (95% confidence interval, 78.2-97.0%). The recommended dose for expansion was determined at 40 mg BID. With up to 8.4 years of treatment, asciminib continued to demonstrate long-term safety and efficacy in this population.
    DOI:  https://doi.org/10.1038/s41375-025-02578-7
  14. Int J Hematol. 2025 Apr 10.
    Synergistic effect of asciminib with reduced doses of ponatinib in human Ph + myeloid leukemia with the T315M mutation.
    Thao Nguyen, Daisuke Harama, Minori Tamai, Keiko Kagami, Chiaki Komatsu, Shin Kasai, Koshi Akahane, Kumiko Goi, Takeshi Inukai.
      In Philadelphia chromosome-positive (Ph +) leukemia, substitution of threonine at the 315 position of BCR::ABL1 with isoleucine (T315I) induces severe resistance to tyrosine kinase inhibitors (TKIs). Of clinical importance, the substitution of the baseline T315I mutation by methionine (I315M) was reported in a Ph + leukemia patient treated with ponatinib. The resultant T315M mutation induces severe TKI-resistance in a murine Ba/F3 model. Asciminib, an allosteric inhibitor of BCR::ABL1, is reportedly active in ponatinib-resistant patients with the T315I mutation. Although asciminib alone is not active in a murine Ba/F3 model with the T315M mutation, asciminib and ponatinib show synergistic activities. In the present study, we introduced the T315M mutation into the intrinsic BCR::ABL1 gene of two Ph + myeloid and one Ph + lymphoid leukemia cell lines using the CRISPR/Cas9 system to directly verify the utility of the combined asciminib and ponatinib in human models. All three T315M-acquired sublines were more resistant to TKIs including ponatinib than T315I-acquired sublines. Notably, asciminib exhibited a stronger synergistic effect with reduced doses of ponatinib in the T315M-acquired sublines of two myeloid cell lines, but not in the lymphoid cell line. This indicates that the combination of ponatinib and asciminib may have a clinical utility in human Ph + myeloid leukemia.
    Keywords:  CRISPR/Cas9; Philadelphia chromosome-positive leukemia; Synergistic effect; T315M mutation; Tyrosine kinase inhibitor resistance
    DOI:  https://doi.org/10.1007/s12185-025-03981-7
  15. Expert Rev Hematol. 2025 Apr 10.
    Novel drug combinations for newly diagnosed multiple myeloma: how can we improve on current regimens?
    Sofía Isabel Quezada-Ramírez, Luz Del Carmen Tarín-Arzaga, Andrés Gómez-De León, David Gómez-Almaguer.
       INTRODUCTION: Multiple myeloma (MM) therapy has greatly evolved over the last decade. Immunomodulators and anti-CD38 antibodies have reshaped the therapeutic landscape. Nevertheless, relapses occur with worsening prognosis each relapse. Achieving deep responses in first-line treatment is key to reducing future disease burden.
    AREAS COVERED: To advance patient outcomes, current regimens must be continuously refined through personalization, incorporation of biomarkers to guide therapy, and novel drugs. This review aims to assess existing therapies and investigate how integrating novel drug combinations and biomarker-driven approaches can improve efficacy and tolerability for newly diagnosed multiple myeloma (NDMM) patients. Meta-analysis, systematic reviews, original articles and real-world studies were included in this review. Databases searched included PubMed, Scopus, and Google Scholar from inception until February 2025.
    EXPERT OPINION: Discerning the best therapy sequence is a challenge for NDMM individuals. Minimal residual disease assessment is becoming a pivotal tool for guiding therapeutic approaches to enhance outcomes and tolerability. Emerging evidence supports early use of potent therapies - such as next-generation anti-CD38 antibodies and CELMoDs - to achieve deeper, more durable responses and possibly delay relapses. Immunotherapies like bispecific antibodies and CAR-T cells are also being explored in front-line settings, though reducing their infectious complications is still under investigation.
    Keywords:  Anti-CD38 antibodies; minimal residual disease; multiple myeloma; newly diagnosed multiple myeloma; novel drugs; quadruplet regimens; treatment-naïve multiple myeloma; triplet regimens
    DOI:  https://doi.org/10.1080/17474086.2025.2490764
  16. Am J Clin Oncol. 2025 Apr 11.
    Advancing MRD Detection in Multiple Myeloma: Technologies, Applications, and Future Perspectives.
    Binbin Chen, Qiongqiong Pan, Yuqing Dong.
      Multiple myeloma (MM) is a malignant hematologic tumor of plasma cells that presents significant challenges in treatment and management. Despite the advent of novel therapies in recent years, which have improved patient outcomes, complete eradication of the disease remains an elusive goal. This underscores the critical need for in-depth research and ongoing innovation to tackle MM. Minimal residual disease (MRD) detection has emerged as a vital tool for evaluating treatment efficacy and predicting prognosis in MM patients, garnering extensive attention and application in recent years. This paper provides a comprehensive review of recent advancements in major MRD detection methods for MM patients, including multiparametric flow cytometry (MFC), allele-specific oligonucleotide real-time quantitative PCR (ASO-qPCR), and next-generation sequencing (NGS). It delves into the clinical applications of MRD detection, anticipates future developments, and offers valuable insights for improving diagnostic and therapeutic strategies. Through persistent research and innovation, we hope to bring better therapeutic prospects to MM patients.
    Keywords:  flow cytometry; minimal residual disease detection; multiple myeloma; next-generation sequencing
    DOI:  https://doi.org/10.1097/COC.0000000000001197
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