bims-hemali Biomed News
on Hematologic malignancies
Issue of 2025–04–20
twelve papers selected by
Alexandros Alexandropoulos, Γενικό Νοσοκομείο Αθηνών Λαϊκό
  1. Prognostic value of minimal residual disease detected by EuroFlow next-generation flow cytometry and next-generation sequencing in patients with multiple myeloma achieving complete response and receiving lenalidomide maintenance after autotransplant: a prospective comparison study.
  2. The decline of transplant for relapsed myeloma.
  3. How I individualize treatment for chronic-phase CML.
  4. DNMT3A mutations are unlikely to affect interferon alfa treatment outcomes in patients with polycythemia vera.
  5. Reduced venetoclax exposure to 7 days vs standard exposure with hypomethylating agents in newly diagnosed AML patients.
  6. Venetoclax based regimens in octogenarian CLL patients: efficacy, safety and comparison to BTKi in a multicenter cohort.
  7. A German multicenter real-world analysis of talquetamab in 138 patients with relapsed/refractory multiple myeloma.
  8. Comment on: "Switching TKIs during CML therapy is frequent, mostly driven by intolerance, and does not affect survival: a prospective Quebec registry study" by Busque et al.
  9. Discovery of XZ338, a highly potent BCL-XL degrader.
  10. Real-world treatment patterns and outcomes with oral azacitidine maintenance therapy in patients with acute myeloid leukemia.
  11. Introduction to a How I Treat series on myeloproliferative neoplasms.
  12. Complete Enzymatic Depolymerization of Polyethylene Terephthalate (PET) Plastic Using a Saccharomyces cerevisiae-Based Whole-Cell Biocatalyst.
  1. Haematologica. 2025 Apr 17.
    Prognostic value of minimal residual disease detected by EuroFlow next-generation flow cytometry and next-generation sequencing in patients with multiple myeloma achieving complete response and receiving lenalidomide maintenance after autotransplant: a prospective comparison study.
    Takeshi Yoroidaka, Hiroyuki Takamatsu, Ryota Urushihara, Mitsuhiro Itagaki, Satoshi Yoshihara, Kota Sato, Naoki Takezako, Shuji Ozaki, Kazuhito Suzuki, Kentaro Kohno, Tsuyoshi Muta, Morio Matsumoto, Yasushi Terasaki, Takeshi Yamashita, Shin-Ichi Fuchida, Jun Sakamoto, Tadao Ishida, Kenshi Suzuki, Hirokazu Murakami, Brian G M Durie, Kazuyuki Shimizu.
      Novel agents inducing deeper responses have improved the prognosis of patients with multiple myeloma (MM). To assess minimal residual disease (MRD) and stratify patients achieving complete response (CR), advanced technologies such as EuroFlow next-generation flow cytometry (NGF) and next-generation sequencing (NGS) are increasingly utilized. This prospective study evaluated responses in newly diagnosed MM patients undergoing autologous stem cell transplantation (ASCT) followed by lenalidomide maintenance therapy across multiple Japanese medical centers. Patients achieving CR or stringent CR within 100-365 days post-ASCT were included. MRD levels in the bone marrow were assessed using both NGF and NGS (cutoff: 1×10-5) at three time points: 100-365 days, 1 year, and 2 years post-ASCT. A total of 52 patients were analyzed. MRD levels determined by NGF and NGS showed a strong correlation (r = 0.9722, P < 0.0001). After a median follow-up of three years, the three-year progression-free survival (PFS) and overall survival (OS) rates were 76.5% (95% confidence interval [CI], 62.3%-85.9%) and 96.2% (95% CI, 85.5%-99.0%), respectively. Patients with sustained MRD negativity for >6 months demonstrated superior three-year PFS compared to those without sustained MRD negativity, as measured by both NGF (100% vs. 67.6%; hazard ratio [HR] 0.06; 95% CI, 0.0005-0.50; P < 0.007) and NGS (90.5% vs. 72.2%; HR 0.23; 95% CI, 0.06-0.94; P = 0.048). These findings highlighted a strong correlation in the MRD levels assessed by NGF and NGS and validated that sustained MRD negativity was significantly associated with prolonged PFS. (Trial registered at UMIN 000022238).
    DOI:  https://doi.org/10.3324/haematol.2025.287411
  2. Blood. 2025 Apr 17. 145(16): 1711-1712
    The decline of transplant for relapsed myeloma.
    Aurore Perrot, Cyrille Touzeau.
      
    DOI:  https://doi.org/10.1182/blood.2024028275
  3. Blood. 2025 Apr 16. pii: blood.2024026508. [Epub ahead of print]
    How I individualize treatment for chronic-phase CML.
    Ariel Monet Leyte-Vidal, Neil P Shah.
      Chronic myeloid leukemia (CML) has served as a paradigm for the development of effective initial and next-generation targeted therapies. The availability of five effective and generally well-tolerated BCR::ABL1 tyrosine kinase inhibitors for the treatment of newly diagnosed chronic phase CML offers patients and their treating physicians a welcome luxury of choice. The long-term outlook for newly diagnosed chronic phase CML patients is excellent, with expected survival similar to age-matched controls. However, most patients are expected to require lifelong treatment. As a result, important considerations when choosing frontline treatment include not only treatment efficacy, but also response durability, tolerability, maximizing quality of life, avoidance of serious and irreversible toxicities, the ease of treatment administration and increasingly, the cost of treatment to the patient as well as to society.
    DOI:  https://doi.org/10.1182/blood.2024026508
  4. Blood. 2025 Apr 15. pii: blood.2024027528. [Epub ahead of print]
    DNMT3A mutations are unlikely to affect interferon alfa treatment outcomes in patients with polycythemia vera.
    Ghaith Abu-Zeinah, Katie Erdos, Neville Lee, Yara Ganom, Christoph Klade, Kurt Krejcy, Heinz Gisslinger, Richard T Silver, Joseph Michael Scandura.
      DNMT3A mutations in polycythemia vera (PV) patients were heterogenous and not enriched in interferon-alpha (IFN)-treated patients. DNMT3A mutations had no detectable impact on hematologic response, molecular response or survival outcomes.
    DOI:  https://doi.org/10.1182/blood.2024027528
  5. Blood Cancer J. 2025 Apr 17. 15(1): 68
    Reduced venetoclax exposure to 7 days vs standard exposure with hypomethylating agents in newly diagnosed AML patients.
    Christophe Willekens, Alexandre Bazinet, Samy Chraibi, Alex Bataller, Justine Decroocq, Naszrin Arani, Benjamin Carpentier, Caitlin Rausch, Delphine Lebon, Abhishek Maiti, Nicolas Gauthier, Nicholas Short, Sarah Bonnet, Koji Sasaki, Sabine Khalife-Hachem, Mahesh Swaminathan, Jean-Baptiste Micol, Florence Pasquier, Christophe Marzac, Damien Roos-Weil, Laurent Pascal, Naval Daver, Tapan Kadia, Didier Bouscary, Farhad Ravandi, Arnaud Pages, Hagop Kantarjian, Stéphane De Botton, Courtney DiNardo.
      Hypomethylating agent (HMA) plus venetoclax (VEN) regimens are standard of care in patients with acute myeloid leukemia (AML) ineligible for intensive chemotherapy. While the VEN label recommends continuous 28-day cycles, shortened VEN durations may induce similar response rates and improve tolerability. It is unknown how a VEN exposure reduced to 7 days during cycles compares to standard HMA + VEN. We retrospectively compared newly diagnosed AML patients treated with azacitidine (AZA) x 7 days plus VEN x 7 days ("7 + 7" regimen) from the first cycle (n = 82) vs patients treated with standard dose HMA + VEN (std-HMA/VEN) (n = 166). Composite complete remission rate was similar between cohorts (72% vs 72%; p = 0.95) and a median number of cycles to best response was 2 with "7 + 7" vs 1 with std-HMA/VEN (p = 0.03). Concerning toxicity, platelet transfusion rates during cycle 1 as well as early mortality at 8-weeks (6% vs 16%; p = 0.03) were lower in "7 + 7" cohort. Finally, the median OS was 11.2 months (2-year 28%) with "7 + 7" vs 10.3 months (2-year 34%) with "std-HMA/VEN" (p = 0.75). In summary, acknowledging limitations of a retrospective comparison, a shortened course of VEN used for 7 days every 28 days resulted in similar response rates and survival when compared to standard VEN exposure.
    DOI:  https://doi.org/10.1038/s41408-025-01269-x
  6. Blood Adv. 2025 Apr 16. pii: bloodadvances.2025015818. [Epub ahead of print]
    Venetoclax based regimens in octogenarian CLL patients: efficacy, safety and comparison to BTKi in a multicenter cohort.
    Andrea Serafin, Alessandro Cellini, Enrica Antonia Martino, Federica Mazzetto, Francesco Angotzi, Anna Maria Frustaci, Monia Marchetti, Riccardo Moia, Alessandro Sanna, Costantino Riemma, Francesca Cibien, Alessandro Noto, Enrico Lista, Myriam Foglietta, Candida Vitale, Vanessa Innao, Martina Bullo, Ester Lovato, Isacco Ferrarini, Costanza Andriola, Laura Ballotta, Idanna Innocenti, Alberto Fresa, Gianmarco Favrin, Marzia Varettoni, Elisa Santambrogio, Lorella Orsucci, Raffaella Pasquale, Massimo Moratti, Luca Laurenti, Marta Coscia, Paolo Sportoletti, Roberto Marasca, Francesca Romana Mauro, Caterina Patti, Enrico Derenzini, Lydia Scarfò, Paolo Ghia, Antonio Cuneo, Alessandra Tedeschi, Livio Trentin, Massimo Gentile, Andrea Visentin.
      Octogenarians represent a significant fraction of patients with Chronic Lymphocytic Leukemia (CLL) but, despite the prevalence of the disease in this age group, limited data is available on the safety and efficacy of novel drugs in this subgroup. We conducted a multicenter, retrospective study enrolling 120 octogenarian patients who received Venetoclax (Ven) regimens in any line. Regarding efficacy, we found Ven to perform similarly to what is reported in younger patients with CLL, with an overall response rate of 91%, a complete response rate of 44% and median progression-free survival of 44 months. Concerning safety, we report a toxicity profile that is consistent with previous reports, with most high-grade adverse events being of hematological or infectious nature, as 37% and 22% of patients experienced neutropenia or infections of grade 3 or higher. As part of our study, we compared the safety and efficacy data we collected with those obtained in a comparable BTKi-treated population. We found that these two treatments were comparable in terms of overall efficacy, barring a higher rate of complete responses with Ven; safety profiles were different among the two groups as BTKi-treated patients had more cardiovascular toxicities (26% vs 4%) and Ven-treated subjects experienced more infectious events (82% vs 49%). Our data points out that Ven-based regimens are safe and effective in octogenarian patients with CLL despite their higher clinical complexity and comorbidity burden and should provide some basis for the design of prospective studies to further evaluate the optimal treatment regimen in this patient population.
    DOI:  https://doi.org/10.1182/bloodadvances.2025015818
  7. Hemasphere. 2025 Apr;9(4): e70114
    A German multicenter real-world analysis of talquetamab in 138 patients with relapsed/refractory multiple myeloma.
    Jan H Frenking, Christine Riedhammer, Raphael Teipel, Florian Bassermann, Britta Besemer, Moritz Bewarder, Jan Braune, Annamaria Brioli, Franziska Brunner, Maria Dampmann, Roland Fenk, Deniz N Gezer, Sarah Goldman-Mazur, Christine Hanoun, Marion Högner, Cyrus Khandanpour, Katja Kolditz, Igor Kos, Jan Krönke, Miriam Kull, Valentine Landrin, Theo Leitner, Maximilian Merz, Ivana von Metzler, Christian S Michel, Carsten Müller-Tidow, Sebastian Theurich, Karolin Trautmann-Grill, Ralph Wäsch, Romans Zukovs, Mathias Hänel, Leo Rasche, Marc S Raab.
      Bispecific T-cell engagers (BTCEs) represent a paradigm shift in the treatment of relapsed/refractory multiple myeloma (RRMM). Talquetamab, a GPRC5DxCD3 BTCE, has shown promising results in the MonumenTAL-1 trial and was recently approved by the Food and Drug Administration and the European Medicines Agency. However, treatment under real-world conditions may not represent patient characteristics in clinical trials with restricted enrollment criteria. We performed a retrospective real-world analysis including 138 RRMM patients treated with talquetamab at 21 German centers. Of evaluable patients, 43% had ISS stage III, 37% had extraosseous disease, and 48% had high-risk cytogenetics. After a median of six prior therapy lines, 58% of patients would not have been eligible for MonumenTAL-1. With a median follow-up of 8.2 months, we observed an overall response rate of 65% and a median progression-free survival of 6.4 months (95% confidence interval 5.1-9.0). Prior BTCE exposure, ISS stage III, extraosseous disease, and penta-drug refractory disease were associated with unfavorable outcomes. Grade ≥ 3 cytokine release syndrome and neurotoxicity occurred in 5.1% and 1.5% of patients, respectively. In summary, our real-world study confirms the efficacy and safety of talquetamab, despite a high proportion of patient- and disease-related risk factors. These results support its use as bridging or long-term treatment, even in advanced stages.
    DOI:  https://doi.org/10.1002/hem3.70114
  8. Blood Cancer J. 2025 Apr 19. 15(1): 70
    Comment on: "Switching TKIs during CML therapy is frequent, mostly driven by intolerance, and does not affect survival: a prospective Quebec registry study" by Busque et al.
    Ahmet Emre Eşkazan.
      
    DOI:  https://doi.org/10.1038/s41408-025-01288-8
  9. Eur J Med Chem. 2025 Apr 15. pii: S0223-5234(25)00389-7. [Epub ahead of print]291 117624
    Discovery of XZ338, a highly potent BCL-XL degrader.
    Xuan Zhang, Dinesh Thummuri, Wanyi Hu, Xingui Liu, Peiyi Zhang, Shuo Zhou, Daohong Zhou, Guangrong Zheng.
      BCL-XL is a crucial anti-apoptotic protein involved in tumorigenesis and resistance to cancer chemotherapy. Transitioning from conventional inhibitors to PROTAC degraders has shown promising potential, particularly in minimizing the on-target thrombocytopenia linked to BCL-XL inhibition. However, reported BCL-XL degraders were mostly derived from BCL-XL/BCL-2 dual inhibitor ABT-263, which also inhibits or degrades BCL-2 and can potentially cause neutropenia when combined with conventional chemotherapy as seen with ABT-263 in the clinic. The goal of the present study is to develop a highly specific BCL-XL degrader without BCL-2 inhibition/degradation. In this study, XZ338, a highly potent and selective BCL-XL degrader derived from BCL-XL specific inhibitor A-1331852, was generated. XZ338 is 70-fold more potent than ABT-263 against MOLT-4 T-ALL cells, with over 89-fold selectivity for MOLT-4 cells over human platelets.
    Keywords:  Apoptosis; BCL-2; BCL-X(L); PROTAC; Platelet
    DOI:  https://doi.org/10.1016/j.ejmech.2025.117624
  10. Cancer. 2025 Apr 15. 131(8): e35845
    Real-world treatment patterns and outcomes with oral azacitidine maintenance therapy in patients with acute myeloid leukemia.
    Brian Leber, Marcia T Ruiz, Hany Elgendy, Filippa Pettersson, Thomas Prebet, Carlos E Vigil, Rohan C Parikh, Siddhi Korgaonkar, Fareedat Bello, Keith L Davis, Lona Gaugler, Maria Strocchia, Jan Sieluk, Yeran Li, Andre C Schuh.
       INTRODUCTION: This study describes baseline and clinical characteristics, treatment patterns, survival, and safety outcomes of patients with acute myeloid leukemia (AML) who received oral azacitidine (oral-AZA) maintenance therapy in Canada following its approval in 2021.
    METHODS: A retrospective, observational medical record review was conducted of patients with AML in remission after induction therapy and who initiated treatment with oral-AZA between March 2021 and July 2023 in Canada. Real-world relapse-free survival and overall survival outcomes were estimated using Kaplan-Meier methodology.
    RESULTS: Data from 119 patients were analyzed. The median age at oral-AZA initiation was 62.5 years. Most patients had favorable (39.5%) or intermediate (39.5%) genetic risk per the 2017/2022 European LeukemiaNet classification. Nearly all patients (99.2%) received cytarabine-based induction regimens. A total of 55.5% of patients received consolidation therapy, with a median of two cycles. After a median follow-up of 9.4 months, 68.1% of all patients were still receiving oral-AZA at last follow-up. After oral-AZA treatment, 21.0% of patients relapsed. Rates of real-world relapse-free survival and overall survival at 12 months from oral-AZA initiation were 66.9% and 74.5%, respectively. During oral-AZA treatment, 67.2% of patients experienced ≥1 adverse event. Concomitant antiemetic treatment was received by 78.2% of patients.
    CONCLUSION: These findings provide real-world evidence further supporting the use of oral-AZA as a standard-of-care maintenance therapy in current routine clinical practice for patients with AML in remission who do not receive hematopoietic stem cell transplantation. These results may inform a broader clinical audience because of the inclusion of patients with diverse demographic and clinical characteristics.
    Keywords:  acute myeloid leukemia; maintenance therapy; oral‐AZA; real‐world evidence
    DOI:  https://doi.org/10.1002/cncr.35845
  11. Blood. 2025 Apr 17. 145(16): 1707-1709
    Introduction to a How I Treat series on myeloproliferative neoplasms.
    Jason Gotlib.
      
    DOI:  https://doi.org/10.1182/blood.2025028401
  12. Environ Sci Technol Lett. 2025 Apr 08. 12(4): 419-424
    Complete Enzymatic Depolymerization of Polyethylene Terephthalate (PET) Plastic Using a Saccharomyces cerevisiae-Based Whole-Cell Biocatalyst.
    Siddhant Gulati, Qing Sun.
      Management of polyethylene terephthalate (PET) plastic waste remains a challenge. PET-hydrolyzing enzymes (PHEs) such as IsPETase and variants like FAST-PETase demonstrate promising PET depolymerization capabilities at ambient temperatures and can be utilized to recycle and upcycle plastic waste. Whole-cell biocatalysts displaying PHEs on their surface offer high efficiency, reusability, and stability for PET depolymerization. However, their efficacy in fully breaking down PET is hindered by the necessity of two enzymes: PETase and MHETase. Current whole-cell systems either display only one enzyme or struggle with performance when displaying larger enzymes such as the MHETase-PETase chimera. We developed a Saccharomyces cerevisiae-based whole-cell biocatalyst for complete depolymerization of PET into its constituent monomers with no accumulation of intermediate products. Leveraging a cellulosome-inspired trifunctional protein scaffoldin displayed on the yeast surface, we co-immobilized FAST-PETase and MHETase, forming a multi-enzyme cluster. This whole-cell biocatalyst achieved complete PET depolymerization at 30 °C, yielding 4.95 mM terephthalic acid (TPA) when tested on a PET film. Furthermore, we showed improved PET depolymerization ability by binding FAST-PETase at multiple sites on the scaffoldin. The whole cells had the added advantage of retained activity over multiple reusability cycles. This breakthrough in complete PET depolymerization marks a step toward a circular plastic economy.
    DOI:  https://doi.org/10.1021/acs.estlett.5c00190
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