bims-hemali Biomed News
on Hematologic malignancies
Issue of 2025–05–11
twenty-two papers selected by
Alexandros Alexandropoulos, Γενικό Νοσοκομείο Αθηνών Λαϊκό
  1. Lee HJ, Ramchandren R, Friedman J, et al. Brentuximab vedotin, nivolumab, doxorubicin, and dacarbazine for advanced-stage classical Hodgkin lymphoma. Blood. 2025;145(3):290-299.
  2. Asciminib remained superior vs bosutinib in late-line CML-CP after nearly 4 years of follow-up in ASCEMBL.
  3. Unusually Indolent CML: Absence of Complete Cytogenetic Response after 10 Years of Tyrosine Kinase Inhibitor Therapy.
  4. Real-World Efficacy Profile of Compassionate Use of Asciminib in an Italian, Multi-Resistant Chronic-Phase Chronic Myeloid Leukemia (CML-CP) Patient Population.
  5. Momelotinib in JAK2 inhibitor-naïve myelofibrosis: pros and cons.
  6. The evolving therapeutic revolution in adult acute lymphoblastic leukemia.
  7. Zanubrutinib is well tolerated and effective in CLL/SLL patients intolerant of ibrutinib/acalabrutinib: Updated results.
  8. GPX1 confers resistance to metabolic stress in BCR/ABL-T315I mutant chronic myeloid leukemia cells.
  9. Luskin MR, Murakami MA, Keating J, et al. Asciminib plus dasatinib and prednisone for Philadelphia chromosome-positive acute leukemia. Blood. 2025;145(6):577-589.
  10. Phosphatidylinositol 3-Kinase Inhibition and Allogeneic Stem Cell Transplantation Can Overcome Chemotherapy Resistance in Refractory Burkitt Lymphoma.
  11. Primary vitreoretinal lymphoma: diagnosis, treatment, and prognosis-a review of current knowledge and future directions.
  12. A multicenter study to assess efficacy, safety, and tolerability of ropeginterferon alfa-2b-njft in patients with essential thrombocythemia in the US and Canada: EXCEED-ET trial.
  13. Real-life experience of luspatercept in transfusion-dependent lower risk myelodysplastic syndrome patients.
  14. Favorable rates of cardiovascular events with stringent cardiovascular monitoring and a lowered dose of ponatinib as second line treatment in chronic phase chronic myeloid leukemia (CML-CP) patients failing or intolerant to first-line second generation tyrosine kinase inhibitor (TKI) treatment: Results of the prospective PONS trial.
  15. Patient-reported toxicity symptoms during tyrosine kinase inhibitor treatment in chronic myeloid leukemia: a systematic review and meta-analysis.
  16. The Role of Transplant for Philadelphia-positive B-cell Acute Lymphoblastic Leukemia in 2025.
  17. Identification of the distinct immune microenvironment features associated with progression following high dose melphalan and autologous stem cell transplant in multiple myeloma.
  18. Event-free survival in early polycythemia vera patients correlates with molecular response to ropeginterferon alfa-2b or hydroxyurea/best available therapy (PROUD-PV/CONTINUATION-PV).
  19. Targeting the Tumor and the Immune System in Smoldering Multiple Myeloma.
  20. Outcomes of the transformation to diffuse large B-cell lymphoma in hodgkin lymphoma and indolent B-cell non-Hodgkin lymphoma: a population-based study.
  21. BTK inhibitors and next-generation BTK-targeted therapeutics for B-cell malignancies.
  22. Targeting leukemic stem cell dormancy in NPM1c/FLT3-ITD-driven acute myeloid leukemia.
  1. Blood. 2025 May 08. 145(19): 2231
    Lee HJ, Ramchandren R, Friedman J, et al. Brentuximab vedotin, nivolumab, doxorubicin, and dacarbazine for advanced-stage classical Hodgkin lymphoma. Blood. 2025;145(3):290-299.
      
    DOI:  https://doi.org/10.1182/blood.2025029278
  2. Blood Adv. 2025 May 07. pii: bloodadvances.2025016042. [Epub ahead of print]
    Asciminib remained superior vs bosutinib in late-line CML-CP after nearly 4 years of follow-up in ASCEMBL.
    Michael J Mauro, Yosuke Minami, Andreas Hochhaus, Elza Lomaia, Sergey Voloshin, Anna Turkina, Dong-Wook Kim, Jane F Apperley, Jorge Cortes, Andre Abdo, Laura Maria Fogliato, Dennis Dong Hwan Kim, Philipp le Coutre, Susanne Saussele, Mario Annunziata, Timothy P Hughes, Naeem Chaudhri, Lynette Chee, Valentin Garcia-Gutierrez, Koji Sasaki, Carla Boquimpani, Shruti Kapoor, Noemi Espurz-Abad, Vishal Dhamal, Delphine Rea.
      The efficacy of and disease control afforded by tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia in chronic phase (CML-CP) has led to increased longevity and thus continued pursuit of alternative therapies that are efficacious and maximize tolerability. The 24- and 96-week analyses from ASCEMBL demonstrated superior efficacy, safety, and tolerability of asciminib compared with bosutinib in later-line therapy, meeting primary and key secondary objectives, respectively. With nearly 4 years of follow-up, data from ASCEMBL continued to demonstrate superior efficacy, better safety, and greater tolerability of asciminib compared with bosutinib. At week 156, the major molecular response (MMR) rates remained higher with asciminib (33.8%) than bosutinib (10.5%); the difference in MMR rates between arms, after adjusting for baseline major cytogenetic response, was 23.2% (95% CI, 13.14%-33.18%; 2-sided P<0.001). Asciminib continued to cause fewer grade ≥3 adverse events (AEs) (59.6% vs 68.4%) and AEs leading to treatment discontinuation (8.3% vs 27.6%) than bosutinib. This updated analysis also includes patients who switched to asciminib due to lack of efficacy with bosutinib. Two of 25 patients who switched achieved MMR by the end of study, suggesting that earlier incorporation of asciminib, before other TKIs, may improve responses, albeit modestly. These long-term results further solidify asciminib as the therapy of choice for patients with CML-CP previously treated with ≥2 prior TKIs. This trial was registered at ClinicalTrials.gov as NCT03106779.
    DOI:  https://doi.org/10.1182/bloodadvances.2025016042
  3. Clin Lymphoma Myeloma Leuk. 2025 Apr 17. pii: S2152-2650(25)00143-0. [Epub ahead of print]
    Unusually Indolent CML: Absence of Complete Cytogenetic Response after 10 Years of Tyrosine Kinase Inhibitor Therapy.
    Qiudan Shen, Fadi G Haddad, Elias J Jabbour, Guilin Tang, Hong Fang, Meng Liu, Aileen Y Hu, Wei Wang, Pei Lin, Ghayas C Issa, Hagop M Kantarjian, L Jeffrey Medeiros, Shimin Hu.
       BACKGROUND: With BCR::ABL1 tyrosine kinase inhibitor (TKI) therapy, most patients with chronic-phase chronic myeloid leukemia (CML-CP) can achieve complete cytogenetic response (CCyR) within 6 months of therapy. However, no studies have investigated patients who do not achieve CCyR yet maintains stable disease on long-term TKI treatment. Here we investigated 30 CML-CP patients who did not achieve CCyR but remained free of blastic progression for at least 10-year while on TKI therapy.
    MATERIALS AND METHODS: Patients diagnosed with CML-CP or accelerated phase who received at least 10 years of TKI treatment, did not achieve CCyR, yet remained free of blastic progression for a minimum of 10 consecutive years during treatment, were included.
    RESULTS: At TKI initiation, the median blast count in the bone marrow was 2%. During TKI therapy, 16 patients had additional chromosomal abnormalities (ACAs). The most common ACAs were +Ph (n = 9) and +8 (n = 8), mostly transient, while high-risk ACAs were less common (n = 3). BCR::ABL1 kinase domain mutations were detected in 20 patients, 12 patients having a single mutation, mostly transient, and 8 having multiple mutations, which were mostly persistent cross TKI therapies. After a median of 4 TKI lines, the best responses included complete hematologic response (CHR) (n = 15), minor cytogenetic response (n = 2), partial cytogenetic response (n = 10), and major molecular response beyond the 10-year period without CCyR (n = 3). Among 15 patients who achieved a response better than CHR, 14 eventually lost their response. After a median follow-up of 245 months from TKI initiation, 6 patients progressed to blast phase after a median of 165 months.
    CONCLUSION: Despite not achieving CCyR, most patients in this cohort maintained long-term stable disease. With careful monitoring and individualized TKI treatment, long-term survival may still be achievable in some non-CCyR responders who do not opt for allogenic stem cell transplantation.
    Keywords:  ABL1 mutation; Additional chromosomal abnormality; Blasts phase; Chronic myeloid leukemia; Chronic phase
    DOI:  https://doi.org/10.1016/j.clml.2025.04.012
  4. Hematol Oncol. 2025 May;43(3): e70101
    Real-World Efficacy Profile of Compassionate Use of Asciminib in an Italian, Multi-Resistant Chronic-Phase Chronic Myeloid Leukemia (CML-CP) Patient Population.
    Massimo Breccia, Antonella Russo Rossi, Valentina Giai, Bruno Martino, Carmen Fava, Mario Annunziata, Elisabetta Abruzzese, Gianni Binotto, Claudia Baratè, Aurelio Pio Nardozza, Alessandra Misto, Paola Coco, Valeria Calafiore, Maria Cristina Carraro, Federica Cattina, Francesco Cavazzini, Maria Teresa Corsetti, Lara Crucitti, Monica Crugnola, Ambra Di Veroli, Paolo Ditonno, Anna Ermacora, Felicetto Ferrara, Angelo Genua, Antonella Gozzini, Stefana Impera, Alessandra Iurlo, Luciano Levato, Luigia Luciano, Maria Cristina Miggiano, Marco De Gobbi, Marco Santoro, Barbara Scappini, Anna Rita Scortechini, Andrea Patriarca, Serena Rosati, Sabina Russo, Rosaria Sancetta, Grazia Sanpaolo, Teresa Maria Santeramo, Silvia Sibilla, Federica Sorà, Paolo Sportoletti, Fabio Stagno, Elena Trabacchi, Fausto Castagnetti.
      Chronic myeloid leukemia (CML) patients who have experienced failure and/or intolerance to multiple lines of treatment have limited therapeutic possibilities. Asciminib is a first-in-class tyrosine kinase inhibitor (TKI) that inhibits the ABL Myristoyl Pocket (STAMP or Specifically Targeting the ABL Myristoyl Pocket) within the BCR::ABL1 oncoprotein. This retrospective Italian analysis reports the efficacy and safety outcomes of asciminib in treating 77 CML patients in chronic phase (CML-CP) within a compassionate use setting. Patients were heavily pretreated with a median of 3 TKIs (55.8% had prior ponatinib exposure). Overall, 57.1% and 42.9% patients switched to asciminib because of resistance and intolerance, respectively. Asciminib maintained or improved molecular responses (MRs) in most patients: as best response, 41 patients (53%) achieved a MR3 or better, with 25 patients (32.5%) reaching deep molecular response (DMR). Greater percentages of intolerant patients achieved MR compared with resistant patients, although the probability of reaching at least a MR3 was not significant between the two groups (p = 0.116). Patients with the T315I mutation responded to asciminib, while ponatinib pre-treated patients showed lower MR improvements compared to naïve patients and had a lower probability to reach a MR3 versus naïve patients (p = 0.0262). These results highlight asciminib remarkable tolerability and efficacy in real-world CML-CP patient population, including heavily pretreated patients, those intolerant and resistant to previous TKIs, and presenting several comorbidities. TRAIL REGISTRATION: The identification code for the MAP is CABL001AIT01M.
    Keywords:  TKI resistance/intolerance; asciminib; chronic myeloid leukemia in chronic phase (CML‐CP); major molecular response (MMR); real‐world; tyrosine kinase inhibitor (TKI)
    DOI:  https://doi.org/10.1002/hon.70101
  5. Blood Cancer J. 2025 May 07. 15(1): 91
    Momelotinib in JAK2 inhibitor-naïve myelofibrosis: pros and cons.
    Naseema Gangat, Ayalew Tefferi.
      
    DOI:  https://doi.org/10.1038/s41408-025-01302-z
  6. Cancer. 2025 May 15. 131(10): e35872
    The evolving therapeutic revolution in adult acute lymphoblastic leukemia.
    Hagop Kantarjian, Nitin Jain, Mark R Litzow, Selina M Luger, Cristina Papayannidis, Josep-Maria Ribera, Nicholas J Short, Helen T Chifotides, Elias Jabbour.
      The past decade has witnessed remarkable advances in deciphering the pathophysiology of acute lymphoblastic leukemia (ALL) and in developing novel targeted therapies. Basic research and genomic mapping have identified new prognostic biomarkers, targets, and ALL subtypes (e.g., Philadelphia-like ALL). The ongoing therapeutic revolution in ALL is driven by the addition to the treatment arsenal of therapies that target the ABL fusions, like the BCR::ABL1 tyrosine kinase inhibitors, as well as novel agents that target CD19 and CD22: the CD22 antibody-drug conjugate inotuzumab ozogamicin, the bispecific CD3/CD19 T-cell engager antibody blinatumomab, and CD19 chimeric antigen receptor T-cell therapies. These combinations have improved the long-term survival rates in B-cell ALL to 70%, and in Philadelphia chromosome-positive ALL to 80%-90%. The desired goals are to achieve cure rates comparable to those in pediatric ALL and to reduce or eliminate the need for prolonged intensive/maintenance chemotherapy and associated toxicities.
    Keywords:  acute lymphoblastic leukemia; blinatumomab; chemotherapy‐free regimen; chimeric antigen receptor (CAR) T‐cell therapy; immunotherapy; inotuzumab; ponatinib; tyrosine kinase inhibitor
    DOI:  https://doi.org/10.1002/cncr.35872
  7. Blood Adv. 2025 May 07. pii: bloodadvances.2024015493. [Epub ahead of print]
    Zanubrutinib is well tolerated and effective in CLL/SLL patients intolerant of ibrutinib/acalabrutinib: Updated results.
    Mazyar Shadman, John M Burke, Jennifer Cultrera, Habte A Yimer, Syed F Zafar, Jamal Misleh, Subramanya S Rao, Charles M Farber, Aileen Cleary Cohen, Hui Yao, Adam Idoine, Qi An, Ian W Flinn, Jeff P Sharman.
      Bruton tyrosine kinase (BTK) inhibitors such as ibrutinib revolutionized chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) treatment, although treatment-related toxicities limit the use of some BTK inhibitors. Zanubrutinib, a potent next-generation BTK inhibitor, has higher selectivity than ibrutinib or acalabrutinib. The ongoing phase 2, single-arm BGB-3111-215 study investigates the safety and efficacy of zanubrutinib in patients with B-cell malignancies who are intolerant of ibrutinib and/or acalabrutinib. Here, results in patients with CLL/SLL are presented. Patients received zanubrutinib 160 mg BID or 320 mg QD. With a 34.5-month median follow-up, 71 patients (ibrutinib intolerant only, n=44; acalabrutinib intolerant only, n=17; ibrutinib and acalabrutinib intolerant, n=10) received ≥1 zanubrutinib dose. On zanubrutinib, 54% (28/52) of ibrutinib-intolerant patients and 70% (19/27) of acalabrutinib-intolerant patients experienced no recurrence of intolerance AEs; 60% and 72% of intolerance AEs did not recur, respectively. Of recurrent ibrutinib-intolerance AEs, 64% were lower grade; 44% of acalabrutinib-intolerance AEs were lower grade. No intolerance AEs recurred at a higher grade with zanubrutinib. The most common recurrent ibrutinib-intolerance and acalabrutinib-intolerance AEs were fatigue and diarrhea, respectively. The most common TEAEs with zanubrutinib were fatigue (32%), COVID-19 (28%), and diarrhea and contusion (each 24%). Grade ≥3 TEAEs occurred in 61%, serious TEAEs in 32%, and TEAEs leading to discontinuation in 11%. Of 67 efficacy-evaluable patients, 94% experienced disease control: 30% had a best response of stable disease and 64% had a partial or complete response. These data demonstrate that patients intolerant of ibrutinib/acalabrutinib may benefit from switching to zanubrutinib therapy. ClinicalTrials.gov: NCT04116437.
    DOI:  https://doi.org/10.1182/bloodadvances.2024015493
  8. Cell Death Discov. 2025 May 09. 11(1): 229
    GPX1 confers resistance to metabolic stress in BCR/ABL-T315I mutant chronic myeloid leukemia cells.
    Jun-Dan Wang, Jin-Xing Wang, Zhi-Li Lin, Na Xu, Ling Zhang, Jia-Jun Liu, Rui Gao, Zi-Jie Long.
      Chronic myeloid leukemia (CML) harboring BCR/ABL-T315I mutation has been a challenging obstacle for targeted therapy due to the acquired resistance to tyrosine kinase inhibitor (TKI)-based therapy. Thus, it is especially urgent to investigate more effective therapeutic targets to overcome T315I-induced resistance. Here, we reported that BCR/ABL-T315I mutant CML cells possessed a long-term proliferative capacity and tolerance to metabolic stress. Importantly, we also found that selenoamino acid metabolism was increased in the bone marrows of BCR/ABL-T315I patients compared with non-T315I patients by GSEA from RNA-Seq data. Indeed, GPX1 was highly expressed in T315I mutant cells, while knockout of GPX1 significantly suppressed cell proliferation and triggered apoptosis under glucose-deprived condition. GPX1 knockout showed decreased cell metabolism signaling as well as mitochondrial gene expression by RNA-Seq. Mechanistically, GPX1 maintained mitochondrial activity and oxygen consumption rate (OCR), retaining mitochondrial redox homeostasis and oxidative phosphorylation (OXPHOS). Additionally, mercaptosuccinic acid (MSA), a GPX inhibitor, inhibited CML colony formation and induced cell apoptosis under glucose-free condition. Therefore, GPX1 is a promising therapeutic target to overcome drug resistance induced by the T315I mutation, which provides a novel approach for BCR/ABL-T315I CML treatment by disturbing mitochondrial OXPHOS.
    DOI:  https://doi.org/10.1038/s41420-025-02502-z
  9. Blood. 2025 May 08. 145(19): 2231
    Luskin MR, Murakami MA, Keating J, et al. Asciminib plus dasatinib and prednisone for Philadelphia chromosome-positive acute leukemia. Blood. 2025;145(6):577-589.
      
    DOI:  https://doi.org/10.1182/blood.2025029277
  10. J Hematol. 2025 Mar;14(2): 94-99
    Phosphatidylinositol 3-Kinase Inhibition and Allogeneic Stem Cell Transplantation Can Overcome Chemotherapy Resistance in Refractory Burkitt Lymphoma.
    Baldeep Wirk, Rajeswari Jayakumar, Jin Lim.
      Induction multiagent chemotherapy can cure 70% of adult Burkitt lymphoma patients. However, for the remaining patients, the majority will relapse either during induction chemotherapy or within 6 months after initial complete remission, as in our patient. In this life-threatening presentation where no standard therapy exists with a response rate to salvage chemotherapy of 0% and a median survival of 6 weeks, there is an urgent need for novel, effective approaches to overcome chemoresistance in Burkitt lymphoma. Our report demonstrates that targeting B-cell receptor signaling via the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway with copanlisib can overcome chemotherapy resistance and achieve complete remission in relapsed Burkitt lymphoma. This novel approach, followed by consolidation with allogeneic hematopoietic stem cell transplantation can provide durable complete remission by harnessing the immune graft-versus-lymphoma effect in chemoresistant Burkitt lymphoma.
    Keywords:  Allogeneic stem cell transplantation; Copanlisib; PI3K inhibitors; Refractory Burkitt lymphoma
    DOI:  https://doi.org/10.14740/jh2043
  11. Blood Sci. 2025 Jun;7(2): e00233
    Primary vitreoretinal lymphoma: diagnosis, treatment, and prognosis-a review of current knowledge and future directions.
    Si-Yu Wang, Suo-Wang Zhou, Jing Gao, Liang Wang.
      Primary vitreoretinal lymphoma (PVRL), a rare subtype of primary central nervous system lymphoma (PCNSL), can lead to permanent vision loss and central nervous system (CNS) involvement, resulting in a poor prognosis. PVRL often masquerades as uveitis, and its partial response to topical corticosteroids further complicates the diagnosis. The gold standard for diagnosis is cytological analysis; however, owing to its low sensitivity, cytokine profiling and genetic testing may serve as supplementary diagnostic tools. There is no universally accepted consensus regarding PVRL treatment protocols. Combined systemic high-dose intravenous methotrexate (MTX) and intravitreal therapy may help manage bilateral ocular lesions, although this combination's ability to delay CNS relapse remains controversial. For relapsed or refractory (R/R) PVRL patients aged <60 years, intensive consolidation chemotherapy followed by autologous stem cell transplantation may be considered. Novel targeted therapies such as ibrutinib and lenalidomide have demonstrated efficacy in R/R cases. Large-scale multicenter prospective studies are urgently needed to determine optimal treatment strategies.
    Keywords:  Autologous stem cell transplantation; Bruton’s tyrosine kinase inhibitors; Methotrexate; Primary central nervous system lymphoma; Primary vitreoretinal lymphoma
    DOI:  https://doi.org/10.1097/BS9.0000000000000233
  12. Front Med (Lausanne). 2025 ;12 1548590
    A multicenter study to assess efficacy, safety, and tolerability of ropeginterferon alfa-2b-njft in patients with essential thrombocythemia in the US and Canada: EXCEED-ET trial.
    Lucia Masarova, Brandi N Reeves, Firas El Chaer, Lynda Foltz, Tsewang Tashi, Ghaith Abu-Zeinah, Jennifer Lucas, Anna B Halpern, Dawn Maze, Albert Qin, Hana Safah, Fengshuo Lan, Casey L O'Connell, Swati Goel, Lindsay Rein, Bruno Fang, Joan How, Sunil Babu, Zhuoyan Li, Sonia Cerquozzi, Stephen T Oh, Anthony M Hunter, Nikolai Podoltsev, Pankit Vachhani, Abdulraheem Yacoub, Julia M Cunningham, Christopher Hillis, Salman Otoukesh, Oleh Zagrijtschuk, Henry Castro, Prithviraj Bose.
      
    Keywords:  clinical trial; complete hematologic response; essential thrombocythemia (ET); higher initial dose and accelerated titration (HDAC) regimen; molecular response; ropeginterferon alfa-2b-njft (ropeg)
    DOI:  https://doi.org/10.3389/fmed.2025.1548590
  13. Br J Haematol. 2025 May 05.
    Real-life experience of luspatercept in transfusion-dependent lower risk myelodysplastic syndrome patients.
    Anthi Bouchla, Sotirios G Papageorgiou, Ioannis Kotsianidis, Panagiotis Diamantopoulos, Eleni Gavriilaki, Eleni Bouronikou, Argiris Symeonidis, Panagiotis Zikos, Mustafa Cetiner, Efthymia Vlachaki, Akrivi Kostourou, Athanasios Galanopoulos, Eleftheria Hatzimichael, Elisavet-Christina Vervesou, Sinem Civriz Bozdağ, Nora-Athina Viniou, Dimitrios Christoulas, Maria Dellatola, Maria Papaioannou, Menelaos Papoutselis, Dimitra Vlachopoulou, Antonia Syrigou, Maria Mainou, Sofia Chatzileontiadou, Vasiliki Pappa.
      Luspatercept has been approved for the treatment of anaemia in transfusion-dependent (TD) patients with lower risk (LR) myelodysplastic syndromes (MDS) after erythroid-stimulated agent (ESA) failure, according to the results of the MEDALIST trial. In this multicentre retrospective study, we report efficacy and safety data of luspatercept administered in 98 TD LR-MDS patients after ESA failure. The percentage of patients that stopped luspatercept due to adverse events was comparable to that reported in the MEDALIST study. Furthermore, we observed that 44.3% patients who had completed 24 weeks of follow-up achieved transfusion independence lasting longer than 8 weeks, compared to 38% in the MEDALIST trial. These positive results may be attributed to the inclusion of patients with lower transfusion needs in our study. All responses were observed within 8 months since luspatercept onset and many were long-lasting, even in the high-transfusion burden patient group. In addition, response to luspatercept and the presence of less than two mutations independently predicted for longer overall survival. Overall, our results confirm luspatercept's safety and efficacy in TD LR-MDS patients who have experienced ESA failure in a real-world setting.
    Keywords:  lower risk MDS; luspatercept; response; survival; transfusion dependence
    DOI:  https://doi.org/10.1111/bjh.20102
  14. Acta Haematol. 2025 May 05. 1-13
    Favorable rates of cardiovascular events with stringent cardiovascular monitoring and a lowered dose of ponatinib as second line treatment in chronic phase chronic myeloid leukemia (CML-CP) patients failing or intolerant to first-line second generation tyrosine kinase inhibitor (TKI) treatment: Results of the prospective PONS trial.
    Philipp le Coutre, Andreas Burchert, Susanne Saußele, Thekla Schwarzer, Sebastian Stintzing, Uwe Pelzer, Lars Bullinger, Ahmet Elmaagacli, Christian Jehn, Frank Stegelmann, Andreas Hochhaus, Thomas Ernst, Joachim R Göthert.
       INTRODUCTION: In chronic myeloid leukemia patients second-line treatment require careful consideration of response and tolerability. As most patients need a more efficient tyrosine kinase inhibitor, ponatinib at a lowered dose should be evaluated in this setting.
    METHODS: We studied a lowered dose of 30 mg ponatinib in 2nd line in patients selected towards a low cardiovascular risk. In 22 screened patients ponatinib was started in 18 patients previously treated with imatinib (n=3), dasatinib (n=9) or nilotinib (n=6). Patients were frequently monitored for cardiovascular toxicities by testing of blood pressure, vital signs, ankle brachial index or duplex, oral glucose tolerance test, echocardiography, ecg and fundoscopy. The study protocol allowed dose reductions in patients achieving MMR. Both previously resistant or intolerant patients were recruited.
    RESULTS: No serious cardiovascular events were observed and low-grade cardiovascular toxicity was negligible. By 12 months, 13 patients (92.9%) were in complete hematologic remission, 10 patients (55.6%) were in MMR and 5 patients (27.8%) were in MR4. Most importantly we demonstrated that thorough monitoring of cardiovascular risk is feasible.
    CONCLUSIONS: We demonstrated that a lowered dose of 30 mg ponatinib in selected patients can be maintained without serious cardiovascular complications provided cardiovascular risk monitoring is performed. In our patient cohort this approach resulted in favorable response rates.
    DOI:  https://doi.org/10.1159/000545826
  15. Support Care Cancer. 2025 May 03. 33(5): 446
    Patient-reported toxicity symptoms during tyrosine kinase inhibitor treatment in chronic myeloid leukemia: a systematic review and meta-analysis.
    Yolba Smit, Pien Scheuter, Myrthe P M Lange, Jeroen J W M Janssen, Eduardus F M Posthuma, Charlotte L Bekker, Rosella P M G Hermens, Nicole M A Blijlevens.
       PURPOSE: One in five chronic myeloid leukemia (CML) patients experiences such intolerability that they switch tyrosine kinase inhibitor (TKI) treatment within 3 years. Information on tolerability is needed to guide shared decision-making. However, an overview of symptoms patients experience per TKI is lacking, and physician-graded toxicity underestimates patients' experiences.
    METHODS: We systematically searched PubMed and Embase from inception to February 2025 and conducted a meta-analysis on the prevalence of patient-reported symptoms in CML per TKI. This study follows the Preferred Reporting Items for Systematic Reviews (PRISMA) guideline for systematic reviews.
    RESULTS: We included 11 studies with 2987 patients, reporting on 47 different symptoms of any severity. The low-grade patient-reported symptom burden was high. No data were available on asciminib and ponatinib, and minimal data were available for bosutinib. In indirect, unadjusted comparisons, 13 out of 47 symptoms (of any severity) showed significant differences in prevalence between common TKI types.
    CONCLUSION: Our findings provide essential information to guide treatment decisions in cases of intolerability. However, there is a clear need for further research with standardized instruments, especially in second and third generation TKI types, including direct comparisons and comparisons adjusted for covariates.
    Keywords:  CML; Chronic myeloid leukemia; Meta-analysis; PROM; Patient-reported outcome measure; TKI; Toxicity; Tyrosine kinase inhibitor
    DOI:  https://doi.org/10.1007/s00520-025-09451-4
  16. Curr Oncol Rep. 2025 May 09.
    The Role of Transplant for Philadelphia-positive B-cell Acute Lymphoblastic Leukemia in 2025.
    Vaibhav Agrawal, Paul Koller, Anthony Stein, Vinod Pullarkat, Ibrahim Aldoss.
       PURPOSE OF REVIEW: This review expands upon the evolving role of allo-HSCT, integrating current clinical evidence, emerging therapies, and novel risk-adapted strategies for managing adult with Ph + ALL in the contemporary era.
    RECENT FINDINGS: Philadelphia chromosome-positive (Ph +) acute lymphoblastic leukemia (ALL) is the most common genetically defined subtype of B-cell ALL. The treatment of Ph + ALL has witnessed significant advancements over the past two decades following the introduction of BCR::ABL1 tyrosine kinase inhibitors (TKIs). Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has long been a cornerstone treatment in adult patients with Ph + ALL, offering the most reliable disease curative potential, and the early use of TKIs has led to successfully transplanting more patients. Lately, the early introduction of more potent TKIs and blinatumomab have further reshaped the frontline treatment paradigm of Ph + ALL and resulted into improved outcomes even in the absence of transplant consolidation. Simultaneously, our ability to stratify disease risk has greatly enhanced with the advent of ultrasensitive measurable residual disease (MRD) assessment tools and the utilization of comprehensive disease molecular profiling, and thus, identifying lower risk patients who can be cured with non-transplant approaches. With evolving treatment options for Ph + ALL, the historical notion that allo-HSCT in first complete remission is essential to cure all adult patients with Ph + ALL is being challenged and the benefit of consolidation with transplant may extend to certain patient populations.
    Keywords:  Allogeneic stem cell transplantation; B-cell ALL; Philadelphia-positive B-cell ALL
    DOI:  https://doi.org/10.1007/s11912-025-01683-1
  17. Cancer Immunol Res. 2025 May 08.
    Identification of the distinct immune microenvironment features associated with progression following high dose melphalan and autologous stem cell transplant in multiple myeloma.
    Parvathi Sudha, Travis S Johnson, Habib Hamidi, Ke Yang, Enze Liu, Brent Smith, Vivek Chopra, Michael Nixon, Faiza Zafar, Sherif S Farag, Gareth J Morgan, Ola Landgren, Kelvin Lee, Attaya Suvannasankha, Magdalena Czader, Rafat Abonour, Mohammad Abu Zaid, Brian A Walker.
      A key treatment for patients with multiple myeloma is high-dose melphalan followed by autologous stem cell transplant (ASCT). It can provide a deep response with long-term remission. However, some patients progress quickly, and it is not clear why that is. Here, we performed single-cell RNA and T-cell receptor (TCR) sequencing of the immune microenvironment of 40 patients before and after ASCT to determine if differences in the immune composition could define those who would progress. Clear differences in cell populations were identified in progressors, including increased T-cell infiltration, decreased TCR diversity, and decreased frequency of monocytes and CD56bright NK cells. We identified cell interactions that predicted progression including increased frequency of CD8+ exhausted T cells and stromal cells and decreased frequency of CD56bright NK cells and plasmacytoid dendritic cells. We propose and validate a model of progression that can also be determined by flow cytometry. Together these data highlight the importance of the immune microenvironment in understanding responses to ASCT.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-25-0019
  18. Hemasphere. 2025 May;9(5): e70137
    Event-free survival in early polycythemia vera patients correlates with molecular response to ropeginterferon alfa-2b or hydroxyurea/best available therapy (PROUD-PV/CONTINUATION-PV).
    PROUD‐PV Study Group
      
    DOI:  https://doi.org/10.1002/hem3.70137
  19. N Engl J Med. 2025 May 08. 392(18): 1858-1860
    Targeting the Tumor and the Immune System in Smoldering Multiple Myeloma.
    Francesco Maura, P Leif Bergsagel.
      
    DOI:  https://doi.org/10.1056/NEJMe2504273
  20. Ann Hematol. 2025 May 05.
    Outcomes of the transformation to diffuse large B-cell lymphoma in hodgkin lymphoma and indolent B-cell non-Hodgkin lymphoma: a population-based study.
    Wenshuai Zheng, Bo Peng, Huaxin Chen, Shenyu Wang, Lixun Guan, Xiaoning Gao.
      Histological transformation (HT) to diffuse large B-cell lymphoma (DLBCL) can occur in both Hodgkin lymphoma (HL) and indolent B-cell non-Hodgkin lymphoma (B-NHL), typically associated with poor clinical outcomes. However, following the introduction of rituximab, the prognosis of transformed DLBCL (t-DLBCL) has shown considerable variability across studies. This study aimed to evaluate the outcomes of t-DLBCL originating from HL and indolent B-NHL, and to compare survival rates between t-DLBCL and primary DLBCL (p-DLBCL). Data were extracted from the Surveillance, Epidemiology, and End Results (SEER) database to identify patients diagnosed with primary HL or indolent B-NHL between 2000 and 2021, and those diagnosed with p-DLBCL during the same time. A total of 3,508 cases of t-DLBCL were identified. Compared to patients without HT, those with HT exhibited significantly worse survival outcomes. The post-transformation survival (PTS) rates at 5-year were 49.4%, 49.4%, 46.2%, 31.4% and 26.4% for t-DLBCL originating from HL, follicular lymphoma (FL), marginal zone lymphoma (MZL), lymphoplasmacytic lymphoma/Waldenström macroglobulinemia and chronic lymphocytic leukemia/small lymphocytic lymphoma, respectively. Factors such as age at HT, sex, marital status at HT, disease stage at HT, initial therapy prior to HT, and treatment regimen at HT were significantly associated with the prognosis of t-DLBCL. Notably, the PTS of specific subgroups of t-DLBCL, including patients younger than 65 years originating from FL with radiotherapy prior to HT, and those originating from MZL with either "watch and wait" or radiotherapy prior to HT, was comparable to that of matched p-DLBCL. Given the heterogeneous prognosis observed in t-DLBCL, treatment strategies should be tailored accordingly.
    Keywords:  Diffuse large B-cell lymphoma; Hodgkin lymphoma; Indolent B-cell non-Hodgkin lymphoma; Survival; Transformation
    DOI:  https://doi.org/10.1007/s00277-025-06395-x
  21. Arch Pharm Res. 2025 May 08.
    BTK inhibitors and next-generation BTK-targeted therapeutics for B-cell malignancies.
    Hyung-Ook Kim.
      Bruton's tyrosine kinase (BTK) is a therapeutically validated drug target. Small-molecule inhibitors of BTK have changed the treatment paradigms of multiple B-cell malignancies and evolved over three generations to overcome clinical challenges. Four drugs are now approved by the FDA, including the first-in-class drug ibrutinib and successively approved acalabrutinib, zanubrutinib, and pirtobrutinib. The third-generation drug pirtobrutinib, which binds non-covalently to BTK, is expected to overcome resistance mutations at the covalent binding Cys481 residue of the first and second-generation drugs that covalently bind to BTK. However, some newly identified non-Cys481 resistance mutations to pirtobrutinib have shown their co-resistance to some of the covalent inhibitors, and this leaves a major unmet need that is promoting the development of next-generation BTK-targeted therapeutics. More non-covalent BTK inhibitors with differentiated binding modes are under development, and the ongoing development focus of next-generation therapeutics involves new and alternative directions to target BTK using dual-binding inhibitors and degraders of BTK, as well as its allosteric inhibitors. Recent exploration of the differentiated features of BTK inhibitors in various aspects has shown the possible link between their different features and different functional and therapeutic consequences. This review summarizes the key differentiated features of the BTK inhibitors approved by the FDA and others under development to add knowledge for their therapeutic application and future development. Long-term follow-up updates of clinical outcomes of the earlier developed drugs are also included, together with direct and indirect comparisons of efficacy and safety between the different generations of drugs. The ongoing development status of next-generation BTK-targeted therapeutics is described, with a discussion on their therapeutic potential and some limitations.
    Keywords:  Allosteric inhibitors; BTK inhibitors; Degraders; Dual-binding inhibitors; Next-generation BTK-targeted therapeutics
    DOI:  https://doi.org/10.1007/s12272-025-01546-0
  22. Haematologica. 2025 May 08.
    Targeting leukemic stem cell dormancy in NPM1c/FLT3-ITD-driven acute myeloid leukemia.
    Patrick Stelmach.
      Not available.
    DOI:  https://doi.org/10.3324/haematol.2025.287644
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