bims-hemali Biomed News
on Hematologic malignancies
Issue of 2025–08–24
fourteen papers selected by
Alexandros Alexandropoulos, Γενικό Νοσοκομείο Αθηνών Λαϊκό
  1. Mechanisms and signaling pathways of tyrosine kinase inhibitor resistance in chronic myeloid leukemia: A comprehensive review.
  2. Newly diagnosed acute myeloid leukemia in unfit patients: 2026 treatment algorithms.
  3. Single-agent rituximab and ultra-low-dose adaptive radiotherapy for the treatment of indolent B-cell non-Hodgkin lymphomas.
  4. Asciminib in late-line CML treatment.
  5. Association of PET4 Response With Outcomes of BV-CHP vs CHOP in the ECHELON-2 Trial in CD30+ Peripheral T-cell Lymphoma.
  6. Effectiveness and Safety of Polatuzumab Vedotin Plus an Anti-CD20 Monoclonal Antibody (Rituximab or Obinutuzumab) and Zanubrutinib in Relapsed/Refractory Diffuse Large B-Cell Lymphoma.
  7. Leukemia Burden Impacts the Efficacy and Toxicity of Blinatumomab in Pediatric B-Cell Acute Lymphoblastic Leukemia.
  8. Tubulin inhibitors: an insight into new strategies to combat leukemia.
  9. Preclinical efficacy of tasquinimod-based combinations in advanced myeloproliferative neoplasms (MPN) in blastic phase.
  10. Zanubrutinib in the treatment of patients with del(17p) and/or TP53 CLL/SLL: analysis across clinical studies.
  11. Arsenic Trioxide and All-Trans Retinoic Acid Combination Therapy for the Treatment of High-Risk Acute Promyelocytic Leukemia: Results From the APOLLO Trial.
  12. A phase 2 study of zanubrutinib in combination with rituximab and lenalidomide in de novo diffuse large B-cell lymphoma.
  13. Venetoclax combined with azacitidine in elderly acute myeloid leukemia: A retrospective comparison of 14-day vs 28-day dosing regimens.
  14. Beneath the surface in autoimmune hemolytic anemia: pathogenetic networks, therapeutic advancements and open questions.
  1. Leuk Res Rep. 2025 ;24 100533
    Mechanisms and signaling pathways of tyrosine kinase inhibitor resistance in chronic myeloid leukemia: A comprehensive review.
    Meriem Lahmouad, Zahrae Rachid, Rawane Bellemrrabet, Jihane Zerrouk, Khan Wen Goh, Abdelhakim Bouyahya, Youssef Aboussalah.
      Chronic Myeloid Leukemia (CML) is characterized by aberrant BCR::ABL1 tyrosine kinase activity in hematopoietic stem cells. Although tyrosine kinase inhibitors (TKIs) have revolutionized CML treatment, resistance remains a major clinical challenge. This review provides a comprehensive overview of CML, including its epidemiology, pathophysiology, diagnosis, and treatment, as outlined in the latest WHO consensus classification. Current treatment paradigms and the prospects for treatment-free remission (TFR) are also explored. The primary focus is on elucidating the molecular mechanisms of TKI resistance, emphasizing both well-known pathways such as PI3K/AKT, MAPK, JAK/STAT, and alternative pathways including SRC/AKT. This review stands out by integrating recent discoveries regarding genetic mutations within the BCR::ABL1 gene, alongside other molecular alterations contributing to resistance. By synthesizing this knowledge, it aims to guide clinical practitioners, investigators, and translational researchers in developing innovative strategies to overcome resistance and improve patient outcomes in CML.
    Keywords:  BCR::ABL1 Mutations; Chronic myeloid leukemia; Signaling pathways; TKI resistance; Tyrosine kinase inhibitors
    DOI:  https://doi.org/10.1016/j.lrr.2025.100533
  2. Blood Cancer J. 2025 Aug 16. 15(1): 139
    Newly diagnosed acute myeloid leukemia in unfit patients: 2026 treatment algorithms.
    Naseema Gangat, Courtney D Dinardo.
      Management paradigms for newly-diagnosed acute myeloid leukemia (ND-AML) in patients considered unfit to receive intensive chemotherapy have evolved with improved understanding of disease biology. In this setting, management requires clear delineation of goals of therapy that should include preservation of quality-of-life (QoL). Combination of venetoclax (Ven) and a hypomethylating agent (HMA) is the current standard-of-care in most circumstances with flexible options in regard to drug dose and duration of treatment as well as the addition (triplet combinations) or alternative use of targeted therapies, such as inhibitors of FLT3, IDH1, IDH2, or menin for patients with NPM1MUT or KMT2A rearrangements (KMT2Ar). Response rates (CR/CRi:40-90%) and overall survival outcomes (3-year: 0-67%) following Ven-HMA therapy are highly variable and depend primarily on tumor genetics while achievement of complete response with (CR) or without count recovery (CRi) and consolidation with allogeneic stem cell transplant (ASCT) are essential in securing long-term survival. Favorable genomic predictors of response to Ven-HMA include NPM1MUT, IDH2MUT, and DDX41MUT, and unfavorable TP53MUT, FLT3-ITD, and K/NRASMUT. Favorable predictors of overall survival include IDH2MUT, and unfavorable TP53MUT, FLT3-ITD, K/NRASMUT, and KMT2Ar. Whether or not triplet regimens provide significant survival gain over Ven-HMA in genetically targetable subgroups remains to be determined. Particularly frail patients who are considered unfit for Ven-HMA might benefit from monotherapy targeting FLT3MUT, IDH1/2MUT, NPM1MUTor KMT2Ar. Future research projects should focus on incorporating patient-reported outcomes in clinical trials, optimization of Ven-HMA dosing and treatment duration especially in triplet combinations and broadening the use of ASCT and clarification of its timing.
    DOI:  https://doi.org/10.1038/s41408-025-01346-1
  3. Front Oncol. 2025 ;15 1617087
    Single-agent rituximab and ultra-low-dose adaptive radiotherapy for the treatment of indolent B-cell non-Hodgkin lymphomas.
    Katherine E Lake, Meredith Jackson, Samantha Hull, Sean All, Akshat M Patel, Xingzhe Li, Neil B Desai, Elif Yilmaz, Heather Wolfe, Mohammad Faizan Zahid, Hsiao-Ching Li, Farrukh Awan, Margaret M Kozak, Praveen Ramakrishnan Geethakumari, Kiran A Kumar.
       Introduction: For indolent B-cell non-Hodgkin lymphomas (iNHLs), ultra-low-dose radiation therapy (ULDRT) with 4 Gy has demonstrated durable local control (70%), although distal relapses may occur. Concurrent systemic chemotherapy with radiation therapy (RT) extends progression-free survival (PFS) but is often avoided due to toxicity. We hypothesize that the combination of adaptive ULDRT, with repeat treatment as needed, and single-agent rituximab results in excellent local and systemic control with minimal toxicity.
    Methods: We conducted an institutional review board (IRB)-approved retrospective review of patients with iNHLs (n=26) who were treated with both ULDRT and rituximab (four weekly doses of 375 mg/m2), either concurrently or within a short interval (median 16 days), at our institution from 2017 to 2024. Treatment response and disease control (local and distant) were measured by PET/CT. Overall survival (OS) and PFS were analyzed using the Kaplan-Meier method. Common Terminology Criteria for Adverse Events (CTCAE) v4 was used to record acute and long-term toxicities.
    Results: Overall response rate (ORR) at the first follow-up was 28/31 (90%), of which 19 sites (61%) achieved complete response (CR) and nine (26%) achieved partial response (PR). One (3%) patient had stable disease (SD). In our cohort, the 2-year in-field, out-of-field, and overall PFS rates were 91%, 78%, and 78%, respectively, and OS was 92%. No patient had disease transformation.
    Discussion: The combination of rituximab and ULDRT demonstrates sustained local and distant disease control with minimal side effects in iNHLs.
    Keywords:  4 Gy; boom boom; follicular lymphoma; iNHL; low-grade lymphoma; radiotherapy; rituximab; ultra-low-dose
    DOI:  https://doi.org/10.3389/fonc.2025.1617087
  4. Blood Adv. 2025 Aug 26. 9(16): 4317-4318
    Asciminib in late-line CML treatment.
    Kendra Sweet, Javier Pinilla-Ibarz.
      
    DOI:  https://doi.org/10.1182/bloodadvances.2025016874
  5. Blood Adv. 2025 Aug 19. pii: bloodadvances.2024015282. [Epub ahead of print]
    Association of PET4 Response With Outcomes of BV-CHP vs CHOP in the ECHELON-2 Trial in CD30+ Peripheral T-cell Lymphoma.
    Swaminathan P Iyer, Neha Mehta-Shah, Ranjana H Advani, Nancy L Bartlett, Jacob Haaber Christensen, Franck Morschhauser, Eva Domingo-Domenech, Giuseppe Rossi, Won Seog Seog Kim, Onder Alpdogan, Tatyana A Feldman, Vincent Camus, Giuseppe Gritti, Pier Luigi Zinzani, David Belada, Jiri Mayer, Ilseung Choi, June-Won Cheong, Evelyn Rustia, Keenan Fenton, Michelle Fanale, Kerry J Savage, Steven M Horwitz.
      In the phase 3 ECHELON-2 trial, brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone (BV-CHP) significantly improved progression-free survival (PFS) and overall survival (OS) compared with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in patients with CD30+ peripheral T-cell lymphoma (PTCL), benefits that were maintained at 5 years. Interim positron emission tomography (PET) scan can be used to assess prognosis and risk stratify patients. The prognostic value of interim PET was assessed in this post hoc exploratory analysis from ECHELON-2 evaluating interim 18F-FDG PET scans after cycle 4 (PET4) and end-of-treatment-based response and correlated with PFS per investigator and OS. PET4 response was determined by Deauville score (scores of 1-3 were considered negative [PET4-negative] and 4-5 positive [PET4-positive]) by independent review. Overall, 452 patients were randomized 1:1 to the BV-CHP (n = 226) and CHOP (n = 226) arms. Of these, 32 in the BV-CHP arm and 41 in the CHOP arm were not evaluable for PET4. In both arms, PET4-negative status was associated with improved PFS (HR [95% CI] BV-CHP 0.36 [0.19-0.66], CHOP 0.26 [0.17-0.41]) and OS (HR [95% CI] BV-CHP 0.38 [0.18-0.78], CHOP 0.24[0.14-0.41]) compared with PET4-positive status. In patients with systemic anaplastic large cell lymphoma, PET4-negative patients had improved PFS (HR [95% CI] BV-CHP 0.28 [0.14-0.60], CHOP 0.31 [0.17-0.56]) and OS (HR [95% CI] BV-CHP 0.38 [0.16-0.94], CHOP 0.25 [0.12-0.55]) compared with PET4-positive patients. In this exploratory analysis, PET4-negative status by Deauville score was associated with improved long-term PFS and OS in both the BV-CHP and CHOP arms.
    DOI:  https://doi.org/10.1182/bloodadvances.2024015282
  6. Cancer Med. 2025 Aug;14(16): e71162
    Effectiveness and Safety of Polatuzumab Vedotin Plus an Anti-CD20 Monoclonal Antibody (Rituximab or Obinutuzumab) and Zanubrutinib in Relapsed/Refractory Diffuse Large B-Cell Lymphoma.
    Yian Zhang, Yuhong Ren, Jingli Zhuang, Ling Yuan, Zhimei Wang, Xuejiao Zhang, Weiguang Wang, Zhixiang Cheng, Luya Cheng, Jing Li, Peng Liu.
       BACKGROUND: Approximately 30% of patients with diffuse large B-cell lymphoma (DLBCL) relapse or are refractory to first-line treatment. This study aimed to determine the effectiveness and tolerability of the combination of Polatuzumab vedotin and Zanubrutinib plus Rituximab (Pola-ZR) or Obinutuzumab (Pola-ZG) in patients with relapsed/refractory (R/R) DLBCL.
    METHODS: We conducted a prospective observational study as part of our registered cohort study (NCT06203652). Patients were planned to receive six 21-day cycles of Pola-ZR/G, followed by Zanubrutinib monotherapy. The primary endpoint was to evaluate the best overall response rate (BOR), while secondary endpoints included the median progression-free survival (mPFS), safety, and complete response rate (CRR). We collected data from 73 R/R DLBCL patients who received traditional salvage therapies (TST). After propensity score matching, they were paired 1:1 with the Pola-ZR/G arm to compare the effectiveness and survival outcomes.
    RESULTS: Twenty-two patients were enrolled (median age 68 years) in the Pola-ZR/G group. After a median follow-up of 16.1 months, the investigators assessed BOR; it was 70% (77.77% for Pola-ZR and 63.6% for Pola-ZG cohort), and CRR was 45% in 20 evaluable R/R patients. The mPFS was 8.3 months and was higher compared to the TST cohort. The median overall survival (OS) of the Pola-ZR/G cohort had not been reached at the time of analysis. The most common grade 3 to 4 adverse events were infections of all types and hematological toxicity.
    CONCLUSION: In our study, patients derived clinical benefit after receiving Pola-ZR/G compared to TST; the regimens had a tolerable safety profile in patients with R/R DLBCL.
    Keywords:  Polatuzumab vedotin; diffuse large B‐cell lymphoma; effectiveness; relapsed/refractory; safety
    DOI:  https://doi.org/10.1002/cam4.71162
  7. Cancer Med. 2025 Aug;14(16): e71159
    Leukemia Burden Impacts the Efficacy and Toxicity of Blinatumomab in Pediatric B-Cell Acute Lymphoblastic Leukemia.
    Weiling Yan, Shaoyan Hu, Wenjin Gao, Lihua Yang, Yan Gu, Yufeng Liu, Yunyan He, Dunhua Zhou, Wenting Hu, Xue Tang, Ming Sun, Lili Song, Wenyu Yang, Yalan You, Yongmin Tang, Xiaojun Xu.
       BACKGROUND: Blinatumomab has been approved for the treatment of pediatric B-cell acute lymphoblastic leukemia (B-ALL). This study aimed to investigate the association between leukemia burden and the efficacy of blinatumomab in real-world applications.
    METHODS: A real-world study was conducted by enrolling patients aged 0-18 years who were diagnosed with CD19-positive B-ALL and treated with blinatumomab between January 2021 and May 2023 from 14 centers in China.
    RESULTS: A total of 304 patients were enrolled in this analysis. In the patients with > 5% blasts before blinatumomab (non-complete remission, NCR group), 75.9% achieved complete remission (CR) and 69.0% of the NCR patients achieved minimal residual disease (MRD) negativity. Among the patients with ≤ 5% blasts but multiparametric flow cytometry MRD (MFC MRD) positive (MRD+ group), 98.9% achieved MRD negativity. Of the MFC MRD negative patients (MRD- group), the quantitative polymerase chain reaction MRD (qPCR MRD) and next-generation sequencing MRD (NGS MRD) clearance rate was 60.0% (12/20) and 65.5% (19/29), respectively. Additionally, patients in the MRD- and MRD+ groups had significantly better outcomes than those in the NCR group, with 30-month overall survival (OS) rates of 95.3% (95% CI: 91.4%-99.3%), 91.2% (95% CI: 85.0%-97.8%), and 77.6% (95% CI: 67.4%-89.4%), respectively (p < 0.001), and 30-month event-free survival (EFS) rates of 93.9% (95% CI: 89.6%-98.3%), 90.8% (95% CI: 85.0%-97.1%), and 56.7% (95% CI: 41.0%-78.6%), respectively (p < 0.001). In this study, 41.4% of patients experienced grade ≥ 3 adverse events (AEs), with hematological toxicity being the most common (33.2%). The severe adverse events, such as cytokine release syndrome (CRS) and neurotoxicity, occurred at a low rate, particularly grade ≥ 3, at 3.6% and 2.6%, respectively.
    CONCLUSIONS: Overall, these results indicate that blinatumomab is effective and well tolerated. Patients with a lower leukemia burden before blinatumomab administration tend to have better OS and EFS with fewer AEs.
    Keywords:  acute lymphoblastic leukemia; blinatumomab; pediatric; real‐world study
    DOI:  https://doi.org/10.1002/cam4.71159
  8. Future Med Chem. 2025 Aug 19. 1-24
    Tubulin inhibitors: an insight into new strategies to combat leukemia.
    Sangeeta Verma, Pankaj Gupta, Rakesh Narang, Sukhbir Lal, Vikramjeet Singh.
      Leukemia is a type of cancer that affects the blood and bone marrow and characterized by the uncontrolled production and accumulation of blood cells. According to the World Health Organization (WHO), leukemia is among the fifteen most commonly diagnosed cancers worldwide and the eleventh leading cause of mortality. Tyrosine kinase inhibitors are the first-line choice for the treatment of acute or chronic leukemia. However, mutations in tyrosine kinase proteins are the major cause of resistance. Therefore, the discovery of new targeted antileukemic molecules is essential for the treatment of leukemia. Amongst the various tyrosine kinase inhibitors, tubulin inhibitors displayed promising results in preventing the proliferation of cancer cells. Microtubule targeting agents (MTAs) bind with tubulin protein and affect their functionalities in leukemia cells. In this context, recently reported antileukemic tubulin inhibitors viz., synthetic, natural, dual/multi-inhibitors, antibody-drug conjugates etc. have been summarized (2018 to present) in this manuscript. Structure activity relationship (SAR) analysis depicted that the presence of trimethoxy phenyl, chalcone, quinoline, and oxadiazole scaffolds improved the tubulin inhibitory activity against acute lymphoblastic leukemia. The present review also reported the recent patents and clinical trial data related to antileukemic tubulin inhibitors.
    Keywords:  Leukemia; antibody drug conjugates; dual/multi target inhibitors; tubulin inhibitors; vincristine resistance
    DOI:  https://doi.org/10.1080/17568919.2025.2546774
  9. Blood Adv. 2025 Aug 19. pii: bloodadvances.2025016898. [Epub ahead of print]
    Preclinical efficacy of tasquinimod-based combinations in advanced myeloproliferative neoplasms (MPN) in blastic phase.
    Warren Fiskus, Lucia Masarova, Christopher P Mill, Christine Birdwell, Kaberi Das, Hanxi Hou, John A Davis, Antrix Jain, Anna Malovannaya, Taghi Manshouri, Andrew Dunbar, Surbhi Sharma, Tapan M Kadia, Courtney D DiNardo, Prithviraj Bose, Naveen Pemmaraju, Sanam Loghavi, Xiaoping Su, Raajit K Rampal, Marie Törngren, Kapil N Bhalla.
      The alarmins, S100A8 (A8) and S100A9 (A9), are low molecular weight proteins belonging to the S100 protein family. A8 and A9 are secreted into the extracellular space and plasma, where they interact with TLR4 (Toll like receptor 4), RAGE (receptor for advanced glycation end products) and CD33. In present studies, we determined the preclinical efficacy of tasquinimod (TQ) against advanced MPN cell lines and patient-derived (PD) CD34+ blastic phase (BP, >5% blasts in PB) MPN cells. TQ induced loss of viability in cell lines and PD MPN-BP cells, but not in normal CD34+ progenitor cells. In TQ-treated PD MPN-AML cells, RNA-Seq analysis showed negative enrichment of the gene-sets of MYC and E2F targets, IL6-JAK-STAT3 signaling, and of inflammatory response. In phenotypically defined, PD, CD34+ MPN-BP stem progenitor cells, CyTOF analysis showed that TQ reduced expression of proteins including A8, A9, and MPO, while increasing expression of GFI1, p21 and cleaved PARP. Co-treatment with TQ and ruxolitinib or BET inhibitor induced synergistic lethality in advanced MPN-BP cells. Monotherapy with TQ significantly improved survival of immune-depleted NSG mice engrafted with PDX cells of MPN-AML. Notably, cotreatment with TQ and ruxolitinib or OTX015 induced significantly greater survival than treatment with single agents in the NSG mice engrafted with the PDX cells. These findings clearly demonstrate the preclinical efficacy of TQ in advanced MPN-BP cells and create the rationale to further interrogate the efficacy of TQ-based combinations with the current, front-line therapies or novel agents in advanced MPNs with excess blasts.
    DOI:  https://doi.org/10.1182/bloodadvances.2025016898
  10. Blood Adv. 2025 Aug 19. pii: bloodadvances.2025015986. [Epub ahead of print]
    Zanubrutinib in the treatment of patients with del(17p) and/or TP53 CLL/SLL: analysis across clinical studies.
    Constantine S Tam, Mary Ann Anderson, Martin Simkovic, Paolo Ghia, Ian W Flinn, Kamel Laribi, Stephen S Opat, Gavin Cull, Talha Munir, Anders Österborg, Alessandra Tedeschi, Megan Der Yu Wang, Andy H Szeto, Heather Allewelt, Tommi Salmi, Jessica Li, Linlin Xu, Kenneth Wu, Remus Vezan, Mazyar Shadman, Jennifer R Brown.
      Patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who harbor del(17p) and/or tumor protein p53 (TP53) mutations represent a high-risk population with a historically poor prognosis. To assess zanubrutinib efficacy and safety outcomes in patients with CLL/SLL with del(17p) and/or TP53 mutations (N=301; n=132, treatment-naive; n=169, relapsed/refractory), data from SEQUOIA (phase 3; treatment-naive; zanubrutinib; NCT03336333), ALPINE (phase 3; relapsed/refractory; zanubrutinib versus ibrutinib; NCT03734016) and AU-003 (phase 1/2; zanubrutinib) were evaluated. In SEQUOIA (n=127; median follow-up, 64.8 months), median progression-free survival (PFS) and overall survival (OS) were not reached; estimated 60-month PFS and OS were 70.7% and 82.3%, respectively. In ALPINE (n=75, each treatment arm; median follow-up, 39.0 months), 36-month PFS rates were 59.2% among zanubrutinib-treated patients and 38.5% among ibrutinib-treated patients, and OS rates were 73.6% and 72.5%, respectively. In AU-003 (n=24; median follow-up, 69.6 months), 10/24 patients experienced progressive disease. Rate of response with zanubrutinib in SEQUOIA was 96.9% (95% CI: 95.2-98.8), in ALPINE was 89.3% (95% CI: 80.1-95.3) with zanubrutinib versus 76.0% (95% CI, 64.7-85.1%) with ibrutinib. Responses deepened over time in both treatment-naive and relapsed/refractory populations. The most frequent non-hematologic treatment-emergent adverse events occurring in >20% zanubrutinib-treated patients with del(17p) and/or TP53 mutations in SEQUOIA and ALPINE were COVID-19, upper respiratory tract infection, arthralgia, diarrhea and contusion. In conclusion, zanubrutinib demonstrated strong efficacy in high-risk del(17p) and/or TP53 CLL/SLL, with a tolerable safety profile, further supporting use of zanubrutinib in both frontline and relapsed/refractory settings.
    DOI:  https://doi.org/10.1182/bloodadvances.2025015986
  11. J Clin Oncol. 2025 Aug 18. JCO2500535
    Arsenic Trioxide and All-Trans Retinoic Acid Combination Therapy for the Treatment of High-Risk Acute Promyelocytic Leukemia: Results From the APOLLO Trial.
    SAL, AMCL-CG, AML-SG, OSHO, PETHEMA, HOVON and GIMEMA study groups
       PURPOSE: The phase III APOLLO trial prospectively compared the efficacy of arsenic trioxide (ATO) in combination with all-trans retinoic acid (ATRA) regimen (ATRA and ATO [ATRA-ATO]) plus low-dose idarubicin versus standard ATRA plus anthracycline-based chemotherapy (ATRA-CHT) regimen (ie, ATRA and idarubicin regimen) in patients with high-risk acute promyelocytic leukemia (APL; EudraCT 2015-01151-68; ClinicalTrials.gov identifier: NCT02688140).
    METHODS: Adult patients with newly diagnosed high-risk APL in the ATRA-ATO arm received ATO 0.15 mg/kg once daily and ATRA 45 mg/m2 twice daily until complete remission (CR), with two doses of idarubicin 12 mg/m2 on days 1 and 3, followed by consolidation therapy (four ATRA-ATO cycles). Patients in the ATRA-CHT arm received induction with ATRA 45 mg/m2 twice daily and idarubicin 12 mg/m2 once daily on days 1, 3, 5, and 7, followed by three cycles of chemotherapy-based consolidation and 2 years of maintenance therapy. The primary study end point was event-free survival (EFS) at 2 years.
    RESULTS: As of July 2022, 133 eligible patients had received either ATRA-ATO (n = 68) or ATRA-CHT (n = 65). The study was discontinued prematurely because of slow accrual during the COVID-19 pandemic. After a median follow-up of 37 months (range, 1.7-88.6 months), 2-year EFS was 88% in the ATRA-ATO arm and 71% in the ATRA-CHT arm (HR, 0.4 [95% CI, 0.17 to 0.92]; log-rank test P = .02). At a median of 7.8 and 12.1 months from achievement of CR, molecular relapse occurred in one (1.5%) ATRA-ATO patient versus eight (12.3%) ATRA-CHT patients (P = .014). Overall, 32% and 68% of patients receiving ATRA-ATO and ATRA-CHT, respectively, reported serious treatment-emergent adverse events (P < .01).
    CONCLUSION: The results of the APOLLO trial support the use of ATO and ATRA for the treatment of newly diagnosed patients with high-risk APL.
    DOI:  https://doi.org/10.1200/JCO-25-00535
  12. Blood. 2025 Aug 19. pii: blood.2025028649. [Epub ahead of print]
    A phase 2 study of zanubrutinib in combination with rituximab and lenalidomide in de novo diffuse large B-cell lymphoma.
    Pengpeng Xu, Yue Zhu, Zi-Yang Shi, Li Wang, Shu Cheng, Ying Qian, Yan Zhao, Yang He, Hongmei Yi, Binshen Ouyang, Xu-Feng Jiang, Biao Li, Qi Song, Rong-Ji Mu, Weili Zhao.
      Older patients with diffuse large B cell lymphoma (DLBCL) present unfavorable genetic and microenvironmental alterations. In this phase 2 trial, we assessed the efficacy and safety of zanubrutinib in combination with rituximab and lenalidomide (ZR2) in patients with de novo DLBCL aged ≥75 years (NCT04460248). Forty patients were enrolled, and the primary endpoint was complete response rate, which was 65.0% (95% confidence interval [CI]: 48.3-78.9) at the end of induction treatment. The 2-year progression-free and overall survival rates were 67.1% (95% CI: 50.1-79.4) and 82.4% (95% CI: 66.5-91.2). The most common grades 3 and 4 hematologic adverse event (AE) was neutropenia (n = 14; 35.0%). The most common grades 3 and 4 non-hematologic AEs were increased alanine transaminase (n = 5; 12.5%) and aspartate transaminase level (n = 5; 12.5%), and pulmonary infection (n = 5; 12.5%). No events of atrial fibrillation were observed. Importantly, the efficacy of ZR2 was more dependent on tumor microenvironmental than genetic alterations, in association with up-regulation of Class I and II human leukocyte antigen, increased number and function of conventional type 1 dendritic cells. Pre-existing expansion of intra-tumoral CD8+T cells and treatment-induced clonal T-cell receptor (TCR) repertoire contributed to better clinical outcome. TCR sequencing of the peripheral blood mononuclear cell samples from patients with durable remission detected the expanded T cell clones 3 years post-treatment. These findings thus provided better understanding of T-cell immunological memory effect on immunotherapy as ZR2, and a paradigm shift in the era of mechanism-based targeted therapy of aggressive lymphoma.
    DOI:  https://doi.org/10.1182/blood.2025028649
  13. Medicine (Baltimore). 2025 Aug 15. 104(33): e43979
    Venetoclax combined with azacitidine in elderly acute myeloid leukemia: A retrospective comparison of 14-day vs 28-day dosing regimens.
    Zhuruohan Yu, Shuangyue Li, Renzhi Pei, Ying Lu, Yuxiao Wang, Jiaojiao Yuan.
      However, this study has several limitations that must be acknowledged. First, the non-randomized allocation of treatment duration introduces potential selection bias, particularly as frailer patients were more likely to receive shorter therapeutic cycles, which may have confounded outcome assessments. Background: Although the standard 28-day venetoclax (VEN) regimen combined with azacitidine (AZA) improves outcomes in elderly patients with acute myeloid leukemia, emerging evidence suggests that shorter VEN cycles may maintain efficacy with enhanced safety. We retrospectively analyzed 90 treatment-naive elderly patients with acute myeloid leukemia receiving VEN + AZA (VA): 47 patients (14-day VEN) and 43 patients (28-day VEN). The outcomes included clinical remission rates, hematologic recovery, adverse events, and survival metrics. Both groups achieved comparable clinical remission rates (CRc: 57.4% vs 58.1%, P = .947). The 14-day cohort demonstrated significantly faster neutrophil recovery (median 12.5 vs 26 days, P < .01) and reduced febrile neutropenia (73.3% vs 90.9%, P < .05), with trends toward fewer grade ≥3 infections. At a median follow-up of 494 days, no significant differences in median overall survival (OS: 494 vs 578 days, HR = 1.17, 95%CI 0.64-2.14) or event-free survival (416 vs 454 days, HR = 1.09, 95%CI 0.61-1.96) were observed. A 14-day VA regimen showed antileukemic efficacy comparable to the 28-day protocol while mitigating myelosuppressive sequelae. This abbreviated approach may optimize tolerability in frail elderly patients who are ineligible for prolonged low-intensity chemotherapy. Prospective validation is warranted to refine risk-adapted dosing strategies.
    Keywords:  acute myeloid leukemia; efficacy; elderly; myelosuppression; short-term; venetoclax
    DOI:  https://doi.org/10.1097/MD.0000000000043979
  14. Front Immunol. 2025 ;16 1624667
    Beneath the surface in autoimmune hemolytic anemia: pathogenetic networks, therapeutic advancements and open questions.
    Alessandro Costa, Olga Mulas, Angela Maria Mereu, Mercede Schintu, Marianna Greco, Giovanni Caocci.
      In recent years, the pathophysiologic framework of autoimmune hemolytic anemias (AIHAs) has evolved considerably, extending beyond the simplistic paradigm of antibody-mediated red blood cell (RBC) destruction, which is now recognized as a downstream consequence of a broader immune dysregulation. AIHA is fundamentally orchestrated by a complex interplay between innate and adaptive immune components, including autoreactive B and T lymphocytes, macrophages, and the reticuloendothelial system. Central to disease pathogenesis are two interrelated mechanisms: clonal B-cell expansion with autoantibody production and complement activation. These immunologic processes support the heterogeneity of AIHA, delineating distinct clinical entities such as warm AIHA, cold agglutinin disease/syndrome (CAD/CAS), and atypical variants, each characterized by specific therapeutic susceptibilities. Glucocorticoids remain the standard first-line therapy for warm AIHA; in contrast, CAD/CAS is increasingly managed with agents targeting B-cell function or complement activation, including rituximab and sutimlimab. However, therapeutic algorithms are rapidly shifting, particularly in the context of treatment-refractory disease. Emerging therapeutics targeting the classical complement pathway include novel anti-C1s monoclonal antibodies such as riliprubart, which exhibits an extended half-life due to enhanced affinity for the neonatal Fc receptor. Parallel strategies aim to disrupt B-cell receptor (BCR) signaling cascades, employing Bruton tyrosine kinase (BTK) inhibitors such as ibrutinib, spleen tyrosine kinase (SYK) inhibitors such as fostamatinib and sovleplenib, and phosphoinositide 3-kinase (PI3K) inhibitors such as parsaclisib. Collectively, these advances are reshaping the therapeutic landscape of AIHA toward a precision medicine model guided by mechanistic insights into disease biology. In this review, we delineate the evolving immunopathogenesis of AIHAs and examine emerging therapeutic strategies, integrating their underlying rationale, clinical data, and implications for future treatment paradigms.
    Keywords:  autoimmune hemolytic anemias; cold agglutinin disease; complement system; immunotherapy; pathogenesis; strategy; target therapy; warm autoimmune hemolytic anemia
    DOI:  https://doi.org/10.3389/fimmu.2025.1624667
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