bims-hemali Biomed News
on Hematologic malignancies
Issue of 2025–08–03
twenty-six papers selected by
Alexandros Alexandropoulos, Γενικό Νοσοκομείο Αθηνών Λαϊκό
  1. A multicenter phase 1/2 trial of lenalidomide and dose-adjusted EPOCH-R in MYC-associated DLBCL.
  2. Safety and Efficacy of Elranatamab in Patients with Relapsed and/or Refractory immunoglobulin Light-Chain Amyloidosis.
  3. Pola-R-CHP performed well in first-line Polarix trial-ineligible and IPI 0-1 DLBCL patients : Article type: research.
  4. Gene expression analysis of patients with chronic myeloid leukemia who discontinued tyrosine kinase inhibitor.
  5. A Phase I Trial of Evorpacept, Lenalidomide and Rituximab for Patients with B-cell Non-Hodgkin Lymphoma.
  6. HSCs with the "SUPER" power to make blood forever.
  7. A phase Ib/II trial combining brentuximab vedotin with cyclophosphamide, procarbazine, prednisone, etoposide and mitoxantrone (BrEPEM) for older patients with untreated classical Hodgkin lymphoma: A multicentre GELTAMO trial.
  8. XPO1 Drives Resistance to Eprenetapopt and Azacitidine and Can Be Targeted in TP53-Mutated Myeloid Malignancies.
  9. Final analysis of the RESONATE-2 study: up to 10 years of follow-up of first-line ibrutinib treatment for CLL/SLL.
  10. Sequential Targeting in Multiple Myeloma: Talquetamab, a GPRC5D bispecific antibody, as a Bridge to BCMA CAR-T cell therapy.
  11. Considerations for the Practical Management of Cardiovascular Risk With Bruton's Tyrosine Kinase Inhibitors for Patients With CLL.
  12. HLH: it is all about communication.
  13. Activity of CAR-T cells and bispecific antibodies in multiple myeloma with extramedullary involvement.
  14. Time to complete remission is an independent determinant of survival after intensive chemotherapy in AML.
  15. A dream or reality: Consideration of 'bloodless' hematopoietic stem cell transplants for Jehovah's witness patients.
  16. The Efficacy of Polatuzumab Vedotin Targeting CD79B in the Treatment of Non-Hodgkin Lymphoma: A Systematic Review and Meta-Analysis.
  17. Genetic subtype-guided immunochemotherapy in relapsed and refractory diffuse large B cell lymphoma: a phase 2 investigator-initiated nonrandomized clinical trial (GUIDANCE-06).
  18. Tyrosine Kinase Inhibitors for the Treatment of Mast Cell Diseases: Review and Update.
  19. Next-generation Bruton tyrosine kinase inhibitors and degraders in the treatment of B-cell malignancies: advances and challenges.
  20. Targeting JAK-STAT in macrophage activation syndrome-no MAS!
  21. Ixazomib decreases the risk of chronic graft-versus-host disease: identification of cGvHD biomarkers.
  22. Opening the Door to Tailored Treatment in Newly Diagnosed Multiple Myeloma.
  23. How I treat patients with CLL after prior treatment with a covalent BTK inhibitor and a BCL-2 inhibitor.
  24. Moving Towards the Delivery of Outpatient T-Cell Engaging Therapy for the Management of Multiple Myeloma.
  25. The bone marrow immune ecosystem shapes daratumumab acquired resistance in plasma cell myeloma.
  26. Molecular Pathways and Targeted Therapies in Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL).
  1. Blood Adv. 2025 Jul 28. pii: bloodadvances.2025017092. [Epub ahead of print]
    A multicenter phase 1/2 trial of lenalidomide and dose-adjusted EPOCH-R in MYC-associated DLBCL.
    Kirk E Cahill, James K Godfrey, Chadi Nabhan, Justin Kline, Peter A Riedell, Kenneth S Cohen, Sunil Narula, Theodore G Karrison, Jessica Robertson, Reem Karmali, Parameswaran Venugopal, Seo-Hyun Kim, Aaron P Rapoport, Seung Tae Lee, Jennie Y Law, Paul A S Fishkin, Iris Isufi, Mario Reyes Velasco, Lynne Kaminer, Sonali M Smith.
      In patients with diffuse large B-cell lymphoma (DLBCL), concurrent deregulation of MYC and BCL2 confers inferior outcomes following R-CHOP. Dose-adjusted EPOCH-R (DA-EPOCH-R) produces favorable results in patients with dual MYC and BCL2 rearrangement (double-hit lymphoma, DHL), but there is limited prospective data in both DHL and DLBCL with dual protein overexpression of Myc and Bcl2 (double-expressor lymphoma, DEL). Lenalidomide (LEN) may enhance the response in MYC-driven lymphomas, prompting this investigator-initiated multicenter phase 1/2 study evaluating LEN with DA-EPOCH-R in adults with newly diagnosed DHL and DEL. Fifty-five patients (23 DHL and 32 DEL) were enrolled and treated. Patients had median age of 65 years (range, 25-82), IPI ≥ 3 in 69% (38/55), and stage III/IV in 91% (50/55). The overall response rate was 90.9% with complete response rate of 83.6%. With median follow-up of 3.4 years, the primary endpoint efficacy criterion was met with 1-year and 2-year progression-free survival (PFS) of 85.5% and 78.2%, respectively. The 2-year overall survival was 83.6%. The most common adverse events (grade ≥ 3) were neutropenia (67%), anemia (67%), thrombocytopenia (49%), and neutropenic fever (35%). There were no grade 5 events. Second primary malignancy occurred in 6 patients (11%). LEN with DA-EPOCH-R for patients with DEL and DHL has a high response rate, encouraging survival, and met the primary PFS efficacy criterion. A randomized trial of DA-EPOCH-R with and without LEN would be needed to determine the specific benefit of LEN in patients with DHL and DEL. This trial was registered at www.clinicaltrials.gov (NCT02213913).
    DOI:  https://doi.org/10.1182/bloodadvances.2025017092
  2. Blood. 2025 Jul 25. pii: blood.2025028383. [Epub ahead of print]
    Safety and Efficacy of Elranatamab in Patients with Relapsed and/or Refractory immunoglobulin Light-Chain Amyloidosis.
    Pedro Vianna, Rajshekhar Chakraborty, Shahrier Hossain, Divaya Bhutani, Shannon Miller, Annemarie Rossi, Sarah Am Cuddy, Rodney H Falk, Suzanne Lentzsch, Jacob Laubach, Giada Bianchi.
      Immunoglobulin light chain (AL) amyloidosis is a plasma cell disorder characterized by progressive organ dysfunction secondary to deposition of organized immunoglobulin light chain aggregates. Achievement of rapid and deep normalization of involved immunoglobulin free light chains is necessary to maximize chances of reversibility of organ dysfunction, which in turn results in improved quality and length of life. There are no FDA-approved therapies for patients with relapsed and/or refractory immunoglobulin light chain (AL) amyloidosis. B cell maturation antigen (BCMA)-targeting bispecific T cell engagers teclistimab and elranatamab have shown high activity and acceptable safety profile in relapsed and/or refractory multiple myeloma patients, leading to their FDA approval. Herein we report on safety and efficacy of elranatamab for patients with relapsed and/or refractory AL amyloidosis. We treated 9 consecutive, advanced-stage AL amyloidosis patients with Elranatamab single agent, observing a 100% overall response and 67% complete response rate, including minimal residual disease (MRD)-negativity, with expected toxicities. Median time to hematological response was 9 days (6-24), with deep suppression in involved free light chains observed within one cycle of therapy, translating in cardiac and renal responses at 3-6 months. These data support prospective studies exploring Elranatamab in relapsed and/or refractory AL amyloidosis patients.
    DOI:  https://doi.org/10.1182/blood.2025028383
  3. Ann Hematol. 2025 Jul 29.
    Pola-R-CHP performed well in first-line Polarix trial-ineligible and IPI 0-1 DLBCL patients : Article type: research.
    Yuhong Ren, Luya Cheng, Jingli Zhuang, Zhimei Wang, Ling Yuan, Zhixiang Cheng, Yang Ke, Weiguang Wang, Jing Li, Peng Liu.
      Polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) improved progression-free survival (PFS) of diffuse large B-cell lymphoma (DLBCL) in Polarix study. But little evidence has been provided for patients with lower international prognostic index (IPI) scores or ineligible for clinical trials. We retrospectively enrolled 117 consecutive DLBCL patients aged over 18 years old who received Pola-R-CHP as first-line therapy to investigate efficacy and safety from April 1, 2023, to October 31, 2024. Polatuzumab vedotin was administered 1.8 mg/KG, rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2 or epirubicin 70 mg/m2, all intravenously on Day 1. Prednisone was given 100 mg orally once daily from Day 1 to Day 5. The primary end point was the complete response (CR) rate after 6 cycles. The median age was 56 years old (range: 18-76). Twenty-four (20.5%) patients had an IPI of 0 to 1. Fifty-seven (48.7%) patients were ineligible for Polarix trial. Forty-seven (40.2%) patients received epirubicin instead of doxorubicin. After a median follow-up of 7.1 months (95% CI: 5.967-8.800), CR rate after 6 cycles was 80.6% in all 72 patients who have reached the primary end point, 91.7% in IPI 0-1 subgroup, and 73.5% in Polarix-ineligible subgroup. Lung infection, neutropenia, and leukopenia were the most common grade 3 to 5 adverse events, accounting for 20.5%, 17.9%, and 12.8%. Dose modification of polatuzumab vedotin occurred in 4 patients in Polarix-ineligible group, and 1 in Polarix-eligible group. Pola-R-CHP performed well in first-line Polarix trial-ineligible and IPI 0-1 DLBCL patients with manageable safety.
    Keywords:  Diffuse large B-cell lymphoma; First-line; Low risk; Polatuzumab vedotin; Trial-ineligible
    DOI:  https://doi.org/10.1007/s00277-025-06526-4
  4. Ann Hematol. 2025 Jul 31.
    Gene expression analysis of patients with chronic myeloid leukemia who discontinued tyrosine kinase inhibitor.
    Hyunkyung Park, Hyeong-Joon Kim, Sang-Kyun Sohn, Yoonsuk Baik, Dongho Kim, Sung-Yeoun Lee, Jee Hyun Kong, Hawk Kim, Dong-Yeop Shin, Jae-Sook Ahn, Jinny Park, Seonyang Park, Inho Kim.
      The immunological mechanism of treatment-free remission is not clearly understood. We aimed to identify immune-related genetic differences that predict molecular relapse after tyrosine kinase inhibitor (TKI) discontinuation in patients with chronic phase chronic myeloid leukemia (CML). In this prospective multicenter study, patients who were treated with TKI for at least 3 years discontinued TKI and were monitored for loss of major molecular response. We used NanoString profiling to find gene expression differences associated with relapse. From August 2019 to April 2020, 42 patients were enrolled from five centers in South Korea. During the median follow-up of 16.9 months, 47.6% (20/42) of patients experienced molecular relapse. The 6- and 12-month molecular relapse-free survival (RFS) rates were 52.5% and 50%, respectively. The e14a2 transcript type and longer duration (≥ 50 months) of deep molecular response before TKI discontinuation were associated with longer molecular RFS. NanoString analysis revealed significant differences in immune-related gene expression between relapsed and non-relapsed patients at the time of TKI discontinuation, including T cell-related genes such as SIGLEC1, ARG2, CD160, and IFNG. In conclusion, differences in expression of immune-related genes may provide a prognostic marker for relapse after TKI discontinuation in patients with CML.
    Keywords:  Chronic myeloid leukemia; Generic difference; NanoString method; Treatment-free remission; Tyrosine kinase inhibitor
    DOI:  https://doi.org/10.1007/s00277-025-06514-8
  5. Clin Cancer Res. 2025 Jul 29.
    A Phase I Trial of Evorpacept, Lenalidomide and Rituximab for Patients with B-cell Non-Hodgkin Lymphoma.
    Paolo Strati, Lei Feng, Andrey Tyshevich, Darya Shavronskaya, Julia Alesse, Noel English, Elizabeth Sheehan, Nikita Syzrantsev, Alexander Nesmelov, Tony Z Zhuang, Dai Chihara, Jason R Westin, Sairah Ahmed, Luis E Fayad, Jared Henderson, Kylie Dent, Elizabeth McChesney, Sattva S Neelapu, Christopher R Flowers.
       INTRODUCTION: SIRPα+ macrophages can mediate resistance to lenalidomide and rituximab (R2) in patients with B-cell non-Hodgkin lymphoma (B-NHL). Evorpacept (ALX148) is a novel CD47 blocker that abrogates interactions between lymphoma cells and SIRPα+ macrophages.
    METHODS: Adult patients with B-NHL who had received at least 2 prior lines of systemic therapy were included in this single arm phase I study (NCT05025800). Evorpacept was administered intravenously (IV), in a 28-day cycle, until progression, at two dose levels (DL): 30 mg/Kg on day (D) 1 and D15 (DL1), or 60 mg/Kg on day 1 (DL2); rituximab 375 mg/m2 IV was given weekly during cycle 1, and on D1 during cycles 2-6; lenalidomide 20 mg was given orally on D1-21 during cycles 1-6. Single-cell RNA sequencing was performed on tumor biopsies collected before treatment and during cycle 1.
    RESULTS: Twenty patients were included in this study. Median age was 61 (27-85) years and 18 (90%) had indolent B-NHL. Three patients were treated at DL1, 17 at DL2, and no dose limiting toxicity was observed. The most common grade 3-4 adverse events included: neutropenia (60%), infections (30%), and alanine transferase increase (15%). Sixteen (80%) patients achieved complete response and after a median follow-up of 28 months 2-year progression-free survival rate was 69%. During treatment, a significant increase in T cells and macrophages was observed, and macrophages pathways associated with anti-tumoral activity were upregulated.
    CONCLUSIONS: ER2 has a safe toxicity profile, promising anti-tumoral activity, and induces favorable biological effects on the tumoral immune microenvironment.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-25-1826
  6. Blood. 2025 Jul 31. 146(5): 521-522
    HSCs with the "SUPER" power to make blood forever.
    Edyta E Wojtowicz.
      
    DOI:  https://doi.org/10.1182/blood.2025029511
  7. Br J Haematol. 2025 Jul 25.
    A phase Ib/II trial combining brentuximab vedotin with cyclophosphamide, procarbazine, prednisone, etoposide and mitoxantrone (BrEPEM) for older patients with untreated classical Hodgkin lymphoma: A multicentre GELTAMO trial.
    Cecilia Carpio, Fátima de la Cruz-Vicente, Ramon García-Sanz, Izaskun Zeberio, Cristina Barrenetxea, Eva Domingo-Domenech, Mariana Bastos, Araceli Rubio Martinez, Pilar Gómez-Prieto, Antonia Rodriguez, Maria Casanova, Antonia Cladera-Serra, Javier Nuñez Cespedes, Carmen Martínez, Miriam Moreno-Velázquez, Eduardo Garcia-Galea, Pau Abrisqueta, Francesc Bosch.
      Classical Hodgkin lymphoma (cHL) has high curability following initial standard treatments. A less favourable outcome is observed in patients aged ≥60 (poorer tolerability and efficacy). Low-intensity chemotherapies are currently employed for this group of patients, although there is still a need for improvement. This phase Ib/II multicentre, single-arm study evaluated the safety and efficacy of the combination of brentuximab vedotin with cyclophosphamide, prednisolone, procarbazine, etoposide, mitoxantrone (BrEPEM) in older untreated patients with cHL. Forty patients were enrolled (6 phase Ib; 34 phase II). Median age was 73 years (range: 67-88), 93% stage III/IV and median Cumulative Illness Rating Scale-Geriatric (CIRS-G) was 5 (range: 1-28). The median follow-up was 43.2 months. The most common adverse events were haematological toxicities (neutropenia G ≥3: 32%). During treatment, five patients died from infections. Per protocol/intention-to-treat analysis showed an overall response of 93%/63% and a complete response of 89%/60% respectively. Median progression-free survival (PFS) and overall survival (OS) were 14.3 months (95% confidence interval [CI] = 11.5-not reached [NR]) and NR (95% CI = 29.5-NR) respectively. Estimated 2-year PFS and OS were 44% (95% CI = 31-62) and 69% (95% CI = 56-85) respectively. BrEPEM is an alternative option for older untreated cHL patients, albeit not exempt from toxicity. Studies directed to better patient selection are needed to improve survival and mitigate toxicities.
    Keywords:  Hodgkin's lymphoma; brentuximab vedotin; first line; older; treatment
    DOI:  https://doi.org/10.1111/bjh.70028
  8. Blood. 2025 Jul 30. pii: blood.2025028803. [Epub ahead of print]
    XPO1 Drives Resistance to Eprenetapopt and Azacitidine and Can Be Targeted in TP53-Mutated Myeloid Malignancies.
    Traci L Kruer, Ariel Quintana-Gonzalez, Hannah L Newman, Meghan C Ferrall-Fairbanks, Ling Zhang, Amy F McLemore, Surendra Neupane, Qin Yang, Nana Adjoa Ben-Crentsil, Maria E Balasis, Christopher T Letson, Rami S Komrokji, Sana Chaudhry, Tulasigeri M Totiger, Joshua A Traina, Maria E Figueroa, Christopher B Ryder, Thomas Cluzeau, Justin Taylor, David A Sallman, Eric Padron.
      TP53 mutated myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are among the most aggressive and chemotherapy refractory myeloid neoplasms with a median overall survival of less than 6 months. An enormous unmet need exists to develop novel therapeutic strategies and understand resistance mechanisms to suboptimal existing therapies for this disease. In two parallel phase 2 clinical trials that combined eprenetapopt with azacitidine in TP53 mutated MDS/AML, we observed complete remission rates of 40-50% and molecular remission rates of 38%. However, unless allogeneic stem cell transplantation was performed, relapse inevitably occurred. To understand the mechanisms of secondary resistance responsible for this, we genotyped sequential clinical trial samples, conducted a genome-wide CRISPR screen in TP53 mutated leukemia cells, and identified XPO1 as a therapeutically tractable mediator of resistance. We demonstrate that XPO1 is overexpressed in patient samples after eprenetapopt and azacitidine treatment, elucidate the mechanism by which this occurs, and determine that it is necessary and sufficient for resistance to combination therapy. Finally, we validate in a variety of model systems including a novel patient derived xenograft model of TP53 mutant MDS, that eprenetapopt in combination with XPO1 inhibitors can overcome this resistance, providing preclinical rationale that this novel combination strategy is a viable therapeutic approach in TP53 mutant MDS/AML patients.
    DOI:  https://doi.org/10.1182/blood.2025028803
  9. Blood. 2025 Jul 30. pii: blood.2024028205. [Epub ahead of print]
    Final analysis of the RESONATE-2 study: up to 10 years of follow-up of first-line ibrutinib treatment for CLL/SLL.
    Jan A Burger, Paul M Barr, Tadeusz Robak, Carolyn Owen, Alessandra Tedeschi, Anita Sarma, Piers Em Patten, Sebastian Grosicki, Helen McCarthy, Fritz Offner, Edith Szafer Glusman, Cathy Zhou, Anita Szoke, Lynne Neumayr, James P Dean, Paolo Ghia, Thomas Kipps.
      With up to 10 years of follow-up, we report results from the final analysis of RESONATE-2 (NCT01722487/NCT01724346), a phase 3 study of first-line ibrutinib versus chlorambucil for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Patients aged ≥65 years with previously untreated CLL/SLL without del(17p) were randomly assigned to receive either single-agent ibrutinib (420 mg/day; n = 136) or chlorambucil (0.5-0.8 mg/kg ≤12 cycles; n = 133) until disease progression/unacceptable toxicity. With a median follow-up of 9.6 in the ibrutinib arm, median PFS was 8.9 years (95% CI, 7.0-NE) versus 1.3 years (95% CI, 0.9-1.6) for the chlorambucil arm. Among patients with unmutated IGHV, del(11q), mutated TP53, or complex karyotype median PFS was 8.4 years (95% CI, 6.8-NE) with ibrutinib and 0.7 years (95% CI, 0.4-1.2) with chlorambucil. Median overall survival (OS) with ibrutinib was not reached. Most common adverse events (AEs) of any grade included diarrhea (52%), fatigue (41%), cough (39%), nausea (32%), arthralgia (31%), peripheral edema (31%), and hypertension (30%). During the entire study period, 34/136 patients (25%) had an ibrutinib dose reduction due to AEs; these AEs improved in 30/34 patients (88%). At study completion, 27% of patients remained on first-line ibrutinib treatment. With the longest follow-up to date from a phase 3 study of any targeted CLL/SLL therapy, this landmark RESONATE-2 study defines median PFS and demonstrates continued OS benefit of first-line ibrutinib treatment for patients with CLL/SLL, including those with high-risk genomic features. Sustained efficacy and tolerability of ibrutinib reemphasize the favorable benefit-risk profile.
    DOI:  https://doi.org/10.1182/blood.2024028205
  10. Blood. 2025 Aug 01. pii: blood.2025029773. [Epub ahead of print]
    Sequential Targeting in Multiple Myeloma: Talquetamab, a GPRC5D bispecific antibody, as a Bridge to BCMA CAR-T cell therapy.
    Binod Dhakal, Othman Salim Akhtar, David Fandrei, Alexandria Jensen, Rahul Banerjee, Darren Pan, Shambavi Richard, Reed Friend, Matthew James Rees, Patrick Costello, Mariola Alejandra Vazquez Martinez, Oren Pasvolsky, Charlotte B Wagner, James A Davis, Omar A Castaneda Puglianini, Ran Reshef, Aimaz Afrough, Danai Dima, Manisha Bhutani, Omar Nadeem, Ricardo D Parrondo, Ciara L Freeman, Lekha Mikkilineni, Shahzad Raza, Larry D Anderson, Prashant Kapoor, Hitomi Hosoya, Saurabh Chhabra, Ariel Grajales-Cruz, Mahmoud R Gaballa, Shonali Midha, Melissa Alsina, Douglas W Sborov, Krina K Patel, Yi Lin, Christopher J Ferreri, Nico Gagelmann, Anupama Deepa Kumar, Doris K Hansen, Andrew J Cowan, Luciano J Costa, Maximilian Merz, Surbhi Sidana.
      Ciltacabtagene autoleucel (cilta-cel) and idecabtagene vicleucel (ide-cel), two BCMA-directed chimeric antigen receptor T cell (CAR-T) therapies, have transformed outcomes for relapsed/refractory multiple myeloma (RRMM); however, the 6-8 weeks manufacturing time risks disease progression or death in up to 10% of patients, highlighting the need for effective bridging strategies. Talquetamab, a GPRC5D-targeting bispecific antibody, represents a promising option. We performed a multi-institutional retrospective analysis across 20 centers (18 US, 2 Germany) evaluating talquetamab as a bridging therapy prior to cilta-cel or ide-cel. Among 134 patients receiving talquetamab, 119 proceeded to CAR-T (n=98 cilta-cel, n=21 ide-cel). Reasons for not proceeding (n=15) included progression (n=7), manufacturing failure (n=6), or patient decision (n=2). Median age was 65 years; patients had received a median 5 prior lines of therapy. High-risk cytogenetics and extramedullary disease were present in 44% and 41% respectively. Notably, 85% would not have met CARTITUDE-1/KarMMa eligibility criteria. Talquetamab was administered for a median 23 days (82% at 0.8 mg/kg biweekly). Toxicity was manageable: no grade ≥3 CRS, 2% grade 3 ICANS and grade 1-2 Talq unique toxicities (70% oral, 38% skin, 17% nail; 60% resolved). Talquetamab achieved 71% response rate. Post CAR-T 88% responded (54% complete response), with low-grade toxicities (2 grade≥3 CRS, 1 grade 3 ICANS and 5% grade≥3 infections). Two cases of facial palsy and one AML occurred. Talquetamab correlated with sustained soluble BCMA decline and peak CAR-T expansion around day 14. Talquetamab bridging appears safe enabling the majority of difficult to treat patients to successfully proceed to BCMA CAR-T therapy.
    DOI:  https://doi.org/10.1182/blood.2025029773
  11. Oncologist. 2025 Jul 30. pii: oyaf237. [Epub ahead of print]
    Considerations for the Practical Management of Cardiovascular Risk With Bruton's Tyrosine Kinase Inhibitors for Patients With CLL.
    Daniel Lenihan, Michelle Bloom, Robert Copeland-Halperin, Matthew R Fleming, Michael Fradley, Rupal O'Quinn, Seema A Bhat.
       BACKGROUND: Bruton's tyrosine kinase inhibitors (BTKis) are central to the medical management of chronic lymphocytic leukemia (CLL). However, accumulating data suggest an important association with cardiovascular (CV) adverse events (AEs), including arrhythmias, hypertension, and bleeding, in patients with CLL and other hematological malignancies treated with this therapeutic class. Data from comparative trials with BTKis suggest second-generation agents, eg, acalabrutinib and zanubrutinib, may be associated with fewer CV AEs than first-in-class BTKi ibrutinib.
    METHODS: PubMed and the proceedings of key hematology congresses were searched for relevant information using broad search terms including CLL, BTKi, and toxicity.
    RESULTS: When managing patients with CLL, screening before and during treatment to assess CV risk is suggested to guide decision-making. Due to the increased toxicity with ibrutinib, the second-generation BTKis are now preferred (per the NCCN Clinical Practice Guidelines in Oncology [NCCN Guidelines®]). For patients with a high CV-risk, the decision between second-generation BTKi or a time-limited alternative, like venetoclax plus an anti-CD20 monoclonal antibody, should be made on an individual basis after patient consultation and consideration of the presenting characteristics of CLL in any given patient. The management of anticoagulant/antiplatelet medication during BTKi treatment requires specific attention, with coexistent medications being carefully assessed before starting a BTKi to reduce the risk of bleeding. For patients with a new-onset or worsening CV events during BTKi therapy, management may involve temporarily stopping the BTKi or switching to another class of therapy. To ensure the best outcomes, a collaborative care approach is essential, and some patients may need to be referred to a cardiologist/cardio-oncologist for specialist management.
    CONCLUSION: Baseline and ongoing CV risk assessment, careful monitoring, management, and a multidisciplinary team approach are all critical to ensure optimal oncologic and CV outcomes for patients with CLL receiving BTKis.
    Keywords:  Bruton’s tyrosine kinase inhibitor; arrhythmia; cardiovascular; chronic lymphocytic leukemia; hemorrhage; hypertension
    DOI:  https://doi.org/10.1093/oncolo/oyaf237
  12. Blood. 2025 Jul 31. 146(5): 522-523
    HLH: it is all about communication.
    Rafal Machowicz, Paul La Rosée.
      
    DOI:  https://doi.org/10.1182/blood.2025029620
  13. Blood Cancer J. 2025 Jul 30. 15(1): 126
    Activity of CAR-T cells and bispecific antibodies in multiple myeloma with extramedullary involvement.
    Maximilian J Steinhardt, Christoph Schaefers, Lisa B Leypoldt, Igor-Wolfgang Blau, Marie Harzer, Xiang Zhou, Christine Riedhammer, Abdulaziz Kamili, Ricardo Kosch, Laura S Topp, Isabel Molwitz, Nils-Ole Gross-Fengels, Yasmin Fede Melzer, Jule Artzenroth, Maximilian Al-Bazaz, Winfried Alsdorf, Max S Topp, Johannes Duell, Julia Mersi, Johannes Waldschmidt, Carsten Bokemeyer, Hermann Einsele, K Martin Kortüm, Katja Weisel, Leo Rasche.
      Extramedullary multiple myeloma (EMD) is associated with low response rates, short progression-free survival, and poor prognosis. CAR T cells and bispecific antibodies (bsABs) have shown efficacy in relapsed myeloma, but it remains uncertain whether one T cell redirection strategy should be preferred. We retrospectively analyzed 80 patients with EMD not adjacent to the bone treated with ide-cel, cilta-cel, teclistamab, or talquetamab at three academic centers in Germany. All patients were heavily pretreated, and a high-risk cytogenetic profile was prevalent in >41% of patients. All cohorts had a median of 5 to 7 prior lines of therapy. The vast majority of patients receiving cilta-cel, ide-cel, or teclistamab were BCMA-naive ( >88%). Response rates after CAR T cell infusion were significantly higher (100% with cilta-cel, 82% with ide-cel) than with bsABs (29% for talquetamab, 36% for teclistamab). Complete resolution of EMD was more frequent after CAR T cell therapies (50% and 41%) than after bsABs (16% and 14%). With a median follow-up of 12.2 months, median (m)PFS was not reached in patients that had received cilta-cel; mPFS was 7.3 months after ide-cel and significantly longer for both CAR T products compared to talquetamab or teclistamab (mPFS 4.0 and 2.6 months). Effective debulking therapy prolonged remissions after CAR T cell infusion compared to no debulking or no response to debulking. Visceral and soft tissue manifestations responded significantly less frequently than EMD in other locations. With significantly higher response rates, deeper remissions, and longer mPFS, our retrospective data suggest CAR T cells may provide a meaningful benefit in EMD.
    DOI:  https://doi.org/10.1038/s41408-025-01330-9
  14. Blood. 2025 Jul 29. pii: blood.2025028594. [Epub ahead of print]
    Time to complete remission is an independent determinant of survival after intensive chemotherapy in AML.
    Rithin Nedumannil, Michael Ashby, James P Rowland, Jacques A J Malherbe, Jared Fairbank, Kelli Gray, Sun Loo, Matthew Wright, John Reynolds, Devendra K Hiwase, Paula Marlton, Shaun A Fleming, Ashish Bajel, Andrew H Wei.
      The purpose of this study was to explore and determine the optimal landmark for defining complete remission after intensive induction therapy that best correlates with long-term survival outcome among patients with newly diagnosed acute myeloid leukemia (AML).
    DOI:  https://doi.org/10.1182/blood.2025028594
  15. Hematol Transfus Cell Ther. 2025 Jul 30. pii: S2531-1379(25)00226-3. [Epub ahead of print]47(3): 103958
    A dream or reality: Consideration of 'bloodless' hematopoietic stem cell transplants for Jehovah's witness patients.
    Michael MacNeill, Adrienne Fulford, Deanna Caldwell, Uday Deotare.
       BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is an important part of treatment for many hematologic conditions. The high-dose chemotherapy used in HSCTs puts patients at risk of significant cytopenias which often necessitate blood product transfusions. Certain populations, including Jehovah's Witnesses, are unable to receive blood product transfusions during their transplant and thus, in the past, they have been seen as unsuitable candidates for transplantations. However, there has been growing evidence of the safety and efficacy of so-called "bloodless" HSCT protocols.
    METHODS: The most recent and relevant literature on "bloodless" transplants were identified through Embase, MEDLINE, and PubMed, and analyzed to construct a "bloodless" HSCT protocol at a Canadian centre. Since 2021, the regimen was utilized for four autologous transplantations in three different Jehovah's Witness patients.
    RESULTS: None of the patients had a significant bleeding event nor a hemoglobin nadir below 8.0 g/dL. Minor bleeding events, predominantly mucositis, resolved with site-specific management. No patient had significant thrombocytopenia, and all the cell lines of patients had normalized without transfusions by the time of discharge. All patients were hospitalized for <30 days, similar to the experience of the centre with "regular" autologous transplants.
    CONCLUSION: Careful planning and tailored regimens support the achievability of "bloodless" HSCTs in patients, such as Jehovah's Witnesses, allowing practitioners to provide care to a previously excluded group and minimize the use of blood products in all HSCT patients.
    Keywords:  Autologous hematopoietic stem cell transplantation; Jehovah’s witness; Multiple myeloma; Non-hodgkin’s lymphoma; Transfusion
    DOI:  https://doi.org/10.1016/j.htct.2025.103958
  16. Int J Mol Sci. 2025 Jul 16. pii: 6836. [Epub ahead of print]26(14):
    The Efficacy of Polatuzumab Vedotin Targeting CD79B in the Treatment of Non-Hodgkin Lymphoma: A Systematic Review and Meta-Analysis.
    Samiyah Alshehri, Bushra Khan, Najeeb Ullah Khan, Ahsanullah Unar.
      Polatuzumab vedotin (PoV) is a novel antibody-drug conjugate that targets CD79B for the treatment of Non-Hodgkin Lymphoma (NHL). This meta-analysis aimed to evaluate the efficacy and safety of PoV in patients with NHL. A systematic review and meta-analysis of clinical trials evaluating PoV in NHL were conducted. The primary outcomes were complete response (CR) rates, progression-free survival (PFS), and overall survival (OS). Safety outcomes were also assessed. Random-effects models were used for the pooled analyses. Thirteen studies with 1533 patients with NHL were included. PoV significantly improved CR rates compared to control treatments (OR 1.50, 95% CI 1.01-2.21, p = 0.04) and PFS (MD 4.17 months, 95% CI 2.18-6.15, p < 0.0001). OS was not significantly different (OR 0.97, 95% CI 0.47-2.01, p = 0.93). Adverse events were more common with PoV (RR 1.38, 95% CI 0.98-1.94, p < 0.0001). PoV improves CR rates and PFS in patients with NHL, particularly those with relapsed/refractory disease, but is associated with increased adverse events. Further research is needed on long-term survival outcomes and optimal patient selection. PoV appears to be a promising targeted therapy option for NHL, which warrants further investigation.
    Keywords:  CD79B; antibody-drug conjugate; non-Hodgkin lymphoma; overall survival; polatuzumab vedotin
    DOI:  https://doi.org/10.3390/ijms26146836
  17. Signal Transduct Target Ther. 2025 Jul 26. 10(1): 232
    Genetic subtype-guided immunochemotherapy in relapsed and refractory diffuse large B cell lymphoma: a phase 2 investigator-initiated nonrandomized clinical trial (GUIDANCE-06).
    Yi-Ge Shen, Qing Shi, Wei Tang, Peng-Peng Xu, Yi-Wen Cao, Meng-Meng Ji, Zhong Zheng, Shu Cheng, Li Wang, Wei-Li Zhao.
      Improving the outcome of relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) remained an unmet need. The aim of this single-center, phase 2 trial was to evaluate the efficacy and safety of genetic subtype-guided immunochemotherapy (R-ICE-X) in patients with R/R DLBCL: R-ICE-zanubrutinib for MCD-like and BN2-like, R-ICE-lenalidomide for N1-like and NOS, R-ICE-decitabine for TP53Mut, R-ICE-chidamide for EZB-like, and R-ICE-tofacitinib for ST2-like subtype. Enrolled patients were treated with assigned regimens for three cycles, and then responders were treated with autologous hematopoietic stem cell transplantation (ASCT) or 3 cycles of R-ICE-X consolidation and lenalidomide maintenance. The primary endpoint was the complete response (CR) rate. The secondary endpoints included overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety assessment. Between April 26, 2022, and July 31, 2024, 76 patients were enrolled, with 74 adhering to and 2 deviating from the protocol. Among all, the CR rate was 56.6% (95% CI, 45.2-68.0%), and the ORR was 76.3% (95% CI, 66.5-86.1%) at the end of induction. With a median follow-up of 19.5 months, the 2-year PFS rate was 69.3% (95% CI, 56.6-79.0%), and the 2-year OS rate was 88.3% (95% CI, 77.6-94.0%). The primary grade 3-4 adverse events were neutropenia (30%) and thrombocytopenia (25%). The presence of bulky disease and CD70 mutation was linked to poor prognosis. Further gene set enrichment analysis revealed that up-regulated PI3K-AKT-mTOR signaling pathway and reduced immune cell infiltration were significantly associated with disease progression. Patients with mesenchymal or inflammatory lymphoma microenvironment subtypes benefited from R-ICE-X treatment. Our findings highlight the efficacy and safety of R-ICE-X, a mechanism-based tailored therapy, which dually targets genetic and microenvironmental alterations in R/R DLBCL.
    DOI:  https://doi.org/10.1038/s41392-025-02316-6
  18. J Investig Allergol Clin Immunol. 2025 Jul 30. 0
    Tyrosine Kinase Inhibitors for the Treatment of Mast Cell Diseases: Review and Update.
    L V Carpio-Escalona, A Prieto-García, C Morales-Cabeza, M Guilarte, A Matito, I Torrado, A Vega-Castro, D González-de-Olano.
      Mast cell diseases (MCDs) comprise several entities that are characterized by activation and/or proliferation of mast cells (MCs), leading to the appearance of cardinal symptoms. Such activation may be due to exaggerated functioning of MCs or to a mutation in a tyrosine kinase (usually the D816V mutation in KIT), which is a characteristic feature of systemic mastocytosis (SM) and/or clonal MC activation syndromes. Depending on the MC burden and tissue infiltration, SM can be classified as advanced or nonadvanced. Traditionally, the treatment of MCDs has been based on best supportive care. In cases of advanced SM that responds poorly to best supportive care, management can also take the form of non-target-directed cytoreductive treatment, administration of monoclonal antibodies, targeted therapies, and even bone marrow transplantation. The advance of personalized medicine has led to the emergence of new and more specific tyrosine kinase inhibitors (TKIs), which achieve greater symptom control and improve disease course, sometimes leading to remission. In recent years, clinical trials have been carried out to evaluate the effectiveness of some of these TKIs in nonadvanced forms of mastocytosis, with eventual approval for this subtype in some cases. TKIs represent a major advance in the management of MCDs, with more patients being able to benefit from a treatment that addresses pathophysiology. We review the main TKIs currently available for SM, their indications, and their safety and effectiveness.
    Keywords:  Avapritinib; Bezuclastinib; Elenestinib; Imatinib; Masitinib; Mast cell; Mastocytosis; Midostaurin
    DOI:  https://doi.org/10.18176/jiaci.1077
  19. Ann Hematol. 2025 Jul 28.
    Next-generation Bruton tyrosine kinase inhibitors and degraders in the treatment of B-cell malignancies: advances and challenges.
    Yao Wang, Yaping Zhang, Jiaqi Liu, Yongning Jiang, Jianyong Li, Wenyu Shi.
      Bruton tyrosine kinase (BTK), a key component of B-cell receptor signaling, is crucial for the development of B-cell malignancies. Covalent BTK inhibitors (cBTKis), such as ibrutinib, have demonstrated remarkable efficacy, but their curative potential is limited by acquired resistance. Next-generation BTK inhibitors, including non-covalent BTK inhibitors and BTK Proteolysis-targeting chimeras, offer new options for patients who have developed resistance to cBTKis. Some of these inhibitors have shown favorable efficacy and safety profiles, leading to Food and Drug Administration approval. This review summarizes the current landscape of BTK inhibitors, focusing on the evolution from cBTKis to next-generation inhibitors in terms of clinical efficacy and challenges, such as resistance mechanisms and off-target effects. We conclude with an outlook on future research and clinical applications.
    Keywords:  B-cell malignancies; BTK PROTACs; Bruton tyrosine kinase; Efficacy; Non-covalent BTK inhibitors; Safety
    DOI:  https://doi.org/10.1007/s00277-025-06515-7
  20. Blood. 2025 Jul 31. 146(5): 528-530
    Targeting JAK-STAT in macrophage activation syndrome-no MAS!
    Paresh P Kulkarni, Keith R McCrae.
      
    DOI:  https://doi.org/10.1182/blood.2025029681
  21. Blood Adv. 2025 Jul 30. pii: bloodadvances.2025016284. [Epub ahead of print]
    Ixazomib decreases the risk of chronic graft-versus-host disease: identification of cGvHD biomarkers.
    Teresa Caballero-Velázquez, Javier Delgado-Serrano, Lucia López-Corral, Christelle Ferrá I Coll, Clara Beatriz García-Calderón, David Valcárcel, Irene García Cadenas, Estefanía Pérez López, Maria-Jose Jimenez, Francisco Manuel Martín-Domínguez, María de Los Reyes Jiménez-Leon, Guillermo Orti, Virginia Escamilla Gómez, Cristina Blázquez-Goñi, Almudena Cabero Martínez, Henry Antonio Andrade Ruiz, Estefanía Menéndez-Pedregal, Fermín M Sánchez-Guijo, Jose Antonio Pérez-Simón.
      Chronic graft-versus-host disease (cGvHD) is the leading cause of long-term morbi-mortality after allogeneic transplantation (allo-HSCT). We hypothesize that it is possible to decrease its risk by manipulating the immune response in late phases of transplantation. We performed a prospective randomized trial including 73 patients. Patients in the treatment arm received 4 mg of Ixazomib (IXZ) every 28 days from day +100. With a median follow-up of 24 months, the cumulative incidence of moderate/severe cGvHD in the IXZ vs control groups at 1 and 2 years were: 3.23% vs 30.2%, HR=0.089, p=0.02 and 13% vs 43% HR=0.23, p=0.01, respectively. Estimates for cGvHD and relapse free survival (GRFS) at 2 years were 81% for IXZ and 49% for control group, HR = 0.30. Increased STAT3 and p38 phosphorylation in T cells, higher proportion of B cells that have undergone immunoglobulin isotype switching and circulating plasma cells on day +180 were associated with a significantly higher risk of developing moderate/severe cGvHD. The administration of Ixazomib decreases the risk of moderate/severe cGvHD. It is possible to identify biological patterns by flow cytometry to predict the risk of cGvHD. ClinicalTrials.gov Identifier: NCT03225417.
    DOI:  https://doi.org/10.1182/bloodadvances.2025016284
  22. N Engl J Med. 2025 Jul 31. 393(5): 498-500
    Opening the Door to Tailored Treatment in Newly Diagnosed Multiple Myeloma.
    Paul G Richardson, Nikhil C Munshi, Dan L Longo.
      
    DOI:  https://doi.org/10.1056/NEJMe2507131
  23. Blood. 2025 Jul 29. pii: blood.2024025482. [Epub ahead of print]
    How I treat patients with CLL after prior treatment with a covalent BTK inhibitor and a BCL-2 inhibitor.
    Mazyar Shadman, Matthew S Davids.
      The treatment landscape for chronic lymphocytic leukemia (CLL) has been revolutionized by the advent of novel agents, particularly covalent BTK inhibitors (cBTKis) and BCL-2 inhibitors (BCL-2is). This has resulted in significant improvement in outcome of patients with CLL many of whom experience a life expectancy comparable to general population. However, patients who are double-refractory, having progressed following exposure to both classes face limited options and poor outcomes. This manuscript presents a practical approach to managing double-exposed or double-refractory CLL, integrating clinical case discussions, trial data, and expert insights. For patients with intolerance to cBTKis, second-generation agents may remain effective. Similarly, re-treatment with venetoclax can be considered after prior fixed-duration use. In double-refractory disease, the non-covalent BTK inhibitor (e.g., pirtobrutinib) and CD19-directed CAR-T therapy (lisocabtagene maraleucel) are available standard-of-care options. Pirtobrutinib provides rapid disease control but often with limited durability, emphasizing the importance of early planning for consolidation with CAR-T or allogeneic stem cell transplant. Persistent disease after CAR-T warrants close follow-up and timely referral for transplant evaluation in eligible patients. While PI3K inhibitors are also available, their role is limited due to toxicity and modest efficacy. Investigational agents-including BTK degraders, bispecific antibodies, and novel cellular therapies-offer promise for the future. A nuanced, individualized treatment strategy that incorporates current therapies and emerging options is essential to optimize outcomes in double-refractory CLL.
    DOI:  https://doi.org/10.1182/blood.2024025482
  24. Clin Lymphoma Myeloma Leuk. 2025 Jun 23. pii: S2152-2650(25)00221-6. [Epub ahead of print]
    Moving Towards the Delivery of Outpatient T-Cell Engaging Therapy for the Management of Multiple Myeloma.
    Maya Rosenberg, Lauren Scarpetti, Gareth J Morgan, Faith E Davies.
      Bispecific antibodies (BsAbs) and chimeric antigen receptor T-cells (CAR-T) are T-cell engagers (TCEs) becoming increasingly important for treatment of multiple myeloma. The purpose of this paper is to review TCE side effects and their management. In doing so, we will demonstrate that outpatient delivery of TCEs can be safe and advantageous for patients and healthcare systems. The initial introduction of TCE therapy has been limited to the inpatient setting due to risk of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). These complications, which typically occur in the first few weeks of initiating therapy, are mediated by an exaggerated inflammatory response triggered by TCE binding to tumor cells. BsAb trials have demonstrated a high overall incidence of CRS, though severe cases are rare as is development of ICANS. The incidence and severity of CRS and ICANS seem to be higher with CAR-T therapy. Predictors of development and severity of CRS and ICANS include disease bulk, lymphodepletion strategy, CAR-T construct used, and pattern of expression of the tumor antigen. Prevention strategies include step-up dosing, disease bulk reduction, prophylactic steroid use and premedication. Treatment strategies include the use of steroids and cytokine binders/blockers, such as anti-IL6 and anti-IL1 agents. Effective prophylaxis and management of CRS and ICANS has reduced the impact of these complications and opened the potential for outpatient delivery. Outpatient delivery of TCEs is possible with appropriate preventative strategies, education, and established pathways for prompt transition to inpatient management if needed.
    Keywords:  Bispecific antibody; CAR-T; Clinical management; Cytokine release syndrome (CRS); Immune effector cell-associated neurotoxicity syndrome (ICANS)
    DOI:  https://doi.org/10.1016/j.clml.2025.06.013
  25. Leukemia. 2025 Aug 01.
    The bone marrow immune ecosystem shapes daratumumab acquired resistance in plasma cell myeloma.
    Yun Wang, Shuzhao Chen, Zhijian Liang, Robert Peter Gale, Shutong Liu, Xiaoqin Chen, Peidong Chi, Yiling Song, Yingchun Zhang, Weida Wang, Juan Li, Zhongjun Xia, Yang Liang, Xiaojun Huang.
      Daratumumab, an anti-CD38 monoclonal antibody, is an effective therapy for plasma cell myeloma (PCM). However, many initial responders relapse. We compared paired samples from subjects pre-therapy and then acquired resistance to daratumumab. We first used single-cell RNA sequencing and digital spatial profiler (DSP). The proportion of cytotoxic CD8-positive T-cells with an exhaustion phenotype and an IFN-γ signature increased in resistance compared with pre-therapy samples, whilst the proportion of NK-cells decreased and had an increased inhibitory phenotype. Transcription of CD38 in neoplastic plasma cells decreased. Numbers of immune cells in cancer centre defined by DSP were significantly decreased in parallel with an increased exhaustion signature. The acquired resistance signature and elevated PCM subset phenotype were associated with worse prognosis in 4 external cohorts (GSE24080, GSE136337, GSE57317, and coMMpass). Using single-cell regulatory network inference, we identified MYC regulation as a key activated factor for acquired resistance in neoplastic plasma cells by intersecting the top 20 upregulated regulons and upregulated genes in acquired resistance. Furthermore, data from in vitro and in vivo experiments indicate that IFN-γ secreted by cells of bone marrow immune ecosystem activates MYC, which correlates with acquired daratumumab resistance. Our data provide insights into acquired daratumumab resistance and suggest potential therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41375-025-02712-5
  26. Cancers (Basel). 2025 Jul 11. pii: 2314. [Epub ahead of print]17(14):
    Molecular Pathways and Targeted Therapies in Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL).
    Jonathan Weiss, Shannon A Carty, Yasmin H Karimi.
      There have been multiple approved agents for relapsed/refractory (r/r) Diffuse Large B-cell Lymphoma (DLBCL) over the last 8 years. The majority of these therapies act on specific signaling pathways in malignant B-cells. These signaling pathways stem from the B-cell receptor (BCR), Toll-Like Receptor (TLR), PI3K/AKT/mTOR, BCL-2, and XPO-1. In addition, novel therapies that target extracellular proteins (CD19, CD20, CD30, ROR1, and PD-1) have been developed. The purpose of this review is to discuss the various therapies that target these pathways and highlight the success and shortcomings of these novel agents.
    Keywords:  BCR; CD19; CD30; PD-1; ROR1; TLR; XPO-1; immunotherapy; non-Hodgkins; signaling; targeted therapy
    DOI:  https://doi.org/10.3390/cancers17142314
This page is being maintained by Thomas Krichel. It was last updated on 2025‒08‒16 at 11:06.