bims-hemali 2025-08-17 papers

bims-hemali

Biomed News

on Hematologic malignancies

Issue of 2025–08–17
twenty-two papers selected by
Alexandros Alexandropoulos, Γενικό Νοσοκομείο Αθηνών Λαϊκό

Clinical Features and T-Cell Repertoire of Chronic Myeloid Leukemia Patients Who Attempt Discontinuation of Tyrosine Kinase Inhibitors: The ISAC-TFR Study.
Camidanlumab Tesirine for Relapsed or Refractory Classic Hodgkin Lymphoma: A Phase 2 Study.
Outcomes and patterns of relapse with ponatinib-based therapy in patients with chronic myeloid leukemia in myeloid blast phase.
Treatment-Free Remission in Ph+ ALL Without Allogeneic Stem Cell Transplantation: Current Evidence and Future Directions.
Cardiovascular Disease in Patients With Chronic Myeloid Leukemia: JACC: CardioOncology State-of-the-Art Review.
Treatment-free remission in chronic myeloid leukaemia patients with accelerated phase or tyrosine kinase inhibitor therapy failure.
Outcomes of immune checkpoint inhibitor rechallenge in relapsed/refractory Hodgkin lymphoma.
Comparative real-world outcomes of CD19-directed CAR T-cell therapies in large B-cell lymphoma.
Design, Docking Analysis, and Structure-Activity Relationship of Ferrocene-Modified Tyrosine Kinase Inhibitors: Insights into BCR-ABL Interactions.
Efficacy of intensive antiemetic therapy including olanzapine in multiple myeloma patients treated with high-dose melphalan with autologous stem cell transplantation.
"Linc-ing" RNA isoforms to function in multiple myeloma.
Giving ALL a SMAC down (and HDAC down) towards cell death.
What platelets tell us about CARs.
Rest, then rejuvenate: CD19 boost to improve CAR persistence.
Imetelstat: A First-in-Class Telomerase Inhibitor for the Treatment of Patients With Lower-Risk Myelodysplastic Syndromes and Anemia.
A roadmap to implementing outpatient administration of bispecific antibodies in multiple myeloma.
Treatment of Relapsed and Refractory Follicular Lymphoma: Which Treatment for Which Patient for Which Line of Therapy?
The Evolving Treatment Landscape for the Elderly Multiple Myeloma Patient: From Quad Regimens to T-Cell Engagers and CAR-T.
CD70-CAR-Ts: a second wind for high-risk myeloma.
VEXAS: A review of current understandings and emerging treatment strategies.
Chilling Controversy: Cold-Stored Platelets for Prophylactic Transfusions.
Evaluating rilzabrutinib in the treatment of immune thrombocytopenia.

Cancer Med. 2025 Aug;14(15): e71142

Clinical Features and T-Cell Repertoire of Chronic Myeloid Leukemia Patients Who Attempt Discontinuation of Tyrosine Kinase Inhibitors: The ISAC-TFR Study.

Hiroshi Ureshino, Yukio Nakamura, Yemima Budirahardja, Iwao Nozawa, Keisuke Kidoguchi, Kazuharu Kamachi, Shinya Kimura.

   BACKGROUND: While tyrosine kinase inhibitor (TKI) discontinuation is an established therapeutic goal, up to 60% of patients relapse after the first attempt. The feasibility of a second or third attempt at TKI discontinuation remains uncertain. Immune surveillance, particularly T-cell and natural killer (NK) cell responses, may influence treatment-free remission (TFR), although no definitive biomarkers for predicting sustained TFR have been identified.
METHODS: This retrospective study included 57 chronic myeloid leukemia (CML) patients who attempted TKI discontinuation. Clinical outcomes after the first, second, and third TFR attempts were analyzed, and T cell receptor (TCR) and B-cell receptor (BCR) repertoire analyses were conducted on peripheral blood samples from 14 patients to investigate the immune landscape associated with TFR.
RESULTS: TFR1 at 1 year was 67.9% (95% confidence interval [CI], 53.9%-78.4%). Sixteen patients attempted a second discontinuation, achieving a 1-year TFR2 rate of 31.2% (95% CI, 11.4%-53.6%). Patients maintaining BCR::ABL1 mRNA levels below MR4.5 at 3 months post-TKI discontinuation had a significantly lower risk of relapse (HR, 0.099; 95% CI, 0.012-0.829; p = 0.033). TCR repertoire analysis did not reveal distinct clonal expansions of T cells; however, a significant age-related decline in T-cell diversity was observed.
CONCLUSION: T-cell immunity in CML patients who have achieved a deep molecular response (DMR) may closely approximate that observed in healthy individuals.

Keywords:  T‐cell immunology; T‐cell receptor repertoire; treatment‐free remission; tyrosine kinase inhibitorchronic myeloid leukemia

DOI:  https://doi.org/10.1002/cam4.71142
Blood Adv. 2025 Aug 14. pii: bloodadvances.2024015600. [Epub ahead of print]

Camidanlumab Tesirine for Relapsed or Refractory Classic Hodgkin Lymphoma: A Phase 2 Study.

Alex F Herrera, Stephen M Ansell, Pier Luigi Zinzani, John Radford, Kami J Maddocks, Antonio Pinto, Graham P Collins, Veronika Bachanova, Nancy L Bartlett, Isabelle Bence-Bruckler, Mehdi Hamadani, Justin Kline, Jiri Mayer, Kerry J Savage, Ranjana H Advani, Paolo F Caimi, Olivier Casasnovas, Tatyana A Feldman, Brian T Hess, Mariana Bastos-Oreiro, Sunil Iyengar, Árpád Szomor, William Townsend, Marc André, Jerzy Dyczkowski, Karin Havenith, Marie Toukam, Serafino Pantano, Hans G Cruz, Luqiang Wang, Yanina Negievich, Melanie Lucero, Jens U Wuerthner, Carmelo Carlo-Stella.

Outcomes in classic Hodgkin lymphoma (cHL) have steadily improved; however, additional therapies are needed for patients who relapse or do not respond to novel agents. Here, we report the efficacy and safety of camidanlumab tesirine (Cami), an anti-CD25 antibody-drug conjugate, in patients with relapsed/refractory cHL following brentuximab vedotin/programmed cell death protein 1 inhibitor therapies from the phase 2 ADCT-301-201 study. Eligible patients were adults with cHL who had received ≥3 prior lines of systemic therapy (or ≥2 if ineligible for hematopoietic stem cell transplant). Patients received 45 μg/kg Cami (intravenously, once every 3 weeks [Q3W]) in cycles 1 to 2, followed by 30 μg/kg IV Q3W for ≤1 year. The primary endpoint was overall response rate (ORR) per 2014 Lugano Classification. Secondary endpoints included complete response rate (CRR), progression-free survival (PFS), and overall survival (OS). In total, 117 patients were enrolled with a median age of 37.0 (range, 19, 87) years. The ORR was 70.1% (95% CI, 60.9, 78.2) with a CRR of 33.3% (24.9, 42.6). The median PFS was 9.13 (95% CI, 5.3, 15.0) months; median OS was not reached. Thirty-three (28.2%) patients discontinued treatment because of treatment-emergent adverse events; the most common reasons were skin and subcutaneous tissue disorders (10 [8.5%] patients), infections and infestations (5 [4.3%]), and nervous systems disorders (5 [4.3%]). Guillain-Barré- or polyradiculopathy-type events occurred in 8 (6.8%) patients. Cami was efficacious in this heavily pretreated population; however, the efficacy was overshadowed by substantial issues with the safety profile. NCT04052997.

DOI: https://doi.org/10.1182/bloodadvances.2024015600
Leuk Lymphoma. 2025 Aug 09. 1-8

Outcomes and patterns of relapse with ponatinib-based therapy in patients with chronic myeloid leukemia in myeloid blast phase.

Omer Karrar, Hagop Kantarjian, Fadi G Haddad, Roberta S Azevedo, Ghayas Issa, Farhad Ravandi, Koji Sasaki, Jayastu Senapati, Hussein Abbas, Sara Dellasala, Elias Jabbour, Nicholas J Short.

  We analyzed 76 patients who received a ponatinib-based regimen, either as monotherapy or in combination with chemotherapy, for chronic myeloid leukemia in myeloid blast phase (CML-MBP). The rate of morphological remission with or without count recovery (i.e. overall response rate [ORR]) was 49%. Patients who received a ponatinib-based regimen as their first therapy for CML-MBP had better ORR than those received ponatinib as salvage (60% versus 27%, respectively; p = 0.006). ORR was also higher with ponatinib combination therapy than monotherapy (54% versus 29%, respectively; p = 0.06). For the entire cohort, the median RFS and OS were 11.9 and 8.5 months, respectively. Responding patients who underwent allogeneic HSCT had superior outcomes to those who did not (2-year OS 79% versus 38%, respectively; p = 0.05). After ponatinib failure, outcomes were dismal (median OS: 3.9 months). Ponatinib-based regimens are effective in CML-MBP, especially when used as first therapy and in combination with chemotherapy, followed by HSCT.

Keywords:  Ponatinib; chronic myeloid leukemia; combination therapy; myeloid blast phase; prognosis

DOI:  https://doi.org/10.1080/10428194.2025.2542946
Cancers (Basel). 2025 Jul 25. pii: 2457. [Epub ahead of print]17(15):

Treatment-Free Remission in Ph+ ALL Without Allogeneic Stem Cell Transplantation: Current Evidence and Future Directions.

Martina Canichella, Malgorzata Monika Trawinska, Carla Mazzone, Paolo de Fabritiis, Elisabetta Abruzzese.

  Over the past two decades, the treatment landscape of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) has undergone a profound transformation. Once considered the subtype with the worst prognosis, Ph+ ALL is now associated with the possibility of long-term survival in a significant proportion of patients. This dramatic improvement has been driven by the advent of tyrosine kinase inhibitors (TKIs) and, more recently, by the incorporation of blinatumomab, a bispecific T-cell engager antibody, into frontline therapeutic strategies. In this evolving context, two major areas have become the focus of clinical investigation: on the one hand, the identification of high-risk patients who truly benefit from allogeneic hematopoietic stem cell transplantation (allo-HSCT); on the other, the characterization of patients who can achieve durable responses without transplantation and who may be candidates for treatment discontinuation of TKIs. This review aims to summarize the current evidence supporting the concept of treatment-free remission (TFR) in Ph+ ALL.

Keywords:  acute lymphoblastic leukemia Philadelphia positive (Ph+ ALL); blinatumomab; treatment-free remission (TFR); tyrosin kinase inhibitors (TKIs)

DOI:  https://doi.org/10.3390/cancers17152457
JACC CardioOncol. 2025 Aug 13. pii: S2666-0873(25)00250-9. [Epub ahead of print]

Cardiovascular Disease in Patients With Chronic Myeloid Leukemia: JACC: CardioOncology State-of-the-Art Review.

Nazanin Aghel, Jeffrey Howard Lipton.

  Cardiovascular (CV) disease and risk factors are notably prevalent among patients with chronic myeloid leukemia (CML). The introduction of BCR::ABL1 tyrosine kinase inhibitors has significantly transformed the treatment paradigm for CML. However, it is imperative to recognize that these therapeutic agents may lead to CV side effects. For instance, dasatinib has been associated with the development of pulmonary arterial hypertension, while nilotinib and ponatinib have been linked to various vascular complications. To accurately evaluate the incidence of CV events associated with CML treatment, systematic documentation of these occurrences in future clinical trials is essential. This approach will facilitate a deeper understanding of the CV implications of tyrosine kinase inhibitor therapy in patients with CML.

Keywords:  cardiovascular disease; chronic myeloid leukemia; coronary artery disease; imatinib; leukemia; nilotin; peripheral arterial disease; peripheral vascular disease; ponatinib; pulmonary hypertension; tyrosine kinase inhibitor

DOI:  https://doi.org/10.1016/j.jaccao.2025.06.007
Br J Haematol. 2025 Aug 13.

Treatment-free remission in chronic myeloid leukaemia patients with accelerated phase or tyrosine kinase inhibitor therapy failure.

Mengyao Yuan, Yanli Zhang, Bingcheng Liu, Li Zhou, Yu Zhu, Zhenling Li, Shaolei Zang, Zhenfang Liu, Weiming Li, Qian Jiang.

  We studied 60 chronic myeloid leukaemia (CML) patients with a prior history of accelerated phase (AP) including de novo AP (n = 19) and transformation to AP (n = 4), or tyrosine kinase inhibitor (TKI) therapy failure in the chronic phase (CP, n = 37), who discontinued TKI therapy. Median interval from diagnosis with AP or TKI therapy failure to achieving a deep molecular response (DMR) was 19 months (interquartile range [IQR], 9-30 months). Median TKI treatment and DMR duration were 108 months (IQR, 72-137 months) and 59 months (IQR, 39-87 months) respectively. At a median follow-up of 21 months (IQR, 11-36 months) after TKI discontinuation, 19 (31%) patients lost the major molecular response (MMR). The 3-year probability of a sustained MMR was 59% (95% confidence interval [CI], [45%, 78%]). In the multivariable analyses, age at discontinuation <32 years (hazard ratio [HR] = 4.1 [1.3, 12.7], p = 0.014) and BCR::ABL1 >0.1% at 12 months on TKI therapy (reference, ≤0.1%; HR = 3.9 [1.4, 11.5], p = 0.011) were significantly associated with a higher probability of MMR loss after TKI discontinuation. CML patients with a history of AP or TKI therapy failure may achieve successful treatment-free remission after an adequate TKI therapy duration and a sustained DMR.

Keywords:  accelerated phase; chronic myeloid leukaemia; therapy failure; treatment‐free remission; tyrosine kinase inhibitor

DOI:  https://doi.org/10.1111/bjh.70080
Blood Neoplasia. 2025 Aug;2(3): 100134

Outcomes of immune checkpoint inhibitor rechallenge in relapsed/refractory Hodgkin lymphoma.

Yoshito Nishimura, Yiqun Han, Nadia Toumeh, Guneet Janda, Yu Fujiwara, Urshila Durani, Grzegorz S Nowakowski, Jonas Paludo, Stephen M Ansell, Jithma P Abeykoon.

Immune checkpoint inhibitors (ICIs) have revolutionized therapy for relapsed/refractory (R/R) Hodgkin lymphoma (HL). Some patients discontinue ICIs after initial response or owing to immune-related adverse events (AEs). Efficacy and safety of ICI rechallenge, defined as reintroducing ICIs after previous discontinuation, remain unclear. A systematic literature search was performed through 10 January 2025, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PROSPERO CRD42023403204). Studies reporting outcomes of ICI rechallenge in patients with R/R HL were included. Data on overall response rate (ORR), complete response (CR) rate, progression-free survival (PFS), and treatment-related AEs were extracted. Pooled response rates and 95% confidence intervals (CIs) were calculated. A total of 207 patients from 17 studies were included. The pooled ORR was 63% (95% CI, 55-70) with a CR rate of 43% (95% CI, 35-52). Median PFS after rechallenge was 13.3 months (95% CI, 7.9-18.8). Any-grade and grade 3 to 5 AEs occurred in 47% (95% CI, 17-80) and 31% (95% CI, 23-40), respectively. ICI rechallenge in R/R classic HL can lead to high response rates and durable remissions comparable with uninterrupted ICI therapy with acceptable safety profiles. This strategy may be a viable option, although careful patient selection and monitoring are still necessary.

DOI: https://doi.org/10.1016/j.bneo.2025.100134
Blood Adv. 2025 Aug 15. pii: bloodadvances.2025016778. [Epub ahead of print]

Comparative real-world outcomes of CD19-directed CAR T-cell therapies in large B-cell lymphoma.

Xavier Deschênes-Simard, Maria Bromberg, Sean M Devlin, Mithat Gonen, Ofrat Beyar-Katz, Andrew Ip, Ronit Marcus, Abraham Avigdor, Annamaria Ballweg, Emma Rabinovich, Mohammad Alhomoud, Alfredo Rivas-Delgado, Magdalena Corona De Lapuerta, Alejandro Luna De Abia, M Lia Palomba, Gunjan L Shah, Richard J Lin, Alexander P Boardman, Lorenzo Falchi, Jennifer K Lue, Gilles A Salles, Miguel-Angel Perales, Roni Shouval, Parastoo B Dahi, Michael Scordo.

Although 3 commercial CD19-targeted CAR T-cell therapies are available for large B-cell lymphoma (LBCL), no randomized clinical trials have compared their efficacy and safety. In this retrospective multicenter cohort study, we evaluated real-world clinical outcomes of patients with relapsed/refractory LBCL treated with axicabtagene ciloleucel (axi-cel), tisagenlecleucel (tisa-cel), or lisocabtagene maraleucel (liso-cel). Between April 2016 and July 2024, 624 patients received CD19-targeted CAR T-cell therapies (344 axi-cel, 142 tisa-cel, and 138 liso-cel). At a median follow-up of 20.9 months, estimated 2-year PFS and OS rates were 46%/63% for axi-cel, 30%/45% for tisa-cel, and 45%/58% for liso-cel. After adjusting for potential confounders in multivariable analyses, tisa-cel was associated with inferior progression-free survival (PFS) (hazard ratio [HR] = 2.25; 95% confidence interval [CI]: 1.65-3.06; p < 0.001) and overall survival (OS) (HR = 1.68; 95% CI: 1.19-2.36; p = 0.003) compared to axi-cel. No significant survival differences were found between liso-cel and axi-cel. Propensity score and subanalyses of patients treated in the second-line vs. third-line or later settings yielded similar outcomes. Compared to axi-cel, the objective response rate at 100 days was higher for liso-cel (odds ratio [OR] = 2.31; 95% CI: 1.21-4.80; p = 0.016) and lower for tisa-cel (OR = 0.36; 95% CI: 0.23-0.57; p < 0.001). Rates of CRS, ICANS, ICAHT, and febrile neutropenia were significantly higher with axi-cel. However, no significant differences in the cumulative incidence of infections or non-relapse mortality were found. Axi-cel was associated with faster vein-to-vein time (axi-cel: 35 days, tisa-cel: 43 days, liso-cel: 41 days; p < 0.001) and fewer out-of-specification products (axi-cel: 2%, tisa-cel: 4%, liso-cel: 11%; p = 0.004). These results provide insights into potential differential outcomes depending on product selection.

DOI: https://doi.org/10.1182/bloodadvances.2025016778
Molecules. 2025 Jul 24. pii: 3101. [Epub ahead of print]30(15):

Design, Docking Analysis, and Structure-Activity Relationship of Ferrocene-Modified Tyrosine Kinase Inhibitors: Insights into BCR-ABL Interactions.

Irena Philipova, Mariyana Atanasova, Rositsa Mihaylova, Asine Dailova-Barzeva, Stefan M Ivanov, Rumyana L Simeonova, Georgi Stavrakov.

  Ferrocene (Fc), a redox-active organometallic scaffold, has attracted significant attention in medicinal chemistry due to its favorable physicochemical and pharmacological properties. The present study explores the therapeutic potential of novel Fc-functionalized analogues of imatinib and nilotinib, aimed at targeting BCR-ABL1+ chronic myeloid leukemia (CML) cells. A series of Fc-based derivatives (compounds 6, 9, 14, and 18) were synthesized by systematically substituting key pharmacophoric regions of the parent tyrosine kinase inhibitors with Fc units. The antiproliferative activity of these compounds was evaluated against four BCR-ABL1-positive leukemia cell lines (K-562, BV-173, AR-230, and LAMA-84), with imatinib serving as a reference drug. Biological assays revealed distinct structure-activity relationships. Compounds 6 and 9 demonstrated superior activity against the K-562 cell line, while compounds 14 and 18 exhibited enhanced potency and higher ligand efficiencies (LEs) against BV-173 and AR-230 cells compared to imatinib. Selectivity assays further indicated favorable toxicity profiles of compounds 9 and 14 toward malignant versus non-malignant cells. Molecular docking studies supported these findings, showing that Fc substitution alters binding interactions within the c-Abl kinase ATP-binding site while retaining key stabilizing contacts. Computationally predicted LEs showed strong correlation with experimental data, especially for K-562 and LAMA-84 cells, confirming the kinase as a relevant target.

Keywords:  bcr-abl; ferrocene; imatinib; leukemia; nilotinib; organometallic chemistry; tyrosine kinase inhibitors

DOI:  https://doi.org/10.3390/molecules30153101
Support Care Cancer. 2025 Aug 11. 33(9): 777

Efficacy of intensive antiemetic therapy including olanzapine in multiple myeloma patients treated with high-dose melphalan with autologous stem cell transplantation.

Junpei Kato, Masashi Uchida, Masayuki Ishikawa, Shinya Tatsuta, Takeshi Yoshimi, Kota Ishida, Osamu Hosoya, Nobuhiro Tsukada, Tadao Ishida, Yuki Shiko, Yohei Kawasaki, Shingo Yamazaki, Itsuko Ishii.

   PURPOSE: Conditioning with high-dose melphalan (MEL) followed by autologous stem cell transplantation (ASCT) is the standard treatment for multiple myeloma (MM). The optimal regimen to prevent chemotherapy-induced nausea and vomiting (CINV) is unclear. We aimed to retrospectively evaluate the antiemetic effect and safety of a four-drug intensive regimen including olanzapine (OLA) on CINV in MM patients receiving MEL/ASCT.
METHODS: MEL (200 mg/m2) was administered on day 1, followed by ASCT on day 3. Patients were classified into the standard group (palonosetron and dexamethasone on day 1, and aprepitant on day 1-3), and the intensive antiemetic regimen (IAR) group (palonosetron on day 1, dexamethasone on day 1-2, and aprepitant, and OLA on day 1-5). The primary endpoint was defined as no vomiting and no rescue medications (complete response) in the delayed phase (day 2-5).
RESULTS: There were no significant differences in baseline characteristics between the OLA (n = 68) and standard (n = 54) groups. The complete response rate in the IAR group was significantly higher in the delayed phase (52.9% vs. 31.4%, p < 0.05). Multivariate analysis revealed that the IAR was associated with the complete response rate (OR, 2.34; 95% CI, 1.09-5.00; p = 0.028). The incidence of nausea (grade 3) in the delayed phase was lower in the IAR group (44.1% vs. 75.9%, p < 0.001).
CONCLUSION: The four-drug intensive regimen including OLA may improve the antiemetic effect on delayed CINV while also ensuring safety in MM patients undergoing MEL/ASCT.

Keywords:  Autologous stem cell transplantation multiple myeloma; Chemotherapy-induced nausea and vomiting; High-dose melphalan; Olanzapine

DOI:  https://doi.org/10.1007/s00520-025-09839-2
Blood. 2025 Aug 14. 146(7): 773-774

"Linc-ing" RNA isoforms to function in multiple myeloma.

Xabier Agirre, Felipe Prósper.

DOI: https://doi.org/10.1182/blood.2025029743
Blood. 2025 Aug 14. 146(7): 774-775

Giving ALL a SMAC down (and HDAC down) towards cell death.

Sarah K Tasian.

DOI: https://doi.org/10.1182/blood.2025029478
Blood. 2025 Aug 14. 146(7): 771-773

What platelets tell us about CARs.

Peter Dreger.

DOI: https://doi.org/10.1182/blood.2025029480
Blood. 2025 Aug 14. 146(7): 767-768

Rest, then rejuvenate: CD19 boost to improve CAR persistence.

Rayne H Rouce.

DOI: https://doi.org/10.1182/blood.2025029272
J Adv Pract Oncol. 2025 Jun 25. 1-7

Imetelstat: A First-in-Class Telomerase Inhibitor for the Treatment of Patients With Lower-Risk Myelodysplastic Syndromes and Anemia.

Hetalkumari Patel, Selamawit Yohannes, Elissa Brunaugh.

Imetelstat is a first-in-class, direct, and competitive inhibitor of telomerase enzymatic activity that selectively induces apoptosis of malignant clones and allows for recovery of erythropoiesis. Imetelstat was approved by the United States Food and Drug Administration in June 2024 and the European Medicines Agency in March 2025 for the treatment of certain patients with lower-risk (low to intermediate-1) myelodysplastic syndromes (LR-MDS) with transfusion-dependent anemia who have failed or lost response to or are ineligible for erythropoiesis-stimulating agents. Imetelstat is infused at 7.1 mg/kg (active dose, equivalent to 7.5 mg/kg sodium salt) intravenously over 2 hours once every 4 weeks. In the pivotal IMerge trial in LR-MDS, significantly more patients treated with imetelstat vs. placebo, respectively, achieved ≥ 8-week RBC-transfusion independence (TI; 40% [95% confidence interval [CI] = 30.9-49.3] vs. 15% [95% CI = 7.1-26.6]) and ≥ 24-week RBC-TI (28% [95% CI = 20.1-37.0] vs. 3% [95% CI = 0.4-11.5]). The safety profile of imetelstat was characterized primarily by cytopenias, including neutropenia (incidence of 74% any grade and 68% grade 3-4 events) and thrombocytopenia (75% and 62%, respectively). Grade 3 to 4 hematologic events occurred early in the treatment and had a median duration of 1.9 weeks for neutropenia and 1.4 weeks for thrombocytopenia; cases resolved to grade ≤ 2 within 2 weeks in 81% and 86% of cases, respectively, with limited severe complications. This review highlights key topics related to the use of imetelstat in patients with LR-MDS, including its mechanism of action, clinical efficacy and safety data, dosing and administration, management of adverse events, and notable clinical practice implications.

DOI: https://doi.org/10.6004/jadpro.2025.16.7.22
Front Oncol. 2025 ;15 1630146

A roadmap to implementing outpatient administration of bispecific antibodies in multiple myeloma.

Alfred L Garfall, Rahul Banerjee, Laurent Frenzel, Cyrus Khandanpour, Yi Lin, Erica Ottoni, Robert Rifkin, Sarah Rockwell, Cesar Rodriguez, Humberto Villefort, Elena Zamagni.

   Introduction: Bispecific antibodies (BsAbs) are novel immunotherapy agents for the treatment of relapsed/refractory multiple myeloma (RRMM). Currently, 3 BsAbs (teclistamab, talquetamab, and elranatamab) are approved for the treatment of RRMM. Administering BsAbs in different practice settings is crucial to improving treatment access and patient outcomes. This report provides actionable guidance to implement safe and effective administration of BsAbs for patients with RRMM in outpatient and community settings.
Methods: Three clinician advisory workshops were held in the United States, Europe, and Latin America to discuss key factors to operationalize BsAb use in outpatient and community settings, focusing on the critical phases of practice setup, treatment initiation, and ongoing management.
Results: BsAb administration in outpatient and community settings requires careful planning, a well-prepared multidisciplinary team (MDT) of healthcare professionals, and clear protocols, including MDT composition, roles/responsibilities, capacity planning, patient selection criteria, step-up dosing procedure, admission processes, patient/caregiver education requirements, and adverse event (AE) monitoring/management. Comprehensive MDT training on protocols and preparedness to manage AEs is essential. Patients initiating outpatient BsAb therapy should have a reliable caregiver, access to a hospital, controlled comorbidities, and no active infections. Ensuring patients and caregivers understand the benefits, risks, and expectations of BsAb therapy is vital for successful treatment and a positive patient experience.
Conclusion: Administering BsAbs in outpatient and community settings can be done safely and effectively with appropriate planning and protocols. Enabling safe and effective BsAb administration in these settings is essential to ensure more patients with RRMM have access to treatment and improved outcomes.

Keywords:  bispecific antibodies; bispecifics; multiple myeloma; outpatient; talquetamab; teclistamab

DOI:  https://doi.org/10.3389/fonc.2025.1630146
Blood. 2025 Aug 14. pii: blood.2024026018. [Epub ahead of print]

Treatment of Relapsed and Refractory Follicular Lymphoma: Which Treatment for Which Patient for Which Line of Therapy?

Carla Casulo, Laurie H Sehn.

Recent advances have transformed the treatment landscape for relapsed and refractory follicular lymphoma. While chemotherapy has long served as the backbone of treatment, the availability of novel targeted, immunomodulatory and immunotherapeutic approaches is challenging its relevance. These approaches have focused on targeting epigenetic regulators, components of the B-cell receptor or its downstream intracellular pathways, and the follicular lymphoma tumor microenvironment. The recent development of bispecific antibodies and chimeric antigen receptor T-cell therapies, which target both tumor-associated and host-specific antigens, has enabled a redirection of the immune system, enhancing the innate anti-tumor immune response. Rational combinations of these strategies are actively being evaluated in the relapsed and refractory setting and will inevitably move forward into earlier lines of treatment. The success of these approaches has led to numerous and parallel options for patients and clinicians. The emerging challenge now lies in how best to approach each individual patient with relapsed or refractory follicular lymphoma, addressing complex decision-making that considers a patient's prior treatment history, goals of care, clinical and biological characteristics of recurrence, as well as personal preferences. Understanding the implications of refractory and transformed disease, as well as the timing and biology of relapse will be critical to support a more personalized treatment approach in the modern era.

DOI: https://doi.org/10.1182/blood.2024026018
Cancers (Basel). 2025 Aug 05. pii: 2579. [Epub ahead of print]17(15):

The Evolving Treatment Landscape for the Elderly Multiple Myeloma Patient: From Quad Regimens to T-Cell Engagers and CAR-T.

Matthew James Rees, Hang Quach.

  Multiple myeloma (MM) is predominantly a disease of the elderly. In recent years, a surge of highly effective plasma cell therapies has revolutionized the care of elderly multiple myeloma (MM) patients, for whom frailty and age-related competing causes of mortality determine management. Traditionally, the treatment of newly diagnosed elderly patients has centered on doublet or triplet combinations composed of immunomodulators (IMIDs), proteasome inhibitors (PIs), anti-CD38 monoclonal antibodies (mAbs), and corticosteroids producing median progression-free survival (PFS) rates between 34 and 62 months. However, recently, a series of large phase III clinical trials examining quadruplet regimens of PIs, IMIDs, corticosteroids, and anti-CD38 mAbs have shown exceptional outcomes, with median PFS exceeding 60 months, albeit with higher rates of peripheral neuropathy (≥Grade 2: 27% vs. 10%) when PIs and IMIDs are combined, and infections (≥Grade 3: 40% vs. 29-41%) with the addition of anti-CD38mAbs. The development of T-cell redirecting therapies including T-cell engagers (TCEs) and CAR-T cells has further expanded the therapeutic arsenal. TCEs have shown exceptional activity in relapsed disease and are being explored in the newly diagnosed setting with promising early results. However, concerns remain regarding the logistical challenges of step-up dosing, which often necessitates inpatient admission, the infectious risks, and the financial burden associated with TCEs in elderly patients. CAR-T, the most potent commercially available therapy for MM, offers the potential of a 'one and done' approach. However, its application to elderly patients has been tempered by significant concerns of cytokine release syndrome, early and delayed neurological toxicity, and its overall tolerability in frail patients. Robust data in frail patients are still needed. How CAR-T and TCEs will be sequenced among the growing therapeutic armamentarium for elderly MM patients remains to be determined. This review explores the safety, efficacy, cost, and logistical barriers associated with the above treatments in elderly MM patients.

Keywords:  CAR-T therapy; T cell engagers; elderly; immunomodulatory agents; multiple myeloma; proteasome inhibitors

DOI:  https://doi.org/10.3390/cancers17152579
Blood. 2025 Aug 14. 146(7): 769-771

CD70-CAR-Ts: a second wind for high-risk myeloma.

Luis Gerardo Rodríguez-Lobato, Carlos Fernández de Larrea.

DOI: https://doi.org/10.1182/blood.2025029577
Front Immunol. 2025 ;16 1644404

VEXAS: A review of current understandings and emerging treatment strategies.

Robert Holden, Yogeshraj Jeelal, Andrew McLean-Tooke, Kylan Pathmanathan, David Nolan.

  VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome is a late-onset autoinflammatory disorder, typically affecting males, caused by somatic mutations in the X-linked gene UBA1 encoding the E1 ubiquitin-activating enzyme. These mutations result in defective ubiquitination and dysregulation of protein degradation, leading to Endoplasmic Reticulum stress and activation of innate immune pathways. This leads to significant inflammatory manifestations including fever, chondritis, neutrophilic dermatoses, and cytopenia's and a range of inflammatory manifestations that define the clinical syndrome. Alongside these autoinflammatory manifestations, VEXAS exhibits features of clonal haematopoiesis, with clonal dominance of UBA1-mutant haematopoietic stem and progenitor cells with preferential myeloid differentiation and impaired generation of megakaryocytes, erythroid and lymphoid cells. The convergence of somatic mutation, inflammation, and bone marrow failure situates VEXAS at the interface of autoinflammation and hematologic neoplasia. Therapeutic approaches have focused on immunosuppression (e.g., corticosteroids, IL-6 inhibitors, JAK inhibitors), though these often yield only partial responses. Targeted therapies aimed at the mutant clone-including hypomethylating agents are under investigation. Allogeneic hematopoietic stem cell transplantation remains the only curative strategy. This review synthesises recent genetic, cellular, and clinical advances to consider VEXAS as an age-related proteosomopathy that unites clonal haematopoiesis with innate-immune dysregulation and provides appraisal of both established immunomodulators and emerging clone-directed therapies in addition to advocating harmonised response criteria, thereby offering a cohesive roadmap for future mechanistic studies and trial design in this rapidly evolving field.

Keywords:  VEXAS; VEXAS syndrome; autoinflamatory diseases; myelodyslastic syndromes; myeloid cells

DOI:  https://doi.org/10.3389/fimmu.2025.1644404
Blood. 2025 Aug 11. pii: blood.2025029252. [Epub ahead of print]

Chilling Controversy: Cold-Stored Platelets for Prophylactic Transfusions.

Moritz Stolla, Andrew P Cap, Philip C Spinella.

The FDA recently licensed 14-day cold-stored platelets for bleeding patients. This policy change represents a reversal from the 1970s when cold-stored platelets were discontinued because of their short circulation time in healthy humans. This change will increase their availability in US hospitals with large trauma populations and in remote and rural settings in the U.S. In some of these hospitals, cold-stored platelets will be the only platelets available. It is currently unclear whether patients with hypoproliferative thrombocytopenia who need platelet transfusion for prophylaxis benefit from cold-stored platelets. However, it is noteworthy that in recent clinical trials using room temperature-stored platelets, the transfusion interval in hematology-oncology patients can be as short as one transfusion per day, very similar to what one would expect to achieve with cold-stored platelets. Furthermore, the emphasis on the post-transfusion count increment and the platelet count as transfusion trigger per se is questionable. In the PLADO trial, there was only a poor correlation between the morning platelet count and bleeding events, implicating other factors, such as red blood cells, coagulation factors, and vascular health, as possible culprits. In this perspective article, we review the history of cold platelets and the reason for their discontinuation, focus on recent clinical trial data using room temperature-stored platelets, and review the platelet count as a transfusion trigger. Overall, using cold platelets for prophylaxis may seem counterintuitive, but a closer look at the available data suggests that the indication expansion may hold more promise.

DOI: https://doi.org/10.1182/blood.2025029252
Immunotherapy. 2025 Aug 11. 1-16

Evaluating rilzabrutinib in the treatment of immune thrombocytopenia.

David J Kuter, Waleed Ghanima.

  There is an unmet need for newer treatment options in immune thrombocytopenia (ITP) that address its underlying complex immune dysregulation, induce durable platelet responses, are well tolerated, and improve fatigue and overall quality of life. Rilzabrutinib, an oral, reversible covalent Bruton tyrosine kinase (BTK) inhibitor, is effective through its multi-immune modulation mechanisms by inhibiting B-cell activation, possibly decreasing autoantibody production, preventing FcγR-mediated phagocytosis in the spleen and liver, and reducing chronic inflammation.Preclinical studies of rilzabrutinib in immune-mediated disease settings demonstrated high selectivity, full reversibility, and durable BTK occupancy. Oral rilzabrutinib 400 mg BID demonstrated rapid, durable platelet count increases in patients with persistent/chronic ITP in the phase 2 LUNA2 study and significantly improved durable platelet response vs placebo in the pivotal phase 3 LUNA3 trial. Additionally, rilzabrutinib improved multiple disease aspects including fatigue and bleeding with a well-tolerated safety profile.Through multi-immune modulation, rilzabrutinib achieves rapid and durable platelet response, improves fatigue, and decreases bleeding in ITP patients. It is well tolerated with an acceptable safety profile. Efficacy may be increased if administered earlier in the course of disease. Longer-term studies, and investigations in pediatric patients and other immune-mediated diseases are underway.

Keywords:  BTK inhibitor; ITP; immune thrombocytopenia; multi-immune modulation; platelet response; rilzabrutinib

DOI:  https://doi.org/10.1080/1750743X.2025.2545170