bims-hemali 2025-06-15 papers

bims-hemali

Biomed News

on Hematologic malignancies

Issue of 2025–06–15
23 papers selected by
Alexandros Alexandropoulos, Γενικό Νοσοκομείο Αθηνών Λαϊκό

Chemotherapy-free combination of ibrutinib and obinutuzumab for untreated advanced follicular lymphoma: results of a phase II study from the German Lymphoma Alliance.
Outcomes of Frontline Triplet Regimens With a Hypomethylating Agent, Venetoclax, and Isocitrate Dehydrogenase Inhibitor for Intensive Chemotherapy-Ineligible Patients With Isocitrate Dehydrogenase-Mutated AML.
Albert Schweitzer, chronic myeloid leukemia, and war.
Acute Lymphoid Leukemia: Is Transplant Indicated for Philadelphia Chromosome Positive ALL?
Non-coding RNAs: Emerging contributors to chemoresistance in chronic myeloid leukemia.
Biallelic antigen escape is a mechanism of resistance to anti-CD38 antibodies in multiple myeloma.
Lowering the Selinexor Dose within the Pomalidomide and Dexamethasone Combination Regimen Elicits Fewer Side Effects While Comparable Efficacy Against Relapsed/Refractory Multiple Myeloma.
Azacitidine, Venetoclax, and Revumenib for Newly Diagnosed NPM1-Mutated or KMT2A-Rearranged AML.
Current Advances in the Diagnosis and Treatment of Major Myeloproliferative Neoplasms.
Rilzabrutinib, the first-in-class BTK inhibitor for ITP.
The integration of blinatumomab consolidation in the CALGB 10403 regimen for adults with B-cell precursor acute lymphoblastic leukaemia in measurable residual disease-negative remission.
Efficacy and safety of Glofitamab in patients with R/R DLBCL in real life setting- a retrospective study.
Combined PET and ctDNA response as a predictor of POD24 for follicular lymphoma after first-line induction treatment.
TET3 stirs up trouble via pathogenic Ig class switching.
International Myeloma Society/International Myeloma Working Group Consensus Recommendations on the Definition of High-Risk Multiple Myeloma.
Blinatumomab and better BCR::ABL1 inhibition begets better bone marrow transplant outcomes.
Preclinical development of mecbotamab vedotin (BA3011), a novel, AXL-specific conditional active biologic antibody-drug conjugate.
Connecting the DOT1L: it's EZH2.
Predicting T-ALL response to pre-TCR and IL-7R coinhibition.
High-Risk Genetic Multiple Myeloma: From Molecular Classification to Innovative Treatment with Monoclonal Antibodies and T-Cell Redirecting Therapies.
Treatment patterns and blood count control in 10,112 patients with polycythemia vera.
Recombinant human erythropoietin plus all-trans retinoic acid and testosterone undecanoate for the treatment of anemia in patients with lower-risk myelodysplastic syndromes: a multicenter, single-arm, prospective trial.
Feasibility of Bruton's Tyrosine Kinase Inhibitor Discontinuation in Chronic Lymphocytic Leukemia: The Patient Perspective.

Haematologica. 2025 Jun 12.

Chemotherapy-free combination of ibrutinib and obinutuzumab for untreated advanced follicular lymphoma: results of a phase II study from the German Lymphoma Alliance.

Christian Schmidt, Gabriel Scheubeck, Vindi Jurinovic, Martin Sökler, Roswitha Forstpointner, Christian Buske, Andreas Viardot, Ulrich Keller, Ullrich Graeven, Reinhard Marks, Mathias Hänel, Rüdiger Liersch, Jan Dürig, Christiane Pott, Eva Hoster, Michael Unterhalt, Wolfgang Hiddemann.

Immunochemotherapy induces long-term response in patients with follicular lymphoma. However, toxicity of chemotherapy remains a relevant challenge. The Bruton's tyrosine kinase inhibitor ibrutinib has shown significant activity in patients with indolent B-cell lymphoma. Combining ibrutinib with obinutuzumab may therefore be an attractive chemotherapy free option. We conducted a prospective, single-arm, multicenter phase 2 trial to evaluate the chemotherapy-free regimen of obinutuzumab plus ibrutinib in patients with previously untreated advanced-stage follicular lymphoma. Patients received six 21-days cycles of ibrutinib and obinutuzumab for induction and 12 additional two-month cycles for maintenance. Primary endpoint was one-year progression-free survival (PFS). The study was powered to detect an improvement of 10 percent over the one-year PFS of 85%. A total of 98 patients was enrolled in the trial. Median follow-up was 5.5 years. After induction, 5 patients (5%) had a complete response (CR) and 82 (85%) a partial response (PR). The one-year PFS was 80%, missing the prospected improvement of a one-year PFS of 85% (p=0.93). Median PFS was 4.5 years, median duration of response and overall survival were not reached. The most common adverse events of grade 3/4 were neutropenia, lung infection, hypertension, fatigue, rash and thrombocytopenia. The trial failed the primary efficacy endpoint of the chemotherapyfree regimen of obinutuzumab and ibrutinib in follicular lymphoma patients. However, the combination achieved durable and deep responses and revealed an acceptable safety profile.

DOI: https://doi.org/10.3324/haematol.2024.287162
J Clin Oncol. 2025 Jun 13. JCO2500640

Outcomes of Frontline Triplet Regimens With a Hypomethylating Agent, Venetoclax, and Isocitrate Dehydrogenase Inhibitor for Intensive Chemotherapy-Ineligible Patients With Isocitrate Dehydrogenase-Mutated AML.

Courtney D DiNardo, Jennifer Marvin-Peek, Sanam Loghavi, Koichi Takahashi, Ghayas C Issa, Wei-Ying Jen, Naval G Daver, Patrick K Reville, Nicholas J Short, Koji Sasaki, Jillian K Mullin, Corey A Bradley, Gautam Borthakur, Abhishek Maiti, Yesid Alvarado, Naveen Pemmaraju, Hussein A Abbas, Danielle E Hammond, Fadi Haddad, Guillermo Montalban Bravo, Kelly S Chien, Musa Yilmaz, Steven M Kornblau, Elias Jabbour, Farhad Ravandi, Tapan Kadia, Guillermo Garcia-Manero, Marina Y Konopleva, Hagop M Kantarjian.

PURPOSE: The development of targeted therapeutics has revolutionized treatment for elderly patients with AML. Two doublet regimens are approved in the frontline setting for intensive chemotherapy (IC)-ineligible AML: venetoclax (VEN) in combination with hypomethylating agent (HMA) therapy and azacitidine (AZA) plus ivosidenib (IVO) specifically for IDH1-mutated AML. Although both regimens have improved AML outcomes, most patients will either not respond to frontline therapy or relapse, with dismal salvage outcomes.
METHODS: We herein report on 60 newly diagnosed IC-ineligible patients treated at our institution with triplet regimens for isocitrate dehydrogenase (IDH)-mutant AML. Patients received either AZA + VEN + IVO on NCT03471260 (IDH1-mutated patients only) or oral decitabine + VEN + IVO/enasidenib on NCT04774393 (arms for IDH1- and IDH2-mutant disease, respectively).
RESULTS: The triplet regimens were well tolerated with low early mortality (n = 1 [2%] in 60 days) and a similar safety profile to HMA + VEN and isocitrate dehydrogenase inhibitor doublet regimens. The composite complete remission rate (CRc) was 92% (55/60), with an overall response rate of 95% (57/60). With a median follow-up of 27.4 months, the median overall survival (OS) has not yet been reached. The 2-year OS was 69% with a 2-year cumulative incidence of relapse of 24%. Patients with treated-secondary AML (tsAML) experienced inferior outcomes with a CRc of 71% (12/17) and a 2-year OS of 34%; the 2-year OS was 84% in patients without tsAML. Nineteen patients (32%) transitioned to stem cell transplant, and 51% remain on study.
CONCLUSION: Given the excellent outcomes of IDH-triplet therapy for newly diagnosed, IC-ineligible IDH-mutant AML, further prospective studies comparing IDH-triplet versus IDH-doublet regimens are warranted.

DOI: https://doi.org/10.1200/JCO-25-00640
Oncol Res Treat. 2025 Jun 10. 1-6

Albert Schweitzer, chronic myeloid leukemia, and war.

Enrico Schalk.

DOI: https://doi.org/10.1159/000546408
Adv Exp Med Biol. 2025 ;1475 149-166

Acute Lymphoid Leukemia: Is Transplant Indicated for Philadelphia Chromosome Positive ALL?

Ryszard Swoboda, Arnon Nagler.

  Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is a distinct subtype of ALL that has historically been associated with a very poor prognosis. Allogeneic hematopoietic stem cell transplantation (alloHSCT) has improved the 5-year overall survival rate to approximately 44% and has been considered the only potentially curative treatment option for these patients. The introduction of tyrosine kinase inhibitors (TKIs) represented a breakthrough in the management of Ph+ ALL, significantly improving patient outcomes. Imatinib, the first-generation TKI, led to high complete remission (CR) rates when added to induction and consolidation chemotherapy. Next-generation TKIs, such as dasatinib and ponatinib, have also demonstrated remarkably high CR rates, even when combined with reduced-intensity chemotherapy or steroids. The advent of immunotherapies, including inotuzumab ozogamicin, blinatumomab, and chimeric antigen receptor T-cell (CAR-T) therapy, was another major milestone in Ph+ ALL treatment. The combination of TKIs with immunotherapy appears to be an optimal therapeutic strategy. Given the efficacy of these chemotherapy-free approaches, the role of alloHSCT in Ph+ ALL needs to be reassessed. Patients treated with next-generation TKIs, particularly in combination with novel immunotherapies, may achieve durable remissions without the need for alloHSCT, provided they do not harbour additional adverse cytogenetic or molecular abnormalities and achieve a deep response following induction and consolidation therapy.

Keywords:  Allogeneic hematopoietic stem cell transplantation (alloHSCT); Blinatumomab; Chemotherapy-free treatment; Chimeric antigen receptor T cell therapy (CAR-T); Immunotherapy; Inotuzumab ozogamicin; Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL); Tyrosine kinase inhibitor (TKI)

DOI:  https://doi.org/10.1007/978-3-031-84988-6_8
Leuk Res Rep. 2025 ;23 100513

Non-coding RNAs: Emerging contributors to chemoresistance in chronic myeloid leukemia.

Laya Ghadyani Nejhad, Mahsa Sohani, Nasrin Alizad Ghandforoush, Mohsen Nikbakht, Saeed Mohammadi, Mohammad Vaezi, Shahrbano Rostami, Bahram Chahardouli.

  Chronic myeloid leukemia (CML), is a myeloproliferative disease characterized by unregulated growth of blood forming cells in bone marrow and blood. The t(9;22)(q34;q11.2) translocation, which results in the formation of a hyperactive tyrosine kinase (BCR-ABL), is a hallmark of this disorder. Tyrosine kinase inhibitors such as imatinib has shown a great promise in reduction of CML cells. However, development of resistance to tyrosine kinase inhibitors has raised a great clinical concern about their future applications. Recently, non-coding RNAs, have shown to play significant regulatory roles in development of chemoresistance in CML cells. Discovering the underlying mechanisms of these non-coding RNAs might provide new opportunities for treating chemo-resistant forms of CML. These non-coding RNAs could be considered valuable therapeutic targets if they are found to play a role in the development of chemoresistance in CML cells. We mentioned the identified non-coding RNAs in development of chemoresistance in CML cells.

Keywords:  Chemoresistance; Chronic myeloid leukemia; Tyrosine kinase inhibitors; long non-coding RNAs; microRNAs

DOI:  https://doi.org/10.1016/j.lrr.2025.100513
Blood. 2025 Jun 10. pii: blood.2024028107. [Epub ahead of print]

Biallelic antigen escape is a mechanism of resistance to anti-CD38 antibodies in multiple myeloma.

Benjamin T Diamond, Linda B Baughn, Mansour Poorebrahim, Alexandra M Poos, Holly Lee, Marcella Kaddoura, J Erin Wiedmeier-Nutor, Michael A Durante, Gregory E Otteson, Dragan Jevremovic, Hongwei Tang, Stefan Fröhling, Marc-Andrea Baertsch, Marios Papadimitriou, Bachisio Ziccheddu, Tomas Jelínek, Cendrine Lemoine, Alexey Rak, Damian J Green, Carl Ola Landgren, Paola Neri, Peter Leif Bergsagel, Esteban Braggio, Shaji K Kumar, Marc S Raab, Rafael Fonseca, Nizar Bahlis, Niels Weinhold, Francesco Maura.

Monoclonal antibodies targeting CD38 are a therapeutic mainstay in multiple myeloma (MM). While they have contributed to improved outcomes, most patients still experience disease relapse, and little is known about tumor-intrinsic mechanisms of resistance to these drugs. Antigen escape has been implicated as a mechanism of tumor cell evasion in immunotherapy. Yet, it is unknown whether MM cells can develop permanent resistance to anti-CD38 antibodies by acquiring genomic events leading to biallelic disruption of the CD38 gene locus. Here, we analyzed whole genome and whole exome sequencing data from 701 newly diagnosed patients, 67 patients at relapse with naivety to anti-CD38 antibodies, and 50 patients collected at relapse following anti-CD38 antibodies. We report a loss of CD38 in 20% (10/50) of patients post-CD38 therapy, three of which exhibited a loss of both copies. Two of these cases showed convergent evolution where distinct subclones independently acquired similar advantageous variants. Functional studies on missense mutations involved in biallelic CD38 events revealed that two variants, L153H and C275Y, decreased binding affinity and antibody-dependent cellular cytotoxicity of the commercial antibodies Daratumumab and Isatuximab. However, a third mutation, R140G, conferred selective resistance to Daratumumab, while retaining sensitivity to Isatuximab. Clinically, patients with MM are often rechallenged with CD38 antibodies following disease progression and these data suggest that next generation sequencing may play a role in subsequent treatment selection for a subset of patients.

DOI: https://doi.org/10.1182/blood.2024028107
Onco Targets Ther. 2025 ;18 695-703

Lowering the Selinexor Dose within the Pomalidomide and Dexamethasone Combination Regimen Elicits Fewer Side Effects While Comparable Efficacy Against Relapsed/Refractory Multiple Myeloma.

Liying Peng, Tiantian Shan, Xinyi Zhou, Zhongyuan Feng, Wanting Qiang, Jing Lu, Haiyan He, Juan Du.

   Background: As a novel oral Exportin 1 (XPO1) inhibitor, selinexor at 80 or 100 mg has demonstrated efficacy in treating relapsed/refractory multiple myeloma (RRMM), nonetheless, this dosage has shown poor tolerability.
Objective: To explore the optimal dosage of selinexor, we evaluated the efficacy and safety of 60 vs 40 mg selinexor, combine with regimen comprising pomalidomide and dexamethasone in RRMM.
Design: 21 patients with RRMM were enrolled to receive selinexor (60 or 40 mg once weekly), together with pomalidomide (4 mg/day on days 1-21) and dexamethasone (40 mg once weekly); the SPD-60 group (6 patients) vs SPD-40 group (15 patients).
Methods: The clinical response and efficacy of the two groups were continuously followed up, and statistical analysis was carried out to screen out the dose group with fewer side effects and better efficacy. The primary endpoint was (objective response rates) ORR. The secondary endpoints included treatment safety and tolerability, progression-free survival (PFS) and overall survival (OS).
Results: The ORR of the SPD-60 and SPD-40 groups were 33.3% and 46.7% respectively (P=0.773). With a median follow-up of 20.9 months, the median PFS was 6.2 months and the median OS was not achieved across all treated patients. The median PFS for SPD-60 group was 4.3 months, while for SPD-40 was 8.0 months (P=0.618). The 1-year OS rate were 66.7% for SPD-60 group and 85.1% for the SPD-40 group (P=0.308). The most common hematological adverse events were neutropenia (SPD-60 group 50% vs SPD-40 group 53.3%) and thrombocytopenia (50% vs 46.7%). Fatigue (83.3% vs 40%), infection (50% vs 53.3%), and nausea (83.3% vs 40%) were the most common non-hematologic adverse effects.
Conclusion: The SPD-40 regimen may be more clinically applicable than SPD-60, as it elicited fewer adverse effects while demonstrating equivalent efficacy.
Trial Registration: ClinicalTrials.gov: NCT04941937.

Keywords:  dexamethasone; pomalidomide; relapsed/refractory multiple myeloma; selinexor

DOI:  https://doi.org/10.2147/OTT.S516486
J Clin Oncol. 2025 Jun 12. JCO2500914

Azacitidine, Venetoclax, and Revumenib for Newly Diagnosed NPM1-Mutated or KMT2A-Rearranged AML.

Joshua F Zeidner, Tara L Lin, Rina Li Welkie, Emily Curran, Kristin Koenig, Wendy Stock, Yazan F Madanat, Ronan Swords, Maria R Baer, William Blum, Eytan M Stein, Rebecca L Olin, Gary Schiller, Angela Nichols, Olatoyosi Odenike, Elie Traer, Curtis Lachowiez, Vu H Duong, Michael J Hochman, Sheng F Cai, Catherine Smith, Mona Stefanos, Molly Martycz, Ying Huang, Len Rosenberg, Sonja Marcus, Timothy L Chen, Ashley O Yocum, Brian J Druker, Ross L Levine, Uma Borate, John C Byrd, Alice S Mims.

PURPOSE: Azacitidine and venetoclax is a standard frontline treatment regimen for newly diagnosed older adults with AML; however, long-term outcomes remain poor. Revumenib is an oral menin inhibitor with clinical activity in AML patients with nucleophosmin-1 mutation (NPM1m) or lysine methyltransferase 2A rearrangements (KMT2Ar).
METHODS: We conducted a phase I dose-escalation and expansion study of azacitidine, venetoclax, and revumenib at two dose levels (113 mg or 163 mg orally every 12 hours in combination with strong cytochrome P450 inhibitor azoles) in patients aged 60 years and older newly diagnosed with AML with NPM1m or KMT2Ar (ClinicalTrials.gov identifier: NCT03013998).
RESULTS: Overall, 43 patients were enrolled and treated. There was no maximal tolerated dose identified. Differentiation syndrome was present in eight (19%) patients and QTc Fridericia prolongation was present in 19 (44%) patients, and neither required permanent discontinuation of revumenib. The overall response rate with an intention-to-treat population was 88.4% (95% CI, 74.9 to 96.1; NPM1m: 85.3%; KMT2Ar: 100%), the rate of composite complete remission (complete remission [CR] + CR with partial or incomplete hematologic recovery) was 81.4% (95% CI, 66.6 to 91.6; NPM1m: 79.4%; KMT2Ar: 88.9%), and the rate of CR was 67.4% (95% CI, 51.5 to 80.9; NPM1m: 65%; KMT2Ar: 78%). No patient had refractory disease after 1-2 cycles of treatment. The median time to first response was 28 days, and 84% of responders achieved remission within the first cycle. All 37 patients evaluated had no evidence of measurable residual disease by a centralized flow cytometry assay.
CONCLUSION: In older adults newly diagnosed with NPM1m or KMT2Ar AML, the combination of azacitidine, venetoclax, and revumenib was able to be safely administered with high rates of CR and clinical activity.

DOI: https://doi.org/10.1200/JCO-25-00914
Cancers (Basel). 2025 May 30. pii: 1834. [Epub ahead of print]17(11):

Current Advances in the Diagnosis and Treatment of Major Myeloproliferative Neoplasms.

Le Wang, Julie Li, Leah Arbitman, Hailing Zhang, Haipeng Shao, Michael Martin, Lynn Moscinski, Jinming Song.

  Myeloproliferative neoplasms (MPNs) are a group of rare blood cancers characterized by the excessive production of blood cells in the bone marrow. These disorders arise from acquired genetic driver mutations, with or without underlying genetic predispositions, resulting in the uncontrolled production of red blood cells, white blood cells, or platelets. The excessive cell production and abnormal signaling from driver mutations cause chronic inflammation and a higher risk of blood clots and vascular complications. The primary goals of MPN treatment are to induce remission, improve quality of life and survival, as well as to reduce the risk of complications such as thrombosis, vascular events, and leukemic transformation. This review provides a comprehensive update on the diagnosis and therapeutic advancements in major MPN subtypes, including chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, and primary myelofibrosis. It examines these complex diseases from a molecular and evolutionary perspective, highlighting key clinical trials' long-term follow-up and therapies targeting driver mutations that have transformed treatment strategies. Additionally, several important advancements in addressing challenges such as anemia in myelofibrosis, along with promising emerging therapies, are also discussed.

Keywords:  Janus kinase 2 (JAK2); chronic myeloid leukemia (CML); cytogenetics response (CyR); essential thrombocythemia (ET); fusion gene between the breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 (BCR::ABL1); minimal residual disease (MRD; molecular response (MR); myeloproliferative neoplasms (MPNs); polycythemia vera (PV); primary myelofibrosis (PMF)

DOI:  https://doi.org/10.3390/cancers17111834
Blood. 2025 Jun 12. 145(24): 2810-2812

Rilzabrutinib, the first-in-class BTK inhibitor for ITP.

Marc Michel.

DOI: https://doi.org/10.1182/blood.2025028584
Br J Haematol. 2025 Jun 10.

The integration of blinatumomab consolidation in the CALGB 10403 regimen for adults with B-cell precursor acute lymphoblastic leukaemia in measurable residual disease-negative remission.

Jose Tinajero, Dat Ngo, Maria Motta, Vaibhav Agrawal, Paul Koller, Hoda Pourhassan, Lindsey Murphy, Shukaib Arslan, Stephen Forman, Anthony Stein, Guido Marcucci, Vinod Pullarkat, Ibrahim Aldoss.

  Blinatumomab consolidation was recently approved for patients with acute lymphoblastic leukaemia (ALL) who achieve measurable residual disease (MRD) negative remission based on the survival benefit yielded in the E1910 trial. The CALGB 10403 (C10403) is the most frequently used paediatric inspired regimen for young adults treated in the United States; however, data and guidance on how to best incorporate blinatumomab consolidation into the C10403 regimen are lacking. Here, we describe our experience of adding blinatumomab consolidation to the C10403 regimen per our institutional consensus. Thirty-one adult patients met inclusion criteria. The median age was 31 years and the majority were males (64.5%) and Hispanic (83.9%). The most common ALL subtype was Philadelphia-like (45.2%). The median follow-up was 13.7 months and the median overall survival was not reached (NR) (95% confidence interval [CI] NR-NR) with one death occurring post allogenic transplant and one relapse (3.2%). All-grade cytokine release syndrome and treatment-related neurological/psychiatric adverse event rates were 9.7% and 19.4%, respectively, and none of the patients permanently discontinued blinatumomab due to toxicity. The majority (84.6%) of patients were able to receive over half of their planned pegaspargase doses. The incorporation of blinatumomab consolidation to C10403 is safe and feasible in adults with ALL.

Keywords:  CALGB 10403; MRD negative; acute lymphoblastic leukaemia; blinatumomab; consolidation

DOI:  https://doi.org/10.1111/bjh.20200
Ann Hematol. 2025 Jun 13.

Efficacy and safety of Glofitamab in patients with R/R DLBCL in real life setting- a retrospective study.

Ronit Gurion, Dmitri Guz, Meirav Kedmi, Chava Perry, Irit Avivi, Netanel A Horowitz, Uri Abadi, Anat Gafter-Gvili, Pia Raanani, Neta Goldschmidt, Boaz Nachmias, Shlomzion Aumann.

  Glofitamab, a CD20-directed CD3 T-cell engager, was recently FDA-approved after demonstrating a 52% overall response rate (ORR) and a 39% complete response (CR) rate in heavily pretreated diffuse large B-cell lymphoma (DLBCL) patients. However, real-world data on its efficacy and safety remain limited. This study evaluated glofitamab's performance in clinical practice. We conducted a retrospective multicenter study of adults with relapsed/refractory (R/R) DLBCL treated via a national compassionate use program. Patients received at least one dose of glofitamab after failing ≥ 2 prior therapies. Recruitment spanned September 2020-January 2023. Outcomes included ORR, CR (per Lugano criteria), progression-free survival (PFS), and overall survival (OS). Adverse events were classified per ASTCT 2019 criteria, and risk factors for PFS and OS were assessed via logistic regression. Thirty-five patients from six Israeli centers were included (median age: 67 years; 66% male). The median number of prior therapies was 5, with 43% being primary refractory and 91% post-CAR-T therapy. ORR was 34%, with 14% achieving CR. Median PFS and OS were 2 and 4 months, respectively. Treatment was prematurely discontinued in 86%, mainly due to disease progression (46%) and to infections in responding patients (17%). Male sex was a significant risk factor for poor PFS and OS. In this real-world cohort, glofitamab's efficacy was lower than in clinical trials, likely due to a more heavily pretreated population. However, its manageable toxicity supports its potential role in r/r DLBCL treatment.

Keywords:  CAR-T failure; Diffuse large B-Cell lymphoma (DLBCL); Glofitamab; Real-world data; Relapsed/refractory lymphoma; T-cell engager

DOI:  https://doi.org/10.1007/s00277-025-06438-3
Blood. 2025 Jun 11. pii: blood.2024027727. [Epub ahead of print]

Combined PET and ctDNA response as a predictor of POD24 for follicular lymphoma after first-line induction treatment.

Alexis Claudel, Anne-Ségolène Cottereau, Emmanuel Bachy, Emmanuel Itti, Pierre Feugier, Cédric Rossi, Francois Lemonnier, Vincent Camus, Nicolas Daguindau, Guillaume Cartron, Emmanuelle Nicolas Virelizier, Diana Laure Mbouma, Christophe Cardoso, Côme Bommier, Benoit Tessoulin, Christophe Fruchart, Adrien Gilbert, Eric Durot, Emmanuel Fleck, Gian Matteo Pica, Hacene Zerazhi, Stéphanie Guidez, Morgane Cheminant, Clémentine Sarkozy, Luc Xerri, Laetitia Vercellino, Nesrine Trabelsi, Lucie Gomes, Cedric Portugues, Pierre-Julien Viailly, Marie-Helene Delfau-Larue, Franck Morschhauser.

Patients with follicular lymphoma (FL) who experience disease progression within 24 months of diagnosis (POD24) have a lower survival. Positron emission tomography (PET) response and circulating tumor DNA (ctDNA) residual disease (MRD) assessment at end of induction therapy (EOI) may allow their early identification. A representative cohort of 141 patients from the RELEVANCE phase III trial with both available serum samples for ctDNA testing and PET images at randomization and at EOI (week 24) was investigated. Twelve percent were POD24. CtDNA was analyzed using a customized 130-kilobase capture panel, with Phased Variant (PV) enriched regions representing 39% of the panel. CtDNA was detected in 140 patients (99.3%) at baseline. To optimize specificity, only PVs, found in 124 patients (88%), were considered for ctDNA MRD assessment at EOI. Median PFS from EOI was not reached (NR) for the 112 patients with undetected ctDNA at EOI versus 17.7 months (95%CI : 1.4-NA) for patients ctDNA MRD (+) (p=0.0038). Similarly, median PFS was NR for the 104 patients with undetected disease on PET at EOI versus 28.3 months (95%CI : 2.9-NR, p=0.0002) for patients with PET(+). Both tests had a negative predictive value (NPV) above 90% for POD24. The positive predictive value was 58.3% for ctDNA MRD and 45% for PET but increased to 85.7% when both parameters were combined, without alteration of NPV. These data show that the combination of PET response and ctDNA MRD at EOI allows for an early prediction of POD24 which may lead to a preemptive treatment decision.

DOI: https://doi.org/10.1182/blood.2024027727
Blood. 2025 Jun 12. 145(24): 2803-2804

TET3 stirs up trouble via pathogenic Ig class switching.

Daigo Hashimoto.

DOI: https://doi.org/10.1182/blood.2024028296
J Clin Oncol. 2025 Jun 09. JCO2401893

International Myeloma Society/International Myeloma Working Group Consensus Recommendations on the Definition of High-Risk Multiple Myeloma.

Hervé Avet-Loiseau, Faith E Davies, Mehmet K Samur, Jill Corre, Mattia D'Agostino, Martin F Kaiser, Marc S Raab, Niels Weinhold, Norma C Gutierrez, S Bruno Paiva, Paola Neri, Katja Weisel, Francesco Maura, Brian A Walker, Mark Bustoros, A Keith Stewart, Saad Z Usmani, Jens Hillengass, Wee Joo Chng, Jonathan J Keats, Joaquin Martinez-Lopez, Adam S Sperling, Cyrille Touzeau, Fenghuang Zhan, Noopur S Raje, Michele Cavo, Niccolò Bolli, Irene M Ghobrial, Madhav V Dhodapkar, Sundar Jagannath, Andrew Spencer, Samir Parekh, Nizar J Bahlis, Sagar Lonial, Pieter Sonneveld, Leif Bergsagel, Robert Z Orlowski, Gareth Morgan, María Victoria Mateos, S Vincent Rajkumar, Jesus F San Miguel, Kenneth C Anderson, Philippe Moreau, Shaji Kumar, Felipe Prósper, Nikhil C Munshi.

Despite significant improvements in survival of patients with multiple myeloma (MM), outcomes remain heterogeneous, and a significant proportion of patients experience suboptimal outcomes. Importantly, traditional prognostic factors based on data from patients treated with older therapies no longer capture prognosis accurately in the contemporary era of novel triplet or quadruplet therapies. Therefore, risk stratification requires refinement in the context of available and investigational treatment options in routine practice and clinical trials, respectively. The current identification of high-risk MM (HRMM) in routine practice is based on the Revised International Staging System, which stratifies patients using a combination of widely available serum biomarkers and chromosomal abnormalities assessed via fluorescence in situ hybridization. In recent years, a substantial body of evidence concerning additional clinical, biological, and molecular/genomic prognostic factors has accumulated, along with new MM risk stratification tools and consensus reports. The International Myeloma Society, along with the International Myeloma Working Group, convened an Expert Panel with the primary aim of revisiting the definition of HRMM and formulating a practical and data-driven consensus definition, based on new evidence from molecular/genomic assays, updated clinical data, and contemporary risk stratification concepts. The Panel proposes the following Consensus Genomic Staging (CGS) of HRMM which relies upon the presence of at least one of these abnormalities: (1) del(17p), with a cutoff of >20% clonal fraction, and/or TP53 mutation; (2) an IgH translocation including t(4;14), t(14;16), or t(14;20) along with 1q+ and/or del(1p32); (3) monoallelic del(1p32) along with 1q+ or biallelic del(1p32); or (4) β2 microglobulin ≥5.5 mg/L with normal creatinine (<1.2 mg/dL).

DOI: https://doi.org/10.1200/JCO-24-01893
Haematologica. 2025 Jun 12.

Blinatumomab and better BCR::ABL1 inhibition begets better bone marrow transplant outcomes.

Marlise R Luskin, Jessica T Leonard.

Not available.

DOI: https://doi.org/10.3324/haematol.2025.288068
Antib Ther. 2025 Apr;8(2): 145-156

Preclinical development of mecbotamab vedotin (BA3011), a novel, AXL-specific conditional active biologic antibody-drug conjugate.

Hwai Wen Chang, Jing Wang, Haizhen Liu, Charles Xing, Jian Chen, Gerhard Frey, William J Boyle, Jay M Short.

   Background: AXL, a tyrosine kinase receptor, is over-expressed in many solid and hematologic cancers, promoting progression and poor clinical outcomes. It also contributes to resistance against chemotherapeutic agents, especially tyrosine kinase inhibitors, by upregulating AXL signaling or switching oncogenic pathways. These factors make AXL an attractive therapeutic target. However, early attempts with naked antibody therapies failed due to the high doses need for efficacy, and antibody-drug conjugates (ADCs) targeting AXL were hindered by off-tumor toxicities due to its expression on normal tissues.
Methods: To address these issues, we developed a novel, conditionally active biologic ADC, mecbotamab vedotin (BA3011), which selectively binds to AXL in the acidic tumor microenvironment. In healthy tissue, binding to AXL is substantially diminished due to a powerful selection mechanism utilizing naturally occurring, physiological chemicals referred to as Protein-associated Chemical Switches. BA3011 was tested in vitro and in vivo against AXL expressing cancer cells.
Results: Mecbotamab vedotin demonstrates the expected AXL, tumor-specific binding properties and effectively induced lysis of AXL-positive cancer cell lines in vitro. In vivo, mecbotamab vedotin exhibited potent and lasting antitumor effects in human cancer xenograft mouse models. Furthermore, in nonhuman primates, mecbotamab vedotin demonstrated excellent tolerability at doses of up to 5 mg/kg and maintained linker-payload stability in vivo.
Conclusions: These findings indicate that mecbotamab vedotin has the potential to be a robust and less toxic therapeutic agent, offering promise as a treatment for patients with AXL-positive cancers.

Keywords:  AXL; antibody–drug conjugate; conditional active biologic; mecbotamab; tumor microenvironment

DOI:  https://doi.org/10.1093/abt/tbaf006
Blood. 2025 Jun 12. 145(24): 2807-2808

Connecting the DOT1L: it's EZH2.

R Eric Davis.

DOI: https://doi.org/10.1182/blood.2025028711
Blood. 2025 Jun 12. 145(24): 2808-2810

Predicting T-ALL response to pre-TCR and IL-7R coinhibition.

Carol Fries.

DOI: https://doi.org/10.1182/blood.2025028611
Cells. 2025 May 25. pii: 776. [Epub ahead of print]14(11):

High-Risk Genetic Multiple Myeloma: From Molecular Classification to Innovative Treatment with Monoclonal Antibodies and T-Cell Redirecting Therapies.

Danilo De Novellis, Pasqualina Scala, Valentina Giudice, Carmine Selleri.

  High-risk genetic multiple myeloma (HRMM) remains a major therapeutic challenge, as patients harboring adverse genetic abnormalities, such as del(17p), TP53 mutations, and biallelic del(1p32), continue to experience poor outcomes despite recent therapeutic advancements. This review explores the evolving definition and molecular features of HRMM, focusing on recent updates in risk stratification and treatment strategies. The new genetic classification proposed at the 2025 EMMA meeting offers improved prognostic accuracy and supports more effective, risk-adapted treatment planning. In transplant-eligible patients, intensified induction regimens, tandem autologous stem cell transplantation, and dual-agent maintenance have shown improved outcomes, particularly when sustained minimal residual disease negativity is achieved. Conversely, in the relapsed or refractory setting, novel agents have demonstrated encouraging activity, although their specific efficacy in HRMM is under investigation. Moreover, treatment paradigms are shifting toward earlier integration of immunotherapy, and therapeutic strategies are individualized based on refined molecular risk profiles and clone dynamics. Therefore, a correct definition of HRMM could help in significantly improving both clinical and therapeutic management of a subgroup of patients with an extremely aggressive disease.

Keywords:  BCMA; BiTEs; CAR-T; CD38; MRD; anti-CD38 agents; genomic stratification; high-risk genetic MM; molecular mechanism; multiple myeloma; proteasome inhibitors

DOI:  https://doi.org/10.3390/cells14110776
Expert Rev Hematol. 2025 Jun 13.

Treatment patterns and blood count control in 10,112 patients with polycythemia vera.

Naveen Pemmaraju, Jingbo Yu, Anupama Vasudevan, Husain Qureshi, Evan Braunstein, Aleksander Chojecki.

   BACKGROUND: Elevated blood counts in polycythemia vera (PV) are associated with increased thrombotic risk, which contribute to morbidity and mortality.
RESEARCH DESIGN AND METHODS: This retrospective study describes treatment patterns and blood count control in patients with PV managed at community oncology practices (January 2014-February 2023; Integra Precision Q database).
RESULTS: Of a total 10,112 patients, most received phlebotomy (68.1%) or hydroxyurea (HU; 28.2%) as initial treatment, with median follow-up of 32.1 (IQR, 13.5-58.5) months and 31.5 (IQR, 16.8-54.9) months, respectively. Changing treatment was less common than remaining on initial treatment despite 67.8% of patients on phlebotomy and 30.4% on HU having elevated hematocrit (≥45%) after 1 year of treatment. In contrast, 85.4% of patients who switched to ruxolitinib from HU achieved hematocrit < 45% after 1 year, and fewer required phlebotomy during ruxolitinib treatment than with HU treatment (RUX, 29.3%; HU, 53.5%). Additionally, 54.2% of patients who switched to ruxolitinib achieved white blood cell counts < 11 × 109/L, and 57.5% achieved platelet counts ≤ 400 × 109/L after 1 year of ruxolitinib treatment.
CONCLUSIONS: This real-world evidence highlights the importance of considering alternative therapies for patients whose initial treatment regimen does not provide adequate clinical benefit.

Keywords:  Hydroxyurea; JAK inhibitor; MPN; myeloproliferative neoplasm; real-world; ruxolitinib

DOI:  https://doi.org/10.1080/17474086.2025.2520316
Haematologica. 2025 Jun 12.

Recombinant human erythropoietin plus all-trans retinoic acid and testosterone undecanoate for the treatment of anemia in patients with lower-risk myelodysplastic syndromes: a multicenter, single-arm, prospective trial.

Chen Mei, Gaixiang Xu, Cuiping Zheng, Yaping Xie, Minming Li, Yanping Shao, Rongxin Yao, Shi Tao, Wei Jiang, Jun Guo, Zhiyin Zheng, Wei Wang, Xinping Zhou, Liya Ma, Li Ye, Yingwan Luo, Chunmei Yang, Wenjuan Yu, Wanzhuo Xie, Jie Jin, Hongyan Tong.

Erythropoiesis-stimulating agents (ESAs) achieve hematological improvement-erythroid (HIE) in only 30% of ESA-naïve lower risk myelodysplastic syndrome (LR-MDS) patients with anemia, highlighting the need for developing novel drugs or new treatment strategies to improve the outcome of these patients. We conducted this multicenter, single-arm trial to investigate the efficacy and safety of a triple regimen consisting of recombinant human erythropoietin (rhEPO), all-trans retinoic acid (ATRA) and testosterone undecanoate in patients with anemia due to lower-risk MDS based on Revised International Prognostic Scoring System. Eligible patients received rhEPO 10000 IU/day, oral ATRA 25 mg/m2/day and oral testosterone undecanoate 80 mg twice daily for 12 weeks. The primary endpoint was the proportion of patients achieving HI-E during 12 weeks of treatment. Of 52 eligible patients, 32 (61.5%, 95%CI 48.0%-73.5%) achieved HI-E, meeting the primary endpoint. Fifteen patients (65.2% [15/23]) with baseline serum erythropoietin ≤500 IU/L had HI-E versus 58.6% of those (17/29) with baseline serum erythropoietin >500 IU/L. More patients with very low or low risk had HI-E than those with intermediate risk (73.3% vs. 45.5%, P = 0.041) and fewer patients with mutated ASXL1 had HI-E than those with wildtype ASXL1 (33.3% vs. 70.0%, P = 0.040). The regimen had an acceptable safety profile compatible with individual agents. In conclusion, the triple regimen of rhEPO combined with ATRA and testosterone undecanoate attained HI-E in approximately 61.5% of patients regardless of baseline serum EPO levels, supporting further development of this regimen for LR-MDS patients with anemia. This study was registered at CHICTR.ORG.CN as ChiCTR2000032845.

DOI: https://doi.org/10.3324/haematol.2024.287055
Clin Lymphoma Myeloma Leuk. 2025 May 16. pii: S2152-2650(25)00174-0. [Epub ahead of print]

Feasibility of Bruton's Tyrosine Kinase Inhibitor Discontinuation in Chronic Lymphocytic Leukemia: The Patient Perspective.

Deborah M Stephens, Chris Stewart, Liza Avruch, Catherine C Coombs, Alexey Danilov, Brian Hill, Mazyar Shadman, Alina Gerrie, Christopher E Jensen, Marc Hoffmann, Allison Winter, Daniel A Ermann, Paul M Barr, Susan O'Brien, Brian Koffman, John C Byrd.

   BACKGROUND: Bruton's tyrosine kinase inhibitors (BTKi) have prolonged survival in chronic lymphocytic leukemia (CLL), however continuous administration increases toxicity. Little is known about clinical outcomes of patients who discontinue BTKi for reasons other than CLL progression. We aimed to report these outcomes.
PATIENTS/METHODS: With the CLL Society, we solicited volunteers with CLL who self-reported BTKi discontinuation for reasons other than CLL progression to participate in a web-based survey.
RESULTS: In 170 patients, BTKi was discontinued for toxicity, because CLL was in remission, or personal choice in 62%, 14% and 8%, respectively. When asked how they felt about stopping the BTKi, most were relieved that they may eliminate toxicity (45%), could focus less on CLL (11%), and would not have to pay for the medicine (7%), while 29% experienced anxiety. A statistically significant increase in perceived quality of life (QOL) was observed from prior- versus post-BTKi discontinuation. Of patients who reported that they experienced clinical CLL progression (n = 80), 46% reported that these events did not happen for ≥ 1 year after BTKi discontinuation. Those that were on a BTKi for ≥ 2 years before discontinuation had more time without CLL relapse.
CONCLUSIONS: These data provide a unique report of patient experiences. The data suggest that BTKi may be feasible and result in a period of treatment-free remission. The data also indicate that patients are generally relieved when they anticipate BTKi discontinuation and observe significant QOL improvements after BTKi discontinuation. As such, these data should prompt prospective study of time-limited BTKi therapy for CLL.

Keywords:  Acalabrutinib; Drug holiday; Ibrutinib; Treatment discontinuation; Zanubrutinib

DOI:  https://doi.org/10.1016/j.clml.2025.05.011