HemaSphere最新文献

{"title":"Efficacy of anti-PD1 therapy in extranodal NK/T cell lymphoma: A matched cohort analysis from the LYSA","authors":"Amira Marouf, Sammara Chaubard, Raphaël Liévin, Jean-Marie Michot, Nicolas Molinari, Julien Rossignol, Doriane Cavalieri, Camille Golfier, Olivier Allangba, Laure Philippe, Benoît Tessoulin, Adrien Chauchet, Bénédicte Deau, Lucie Oberic, Jacques Vargaftig, Aline Moignet, Aline Clavert, Rémy Dulery, Gabriel Brisou, Stéphanie Tardy, Virginie Fataccioli, Roch Houot, René O. Casasnovas, Catherine Thieblemont, Hervé Ghesquières, Sylvain Carras, Steven Le Gouill, Guillaume Cartron, Vincent Ribrag, Morgane Cheminant, Ambroise Marçais, Felipe Suarez, Aurélien Marabelle, Olivier Tournilhac, Gandhi Damaj, Philippe Gaulard, Laurence De Leval, François Lemonnier, Emmanuel Bachy, Sylvie Chevret, Olivier Hermine, Lucile Couronné, Arnaud Jaccard","doi":"10.1002/hem3.70081","DOIUrl":"10.1002/hem3.70081","url":null,"abstract":"<p>Extranodal NK/T cell lymphoma (ENKTCL) is a mature T/NK-cell malignancy associated with Epstein Barr Virus.<span><sup>1</sup></span> Although asparaginase-based treatments have improved outcomes, the prognosis remains poor for relapsed or refractory (R/R) patients. Increased expression of PD-L1at tumor cell surface is a frequent mechanism of immune evasion in ENKTCL.<span><sup>2, 3</sup></span> Consequently, anti-PD1 (aPD1) therapy, either alone<span><sup>4-9</sup></span> or combined with chemotherapy,<span><sup>10, 11</sup></span> has been evaluated in patients with R/R ENKTCL, showing promising results. These initial findings were primarily observed in Asian patients where the prevalence of the disease is higher. Due to the limited data from Western countries and the lack of comparative studies, we assessed the efficacy of aPD1 therapy in a large French cohort of ENKTCL patients and compared it with a historical national cohort of R/R ENKTCL patients treated before the introduction of immunotherapies.</p><p>This study included 37 patients from 24 French centers treated with at least one cycle of aPD1 therapy for relapse or progression between March 2017 and March 2022. Among them, 12 patients were enrolled in the prospective AcSé Pembrolizumab study (Unicancer), a phase II, open-label, multicentric study investigating pembrolizumab monotherapy in rare cancers (NCT03012620). The remaining 25 patients were treated with aPD1 alone or combined with chemotherapy or targeted therapy (Supporting Information S1: Table 1), following the recommendations issued by the T-cell lymphomas committee (TENOMIC) of the LYmphoma Study Association (LYSA). These patients were designated as “real-life” patients. The inclusion criteria are detailed in the Supporting Information Methods.</p><p>The median age was 52 [19–79], with a sex ratio M/F of 2/1. At diagnosis, 21 patients (57%) presented with disseminated disease, and 15 patients (42%) had a high PINK score. Overall, the clinical characteristics of patients included in the AcSé study were comparable to those of the “real-life” patients. Although not reaching statistical significance, the rate of disseminated disease and high PINK score at diagnosis tended to be higher in the “real-life” group (64% vs. 41.7%, <i>p</i> = 0.35, and 50% vs. 25%, <i>p</i> = 0.22, respectively). At relapse, no significant difference was observed except for LDH serum level, which was higher in the “real-life” cohort (<i>p</i> = 0.023) (Supporting Information S1: Table 2).</p><p>All patients had previously received frontline chemotherapy containing asparaginase including MOGAD or MGAD (in accordance with current French guidelines) in 17 (46%) and 12 (32%) patients, respectively, resulting in a 70% complete response (CR) rate after first-line therapy. Prior treatments before aPD1 salvage also included autologous (<i>n</i> = 5) and allogenic (<i>n</i> = 1) stem cell transplants and external radiotherapy (<i>n</i> = 21).</p><p>Thirty-six","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11746926/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143004485","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Secondary lesions and sensitivity to signaling inhibitors in iAMP21 acute lymphoblastic leukemia","authors":"Femke M. Hormann,&nbsp;Anna Østergaard,&nbsp;Stijn van den Broek,&nbsp;Aurélie Boeree,&nbsp;Cesca van de Ven,&nbsp;Gabriele Escherich,&nbsp;Edwin Sonneveld,&nbsp;Judith M. Boer,&nbsp;Monique L. den Boer","doi":"10.1002/hem3.70069","DOIUrl":"10.1002/hem3.70069","url":null,"abstract":"<p>Intrachromosomal amplification of chromosome 21 (iAMP21) B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in children is a high-risk subtype for which targeted drugs are lacking. In this study, we determined the frequency of secondary lesions in 28 iAMP21 BCP-ALL patient samples and investigated cellular sensitivity for candidate-targeted drugs. iAMP21 was enriched in <i>FLT3</i> aberrations (10.7% vs. 50.0%, <i>p</i> = 0.003) and <i>SH2B3</i> inactivation (7.14% vs. 46.4%, <i>p</i> = 0.002), compared with 28 B-other cases, and these alterations co-occurred in 21.4%. The occurrence of lesions in <i>CRLF2</i> and <i>IL7R</i> was similar between iAMP21 and B-other cases (25% vs. 17.9%, <i>p</i> = 0.746 and 7.14% vs. 0%, <i>p</i> = 0.491 respectively) as were mutations in <i>JAK1</i> and <i>JAK2</i> (3.57% vs. 0% and 10.7% vs. 10.7%, <i>p</i> = 1 for both). Sensitivity to the FLT3 inhibitor gilteritinib did not differ between iAMP21 and B-other cases irrespective of FLT3 status. However, iAMP21 samples harboring both <i>FLT3-</i>ITD and <i>SH2B3</i> lesions showed the highest sensitivity. <i>CRLF2-</i>rearranged iAMP21 samples were slightly more sensitive to JAK inhibitor ruxolitinib than those without, although a lack of sensitivity was present in 50% of iAMP21 cases. Trametinib sensitivity varied among iAMP21 samples with over half of iAMP21 samples being sensitive irrespective of RAS-pathway mutation status or other secondary lesions. In summary, iAMP21 leukemias were enriched in <i>FLT3</i> and in <i>SH2B3</i> lesions, which when co-occurring affected sensitivity to FLT3 inhibition by gilteritinib but not JAK inhibition by ruxolitinib. Together, our results suggest that FLT3 and RAS signaling inhibitors are of interest for further (pre)clinical evaluation in iAMP21 BCP-ALL.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11746935/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143004545","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The CD123 antibody–drug conjugate pivekimab sunirine exerts profound activity in preclinical models of pediatric acute lymphoblastic leukemia","authors":"Ben Watts,&nbsp;Christopher M. Smith,&nbsp;Kathryn Evans,&nbsp;Andrew J. Gifford,&nbsp;Sara M. A. Mohamed,&nbsp;Stephen W. Erickson,&nbsp;Eric J. Earley,&nbsp;Steven Neuhauser,&nbsp;Timothy M. Stearns,&nbsp;Vivek M. Philip,&nbsp;Jeffrey H. Chuang,&nbsp;Patrick A. Zweidler-McKay,&nbsp;Sribalaji Lakshmikanthan,&nbsp;Emily L. Jocoy,&nbsp;Carol J. Bult,&nbsp;Beverly A. Teicher,&nbsp;Malcolm A. Smith,&nbsp;Richard B. Lock","doi":"10.1002/hem3.70063","DOIUrl":"10.1002/hem3.70063","url":null,"abstract":"<p>Antibody–drug conjugates (ADCs) combining monoclonal antibodies with cytotoxic payloads are a rapidly emerging class of immune-based therapeutics with the potential to improve the treatment of cancer, including children with relapse/refractory acute lymphoblastic leukemia (ALL). CD123, the α subunit of the interleukin-3 receptor, is overexpressed in ALL and is a potential therapeutic target. Here, we show that pivekimab sunirine (PVEK), a recently developed ADC comprising the CD123-targeting antibody, G4723A, and the cytotoxic payload, DGN549, was highly effective in vivo against a large panel of pediatric ALL patient-derived xenograft (PDX) models (<i>n</i> = 39). PVEK administered once weekly for 3 weeks resulted in a median event-free survival (EFS) of 57.2 days across all PDXs. CD123 mRNA and protein expression was significantly higher in B-lineage (<i>n</i> = 65) compared with T-lineage (<i>n</i> = 25) ALL PDXs (<i>p</i> &lt; 0.0001), and mice engrafted with B-lineage PDXs achieved significantly longer EFS than those engrafted with T-lineage PDXs (<i>p</i> &lt; 0.0001). PVEK treatment also resulted in significant clearance of human leukemia cells in hematolymphoid organs in mice engrafted with B-ALL PDXs. Notably, our results showed no direct correlation between CD123 expression and mouse EFS, indicating that CD123 is necessary but not sufficient for in vivo PVEK activity. Importantly, a PDX with very high CD123 cell surface expression but resistant to in vivo PVEK treatment, failed to internalize the G4723A antibody while remaining sensitive to the PVEK payload, DGN549, suggesting a novel mechanism of resistance. In conclusion, PVEK was highly effective against a large panel of B-ALL PDXs supporting its clinical translation for B-lineage pediatric ALL.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11739898/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143004590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disease characteristics and outcomes of acute myeloid leukemia in germline RUNX1 deficiency (Familial Platelet Disorder with associated Myeloid Malignancy)","authors":"Martijn P. T. Ernst,&nbsp;Jurjen Versluis,&nbsp;Peter J. M. Valk,&nbsp;Marc Bierings,&nbsp;Rienk Y. J. Tamminga,&nbsp;Louise H. Hooimeijer,&nbsp;Konstanze Döhner,&nbsp;Paolo Gresele,&nbsp;Kiran Tawana,&nbsp;Saskia M. C. Langemeijer,&nbsp;Bert A. Van der Reijden,&nbsp;Helena Podgornik,&nbsp;Matjaz Sever,&nbsp;Tor H. A. Tvedt,&nbsp;Tom Vulliamy,&nbsp;Jude Fitzgibbon,&nbsp;Inderjeet Dokal,&nbsp;Panagiotis Baliakas,&nbsp;José M. Bastida,&nbsp;Christian Pohlkamp,&nbsp;Torsten Haferlach,&nbsp;Lise Larcher,&nbsp;Jean Soulier,&nbsp;Roger E. G. Schutgens,&nbsp;Kathleen Freson,&nbsp;Nicolas Duployez,&nbsp;Bob Löwenberg,&nbsp;Katrin Ericson,&nbsp;Jörg Cammenga,&nbsp;Tim Ripperger,&nbsp;Marc H. G. P. Raaijmakers","doi":"10.1002/hem3.70057","DOIUrl":"10.1002/hem3.70057","url":null,"abstract":"<p>Familial Platelet Disorder with associated Myeloid Malignancy (FPDMM, FPD/AML, <i>RUNX1</i>-FPD), caused by monoallelic deleterious germline <i>RUNX1</i> variants, is characterized by bleeding diathesis and predisposition for hematologic malignancies, particularly myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Clinical data on FPDMM-associated AML (FPDMM-AML) are limited, complicating evidence-based clinical decision-making. Here, we present retrospective genetic and clinical data of the largest cohort of FPDMM patients reported to date. We describe 159 European patients (from 94 families) of whom 134 were evaluable for the development of malignant disease. Sixty developed a hematologic malignancy (44.8%), most frequently AML (36/134, 26.9%) or MDS (18/134, 13.4%). Somatic alterations of <i>RUNX1</i> by gene mutation (48%) and chromosome 21 aberrations (14.3%) were the most common somatic genetic aberrations in FPDMM-AML, followed by <i>FLT3-ITD</i> mutations (24.1%). Somatic <i>RUNX1</i> and <i>FLT3-ITD</i> mutations were not detected in FPDMM-associated MDS, suggesting important contributions to leukemic transformation. Remission-induction chemotherapy resulted in complete remission in 80% of FPDMM-AML patients with a 5-year overall survival (OS) of 50.4%. Survival outcome was non-inferior compared to a large cohort of newly diagnosed adult <i>RUNX1</i>-mutated AML (5-year OS 36.6%, <i>p</i> = 0.5), with relatively infrequent concurrent adverse risk somatic aberrations (<i>ASXL1</i> mutation, monosomal karyotype, monosomy 5/del 5q) in FPDMM-AML. Collectively, data support the notion that step-wise leukemic evolution in FPDMM is associated with distinct genetic events and indicate that a substantial subset of FPDMM-AML patients achieves prolonged survival with conventional AML treatment, including allogeneic stem cell transplant. These findings are anticipated to inform personalized clinical decision-making in this rare disorder.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11735945/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143004482","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extracellular vesicles from chronic lymphocytic leukemia cells promote leukemia aggressiveness by inducing the differentiation of monocytes into nurse-like cells via an RNA-dependent mechanism","authors":"Nathan Dubois,&nbsp;David Van Morckhoven,&nbsp;Laurentijn Tilleman,&nbsp;Filip Van Nieuwerburgh,&nbsp;Dominique Bron,&nbsp;Laurence Lagneaux,&nbsp;Basile Stamatopoulos","doi":"10.1002/hem3.70068","DOIUrl":"10.1002/hem3.70068","url":null,"abstract":"<p>Chronic lymphocytic leukemia (CLL) cells receive several stimuli from surrounding cells, such as B-cell receptor (BCR) stimulation, and can manipulate their microenvironment via extracellular vesicle (EV) release. Here, we investigated the small RNA content (microRNA and YRNA) of CLL-EVs from leukemic cells cultured with/without BCR stimulation. We highlight an increase of miR-155-5p, miR-146a-5p, and miR-132-3p in EVs and in cells after BCR stimulation (<i>p</i> &lt; 0.05, <i>n</i> = 25). CLL-EVs were preferentially internalized by monocytes (<i>p</i> = 0.0019, <i>n</i> = 6) and able to deliver microRNAs and the hY4 RNA. Furthermore, BCR CLL-EV induced modifications in monocytes (shape change, microRNA and gene expression, secretome) suggesting nurse-like cell (NLC) differentiation, the tumor-associated macrophages of CLL. Functionally, monocytes treated with BCR CLL-EVs protect CLL cells from spontaneous apoptosis by pro-survival cytokine production and induce their migration as well as the migration of other immune cells. We finally reported by transfection experiments that hY4 is able to induce the expression of CCL24, a key gene in M2 macrophage differentiation. In conclusion, we showed that BCR stimulation modifies the small RNA content of CLL-EVs and that the addition of leukemic EVs to monocytes leads to monocyte differentiation into NLCs establishing a protective microenvironment that supports leukemic cell survival.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11735956/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143004500","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Idecabtagene vicleucel or ciltacabtagene autoleucel for relapsed or refractory multiple myeloma: An international multicenter study","authors":"Maximilian Merz,&nbsp;Anca-Maria Albici,&nbsp;Bastian von Tresckow,&nbsp;Kristin Rathje,&nbsp;Roland Fenk,&nbsp;Tobias Holderried,&nbsp;Fabian Müller,&nbsp;Natalia Tovar,&nbsp;Aina Oliver-Cáldes,&nbsp;Vladan Vucinic,&nbsp;Soraya Kharboutli,&nbsp;Ben-Niklas Bärmann,&nbsp;Francis Ayuk,&nbsp;Uwe Platzbecker,&nbsp;Friedrich Stölzel,&nbsp;Nathalie Schub,&nbsp;Friederike Schmitz,&nbsp;David Fandrei,&nbsp;Patrick Born,&nbsp;Cyrus Khandanpour,&nbsp;Christine Hanoun,&nbsp;Keven Hörster,&nbsp;Marcel Teichert,&nbsp;Barbara Jeker,&nbsp;Michele Hoffmann,&nbsp;Nicolaus Kröger,&nbsp;Carlos Fernández de Larrea,&nbsp;Thomas Pabst,&nbsp;Nico Gagelmann","doi":"10.1002/hem3.70070","DOIUrl":"10.1002/hem3.70070","url":null,"abstract":"<p>Idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) have revolutionized the treatment of relapsed/refractory multiple myeloma (RRMM), but direct comparisons are lacking. Leveraging an international multicenter RRMM cohort, we compared the outcome of ide-cel (<i>n</i> = 162) versus cilta-cel (<i>n</i> = 42). Co-primary efficacy endpoints of the study were overall response rate (ORR) and progression-free survival (PFS). Co-primary safety endpoints were the incidence of cytokine release syndrome (CRS) and immune-effector cell-associated neurotoxicity syndrome (ICANS). Median turnaround time between apheresis and infusion was 47 days for ide-cel versus 68 days for cilta-cel (<i>p</i> &lt; 0.001). Cilta-cel showed significantly higher ORR (93% vs. 79%; <i>p</i> &lt; 0.001), with complete response at Day 30 of 48% versus 26% (<i>p</i> &lt; 0.001). The 10-month PFS and overall survival (OS) was 82% and 90% for cilta-cel versus 47% and 77% ide-cel (<i>p</i> &lt; 0.001 and <i>p</i> = 0.06), and improved outcome for cilta-cel was confirmed after multivariable adjustment. Incidence of CRS and ICANS appeared similar (81% and 19% for cilta-cel versus 85% and 19% for ide-cel), while 10% and 7% in the cilta-cel group versus 4% and 2% in the ide-cel group showed severe CRS and ICANS grade 3–4, with CRS occurring significantly earlier for ide-cel (median, 2 days vs. 4 days; <i>p</i> &lt; 0.001). Nonrelapse mortality was 5% for cilta-cel versus 3% for ide-cel (<i>p</i> = 0.51). Cilta-cel showed later peak of CAR-T expansion at Day 14 versus Day 7 for ide-cel, while cilta-cel expansion was associated with ICANS. Our study provides real-world evidence that cilta-cel was associated with superior outcomes and distinct cellular dynamics versus ide-cel in triple-class exposed RRMM.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11735948/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143004501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long-term results of a phase 1/1b study of ibrutinib plus umbralisib for relapsed/refractory chronic lymphocytic leukemia","authors":"Christine E. Ryan,&nbsp;Yue Ren,&nbsp;Svitlana Tyekucheva,&nbsp;Jon E. Arnason,&nbsp;Adam M. Boruchov,&nbsp;Caron A. Jacobson,&nbsp;David C. Fisher,&nbsp;Hari Miskin,&nbsp;Peter Sportelli,&nbsp;Jennifer R. Brown,&nbsp;Matthew S. Davids","doi":"10.1002/hem3.70067","DOIUrl":"10.1002/hem3.70067","url":null,"abstract":"&lt;p&gt;Given the fundamental importance of the B-cell receptor (BCR) pathway in chronic lymphocytic leukemia (CLL) pathophysiology,&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; we investigated dual BCR blockade in treating relapsed or refractory (R/R) disease. We hypothesized that combining the Bruton tyrosine kinase inhibitor (BTKi) ibrutinib, which is highly effective in R/R CLL,&lt;span&gt;&lt;sup&gt;2, 3&lt;/sup&gt;&lt;/span&gt; with the next-generation oral phosphoinositide-3-kinase-delta isoform inhibitor (PI3Kδi) umbralisib would be an effective, well-tolerated, and convenient therapeutic approach that could lead to more durable remissions than historical results with ibrutinib alone. Unlike the approved PI3Kis idelalisib and duvelisib, umbralisib also targets casein-kinase-1-epsilon,&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; which may spare regulatory T cell functioning through downregulation of WNT signaling,&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; and thereby lead to less immune-mediated toxicity. A large integrated safety analysis across four early-phase umbralisib monotherapy studies demonstrated favorable long-term tolerability.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; Our initial results of this combination indeed found the combination achieved a high overall response rate (ORR; 90%) with a promising 2-year progression-free-survival (PFS) rate of 90%.&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; Here, we report long-term results with a median follow-up for survivors of just under 5 years.&lt;/p&gt;&lt;p&gt;The design of this multicenter, investigator-sponsored trial (NCT02268851) has been described previously.&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; Of note, the study also included patients with R/R mantle cell lymphoma (MCL), but here we report only on long-term follow-up for the patients with CLL, as nearly all of the patients with MCL had either progressed or died soon after the data cut for the prior publication. Briefly, key inclusion criteria were R/R CLL with progression after ≥1 prior therapy, indication for treatment per iwCLL guidelines,&lt;span&gt;&lt;sup&gt;8&lt;/sup&gt;&lt;/span&gt; and ECOG performance status ≤2. Key exclusion criteria were allogeneic transplantation within 12 months, active graft versus host disease, or central nervous system involvement. Patients received daily oral dosing of ibrutinib 420 mg and umbralisib at 3 dose levels. Study treatment was continued until progressive disease (PD) or unacceptable toxicity. Toxicity was by CTCAE 4.0 and iwCLL hematologic criteria, and response was by iwCLL criteria. Median duration on treatment was estimated by reverse Kaplan-Meier method. PFS and overall survival (OS) were estimated by Kaplan–Meier method. Statistical analyses used R version 4.3.1 (R Foundation for Statistical Computing).&lt;/p&gt;&lt;p&gt;Twenty-one patients with CLL were enrolled; median age was 67 years (range 48–85) with full characteristics previously described.&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; Patients had a median of 1 prior line of therapy (range 1–6), with 43% of patients having received ≥2 lines. Two patients had prior BTKi exposure (both treated with ibrutinib for &lt;","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11733307/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143004527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Postoperative stage 0 Hodgkin lymphoma. Is surgery alone a curative option?","authors":"Audrey Couturier,&nbsp;Alexandra Judet,&nbsp;Mohamed Touati,&nbsp;Thomas Nivet,&nbsp;Pierre Daufresne,&nbsp;Fabien Claves,&nbsp;Eric Durot,&nbsp;Rémy Duléry,&nbsp;Roch Houot,&nbsp;Guillaume Manson","doi":"10.1002/hem3.70076","DOIUrl":"10.1002/hem3.70076","url":null,"abstract":"&lt;p&gt;Classic Hodgkin lymphoma (HL) is a rare hematologic malignancy with high curative potential. Diagnosis is based on pathologic examination of an involved lymph node through microbiopsy or lymphadenectomy. The disease is then classified by PET/CT imaging as either early stage (Ann Arbor stage I or II) or advanced stage (Ann Arbor stage III or IV).&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Standard treatment includes chemotherapy (CT), often combined with radiotherapy (combined modality treatment [CMT]), and is guided by established prognostic factors (i.e., patient age, presence of a large mediastinal mass, B symptoms, inflammation, or 4 or more involved sites). In addition, PET/CT is extensively used for prognostication,&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; treatment guidance,&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; and response assessment.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;In some cases, patients undergo radical resection of affected lymph nodes or lesions and no further disease is found on PET/CT staging (i.e., “postoperative stage 0”). In 1965, Lacher reported the clinical outcomes of 11 patients with radical excision of Hodgkin's lymphoma.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; Eight of these 11 patients received postoperative treatment (radiation, chemotherapy, or a combination of both). Of the three patients who received no further treatment, two patients experienced disease relapse. Neither relapse occurred at the primary disease site. These observations were made before the development of modern imaging techniques, thus limiting the assessment of initial disease extension. Long-term remissions induced by surgery alone have recently been reported in patients with heavily pretreated relapsed or refractory disease&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt;; however, such outcomes have not been reported for newly diagnosed patients.&lt;/p&gt;&lt;p&gt;Patients with postoperative stage 0 HL may meet the criteria for early-stage favorable disease, whether these patients should be treated as such is unknown. This is a rare clinical scenario, and these patients were excluded from clinical studies due to the absence of measurable disease.&lt;/p&gt;&lt;p&gt;In this study, we describe the characteristics and outcomes of 13 patients with postoperative stage 0 HL.&lt;/p&gt;&lt;p&gt;We retrospectively analyzed adult patients with localized HL who underwent radical resection (i.e., adenectomy). Only patients with negative postoperative staging PET/CT were included. Patients with nodular lymphocyte-predominant Hodgkin lymphoma were excluded from the analysis.&lt;/p&gt;&lt;p&gt;We identified 13 patients from seven centers in France who underwent complete surgical tumor resection between 2008 and 2023. All resections were performed with negative surgical margins. Staging PET/CT was systematically conducted for all patients, and no evidence of persistent disease was detected after surgery. Outcomes for the entire cohort are summarized in Table 1 and Figure 1. After a median follow-up of 55 months (6–154) after surgical resection, only one patient relapsed, who had not received any","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11733436/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143004543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of myelodysplasia-related and additional gene mutations in intensively treated patients with NPM1-mutated AML","authors":"Sibylle Cocciardi,&nbsp;Maral Saadati,&nbsp;Nina Weiß,&nbsp;Daniela Späth,&nbsp;Silke Kapp-Schwoerer,&nbsp;Isabelle Schneider,&nbsp;Annika Meid,&nbsp;Verena I. Gaidzik,&nbsp;Sabrina Skambraks,&nbsp;Walter Fiedler,&nbsp;Michael W. M. Kühn,&nbsp;Ulrich Germing,&nbsp;Karin T. Mayer,&nbsp;Michael Lübbert,&nbsp;Elli Papaemmanuil,&nbsp;Felicitas Thol,&nbsp;Michael Heuser,&nbsp;Arnold Ganser,&nbsp;Lars Bullinger,&nbsp;Axel Benner,&nbsp;Hartmut Döhner,&nbsp;Konstanze Döhner","doi":"10.1002/hem3.70060","DOIUrl":"10.1002/hem3.70060","url":null,"abstract":"<p>This study aimed to evaluate the impact of the myelodysplasia-related gene (MRG) as well as additional gene mutations on outcomes in intensively treated patients with <i>NPM1</i>-mutated (<i>NPM1</i>^mut) AML. Targeted DNA sequencing of 263 genes was performed in 568 <i>NPM1</i>^mut AML patients (median age: 59 years) entered into the prospective AMLSG 09-09 treatment trial. Most commonly co-mutated genes were <i>DNMT3A</i> (49.8%), <i>FLT3</i>-TKD (25.9%), <i>PTPN11</i> (24.8%), <i>NRAS</i> (22.7%), <i>TET2</i> (21.7%), <i>IDH2</i> (21.3%), <i>IDH1</i> (18%), and <i>FLT3</i>-ITD (17.3%). MRG mutations were identified in 18.1% of cases (18–60 years: 9.8%; &gt;60 years: 28.7%). When focusing on the 470 patients with 2022 ELN favorable-risk <i>NPM1</i>^mut AML, multivariable analysis for event-free survival (EFS) identified age (<i>p</i> &lt; 0.001), <i>DNMT3A</i>^R882 (<i>p</i> &lt; 0.001), <i>IDH1</i> (<i>p</i> = 0.007), and MRG mutations (<i>p</i> = 0.03) as unfavorable factors, cohesin gene co-mutations (<i>p</i> = 0.001) and treatment with gemtuzumab ozogamicin (<i>p</i> = 0.007) as favorable factors. Restricting the analysis to a subset of CR/CRi patients with available data on <i>NPM1</i>^mut measurable residual disease (MRD) status in blood post cycle 2 in the model, MRG mutations lost their significant effect, whereas <i>DNMT3A</i>^R882, <i>MYC</i>, and cohesin gene mutations retained the adverse and favorable effects. For OS, age (<i>p</i> &lt; 0.001), <i>DNMT3A</i>^R882 (<i>p</i> = 0.042), <i>IDH1</i> (<i>p</i> = 0.045), and <i>KRAS</i> (0.003) mutations were unfavorable factors, sole favorable factor was <i>IDH2</i> co-mutation (<i>p</i> = 0.037). In 2022 ELN favorable-risk <i>NPM1</i>^mut AML, MRG mutations are associated with inferior EFS; however, this effect is no longer present when considering <i>NPM1</i>^mut MRD status post cycle 2; <i>DNMT3A</i>^R882 and <i>MYC</i> mutations remained adverse, and cohesin gene mutations favorable prognostic factors independent of the <i>NPM1</i>^mut MRD status.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11733593/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143004524","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prognostic significance of immune reconstitution following CD19 CAR T-cell therapy for relapsed/refractory B-cell lymphoma","authors":"Sophia Stock,&nbsp;Veit L. Bücklein,&nbsp;Viktoria Blumenberg,&nbsp;Giulia Magno,&nbsp;Alica-Joana Emhardt,&nbsp;Alessandra M. E. Holzem,&nbsp;David M. Cordas dos Santos,&nbsp;Christian Schmidt,&nbsp;Stefanie Grießhammer,&nbsp;Lisa Frölich,&nbsp;Sebastian Kobold,&nbsp;Michael von Bergwelt-Baildon,&nbsp;Kai Rejeski,&nbsp;Marion Subklewe","doi":"10.1002/hem3.70062","DOIUrl":"10.1002/hem3.70062","url":null,"abstract":"<p>Immune deficits after CD19 chimeric antigen receptor (CAR) T-cell therapy can be long-lasting, predisposing patients to infections and non-relapse mortality. In B-cell non-Hodgkin lymphoma (B-NHL), the prognostic impact of immune reconstitution (IR) remains ill-defined, and detailed cross-product comparisons have not been performed to date. In this retrospective observational study, we longitudinally characterized lymphocyte subsets and immunoglobulin levels in 105 B-NHL patients to assess patterns of immune recovery arising after CD19 CAR-T. Three key IR criteria were defined as CD4⁺ T helper (T_H) cells &gt; 200/µL, any detectable B cells, and serum immunoglobulin G (IgG) levels &gt;4 g/L. After a median follow-up of 24.6 months, 38% of patients displayed T_H cells, 11% showed any B cells, and 41% had IgG recovery. Notable product-specific differences emerged, including deeper T_H cell aplasia with CD28z- versus longer B-cell aplasia with 41BBz-based products. Patients with any IR recovery experienced extended progression-free survival (PFS) (median 20.8 vs. 1.7 months, <i>p</i> &lt; 0.0001) and overall survival (OS) (34.9 vs. 4.0 months, <i>p</i> &lt; 0.0001). While landmark analysis at 90 days confirmed improved PFS in patients with any recovery (34.9 vs. 8.6 months, <i>p</i> = 0.005), no significant OS difference was noted. Notably, 72% of patients with refractory disease never displayed recovery of any IR criteria. Early progressors showed diminished IR at the time of progression/relapse compared to patients with late progression/recurrence (after Day 90). Our results highlight the profound immune deficits observed after CD19 CAR-T and shed light on the intersection of IR and efficacy in B-NHL. Importantly, IR was impaired considerably postprogression, carrying significant implications for subsequent T-cell-engaging therapies and treatment sequencing.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11726691/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142978319","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}