Pub Date : 2025-10-24DOI: 10.1016/j.bneo.2025.100178
Giovanni Martinelli , Scott R. Solomon , Sudipto Mukherjee , Armando Santoro , Stephen A. Strickland , Susana Vives , Farhad Ravandi , Roland B. Walter , Rachel J. Cook , Ewa Lech-Maranda , Maria Calbacho , Agnieszka Wierzbowska , Giovanni Marconi , Evelyn Acuña-Cruz , Isabel Cano-Ferri , Francesco Bertolini , Tomasz Rzymski , Alessandro Paoli , Giovanni Marino Merlo , Faten Koraichi Auriol , Pau Montesinos
Abstract
Acute myeloid leukemia (AML) is an aggressive hematopoietic cancer with poor survival outcomes. Despite improvements with recent FMS-like tyrosine kinase 3 (FLT3) inhibitors, resistance is common, and responses are short. Dapolsertib (MEN1703) is a novel, first-in-class dual inhibitor of PIM (proviral integration site for Moloney murine leukemia virus) and FLT3 kinases, with activity in both FLT3-mutated and wild-type cells. A phase 1/2 open-label, multicenter, dose-escalation study (DIAMOND-01) investigated the maximum tolerated dose (MTD) of single-agent dapolsertib and assessed its safety, efficacy, pharmacokinetic (PK) profile, pharmacodynamic biomarkers, and genomics in patients with AML with no standard therapeutic options available. Seventy-three patients received oral doses of dapolsertib ranging from 25 to 150 mg per day (14 consecutive days over 21-day cycles). In the dose-escalation phase, the MTD was 125 mg and was selected for dose expansion. The most common grade ≥3 adverse events in patients receiving 125 mg were pneumonia (38%), thrombocytopenia (30%), and anemia (27%); most of these events were deemed not treatment related. For patients receiving 125 mg dapolsertib (n = 55), the overall response rate was 9%, with a median 2.07-month duration of response, and 4 of 5 responses were observed in patients with isocitrate dehydrogenase 1 (IDH1)/IDH2 mutations. PK analysis indicated rapid absorption of oral dapolsertib, an elimination half-life suitable for once daily dosing and a PK independent of formulation and IDH mutational status. Pharmacodynamic activity was confirmed in 50% of evaluable patients. Overall, dapolsertib demonstrated modest single-agent activity in patients with AML. This trial was registered at www.clinicaltrials.gov as #NCT03008187.
{"title":"Dual FLT3/PIM inhibitor dapolsertib in acute myeloid leukemia: results from the phase 1/2 DIAMOND-01 trial","authors":"Giovanni Martinelli , Scott R. Solomon , Sudipto Mukherjee , Armando Santoro , Stephen A. Strickland , Susana Vives , Farhad Ravandi , Roland B. Walter , Rachel J. Cook , Ewa Lech-Maranda , Maria Calbacho , Agnieszka Wierzbowska , Giovanni Marconi , Evelyn Acuña-Cruz , Isabel Cano-Ferri , Francesco Bertolini , Tomasz Rzymski , Alessandro Paoli , Giovanni Marino Merlo , Faten Koraichi Auriol , Pau Montesinos","doi":"10.1016/j.bneo.2025.100178","DOIUrl":"10.1016/j.bneo.2025.100178","url":null,"abstract":"<div><h3>Abstract</h3><div>Acute myeloid leukemia (AML) is an aggressive hematopoietic cancer with poor survival outcomes. Despite improvements with recent FMS-like tyrosine kinase 3 (FLT3) inhibitors, resistance is common, and responses are short. Dapolsertib (MEN1703) is a novel, first-in-class dual inhibitor of PIM (proviral integration site for Moloney murine leukemia virus) and FLT3 kinases, with activity in both <em>FLT3</em>-mutated and wild-type cells. A phase 1/2 open-label, multicenter, dose-escalation study (DIAMOND-01) investigated the maximum tolerated dose (MTD) of single-agent dapolsertib and assessed its safety, efficacy, pharmacokinetic (PK) profile, pharmacodynamic biomarkers, and genomics in patients with AML with no standard therapeutic options available. Seventy-three patients received oral doses of dapolsertib ranging from 25 to 150 mg per day (14 consecutive days over 21-day cycles). In the dose-escalation phase, the MTD was 125 mg and was selected for dose expansion. The most common grade ≥3 adverse events in patients receiving 125 mg were pneumonia (38%), thrombocytopenia (30%), and anemia (27%); most of these events were deemed not treatment related. For patients receiving 125 mg dapolsertib (n = 55), the overall response rate was 9%, with a median 2.07-month duration of response, and 4 of 5 responses were observed in patients with isocitrate dehydrogenase 1 (<em>IDH1</em>)/<em>IDH2</em> mutations. PK analysis indicated rapid absorption of oral dapolsertib, an elimination half-life suitable for once daily dosing and a PK independent of formulation and IDH mutational status. Pharmacodynamic activity was confirmed in 50% of evaluable patients. Overall, dapolsertib demonstrated modest single-agent activity in patients with AML. This trial was registered at <span><span>www.clinicaltrials.gov</span><svg><path></path></svg></span> as #NCT03008187.</div></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"3 1","pages":"Article 100178"},"PeriodicalIF":0.0,"publicationDate":"2025-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145840567","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-24DOI: 10.1016/j.bneo.2025.100175
Tapan M. Kadia , Akhil Jain , Caitlin R. Rausch , Alex Bataller , Farhad Ravandi , Elias Jabbour , Wei Qiao , Gautam Borthakur , Nicholas Short , Guillermo Montalban-Bravo , Andres E. Quesada , Jan Burger , Alessandra Ferrajoli , William Wierda , Chitra Hosing , Hagop Kantarjian
Abstract
T-cell prolymphocytic leukemia (T-PLL) is a mature T-cell neoplasm with an aggressive clinical course. Overall prognosis is poor, and treatment relies on alemtuzumab because of inadequate response to conventional chemotherapy. Three-quarters of cases harbor activating mutations in the JAK-STAT pathway (JAK1, JAK3, STAT5B, IL2RG). We report safety and efficacy from a phase 1B study evaluating the combination of the JAK1 inhibitor itacitinib with alemtuzumab. Patients (N = 15) were aged >18 years, with treatment-naïve (n = 8) or relapsed/refractory (n = 7) T-PLL with adequate organ function, European Cooperative Oncology Group Performance Status ≤2, and platelet >30 × 103/μL. Cycle 1 included a lead-in phase with itacitinib monotherapy days 1-14. Beginning day 15, patients also received alemtuzumab 30mg IV 3 times weekly for up to 4 (28-day) cycles or until best response. At best response, up to 8 cycles of maintenance with single-agent itacitinib was allowed. Median age was 65 years (range, 39-83). Ten patients (67%) had complex cytogenetics, 11 (73%) had chromosome 14 abnormality, and 13 (87%) were TCL1A positive by fluorescence in situ hybridization. Among frontline patients, overall response rate (ORR) was 88% (complete remission [CR]: 75%), median event-free survival (EFS) and overall survival (OS) were 11.6 and 19.5 months, respectively. Three frontline patients proceeded to allogeneic stem cell transplantation. The ORR in the relapsed/refractory cohort was 57% (CR: 43%), whereas median EFS and OS were 11.1 months. Most (85%) adverse events were grade 1 to 2 and none were attributed to itacitinib. Continued studies evaluating JAK inhibitors in patients with T-PLL are warranted. This trial was registered at www.clinicaltrials.gov as #NCT03989466.
{"title":"Phase 1B pilot study of itacitinib with alemtuzumab in patients with T-cell prolymphocytic leukemia","authors":"Tapan M. Kadia , Akhil Jain , Caitlin R. Rausch , Alex Bataller , Farhad Ravandi , Elias Jabbour , Wei Qiao , Gautam Borthakur , Nicholas Short , Guillermo Montalban-Bravo , Andres E. Quesada , Jan Burger , Alessandra Ferrajoli , William Wierda , Chitra Hosing , Hagop Kantarjian","doi":"10.1016/j.bneo.2025.100175","DOIUrl":"10.1016/j.bneo.2025.100175","url":null,"abstract":"<div><h3>Abstract</h3><div>T-cell prolymphocytic leukemia (T-PLL) is a mature T-cell neoplasm with an aggressive clinical course. Overall prognosis is poor, and treatment relies on alemtuzumab because of inadequate response to conventional chemotherapy. Three-quarters of cases harbor activating mutations in the JAK-STAT pathway (<em>JAK1</em>, <em>JAK3</em>, <em>STAT5B</em>, <em>IL2RG</em>). We report safety and efficacy from a phase 1B study evaluating the combination of the JAK1 inhibitor itacitinib with alemtuzumab. Patients (N = 15) were aged >18 years, with treatment-naïve (n = 8) or relapsed/refractory (n = 7) T-PLL with adequate organ function, European Cooperative Oncology Group Performance Status ≤2, and platelet >30 × 10<sup>3</sup>/μL. Cycle 1 included a lead-in phase with itacitinib monotherapy days 1-14. Beginning day 15, patients also received alemtuzumab 30mg IV 3 times weekly for up to 4 (28-day) cycles or until best response. At best response, up to 8 cycles of maintenance with single-agent itacitinib was allowed. Median age was 65 years (range, 39-83). Ten patients (67%) had complex cytogenetics, 11 (73%) had chromosome 14 abnormality, and 13 (87%) were <em>TCL1A</em> positive by fluorescence in situ hybridization. Among frontline patients, overall response rate (ORR) was 88% (complete remission [CR]: 75%), median event-free survival (EFS) and overall survival (OS) were 11.6 and 19.5 months, respectively. Three frontline patients proceeded to allogeneic stem cell transplantation. The ORR in the relapsed/refractory cohort was 57% (CR: 43%), whereas median EFS and OS were 11.1 months. Most (85%) adverse events were grade 1 to 2 and none were attributed to itacitinib. Continued studies evaluating JAK inhibitors in patients with T-PLL are warranted. This trial was registered at <span><span>www.clinicaltrials.gov</span><svg><path></path></svg></span> as #NCT03989466.</div></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"3 1","pages":"Article 100175"},"PeriodicalIF":0.0,"publicationDate":"2025-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145840566","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-16DOI: 10.1016/j.bneo.2025.100174
Anna Maria Corsale , Mojtaba Shekarkar Azgomi , Emilia Gigliotta , Marta Di Simone , Paola Pacelli , Francesca Cioffi , Elena Bestoso , Donatella Raspadori , Alessandro Gozzetti , Antonio Solimando , Paula Tabares , Andreas Beilhack , Maria Speciale , Giusy Corsale , Miriam Sciortino , Cristina Aquilina , Fulvio Brucato , Michele Cea , Renato Zambello , Francesca Garofano , Cirino Botta
Abstract
The progression of multiple myeloma (MM) is characterized by intricate interactions between clonal plasma cells and the bone marrow (BM) microenvironment. In this study, we conducted a comprehensive analysis of BM immune cell composition spanning from premalignant stages to MM, using FlowCT, a semiautomated workspace empowered to analyze large data sets. Our cohort comprised 159 patients, covering monoclonal gammopathy of undetermined significance, smoldering MM, and MM, with most undergoing treatment with a daratumumab-based regimen. The evolving disease showed alterations in immune cell populations, including a reduction in the granulocyte-to-lymphocyte ratio (GLR) and granulocyte–to–T-lymphocyte (GTL) ratio, alongside an increase in T lymphocytes. Higher baseline levels of BM GLR and GTL ratio were associated with extended progression-free survival. Moreover, improved outcomes were observed in patients with a higher GTL ratio treated with daratumumab-based regimens. Furthermore, autologous BM-derived granulocytes enhance daratumumab-mediated cytotoxicity against primary autologous neoplastic plasma cells, unveiling a novel BM-granulocyte–dependent mechanism of action for daratumumab in patients with MM. These findings emphasize the dynamic nature of the BM immune compartment during MM progression and underscore the prognostic significance of immune cell composition in guiding therapeutic approaches and enhancing patient outcomes.
{"title":"Bone marrow immune cell composition reflects multiple myeloma progression and affects treatment response","authors":"Anna Maria Corsale , Mojtaba Shekarkar Azgomi , Emilia Gigliotta , Marta Di Simone , Paola Pacelli , Francesca Cioffi , Elena Bestoso , Donatella Raspadori , Alessandro Gozzetti , Antonio Solimando , Paula Tabares , Andreas Beilhack , Maria Speciale , Giusy Corsale , Miriam Sciortino , Cristina Aquilina , Fulvio Brucato , Michele Cea , Renato Zambello , Francesca Garofano , Cirino Botta","doi":"10.1016/j.bneo.2025.100174","DOIUrl":"10.1016/j.bneo.2025.100174","url":null,"abstract":"<div><h3>Abstract</h3><div>The progression of multiple myeloma (MM) is characterized by intricate interactions between clonal plasma cells and the bone marrow (BM) microenvironment. In this study, we conducted a comprehensive analysis of BM immune cell composition spanning from premalignant stages to MM, using FlowCT, a semiautomated workspace empowered to analyze large data sets. Our cohort comprised 159 patients, covering monoclonal gammopathy of undetermined significance, smoldering MM, and MM, with most undergoing treatment with a daratumumab-based regimen. The evolving disease showed alterations in immune cell populations, including a reduction in the granulocyte-to-lymphocyte ratio (GLR) and granulocyte–to–T-lymphocyte (GTL) ratio, alongside an increase in T lymphocytes. Higher baseline levels of BM GLR and GTL ratio were associated with extended progression-free survival. Moreover, improved outcomes were observed in patients with a higher GTL ratio treated with daratumumab-based regimens. Furthermore, autologous BM-derived granulocytes enhance daratumumab-mediated cytotoxicity against primary autologous neoplastic plasma cells, unveiling a novel BM-granulocyte–dependent mechanism of action for daratumumab in patients with MM. These findings emphasize the dynamic nature of the BM immune compartment during MM progression and underscore the prognostic significance of immune cell composition in guiding therapeutic approaches and enhancing patient outcomes.</div></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"3 1","pages":"Article 100174"},"PeriodicalIF":0.0,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145738216","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-09DOI: 10.1016/j.bneo.2025.100172
Anna Palau ∗ , Jonas Thier ∗ , Aonghus Naughton ∗ , Andrew Tae-Jun Kwon , David Cabrerizo Granados , Sophia Hofmann , Bogumił Kaczkowski , Xiangfu Zhong , Sören Lehmann , Erik Arner , Vanessa Lundin † , Andreas Lennartsson †
Abstract
KMT2A chromosomal rearrangements (KMT2A-r) are frequent in pediatric acute myeloid leukemia (AML) and are associated with poor prognosis. The KMT2A gene encodes a histone lysine methyltransferase responsible for maintaining active chromatin marks (H3K4me3) at gene promoters and enhancers. KMT2A-r lead to the formation of oncogenic KMT2A fusion proteins with over 70 potential partners, disrupting normal hematopoiesis and driving leukemogenesis. Among these, KMT2A::MLLT3, a fusion of KMT2A and MLLT3, is one of the most prevalent in AML. Disruption of the epigenome is a hallmark of AML, with recurrent abnormalities in epigenetic regulators. These alterations often occur early as disease-initiating events, making epigenetic-targeted therapeutics a promising avenue for treatment. Induced pluripotent stem cells (iPSCs) have emerged as faithful models of human AML pathogenesis, recapitulating the underlying genomic lesions and epigenetic profiles. We investigated transcriptional regulation of hematopoietic development using iPSCs derived from a patient with AML with the KMT2A::MLLT3 rearrangement. Our analysis identified key transcriptional activators and repressors that contribute to the altered regulatory landscape in KMT2A::MLLT3 AML. Further analysis of chromatin immunoprecipitation sequencing data indicated that a significant subset of genes, whose expression was downregulated in AML iPSC-derived hematopoietic stem and progenitor cells (AML-HSPCs), were direct targets of Polycomb Repressive Complex 2 (PRC2). Treatment with the dual EZH1/2 inhibitor UNC1999 and 5-azacytidine reactivated these PRC2 target genes, specifically in AML-HSPCs, toward normal gene expression patterns. These findings suggest that targeting Polycomb repression offers a promising epigenetic strategy for improving outcomes in KMT2A-rearranged AML.
{"title":"Targeting dysregulated epigenetic and transcription factor networks in KMT2A-rearranged AML using iPSC models","authors":"Anna Palau ∗ , Jonas Thier ∗ , Aonghus Naughton ∗ , Andrew Tae-Jun Kwon , David Cabrerizo Granados , Sophia Hofmann , Bogumił Kaczkowski , Xiangfu Zhong , Sören Lehmann , Erik Arner , Vanessa Lundin † , Andreas Lennartsson †","doi":"10.1016/j.bneo.2025.100172","DOIUrl":"10.1016/j.bneo.2025.100172","url":null,"abstract":"<div><h3>Abstract</h3><div><em>KMT2A</em> chromosomal rearrangements (<em>KMT2A-</em>r) are frequent in pediatric acute myeloid leukemia (AML) and are associated with poor prognosis. The <em>KMT2A</em> gene encodes a histone lysine methyltransferase responsible for maintaining active chromatin marks (H3K4me3) at gene promoters and enhancers. <em>KMT2A-</em>r lead to the formation of oncogenic <em>KMT2A</em> fusion proteins with over 70 potential partners, disrupting normal hematopoiesis and driving leukemogenesis. Among these, <em>KMT2A</em>::<em>MLLT3</em>, a fusion of <em>KMT2A</em> and <em>MLLT3</em>, is one of the most prevalent in AML. Disruption of the epigenome is a hallmark of AML, with recurrent abnormalities in epigenetic regulators. These alterations often occur early as disease-initiating events, making epigenetic-targeted therapeutics a promising avenue for treatment. Induced pluripotent stem cells (iPSCs) have emerged as faithful models of human AML pathogenesis, recapitulating the underlying genomic lesions and epigenetic profiles. We investigated transcriptional regulation of hematopoietic development using iPSCs derived from a patient with AML with the <em>KMT2A</em>::<em>MLLT3</em> rearrangement. Our analysis identified key transcriptional activators and repressors that contribute to the altered regulatory landscape in <em>KMT2A</em>::<em>MLLT3</em> AML. Further analysis of chromatin immunoprecipitation sequencing data indicated that a significant subset of genes, whose expression was downregulated in AML iPSC-derived hematopoietic stem and progenitor cells (AML-HSPCs), were direct targets of Polycomb Repressive Complex 2 (PRC2). Treatment with the dual EZH1/2 inhibitor UNC1999 and 5-azacytidine reactivated these PRC2 target genes, specifically in AML-HSPCs, toward normal gene expression patterns. These findings suggest that targeting Polycomb repression offers a promising epigenetic strategy for improving outcomes in <em>KMT2A-</em>rearranged AML.</div></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"3 1","pages":"Article 100172"},"PeriodicalIF":0.0,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145694812","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-09DOI: 10.1016/j.bneo.2025.100171
Jayanshu Jain ∗ , Kelly Pugh ∗ , Shivani Handa , Kaitlyn M. Dvorak-Kornaus , Qiuhong Zhao , Roland B. Walter , Rachel Cook , Jennifer Saultz , Ronan Swords , Junyang Li , George S. Laszlo , Nicole R. Grieselhuber , Alice S. Mims , Karilyn T. M. Larkin , Kieran Sahasrabudhe , James S. Blachly , Gregory K. Behbehani , Ann-Kathrin Eisfeld , Meixiao Long , Andrew Srisuwananukorn , Uma Borate
Abstract
This phase 1 study investigated the addition of gemtuzumab ozogamicin (GO) to intensive chemotherapy with cytarabine, daunorubicin, and midostaurin in 21 patients with newly diagnosed (ND) FMS-like tyrosine kinase 3 (FLT3)–mutated acute myeloid leukemia (AML). Four dose levels of GO were evaluated. The use of GO was tolerable, with all dose-limiting toxicities similar to those seen in standard-of-care treatment. After induction, the median time to platelet recovery was 26 days, and the median time to absolute neutrophil count (ANC) recovery was 27 days. The maximum tolerated dose was cytarabine 100 mg/m2 on days 1 to 7, midostaurin 50 mg twice daily on days 8 to 21, daunorubicin 60 mg/m2 on days 1 to 3, and GO 3 mg/m2 on days 1 and 4. For the 18 patients who were evaluable for response after induction therapy, 16 patients (76%) achieved a composite complete response (complete remission [CR] + CR with incomplete hematologic recovery), and 2 (10%) had stable disease. Of the 14 patients who proceeded to consolidation, 5 discontinued the study for transplant, 1 for disease progression, and 1 for physician discretion. Seven patients completed consolidation therapy, all of whom achieved a CR. In total, 13 of the 21 patients (62%) received a hematopoietic stem cell transplant. Our results show that GO can safely be combined with intensive chemotherapy with midostaurin in ND, FLT3-mutated AML. This trial was registered at www.clinicaltrials.gov as #NCT03900949.
{"title":"Safety of gemtuzumab ozogamicin with cytarabine, daunorubicin, and midostaurin induction in FLT3-mutated AML","authors":"Jayanshu Jain ∗ , Kelly Pugh ∗ , Shivani Handa , Kaitlyn M. Dvorak-Kornaus , Qiuhong Zhao , Roland B. Walter , Rachel Cook , Jennifer Saultz , Ronan Swords , Junyang Li , George S. Laszlo , Nicole R. Grieselhuber , Alice S. Mims , Karilyn T. M. Larkin , Kieran Sahasrabudhe , James S. Blachly , Gregory K. Behbehani , Ann-Kathrin Eisfeld , Meixiao Long , Andrew Srisuwananukorn , Uma Borate","doi":"10.1016/j.bneo.2025.100171","DOIUrl":"10.1016/j.bneo.2025.100171","url":null,"abstract":"<div><h3>Abstract</h3><div>This phase 1 study investigated the addition of gemtuzumab ozogamicin (GO) to intensive chemotherapy with cytarabine, daunorubicin, and midostaurin in 21 patients with newly diagnosed (ND) FMS-like tyrosine kinase 3 (<em>FLT3</em>)–mutated acute myeloid leukemia (AML). Four dose levels of GO were evaluated. The use of GO was tolerable, with all dose-limiting toxicities similar to those seen in standard-of-care treatment. After induction, the median time to platelet recovery was 26 days, and the median time to absolute neutrophil count (ANC) recovery was 27 days. The maximum tolerated dose was cytarabine 100 mg/m<sup>2</sup> on days 1 to 7, midostaurin 50 mg twice daily on days 8 to 21, daunorubicin 60 mg/m<sup>2</sup> on days 1 to 3, and GO 3 mg/m<sup>2</sup> on days 1 and 4. For the 18 patients who were evaluable for response after induction therapy, 16 patients (76%) achieved a composite complete response (complete remission [CR] + CR with incomplete hematologic recovery), and 2 (10%) had stable disease. Of the 14 patients who proceeded to consolidation, 5 discontinued the study for transplant, 1 for disease progression, and 1 for physician discretion. Seven patients completed consolidation therapy, all of whom achieved a CR. In total, 13 of the 21 patients (62%) received a hematopoietic stem cell transplant. Our results show that GO can safely be combined with intensive chemotherapy with midostaurin in ND, <em>FLT3</em>-mutated AML. This trial was registered at <span><span>www.clinicaltrials.gov</span><svg><path></path></svg></span> as #NCT03900949.</div></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"3 1","pages":"Article 100171"},"PeriodicalIF":0.0,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145738217","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-09DOI: 10.1016/j.bneo.2025.100173
Reid W. Merryman ∗ , Justin Kline ∗ , Robert A. Redd , Harrison Olszewski , Emma Welsh , Kathleen Pfaff , Hannah Lee , Mikaela McDonough , Inhye E. Ahn , Jennifer R. Brown , Jennifer L. Crombie , Matthew S. Davids , David C. Fisher , Eric D. Jacobsen , Caron A. Jacobson , Austin I. Kim , Oreofe O. Odejide , Erin Michelle Parry , Christine E. Ryan , Margaret A. Shipp , Ann S. LaCasce
{"title":"Ipilimumab with and without nivolumab in patients with classic Hodgkin lymphoma with progression after PD-1 blockade","authors":"Reid W. Merryman ∗ , Justin Kline ∗ , Robert A. Redd , Harrison Olszewski , Emma Welsh , Kathleen Pfaff , Hannah Lee , Mikaela McDonough , Inhye E. Ahn , Jennifer R. Brown , Jennifer L. Crombie , Matthew S. Davids , David C. Fisher , Eric D. Jacobsen , Caron A. Jacobson , Austin I. Kim , Oreofe O. Odejide , Erin Michelle Parry , Christine E. Ryan , Margaret A. Shipp , Ann S. LaCasce","doi":"10.1016/j.bneo.2025.100173","DOIUrl":"10.1016/j.bneo.2025.100173","url":null,"abstract":"","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"3 1","pages":"Article 100173"},"PeriodicalIF":0.0,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145694813","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-01DOI: 10.1016/j.bneo.2025.100164
Chathuri Abeyakoon , Sita Bhella , Katrina Hueniken , Rachel Aitken , Carmel Waldron , Anca Prica , Vishal Kukreti , Robert Kridel , Abi Vijenthira , Christine Chen , Chloe Yang , Richard Tsang , David Hodgson , Danielle Rodin , Nauman Malik , Woodrow Wells , Michael Crump , John Kuruvilla
Abstract
Outcomes following CD19 chimeric antigen receptor (CAR) T-cell therapy in third-line treatment and beyond for patients with large B-cell lymphoma (LBCL) refractory to both an anthracycline during initial and platinum-based salvage therapy, referred to as double refractory (DR), are not well-described. It is also unclear if these patients may be less likely to proceed to CAR T-cell infusion. Our objectives were to assess third-line CAR T-cell survival outcomes in DR- and non-DR (NDR)-LBCL cohorts including the failure rates to proceed to cell infusion. Review of 199 patients with LBCL referred for CAR T-cell treatment at our center, demonstrates that the DR-LBCL patients (n = 68) have an inferior 12-month (overall survival [OS], 47.1% vs 66.7%, respectively;) when compared to the patients with NDR-LBCL (n = 131). This OS difference is driven by a higher failure rate to proceed to CAR T-cell infusion (32% vs 18%). For patients unable to proceed to CAR T-cell infusion median OS was 2.56 months; DR-LBCL 1.94 months vs NDR-LBCL 3.42 months. The 12-month OS (65% vs 72.3%) and 6-month progression-free survival (46.5% vs 57.2%) of patients with DR- and NDR-LBCL proceeding to CAR T-cell infusion, appears similar. Our study highlights a high-risk subgroup characterized by inferior OS with challenges in getting to CAR T-cell infusion and could benefit from different management approaches such as novel bridging or “off-the-shelf” strategies.
{"title":"Inferior survival in double refractory large B-cell lymphoma eligible for third-line CD19 CAR T-cell therapy","authors":"Chathuri Abeyakoon , Sita Bhella , Katrina Hueniken , Rachel Aitken , Carmel Waldron , Anca Prica , Vishal Kukreti , Robert Kridel , Abi Vijenthira , Christine Chen , Chloe Yang , Richard Tsang , David Hodgson , Danielle Rodin , Nauman Malik , Woodrow Wells , Michael Crump , John Kuruvilla","doi":"10.1016/j.bneo.2025.100164","DOIUrl":"10.1016/j.bneo.2025.100164","url":null,"abstract":"<div><h3>Abstract</h3><div>Outcomes following CD19 chimeric antigen receptor (CAR) T-cell therapy in third-line treatment and beyond for patients with large B-cell lymphoma (LBCL) refractory to both an anthracycline during initial and platinum-based salvage therapy, referred to as double refractory (DR), are not well-described. It is also unclear if these patients may be less likely to proceed to CAR T-cell infusion. Our objectives were to assess third-line CAR T-cell survival outcomes in DR- and non-DR (NDR)-LBCL cohorts including the failure rates to proceed to cell infusion. Review of 199 patients with LBCL referred for CAR T-cell treatment at our center, demonstrates that the DR-LBCL patients (n = 68) have an inferior 12-month (overall survival [OS], 47.1% vs 66.7%, respectively;) when compared to the patients with NDR-LBCL (n = 131). This OS difference is driven by a higher failure rate to proceed to CAR T-cell infusion (32% vs 18%). For patients unable to proceed to CAR T-cell infusion median OS was 2.56 months; DR-LBCL 1.94 months vs NDR-LBCL 3.42 months. The 12-month OS (65% vs 72.3%) and 6-month progression-free survival (46.5% vs 57.2%) of patients with DR- and NDR-LBCL proceeding to CAR T-cell infusion, appears similar. Our study highlights a high-risk subgroup characterized by inferior OS with challenges in getting to CAR T-cell infusion and could benefit from different management approaches such as novel bridging or “off-the-shelf” strategies.</div></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"2 4","pages":"Article 100164"},"PeriodicalIF":0.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145324410","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-25DOI: 10.1016/j.bneo.2025.100166
Tomoyasu Jo , Tadakazu Kondo , Shohei Mizuno , Shinichi Kako , Noriko Doki , Naoyuki Uchida , Masatsugu Tanaka , Tetsuya Nishida , Takahiro Fukuda , Masashi Sawa , Yoshinobu Kanda , Satoru Takada , Yuta Hasegawa , Yuta Katayama , Satoshi Yoshihara , Koji Kawamura , Marie Ohbiki , Yoshiko Atsuta , Masamitsu Yanada , Yasuyuki Arai
Abstract
Mixed-phenotype acute leukemia (MPAL) is associated with poor prognosis. Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) can achieve long-term survival, optimal transplantation strategies remain unclear. We analyzed a national registry of adult patients with MPAL who underwent allo-HSCT between 2008 and 2022 in Japan. Among 417 patients, median age at transplant was 44 years (interquartile range, 32-55); 61% were male, 20% were BCR::ABL1-positive, and 66% underwent transplant during the first complete remission (CR; CR1). At 5 years posttransplant, overall survival (OS) was 54%, disease-free survival was 49%, relapse was 28%, and nonrelapse mortality was 23%. Multivariate analysis identified older age (adjusted hazard ratio [aHR], 1.78 [95% confidence interval (CI), 1.11-2.84] for ages 50-59 years; aHR, 2.65 [95% CI, 1.54-4.55] for ≥60 years; both vs <40 years), male sex (aHR, 1.56; 95% CI, 1.07-2.27), Eastern Cooperative Oncology Group performance status scale ≥2 (aHR, 3.05; 95% CI, 1.72-5.40), BCR::ABL1 -negative status (aHR, 1.64; 95% CI, 1.02-2.64), advanced disease status (aHR, 1.642 [95% CI, 0.80-3.36] for second CR; aHR, 4.01 [95% CI, 2.61-6.15] for third or higher CR, or non-CR vs CR1), and low conditioning intensity (aHR, 2.49 [95% CI, 1.21-5.13] for low transplant conditioning intensity [TCI] vs high TCI) as adverse prognostic factors for OS. A propensity score–matched comparison with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) during the same period showed that MPAL did not have significantly worse prognosis than AML or ALL. These findings suggest that allo-HSCT offers long-term survival in MPAL, with outcomes not inferior to those of AML and ALL.
{"title":"Analyses of transplantation outcomes for adult patients with mixed-phenotype acute leukemia","authors":"Tomoyasu Jo , Tadakazu Kondo , Shohei Mizuno , Shinichi Kako , Noriko Doki , Naoyuki Uchida , Masatsugu Tanaka , Tetsuya Nishida , Takahiro Fukuda , Masashi Sawa , Yoshinobu Kanda , Satoru Takada , Yuta Hasegawa , Yuta Katayama , Satoshi Yoshihara , Koji Kawamura , Marie Ohbiki , Yoshiko Atsuta , Masamitsu Yanada , Yasuyuki Arai","doi":"10.1016/j.bneo.2025.100166","DOIUrl":"10.1016/j.bneo.2025.100166","url":null,"abstract":"<div><h3>Abstract</h3><div>Mixed-phenotype acute leukemia (MPAL) is associated with poor prognosis. Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) can achieve long-term survival, optimal transplantation strategies remain unclear. We analyzed a national registry of adult patients with MPAL who underwent allo-HSCT between 2008 and 2022 in Japan. Among 417 patients, median age at transplant was 44 years (interquartile range, 32-55); 61% were male, 20% were <em>BCR::ABL1</em>-positive, and 66% underwent transplant during the first complete remission (CR; CR1). At 5 years posttransplant, overall survival (OS) was 54%, disease-free survival was 49%, relapse was 28%, and nonrelapse mortality was 23%. Multivariate analysis identified older age (adjusted hazard ratio [aHR], 1.78 [95% confidence interval (CI), 1.11-2.84] for ages 50-59 years; aHR, 2.65 [95% CI, 1.54-4.55] for ≥60 years; both vs <40 years), male sex (aHR, 1.56; 95% CI, 1.07-2.27), Eastern Cooperative Oncology Group performance status scale ≥2 (aHR, 3.05; 95% CI, 1.72-5.40), <em>BCR::ABL1</em> -negative status (aHR, 1.64; 95% CI, 1.02-2.64), advanced disease status (aHR, 1.642 [95% CI, 0.80-3.36] for second CR; aHR, 4.01 [95% CI, 2.61-6.15] for third or higher CR, or non-CR vs CR1), and low conditioning intensity (aHR, 2.49 [95% CI, 1.21-5.13] for low transplant conditioning intensity [TCI] vs high TCI) as adverse prognostic factors for OS. A propensity score–matched comparison with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) during the same period showed that MPAL did not have significantly worse prognosis than AML or ALL. These findings suggest that allo-HSCT offers long-term survival in MPAL, with outcomes not inferior to those of AML and ALL.</div></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"2 4","pages":"Article 100166"},"PeriodicalIF":0.0,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145266584","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-25DOI: 10.1016/j.bneo.2025.100165
Abdulraheem Yacoub ∗ , Haris Ali ∗ , Vikas Gupta , Eunice S. Wang , Mrinal M. Patnaik , Gary J. Schiller , Minakshi Taparia , Tariq I. Mughal , Ross Lindsay , Antonio Galleu , Ira Gupta , Naveen Pemmaraju
Abstract
Patients with myelofibrosis (MF) who are resistant to or relapse after Janus kinase inhibitor (JAKi) therapy have limited treatment options and typically poor prognoses. CD123 is overexpressed in various myeloid malignancies, including MF. Tagraxofusp is a first-in-class CD123-targeted therapy, and the only drug approved globally for the rare myeloid malignancy blastic plasmacytoid dendritic cell neoplasm. We conducted a phase 1/2 trial to determine optimal dosing, and evaluate safety and efficacy of tagraxofusp monotherapy in treatment-naïve (n = 5) MF and patients with MF resistant/refractory to JAKi (n = 25) and not eligible for stem cell transplant. There were no dose-limiting toxicities. The recommended phase 2 dose of tagraxofusp was 12 μg/kg per day for 3 consecutive days per cycle. In the safety population (n = 36) treated at 12 μg/kg per day, the most frequent grade ≥3 treatment-emergent adverse events were thrombocytopenia (19%), anemia (22%), and dyspnea (11%). Capillary leak syndrome occurred in 11% of patients, all during cycle 1 with resolution in all patients. Thirty patients treated at 12 μg/kg per day were efficacy evaluable. Of 18 (n = 2 treatment-naïve, n = 16 relapsed/refractory) patients with baseline splenomegaly, 2 relapsed/refractory patients had spleen volume reduction ≥35%. In relapsed/refractory patients, 40% had total symptom score (TSS) ≥50%, and median overall survival (OS) was 19.3 months. In patients who were treatment naïve, 40% had TSS ≥50%, and median OS was 26.6 months. In this trial, tagraxofusp monotherapy in MF was well tolerated, without cumulative myelotoxicity, and with symptom score improvements, warranting further investigation in combination therapy. This trial was registered at www.clincaltrials.gov as #NCT02268253.
{"title":"Final safety and efficacy results from a phase 1/2 study of tagraxofusp, a CD123-targeted therapy, for myelofibrosis","authors":"Abdulraheem Yacoub ∗ , Haris Ali ∗ , Vikas Gupta , Eunice S. Wang , Mrinal M. Patnaik , Gary J. Schiller , Minakshi Taparia , Tariq I. Mughal , Ross Lindsay , Antonio Galleu , Ira Gupta , Naveen Pemmaraju","doi":"10.1016/j.bneo.2025.100165","DOIUrl":"10.1016/j.bneo.2025.100165","url":null,"abstract":"<div><h3>Abstract</h3><div>Patients with myelofibrosis (MF) who are resistant to or relapse after Janus kinase inhibitor (JAKi) therapy have limited treatment options and typically poor prognoses. CD123 is overexpressed in various myeloid malignancies, including MF. Tagraxofusp is a first-in-class CD123-targeted therapy, and the only drug approved globally for the rare myeloid malignancy blastic plasmacytoid dendritic cell neoplasm. We conducted a phase 1/2 trial to determine optimal dosing, and evaluate safety and efficacy of tagraxofusp monotherapy in treatment-naïve (n = 5) MF and patients with MF resistant/refractory to JAKi (n = 25) and not eligible for stem cell transplant. There were no dose-limiting toxicities. The recommended phase 2 dose of tagraxofusp was 12 μg/kg per day for 3 consecutive days per cycle. In the safety population (n = 36) treated at 12 μg/kg per day, the most frequent grade ≥3 treatment-emergent adverse events were thrombocytopenia (19%), anemia (22%), and dyspnea (11%). Capillary leak syndrome occurred in 11% of patients, all during cycle 1 with resolution in all patients. Thirty patients treated at 12 μg/kg per day were efficacy evaluable. Of 18 (n = 2 treatment-naïve, n = 16 relapsed/refractory) patients with baseline splenomegaly, 2 relapsed/refractory patients had spleen volume reduction ≥35%. In relapsed/refractory patients, 40% had total symptom score (TSS) ≥50%, and median overall survival (OS) was 19.3 months. In patients who were treatment naïve, 40% had TSS ≥50%, and median OS was 26.6 months. In this trial, tagraxofusp monotherapy in MF was well tolerated, without cumulative myelotoxicity, and with symptom score improvements, warranting further investigation in combination therapy. This trial was registered at <span><span>www.clincaltrials.gov</span><svg><path></path></svg></span> as #NCT02268253.</div></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"2 4","pages":"Article 100165"},"PeriodicalIF":0.0,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145324411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-19DOI: 10.1016/j.bneo.2025.100161
Vijay Negi ∗ , Ryan Bertoli ∗ , Olivia Tuckey , Yuelin Jack Zhu , Robert L. Walker , Michael J. Difilippantonio , James H. Doroshow , Paul S. Meltzer , Peter D. Aplan
Abstract
5-Aza-4'-thio-2'-deoxycytidine (ATC) is an azanucleoside cytidine analog under investigation in preclinical studies for solid tumors as a promising DNA methyltransferase 1 (DNMT1) inhibitor. Repeated treatment with ATC has previously been shown to induce acute lymphoblastic leukemia (ALL) of both B-cell and T-cell origin in mice. Herein, RAG-1 deficient or “knockout” (KO) mice (B6.129S7-RAG-1tm1Mom/J) were treated with ATC to determine if ATC could be oncogenic in nonlymphoid cells. However, ATC treatment targeted early B progenitors and invariably led to B-lineage ALL, with a gene expression signature similar to human B-cell precursor (BCP)-ALL. Whole-exome sequencing revealed numerous single base substitutions of cytosine, primarily C>G transversions at CpG dinucleotides, within genes important for BCP-ALL. Bisulfite sequencing and treatment with a noncovalent DNMT1 inhibitor indicated that methylated cytosines were preferred targets for mutagenesis. This study reveals that ATC exposure leads to both DNMT1-dependent and -independent mutagenesis and provides a direct link between ATC exposure, a complex mutational signature, and malignant transformation.
{"title":"Azanucleoside treatment leads to B-cell precursor acute lymphoblastic leukemia","authors":"Vijay Negi ∗ , Ryan Bertoli ∗ , Olivia Tuckey , Yuelin Jack Zhu , Robert L. Walker , Michael J. Difilippantonio , James H. Doroshow , Paul S. Meltzer , Peter D. Aplan","doi":"10.1016/j.bneo.2025.100161","DOIUrl":"10.1016/j.bneo.2025.100161","url":null,"abstract":"<div><h3>Abstract</h3><div>5-Aza-4'-thio-2'-deoxycytidine (ATC) is an azanucleoside cytidine analog under investigation in preclinical studies for solid tumors as a promising DNA methyltransferase 1 (DNMT1) inhibitor. Repeated treatment with ATC has previously been shown to induce acute lymphoblastic leukemia (ALL) of both B-cell and T-cell origin in mice. Herein, RAG-1 deficient or “knockout” (KO) mice (B6.129S7-RAG-1tm1Mom/J) were treated with ATC to determine if ATC could be oncogenic in nonlymphoid cells. However, ATC treatment targeted early B progenitors and invariably led to B-lineage ALL, with a gene expression signature similar to human B-cell precursor (BCP)-ALL. Whole-exome sequencing revealed numerous single base substitutions of cytosine, primarily C>G transversions at CpG dinucleotides, within genes important for BCP-ALL. Bisulfite sequencing and treatment with a noncovalent DNMT1 inhibitor indicated that methylated cytosines were preferred targets for mutagenesis. This study reveals that ATC exposure leads to both DNMT1-dependent and -independent mutagenesis and provides a direct link between ATC exposure, a complex mutational signature, and malignant transformation.</div></div>","PeriodicalId":100189,"journal":{"name":"Blood Neoplasia","volume":"2 4","pages":"Article 100161"},"PeriodicalIF":0.0,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145324408","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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