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Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive, orphan hematologic malignancy characterized by cells expressing CD123 and other markers. The only drug approved for BPDCN is tagraxofusp, a first-in-class CD123-targeted therapy. Tagraxofusp has a boxed warning for capillary leak syndrome (CLS) in the US prescribing information. CLS symptoms include hypoalbuminemia, weight gain, edema, and in severe cases, hypotension and hemodynamic instability. In the tagraxofusp registrational trial, 21% of patients receiving 12 µg/kg/day developed CLS. Most events were grade 2; higher grade CLS events including 2% grade 3, 2% grade 4, and two deaths occurred. During tagraxofusp treatment, strict monitoring for early recognition of CLS symptoms and directed intervention is essential for managing CLS; with this approach CLS is typically mild and occurs mostly in cycle 1, without recurrence. We discuss patient selection and optimization, monitoring, and early intervention for successful identification and optimized management of CLS in real-world practice.
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Síndrome de Fuga Capilar , Células Dendríticas , Neoplasias Hematológicas , Proteínas Recombinantes de Fusión , Humanos , Síndrome de Fuga Capilar/prevención & control , Síndrome de Fuga Capilar/etiología , Síndrome de Fuga Capilar/diagnóstico , Células Dendríticas/patología , Células Dendríticas/efectos de los fármacos , Neoplasias Hematológicas/tratamiento farmacológico , Neoplasias Hematológicas/complicaciones , Neoplasias Hematológicas/patología , Proteínas Recombinantes de Fusión/efectos adversos , Proteínas Recombinantes de Fusión/uso terapéutico , Proteínas Recombinantes de Fusión/administración & dosificación , Manejo de la Enfermedad , Neoplasia de Células Dendríticas Plasmocitoides BlásticasRESUMEN
Preclinical data suggest CPX-351, approved for patients with newly diagnosed therapy-related acute myeloid leukemia (AML) or AML with myelodysplasia-related changes, may exhibit synergy with targeted agents, suggesting a rationale for combining targeted agents with CPX-351 as a chemotherapy backbone. The V-FAST (Vyxeos - First Phase ASsessment With Targeted Agents) phase 1b trial evaluated CPX-351 with the targeted agents venetoclax (arm A), midostaurin (arm B), and enasidenib (arm C) in adults with newly diagnosed AML fit for intensive chemotherapy. The dose exploration phase used a 3+3 design to determine the recommended phase 2 dose (RP2D) for each combination. The expansion phase enrolled additional patients to confirm the RP2D. Primary end points were the RP2D and safety. Secondary end points included initial efficacy assessments. Overall, 57 patients were enrolled (arm A, n = 27; arm B, n = 23; arm C, n = 7). In arms A and B, the RP2D was established: CPX-351 (daunorubicin 44 mg/m2 and cytarabine 100 mg/m2) plus venetoclax 400 mg or midostaurin 50 mg, respectively. Arm C was stopped early by the sponsor (not due to safety concerns), and the RP2D was not determined. The safety profiles of the combinations were consistent with those known for CPX-351, venetoclax, and midostaurin alone; the most common adverse events were hematologic and gastrointestinal. The best response (complete remission [CR]/CR with incomplete/partial hematologic recovery) was 44% (12/27 patients) and 86% (19/22 patients) in arms A and B, respectively. Although few patients received CPX-351 with enasidenib, these results suggest that CPX-351 may be safely combined with venetoclax or midostaurin. This trial was registered at www.clinicaltrials.gov as #NCT04075747.
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IO-202 is a humanized immunoglobulin G1 monoclonal antibody with high affinity and specificity for leukocyte immunoglobulin-like receptor B4 (LILRB4; ILT3), which is predominantly expressed in monocytes and monocytic blasts. IO-202 induces antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis in vitro and in patients with leukemia. Herein, we present the phase 1a dose escalation data of IO-202 as monotherapy and in combination with azacitidine (AZA) in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) and R/R chronic myelomonocytic leukemia (CMML), and the phase 1b dose expansion data of IO-202 combined with AZA for the treatment of hypomethylating agent (HMA)-naïve CMML. IO-202 was well tolerated as monotherapy and in combination with AZA. Patients with R/R monocytic AML expressing high LILRB4 on leukemia blasts demonstrated clinical activity, including a complete response (CR) in dose escalation with IO-202 + AZA. In patients with HMA-naïve CMML, IO-202 + AZA led to a 27.8% CR rate and 66.7% overall response rate, based on the 2015 International Working Group response criteria for myelodysplastic/myeloproliferative neoplasms. All 18 efficacy-evaluable patients with HMA-naïve CMML (100%) achieved some form of investigator-assessed clinical benefit, including symptomatic improvement, a decrease in transfusions, reduced blasts and/or monocytes, and resolution of thrombocytopenia. Seven patients (38.9%) proceeded to allogeneic hematopoietic cell transplantation. Translational data suggest that efficacy favors patients with high LILRB4 expression, supporting the mechanism of action of IO-202. Overall, the data support a future pivotal study of IO-202 + AZA in patients with HMA-naïve CMML. This trial was registered at www.clinicaltrials.gov as #NCT04372433.
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ABSTRACT: The prognosis for relapsed or refractory (R/R) nucleophosmin 1-mutated (NPM1m) acute myeloid leukemia (AML) is poor and represents an urgent unmet medical need. Revumenib, a potent, selective menin inhibitor, was recently approved for the treatment of R/R acute leukemia with a KMT2A translocation in patients aged ≥1 year based on results from the phase 1/2 AUGMENT-101 study. Here, we present results from patients with R/R NPM1m AML enrolled in the phase 2 portion of AUGMENT-101. Enrolled patients received revumenib with or without a strong CYP3A4 inhibitor every 12 hours in 28-day cycles. Primary end points were rate of complete remission (CR) or CR with partial hematologic recovery (CRh; CR + CRh), safety, and tolerability. Secondary end points included overall response rate (ORR) and duration of response. As of 18 September 2024, 84 patients received ≥1 dose of revumenib. Median age was 63 years; 1 patient was aged <18 years. The protocol-defined, efficacy-evaluable population for the primary analysis included 64 adult patients (≥3 previous lines of therapy, 35.9%; previous venetoclax, 75.0%). The CR + CRh rate was 23.4% (1-sided P = .0014); the ORR was 46.9%. Median duration of CR + CRh was 4.7 months. Of 30 responders, 5 (16.7%) proceeded to hematopoietic stem cell transplant (HSCT) and 3 resumed revumenib after HSCT. Treatment-related adverse events led to treatment discontinuation in 4 patients (4.8%). Revumenib demonstrated clinically meaningful responses in this heavily pretreated, older population with NPM1m AML, including remissions that enabled HSCT. The safety profile of revumenib was consistent with previously reported results. This trial was registered at www.clinicaltrials.gov as #NCT04065399.
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Leucemia Mieloide Aguda , Mutación , Proteínas Nucleares , Proteínas Proto-Oncogénicas , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Proteínas Nucleares/genética , Nucleofosmina , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Recurrencia , Benzamidas , Compuestos de EspiroRESUMEN
Introduction: This phase 2 study evaluated magrolimab+venetoclax (VEN)+azacitidine (AZA) in untreated, unfit acute myeloid leukaemia (AML) and magrolimab+mitoxantrone+etoposide+cytarabine in relapsed/refractory (R/R) AML. Methods: Endpoints included complete remission rate (CRR), overall response rate (ORR), overall survival (OS) and safety. Results: Eighteen and 36 patients were enrolled into the unfit and R/R AML arms, respectively. CRR was 38.9% and 25.0%, ORR was 66.7% and 38.9%, and median OS was 15.3 and 10.5 months in the unfit AML and R/R AML arms, respectively. No dose-limiting toxicities or magrolimab-related deaths occurred. Conclusion: Magrolimab was safely combined with existing AML therapies with no new safety signals. Clinical Trial Registration: This trail was registered at www.clinicaltrials.gov as NCT04778410.
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Leucemia Mieloide Aguda , Trombocitopenia , Femenino , Humanos , Síndromes Congénitos de Insuficiencia de la Médula Ósea/genética , Leucemia Mieloide Aguda/genética , Cromosoma Filadelfia , Radio (Anatomía)/anomalías , Trombocitopenia/genética , Deformidades Congénitas de las Extremidades Superiores/genética , AncianoRESUMEN
OBJECTIVES: Measurable residual disease flow cytometry (MRD-FC) and molecular studies are the most sensitive methods for detecting residual malignant populations after therapy for TP53-mutated acute myeloid leukemia and myelodysplastic neoplasms (TP53+ AML/MDS). However, their sensitivity is limited in suboptimal aspirates or when the immunophenotype of the neoplastic blasts overlaps with erythroids or normal maturing myeloid cells. In this study, we set out to determine if p53 immunohistochemistry (IHC) correlates with MRD-FC and next-generation sequencing (NGS) in the posttherapy setting and to determine the utility of p53 IHC to detect residual disease in the setting of negative or equivocal MRD-FC. METHODS: We retrospectively identified 28 pre- and posttherapy bone marrow biopsy specimens from 9 patients with TP53+ AML/MDS and a p53 overexpressor phenotype by IHC (strong 3+ staining at initial diagnosis). Next-generation sequencing and/or MRD-FC results were collected for each specimen. RESULTS: Using a threshold of more than ten 2-3+ cells in any one 400× field, p53 IHC detected residual disease with a sensitivity of 94% and a specificity of 89%. The threshold used in this study showed a high degree of concordance among 6 blinded pathologists (Fleiss κ = 0.97). CONCLUSIONS: Our study suggests that p53 IHC can be used as a rapid tool (within 24 hours) to aid in the detection of residual disease that may complement MRD-FC or NGS in cases in which the flow cytometry immunophenotype is equivocal and/or the bone marrow aspirate is suboptimal.
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Inmunohistoquímica , Leucemia Mieloide Aguda , Mutación , Síndromes Mielodisplásicos , Neoplasia Residual , Proteína p53 Supresora de Tumor , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Leucemia Mieloide Aguda/diagnóstico , Neoplasia Residual/diagnóstico , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/patología , Síndromes Mielodisplásicos/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Estudios Retrospectivos , Masculino , Persona de Mediana Edad , Femenino , Anciano , Secuenciación de Nucleótidos de Alto Rendimiento , Citometría de Flujo , Anciano de 80 o más Años , Adulto , Inmunofenotipificación , Sensibilidad y Especificidad , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/análisisAsunto(s)
Anticuerpos Monoclonales , Compuestos Bicíclicos Heterocíclicos con Puentes , Neoplasias Hematológicas , Neoplasias , Proteínas Recombinantes de Fusión , Neoplasias Cutáneas , Sulfonamidas , Humanos , Subunidad alfa del Receptor de Interleucina-3 , Células Dendríticas , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Neoplasias Hematológicas/terapiaRESUMEN
BPDCN is an aggressive myeloid malignancy with a poor prognosis. It derives from the precursors of plasmacytoid dendritic cells and is characterized by CD123 overexpression, which is seen in all patients with BPDCN. The CD123-directed therapy tagraxofusp is the only approved treatment for BPDCN; it was approved in the US as monotherapy for the treatment of patients aged ≥2 years with treatment-naive or relapsed/refractory BPDCN. Herein, we review the available data supporting the utility of tagraxofusp in treating patients with BPDCN. In addition, we present best practices and real-world insights from clinicians in academic and community settings in the US on how they use tagraxofusp to treat BPDCN. Several case studies illustrate the efficacy of tagraxofusp and discuss its safety profile, as well as the prevention, mitigation, and management of anticipated adverse events.
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Células Dendríticas , Humanos , Resultado del Tratamiento , Subunidad alfa del Receptor de Interleucina-3/metabolismo , Subunidad alfa del Receptor de Interleucina-3/análisis , Neoplasias Hematológicas/terapia , Neoplasias Hematológicas/patología , Neoplasias Hematológicas/diagnóstico , Manejo de la Enfermedad , Trastornos Mieloproliferativos/diagnóstico , Trastornos Mieloproliferativos/terapia , Trastornos Mieloproliferativos/patología , Proteínas Recombinantes de Fusión/uso terapéutico , PronósticoRESUMEN
The rate of MRD clearance in AML with standard consolidation chemotherapy is not well defined. A multi-institution retrospective analysis was performed on 107 consecutively treated AML patients in morphologic complete remission with detectable MRD post-induction therapy who received standard chemotherapy consolidation. In response to standard intermediate/high-dose cytarabine consolidation therapy, 26 of 60 patients (43.3%) with MRD threshold of detection of at least 0.1% converted to MRD-negative status (undetectable with assay used), and 6 of 47 patients (12.8%) with MRD threshold of detection > 0.1% converted to MRD-negative status. Multivariable logistic regression for patients with MRD threshold of detection of at least 0.1% showed that, when controlling for age, ELN risk category, dose of cytarabine, and use of a combination agent, treatment with 1 cycle of consolidation cytarabine versus ≥2 cycles decreased the odds of conversion of AML to MRD-negative (OR = 0.24, 95% CI 0.07-0.85, p = 0.03).
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Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Humanos , Quimioterapia de Consolidación , Estudios Retrospectivos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamiento farmacológico , Inducción de Remisión , Citarabina , Neoplasia Residual/diagnóstico , PronósticoRESUMEN
INTRODUCTION: Allogeneic hematopoietic cell transplantation (alloHCT) is increasingly offered to older adults, and its potential impact on cognition in this population is understudied. This work aims to evaluate the ability of cancer-specific geriatric assessments (cGA) and a global frailty index based on accumulation of deficits identified in the cGA to predict the risk of cognitive decline after alloHCT in older adults. MATERIALS AND METHODS: AlloHCT recipients aged 50 years or older completed a cGA, including a cognitive evaluation by the Blessed Orientation Memory Concentration (BOMC) test, at baseline prior to alloHCT and then at 3, 6, and 12 months after transplant. Baseline frailty was assessed using a deficit accumulation frailty index (DAFI) calculated from the cGA. A multinomial logit model was used to examine the association between predictors (individual cGA measures, DAFI) and the following three outcomes: alive with stable or improved cognition, alive with cognitive decline, and deceased. In post-hoc analyses, analysis of variance was used to compare BOMC scores at baseline, 3, 6, and 12 months across frailty categories. RESULTS: In total, 148 participants were included, with a median age of 62 (range 50-76). At baseline, 12% had cognitive impairment; at one year, 29% of survivors had improved BOMC scores, 33% had stable BOMC, and 37% had worse BOMC. Prior to transplant, 25% were pre-frail and 11% were frail. Individual baseline cGA measures were not associated with cognitive change at one year as assessed by BOMC. Adjusting for age, sex, and education, those who were frail at baseline were 7.4 times as likely to develop cognitive decline at one year than those who were non-frail, although this finding did not reach statistical significance (95% confidence interval [CI] 0.74-73.8, p = 0.09). The probability of being alive with stable/improved cognition at 12 months for the non-frail, pre-frail, and frail groups was 43%, 34%, and 8%, respectively. DISCUSSION: Baseline geriatric measures and frailty were not significantly associated with cognitive change as assessed by BOMC in adults aged 50 or older after alloHCT. However, the study was underpowered to detect clinically meaningful differences, and future work to elucidate potential associations between frailty and cognitive outcomes is warranted.
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Disfunción Cognitiva , Fragilidad , Trasplante de Células Madre Hematopoyéticas , Neoplasias , Anciano , Humanos , Fragilidad/diagnóstico , Anciano Frágil/psicología , Disfunción Cognitiva/etiología , Disfunción Cognitiva/complicaciones , Cognición , Evaluación Geriátrica , Neoplasias/complicaciones , Trasplante de Células Madre Hematopoyéticas/efectos adversosRESUMEN
PURPOSE: Magrolimab is a first-in-class humanized monoclonal antibody against cluster of differentiation 47, an antiphagocytic signal used by cancer cells to evade phagocytosis. Azacitidine upregulates prophagocytic signals on AML cells, further increasing phagocytosis when combined with magrolimab. We report final phase Ib data for magrolimab with azacitidine in patients with untreated AML ineligible for intensive chemotherapy (ClinicalTrials.gov identifier: NCT03248479). PATIENTS AND METHODS: Patients with previously untreated AML, including TP53-mutant AML, received magrolimab intravenously as an initial dose (1 mg/kg, days 1 and 4), followed by 15 mg/kg once on day 8 and 30 mg/kg once weekly or every 2 weeks as maintenance. Azacitidine 75 mg/m2 was administered intravenously/subcutaneously once daily on days 1-7 of each 28-day cycle. Primary end points were safety/tolerability and proportion with complete remission (CR). RESULTS: Eighty-seven patients were enrolled and treated; 72 (82.8%) had TP53 mutations with a median variant allele frequency of 61% (range, 9.8-98.7). Fifty-seven (79.2%) of TP53-mutant patients had European LeukemiaNet 2017 adverse-risk cytogenetics. Patients received a median of 4 (range, 1-39) cycles of treatment. The most common treatment-emergent adverse events included constipation (49.4%), nausea (49.4%), and diarrhea (48.3%). Thirty (34.5%) experienced anemia, and the median hemoglobin change from baseline to first postdose assessment was -0.9 g/dL (range, -3.6 to 2.5 g/dL). Twenty-eight (32.2%) patients achieved CR, including 23 (31.9%) patients with TP53 mutations. The median overall survival in TP53-mutant and wild-type patients were 9.8 months and 18.9 months, respectively. CONCLUSION: Magrolimab with azacitidine was relatively well tolerated with promising efficacy in patients with AML ineligible for intensive induction chemotherapy, including those with TP53 mutations, warranting further evaluation of magrolimab with azacitidine in AML. The phase III randomized ENHANCE-2 (ClinicalTrials.gov identifier: NCT04778397) and ENHANCE-3 (ClinicalTrials.gov identifier: NCT05079230) studies are recruiting frontline patients with AML.
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Azacitidina , Leucemia Mieloide Aguda , Humanos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Inducción de Remisión , Leucemia Mieloide Aguda/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
The existence of two acute myeloid leukaemia classification systems-one put forth by WHO and one by the International Consensus Classification in 2022-is concerning. Although both systems appropriately move towards genomic disease definitions and reduced emphasis on blast enumeration, there are consequential disagreements between the two systems on what constitutes a diagnosis of acute myeloid leukaemia. This fundamental problem threatens the ability of heath-care providers to diagnose acute myeloid leukaemia, communicate with patients and other health-care providers, and deliver appropriate and consistent management strategies for patients with the condition. Clinical trial eligibility, standardised response assessments, and eventual drug development and regulatory pathways might also be negatively affected by the discrepancies. In this Viewpoint, we review the merits and limitations of both classification systems and illustrate how the coexistence, as well as application of both systems is an undue challenge to patients, clinicians, hematopathologists, sponsors of research, and regulators. Lastly, we emphasise the urgency and propose a roadmap, by which the two divergent classification systems can be harmonised.
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Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/diagnósticoAsunto(s)
Antineoplásicos , Leucemia Mieloide Aguda , Humanos , Adulto , Terapia Recuperativa , Antineoplásicos/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by the clonal expansion of myeloid blasts in the peripheral blood, bone marrow, and/or other tissues. It is the most common form of acute leukemia among adults and accounts for the largest number of annual deaths from leukemias in the United States. Like AML, blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a myeloid malignancy. It is a rare malignancy characterized by the aggressive proliferation of precursors of plasmacytoid dendritic cells that frequently involves the bone marrow, skin, central nervous system, and other organs and tissues. This discussion section focuses on the diagnosis and management of BPDCN as outlined in the NCCN Guidelines for AML.
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Neoplasias Hematológicas , Leucemia Mieloide Aguda , Neoplasias Cutáneas , Adulto , Humanos , Células Dendríticas/patología , Neoplasias Hematológicas/diagnóstico , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/patología , Oncología Médica , Neoplasias Cutáneas/diagnósticoRESUMEN
Over the past decade, our understanding of AML pathogenesis and pathophysiology has improved significantly with mutational profiling. This has led to translational advances in therapeutic options, as there have been 10 new US Food and Drug Administration (FDA) approvals for AML therapies since 2017, half of which target specific driver mutations in FLT3, IDH1, or IDH2. These new agents have expanded the therapeutic armamentarium for AML, particularly for patients who are considered ineligible for intensive chemotherapy with anthracycline- and cytarabine-containing regimens. These new treatment options are relevant because the median age at diagnosis is 68 years, and outcomes for patients older than 60 years have historically been dismal. However, the optimal approach to incorporating novel agents into frontline regimens remains a clinical challenge, particularly with regard to sequencing of therapies, considering the role of allogeneic hematopoietic stem cell transplantation and managing toxicities.