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PURPOSE: Acute lymphoblastic leukemia (ALL) can occur across all age groups, with a strikingly higher cure rate in children compared with adults. However, the pharmacological basis of age-related differences in ALL treatment response remains unclear. METHODS: Studying 767 children and 309 adults with newly diagnosed B-cell ALL enrolled on frontline trials at St Jude Children's Research Hospital, MD Anderson Cancer Center, the Alliance for Clinical Trials in Oncology, and the ECOG-ACRIN Cancer Research Group, we determined the ex vivo sensitivity of leukemia cells to 21 drugs. Twenty-three ALL molecular subtypes were identified using RNA sequencing. We systematically characterized the associations between drug response and ALL genomics in children, adolescents and young adults, and elderly adults. We evaluated the effect of age-related gene expression signature on ALL treatment outcomes. RESULTS: Seven ALL drugs (asparaginase, prednisolone, mercaptopurine, dasatinib, nelarabine, daunorubicin, and inotuzumab ozogamicin) showed differential activity between children and adults, of which six were explained by age-related differences in leukemia molecular subtypes. Adolescents and young adults showed similar patterns of drug resistance as older adults, relative to young children. Mercaptopurine exhibited subtype-independent greater sensitivity in children. Transcriptomic profiling uncovered subclusters within CRLF2-, DUX4-, and KMT2A-rearranged ALL that were linked to age and cytotoxic drug resistance. In particular, a subset of children had adult-like ALL on the basis of leukemia gene expression patterns across subtypes, despite their chronological age. Resistant to cytotoxic drugs, children with adult-like ALL exhibited poor prognosis in pediatric ALL trials, even after adjusting for age and minimal residual diseases. CONCLUSION: Our results provide pharmacogenomic insights into age-related disparities in ALL cure rates and identify leukemia prognostic features for treatment individualization across age groups.
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Acute myeloid leukemia (AML) is an aggressive hematologic malignancy that continues to have poor prognosis despite recent therapeutic advances. Venetoclax (Ven), a BCL2-inhibitor has shown a high response rate in AML; however, relapse is invariable due to mitochondrial dysregulation that includes upregulation of the antiapoptotic protein MCL1, a central mechanism of Ven resistance (Ven-res). We have previously demonstrated that the transcription factor STAT3 is upregulated in AML hematopoietic stem and progenitor cells (HSPCs) and can be effectively targeted to induce apoptosis of these aberrant cells. We now show that overexpression of STAT3 alone is sufficient to initiate a strong AML phenotype in a transgenic murine model. Phospho-proteomic data from Ven treated AML patients show a strong correlation of high total STAT3 and phospho-STAT3 [both p-STAT3(Y705) and p-STAT3(S727)] expression with worse survival and reduced remission duration. Additionally, significant upregulation of STAT3 was observed in Ven-res cell lines, in vivo models and primary patient samples. A novel and specific degrader of STAT3 demonstrated targeted reduction of total STAT3 and resulting inhibition of its active p-STAT3(Y705) and p-STAT3(S727) forms. Treatment with the STAT3 degrader induced apoptosis in parental and Ven-res AML cell lines and decreased mitochondrial depolarisation, and thereby dependency on MCL1 in Ven-res AML cell line, as observed by BH3 profiling assay. STAT3 degrader treatment also enhanced differentiation of myeloid and erythroid colonies in Ven-res peripheral blood mononuclear cells (PBMNCs). Upregulation of p-STAT3(S727) was also associated with pronounced mitochondrial structural and functional dysfunction in Ven-res cell lines, that were restored by STAT3 degradation. Treatment with a clinical-stage STAT3 degrader, KT-333 resulted in a significant reduction in STAT3 and MCL1 protein levels within two weeks of treatment in a cell derived xenograft model of Ven-res AML. Additionally, this treatment significant improvement in the survival of a Ven-res patient-derived xenograft in-vivo study. Degradation of STAT3 resulting in downregulation of MCL1 and improvements in global mitochondrial dysfunction suggests a novel mechanism of overcoming Ven-res in AML. Statement of Purpose: Five-year survival from AML is dismal at 30%. Our prior research demonstrated STAT3 over-expression in AML HSPC's to be associated with inferior survival. We now explore STAT3 over-expression in Ven-res AML, explain STAT3 mediated mitochondrial perturbations and describe a novel therapeutic strategy, STAT3 degradation to overcome Ven-res.
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OBJECTIVES: Adult T-cell leukemia/lymphoma (ATLL) is an aggressive mature T-cell neoplasm caused by human T-cell lymphotropic virus type 1 (HTLV-1). Its most common immunophenotype is CD4+/CD7-/CD25+, although unusual immunophenotypes can occur and may lead to misdiagnosis. METHODS: The immunophenotypes, cytogenetics, molecular features, clinical presentations, treatment, and prognosis of 131 patients with ATLL were retrospectively studied in a large tertiary medical center in the United States. RESULTS: All cases showed loss of CD7 expression. While 82.4% of cases demonstrated CD4+, 17.6% exhibited unusual phenotypes, including CD4+/CD8+ (6.9%), CD4-/CD8- (2.3%), CD5- (3.1%), CD2-, and CD3-. The most common cytogenetics abnormalities included polysomy 3 (34.6%), translocation 1 (23.1%), and abnormalities found on chromosome 11 (30.8%) and chromosome 14 (26.9%). The common gene mutations identified by the next-generation sequencing study were TP53 (16.7%), TBL1XR1 (16.7%), EP300 (14.3%), and NOTCH1 (14.3%). TBL1XR1 mutation is associated with genetic instabilities. There was no significant difference between the clinical presentations of these 2 groups. CONCLUSIONS: Adult T-cell leukemia/lymphoma exhibits versatile immunophenotypic, cytogenetic, and molecular features. Simultaneous involvement of blood, lymph nodes, and other organs, along with hypercalcemia in a patient from an endemic area, necessitates HTLV-1 testing to avoid underdiagnosis of this dismal disease that might need aggressive chemotherapy followed by bone marrow transplant.
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The influence of demographic characteristics and social determinants on cancer outcomes is widely recognized in various malignancies but remains understudied in myelofibrosis (MF). This study aims to investigate social and demographic variables associated with MF survival. We retrospectively reviewed data of biopsy-proven MF patients from the Surveillance, Epidemiology and End Results (SEER) database (2000-2021) and Montefiore Medical Center (2000-2023), an underserved inner-city hospital. The SEER cohort included 5,403 MF patients and was predominantly Non-Hispanic (NH) White (82%) with a median age of 69 years. The age-adjusted incidence rate of MF was 0.32 cases per 100,000 person-years, increasing annually by 1.3% from 2000 to 2021. Two- and five- year overall survival rates were 69% and 42%, respectively. Worse cause-specific survival was associated with older age, male sex, and diagnosis before 2011 (year of Ruxolitinib approval). NH-Black ethnicity, unmarried status and lower median income were independent predictors of worse overall survival. The single-center analysis included 84 cases, with a median age of 66 years. NH-White patients comprised 37% of the sample, followed by NH-Black (28.5%). Two- and five- year overall survival rates were 90% and 61%, respectively, with NH-Black patients exhibiting the lowest median survival, although the difference was not statistically significant. Age was a significant predictor of worse survival in this cohort. NH-Black and Hispanic patients lived in areas with higher socioeconomic and demographic stress compared to NH-White patients. Overall, this study highlights the association of social and demographic factors with MF survival and emphasizes the need for equitable healthcare and further exploration of social-demographic factors affecting MF survival.
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Mielofibrosis Primaria , Programa de VERF , Humanos , Mielofibrosis Primaria/epidemiología , Mielofibrosis Primaria/mortalidad , Masculino , Femenino , Anciano , Persona de Mediana Edad , Estudios Retrospectivos , Tasa de Supervivencia , Anciano de 80 o más Años , Factores Socioeconómicos , Adulto , Bases de Datos Factuales , Estados Unidos/epidemiología , IncidenciaRESUMEN
We conducted a phase 1 study evaluating 3 dose levels of quizartinib (30â¯mg, 40â¯mg or 60â¯mg) in combination with azacitidine for HMA-naïve or relapsed/refractory MDS or MDS/MPN with FLT3 or CBL mutations. Overall, 12 patients (HMA naïve: n=9, HMA failure: n=3) were enrolled; 7 (58â¯%) patients had FLT3 mutations and 5 (42â¯%) had CBL mutations. The maximum tolerated dose was not reached. Most common grade 3-4 treatment-emergent adverse events were thrombocytopenia (n=5, 42â¯%), anemia (n=4, 33â¯%), lung infection (n=2, 17â¯%), skin infection (n=2, 17â¯%), hyponatremia (n=2, 17â¯%) and sepsis (n=2, 17â¯%). The overall response rate was 83â¯% with median relapse-free and overall survivals of 15.1 months (95â¯% CI 0.0-38.4 months) and 17.5 months (95â¯% CI NC-NC), respectively. FLT3 mutation clearance was observed in 57â¯% (n=4) patients. These data suggest quizartinib is safe and shows encouraging activity in FLT3-mutated MDS and MDS/MPN. This study is registered at Clinicaltrials.gov as NCT04493138.
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Azacitidina , Benzotiazoles , Mutación , Síndromes Mielodisplásicos , Compuestos de Fenilurea , Tirosina Quinasa 3 Similar a fms , Humanos , Tirosina Quinasa 3 Similar a fms/genética , Masculino , Anciano , Femenino , Persona de Mediana Edad , Síndromes Mielodisplásicos/tratamiento farmacológico , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/mortalidad , Síndromes Mielodisplásicos/patología , Benzotiazoles/administración & dosificación , Benzotiazoles/uso terapéutico , Benzotiazoles/efectos adversos , Compuestos de Fenilurea/administración & dosificación , Compuestos de Fenilurea/efectos adversos , Compuestos de Fenilurea/uso terapéutico , Azacitidina/administración & dosificación , Azacitidina/efectos adversos , Azacitidina/uso terapéutico , Anciano de 80 o más Años , Proteínas Proto-Oncogénicas c-cbl/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Trastornos Mieloproliferativos/tratamiento farmacológico , Trastornos Mieloproliferativos/genética , AdultoRESUMEN
Acute myeloid leukemia (AML) is driven by complex mutations and cytogenetic abnormalities with profound tumoral heterogeneity, making it challenging to treat. Ten years ago, the 5-year survival rate of patients with AML was only 29% with conventional chemotherapy and stem cell transplantation. All attempts to improve conventional therapy over the previous 40 years had failed. Now, new genomic, immunological, and molecular insights have led to a renaissance in AML therapy. Improvements to standard chemotherapy and a wave of new targeted therapies have been developed. However, how best to incorporate these advances into frontline therapy and sequence them in relapse is not firmly established. In this review, we highlight current treatments of AML, targeted agents, and pioneering attempts to synthesize these developments into a rational standard of care (SoC).
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Antineoplásicos , Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Terapia Molecular Dirigida , AnimalesRESUMEN
Tagraxofusp is a first-in-class CD123-directed conjugate of an amended diphtheria toxin platform and recombinant interleukin 3. Binding and subsequent internalization of the drug result in cell death via disruption of intracellular protein synthesis. CD123 is a surface marker that is expressed in several hematological malignancies, especially blastic plasmacytoid dendritic cell neoplasm (BPDCN), where its expression is ubiquitous. A pivotal study of tagraxofusp in BPDCN resulted in its approval for the treatment of BPDCN, the first treatment approved for this indication. Since the introduction of tagraxofusp, research has focused on the management of adverse effects, combination therapy to improve outcomes in fit patients, and dosing and combination strategies to mitigate toxicities while preserving efficacy, especially among older patients. The successful targeting of CD123 in BPDCN has also encouraged research into a variety of other CD123-positive hematological neoplasms, including acute myeloid leukemia (AML), and informed the development of other novel agents targeting CD123. This review examines the clinical data leading to the development and approval of tagraxofusp in BPDCN, how it is being used in combination to improve outcomes in BPDCN and AML, and its developing role in other hematological malignancies.
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Subunidad alfa del Receptor de Interleucina-3 , Humanos , Subunidad alfa del Receptor de Interleucina-3/metabolismo , Neoplasias Hematológicas/tratamiento farmacológico , Neoplasias Hematológicas/patología , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/patología , Leucemia Mieloide Aguda/metabolismo , Células Dendríticas/efectos de los fármacos , Células Dendríticas/metabolismo , Proteínas Recombinantes de FusiónAsunto(s)
Imidazoles , Cromosoma Filadelfia , Leucemia-Linfoma Linfoblástico de Células Precursoras , Piridazinas , Recurrencia , Humanos , Piridazinas/uso terapéutico , Piridazinas/efectos adversos , Piridazinas/administración & dosificación , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Imidazoles/uso terapéutico , Imidazoles/efectos adversos , Imidazoles/administración & dosificación , Masculino , Femenino , Persona de Mediana Edad , Anciano , Adulto , Antineoplásicos/uso terapéutico , Antineoplásicos/efectos adversos , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversosAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Compuestos Bicíclicos Heterocíclicos con Puentes , Decitabina , Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Sulfonamidas , Humanos , Decitabina/uso terapéutico , Decitabina/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Síndromes Mielodisplásicos/tratamiento farmacológico , Síndromes Mielodisplásicos/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Sulfonamidas/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Masculino , Anciano , Femenino , Resultado del Tratamiento , Persona de Mediana Edad , AdultoRESUMEN
Leukemia can arise at various stages of the hematopoietic differentiation hierarchy, but the impact of developmental arrest on drug sensitivity is unclear. Applying network-based analyses to single-cell transcriptomes of human B cells, we define genome-wide signaling circuitry for each B cell differentiation stage. Using this reference, we comprehensively map the developmental states of B cell acute lymphoblastic leukemia (B-ALL), revealing its strong correlation with sensitivity to asparaginase, a commonly used chemotherapeutic agent. Single-cell multi-omics analyses of primary B-ALL blasts reveal marked intra-leukemia heterogeneity in asparaginase response: resistance is linked to pre-pro-B-like cells, with sensitivity associated with the pro-B-like population. By targeting BCL2, a driver within the pre-pro-B-like cell signaling network, we find that venetoclax significantly potentiates asparaginase efficacy in vitro and in vivo. These findings demonstrate a single-cell systems pharmacology framework to predict effective combination therapies based on intra-leukemia heterogeneity in developmental state, with potentially broad applications beyond B-ALL.
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Leucemia , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Humanos , Asparaginasa/farmacología , Farmacología en Red , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Transducción de Señal , Leucemia/tratamiento farmacológicoRESUMEN
PURPOSE OF REVIEW: This review seeks to identify and describe novel genetic and protein targets and their associated therapeutics currently being used or studied in the treatment of acute myeloid leukemia (AML). RECENT FINDINGS: Over the course of the last 5-6 years, several targeted therapies have been approved by the FDA, for the treatment of both newly diagnosed as well as relapsed/refractory AML. These novel therapeutics, as well as several others currently under investigation, have demonstrated activity in AML and have improved outcomes for many patients. Patient outcomes in AML have slowly improved over time, though for many patients, particularly elderly patients or those with relapsed/refractory disease, mortality remains very high. With the identification of several molecular/genetic drivers and protein targets and development of therapeutics which leverage those mechanisms to target leukemic cells, outcomes for patients with AML have improved and continue to improve significantly.
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Leucemia Mieloide Aguda , Humanos , Anciano , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genéticaRESUMEN
ABSTRACT: Inotuzumab ozogamicin (InO) is an antibody-drug conjugate that delivers calicheamicin to CD22-expressing cells. In a retrospective cohort of InO-treated patients with B-cell acute lymphoblastic leukemia, we sought to understand the genomic determinants of the response and resistance to InO. Pre- and post-InO-treated patient samples were analyzed by whole genome, exome, and/or transcriptome sequencing. Acquired CD22 mutations were observed in 11% (3/27) of post-InO-relapsed tumor samples, but not in refractory samples (0/16). There were multiple CD22 mutations per sample and the mechanisms of CD22 escape included epitope loss (protein truncation and destabilization) and epitope alteration. Two CD22 mutant cases were post-InO hyper-mutators resulting from error-prone DNA damage repair (nonhomologous/alternative end-joining repair, or mismatch repair deficiency), suggesting that hypermutation drove escape from CD22-directed therapy. CD22-mutant relapses occurred after InO and subsequent hematopoietic stem cell transplantation (HSCT), suggesting that InO eliminated the predominant clones, leaving subclones with acquired CD22 mutations that conferred resistance to InO and subsequently expanded. Acquired loss-of-function mutations in TP53, ATM, and CDKN2A were observed, consistent with a compromise of the G1/S DNA damage checkpoint as a mechanism for evading InO-induced apoptosis. Genome-wide CRISPR/Cas9 screening of cell lines identified DNTT (terminal deoxynucleotidyl transferase) loss as a marker of InO resistance. In conclusion, genetic alterations modulating CD22 expression and DNA damage response influence InO efficacy. Our findings highlight the importance of defining the basis of CD22 escape and eradication of residual disease before HSCT. The identified mechanisms of escape from CD22-targeted therapy extend beyond antigen loss and provide opportunities to improve therapeutic approaches and overcome resistance. These trials were registered at www.ClinicalTrials.gov as NCT01134575, NCT01371630, and NCT03441061.
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Resistencia a Antineoplásicos , Inotuzumab Ozogamicina , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Lectina 2 Similar a Ig de Unión al Ácido Siálico , Humanos , Lectina 2 Similar a Ig de Unión al Ácido Siálico/genética , Resistencia a Antineoplásicos/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patología , Femenino , Mutación , Masculino , Antineoplásicos Inmunológicos/uso terapéutico , Antineoplásicos Inmunológicos/farmacología , Adulto , Persona de Mediana Edad , Estudios Retrospectivos , AdolescenteRESUMEN
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematological malignancy with limited treatment options and poor prognosis. This case report presents the clinical course and management of a 62-year-old man with BPDCN in a resource-limited setting. The patient presented with constitutional symptoms and abnormal complete blood count findings. Initial treatment was performed with an acute lymphoblastic leukemia-based chemotherapy regimen, and the patient achieved complete remission, but the disease recurred 7 months after the initial diagnosis was confirmed in April 2022. The subsequent therapy was not effective, and the patient died during treatment. This case highlights the challenges in managing BPDCN and the need for further research to improve outcomes.
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Neoplasias Hematológicas , Neoplasias Cutáneas , Masculino , Humanos , Persona de Mediana Edad , Configuración de Recursos Limitados , Células Dendríticas , Neoplasias Cutáneas/patología , Neoplasias Hematológicas/terapia , RecurrenciaAsunto(s)
Diferenciación Celular , Leucemia Mieloide Aguda , Mastocitos , Proteína p53 Supresora de Tumor , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/patología , Mastocitos/patología , Mastocitos/metabolismo , Proteína p53 Supresora de Tumor/genética , Pronóstico , Masculino , Femenino , Persona de Mediana Edad , Mutación , Anciano , Cariotipo , AdultoRESUMEN
BACKGROUND: Hypomethylating agents combined with venetoclax are effective regimens in patients with acute myeloid leukaemia who are ineligible for intensive chemotherapy. Decitabine and cedazuridine (ASTX727) is an oral formulation of decitabine that achieves equivalent area-under-curve exposure to intravenous decitabine. We performed a single centre phase 2 study to evaluate the efficacy and safety of ASTX727 plus venetoclax. METHODS: This study enrolled patients with newly diagnosed (frontline treatment group) acute myeloid leukaemia who were ineligible for intensive chemotherapy (aged ≥75 years, an Eastern Cooperative Oncology Group [ECOG] performance status of 2-3, or major comorbidities) or relapsed or refractory acute myeloid leukaemia. Being aged 18 years or older and having an ECOG performance status of 2 or less were requirements for the relapsed or refractory disease treatment cohort, without any limits in the number of previous lines of therapy. Treatment consisted of ASTX727 (cedazuridine 100 mg and decitabine 35 mg) orally for 5 days and venetoclax 400 mg orally for 21-28 days in 28-day cycles. The primary outcome was overall response rate of ASTX727 plus venetoclax. Living patients who have not completed cycle one were not evaluable for response. Safety was analysed in all patients who started treatment. This study was registered on ClinicalTrials.gov (NCT04746235) and is ongoing. The data cutoff date for this analysis was Sept 22, 2023. FINDINGS: Between March 16, 2021, and Sept 18, 2023, 62 patients were enrolled (49 frontline and 13 relapsed or refractory) with a median age of 78 years (IQR 73-82). 36 (58%) were male; 53 (85%) were White, 4 (6%) Black, 2 (3%) Asian and 3 (5%) other or did not answer. 48 (77%) of 62 patients were European LeukemiaNet 2022 adverse risk, 24 (39%) had antecedent myelodysplastic syndromes, 12 (19%) had previously failed a hypomethylating agent, ten (16%) had therapy-related acute myeloid leukaemia, and 11 (18%) had TP53 mutations. The median follow-up time was 18·3 months (IQR 8·8-23·3). The overall response rate was 30 (64%) of 47 patients (95% CI 49-77) in frontline cohort and six (46%) of 13 patients (19-75) in relapsed or refractory cohort. The most common grade 3 or worse treatment-emergent adverse events were febrile neutropenia in 11 (18%) of 62 patients, pneumonia in eight (13%), respiratory failure in five (8%), bacteraemia in four (6%), and sepsis in four (6%). Three deaths occurred in patients in remission (one sepsis, one gastrointestinal haemorrhage, and one respiratory failure) and were potentially treatment related. INTERPRETATION: ASTX727 plus venetoclax is an active fully oral regimen and safe in most older or unfit patients with acute myeloid leukaemia. Our findings should be confirmed in larger multicentric studies. FUNDING: MD Anderson Cancer Center Support Grant, Myelodysplastic Syndrome/Acute Myeloid Leukaemia Moon Shot, Leukemia SPORE, Taiho Oncology, and Astex Pharmaceuticals.
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Compuestos Bicíclicos Heterocíclicos con Puentes , Combinación de Medicamentos , Leucemia Mieloide Aguda , Insuficiencia Respiratoria , Sepsis , Sulfonamidas , Uridina/análogos & derivados , Humanos , Masculino , Anciano , Anciano de 80 o más Años , Femenino , Decitabina/efectos adversos , Resultado del Tratamiento , Leucemia Mieloide Aguda/diagnóstico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Insuficiencia Respiratoria/inducido químicamente , Insuficiencia Respiratoria/tratamiento farmacológico , Sepsis/inducido químicamente , Sepsis/tratamiento farmacológicoRESUMEN
DNA damage resistance is a major barrier to effective DNA-damaging therapy in multiple myeloma (MM). To discover mechanisms through which MM cells overcome DNA damage, we investigate how MM cells become resistant to antisense oligonucleotide (ASO) therapy targeting Interleukin enhancer binding factor 2 (ILF2), a DNA damage regulator that is overexpressed in 70% of MM patients whose disease has progressed after standard therapies have failed. Here, we show that MM cells undergo adaptive metabolic rewiring to restore energy balance and promote survival in response to DNA damage activation. Using a CRISPR/Cas9 screening strategy, we identify the mitochondrial DNA repair protein DNA2, whose loss of function suppresses MM cells' ability to overcome ILF2 ASO-induced DNA damage, as being essential to counteracting oxidative DNA damage. Our study reveals a mechanism of vulnerability of MM cells that have an increased demand for mitochondrial metabolism upon DNA damage activation.
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Mieloma Múltiple , Humanos , Mieloma Múltiple/genética , ADN Helicasas/metabolismo , Reprogramación Metabólica , Reparación del ADN , Daño del ADNRESUMEN
BACKGROUND: Pivekimab sunirine (IMGN632) is a first-in-class antibody-drug conjugate comprising a high-affinity CD123 antibody, cleavable linker, and novel indolinobenzodiazepine pseudodimer payload. CD123 is overexpressed in several haematological malignancies, including acute myeloid leukaemia. We present clinical data on pivekimab sunirine in relapsed or refractory acute myeloid leukaemia. METHODS: This first-in-human, phase 1/2 dose-escalation and dose-expansion study enrolled participants aged 18 years or older at nine hospitals in France, Italy, Spain, and the USA with CD123+ haematological malignancies (Eastern Cooperative Oncology Group performance status of 0-1); participants reported here were in a cohort of participants with acute myeloid leukaemia who were refractory to or had relapsed on one or more previous treatments for acute myeloid leukaemia. The 3â+â3 dose-escalation phase evaluated two dosing schedules: schedule A (once every 3 weeks, on day 1 of a 3-week cycle) and fractionated schedule B (days 1, 4, and 8 of a 3-week cycle). The dose-expansion phase evaluated two cohorts: one cohort given 0·045 mg/kg of bodyweight (schedule A) and one cohort given 0·090 mg/kg of bodyweight (schedule A). The primary endpoints were the maximum tolerated dose and the recommended phase 2 dose. Antileukaemia activity (overall response and a composite complete remission assessment) was a secondary endpoint. The study is ongoing and registered with ClinicalTrials.gov, NCT03386513. FINDINGS: Between Dec 29, 2017, and May 27, 2020, 91 participants were enrolled (schedule A, n=68; schedule B, n=23). 30 (44%) of schedule A participants were female and 38 (56%) were male; 60 (88%) were White, six (9%) were Black or African American, and two (3%) were other races. Pivekimab sunirine at doses of 0·015 mg/kg to 0·450 mg/kg in schedule A was administered in six escalating doses with no maximum tolerated dose defined; three dose-limiting toxicities were observed (reversible veno-occlusive disease; 0·180 mg/kg, n=1 and 0·450 mg/kg, n=1; and neutropenia; 0·300 mg/kg, n=1). Schedule B was not pursued further on the basis of comparative safety and antileukaemia findings with schedule A. The recommended phase 2 dose was selected as 0·045 mg/kg once every 3 weeks. At the recommended phase 2 dose (n=29), the most common grade 3 or worse treatment-related adverse events were febrile neutropenia (three [10%]), infusion-related reactions (two [7%]), and anaemia (two [7%]). Treatment-related serious adverse events occurring in 5% or more of participants treated at the recommended phase 2 dose were febrile neutropenia (two [7%]) and infusion-related reactions (two [7%]). Among 68 participants who received schedule A, one death (1%) was considered to be treatment-related (cause unknown; 0·300 mg/kg cohort). At the recommended phase 2 dose, the overall response rate was 21% (95% CI 8-40; six of 29) and the composite complete remission rate was 17% (95% CI 6-36; five of 29). INTERPRETATION: Pivekimab sunirine showed single-agent activity across multiple doses, with a recommended phase 2 dose of 0·045 mg/kg once every 3 weeks. These findings led to a phase 1b/2 study of pivekimab sunirine plus azacitidine and venetoclax in patients with CD123-positive acute myeloid leukaemia. FUNDING: ImmunoGen.
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Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Neutropenia Febril , Neoplasias Hematológicas , Inmunoconjugados , Leucemia Mieloide Aguda , Humanos , Femenino , Masculino , Inmunoconjugados/efectos adversos , Subunidad alfa del Receptor de Interleucina-3 , Leucemia Mieloide Aguda/tratamiento farmacológicoRESUMEN
Interferon gamma (IFNγ) is a critical cytokine known for its diverse roles in immune regulation, inflammation, and tumor surveillance. However, while IFNγ levels were elevated in sera of most newly diagnosed acute myeloid leukemia (AML) patients, its complex interplay in AML remains insufficiently understood. We aim to characterize these complex interactions through comprehensive bulk and single-cell approaches in bone marrow of newly diagnosed AML patients. We identify monocytic AML as having a unique microenvironment characterized by IFNγ producing T and NK cells, high IFNγ signaling, and immunosuppressive features. IFNγ signaling score strongly correlates with venetoclax resistance in primary AML patient cells. Additionally, IFNγ treatment of primary AML patient cells increased venetoclax resistance. Lastly, a parsimonious 47-gene IFNγ score demonstrates robust prognostic value. In summary, our findings suggest that inhibiting IFNγ is a potential treatment strategy to overcoming venetoclax resistance and immune evasion in AML patients.
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Interferón gamma , Leucemia Mieloide Aguda , Sulfonamidas , Humanos , Interferón gamma/farmacología , Pronóstico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/diagnóstico , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Microambiente TumoralRESUMEN
Recent advances in graft-versus-host disease (GVHD) prophylaxis including post-transplant cyclophosphamide (PTCy) and abatacept have significantly improved outcomes following HLA-mismatched allogenic hematopoietic stem cell transplantation (allo-HSCT) and have tremendous potential for reducing racial disparities in donor availability. A recent small study employing bone marrow as the source of stem cells showed similar outcomes after 5/8 versus 7/8 matches and is currently being tested in a larger study using peripheral blood stem cells. In this study, we examine real-world alternative donor HSCT options for a minority-predominant cohort in the Bronx, NY, focusing on the availability of lesser-matched (5/8 to 7/8) donors. Records of patients who underwent HLA typing at Montefiore Medical Center (2019 to 2022) were reviewed. The National Marrow Donor Program registry was queried to evaluate the availability of donors with at least 99% likelihood of HLA match at various levels (5/8, 6/8, 7/8, 8/8). Two hundred forty-one patients were included, 70% were non-White. Although the availability of ≥7/8 donors was less common in non-White patients, 100% of patients from each group had at least one or more 5/8 and 6/8 HLA-matched donors and more than 80% of these patients had >100 potential 5/8 and 6/8 HLA-matched donors. There was no statistical difference by race or ethnicity in the mean number of donors at 5/8 and 6/8 HLA-match levels. We demonstrate through real-world data that patients from diverse ethnic and racial backgrounds have access to 5/8 and 6/8 HLA-matched donors for allo-HSCT, potentially eliminating disparities in donor availability and allowing prioritization of other donor selection characteristics such as donor age, sex, ABO, and B leader matching. Further work is needed to study whether the use of mismatched donors offers a more potent graft-versus malignancy effect and optimal GVHD prophylaxis.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Prueba de Histocompatibilidad , Donante no Emparentado , Humanos , Femenino , Masculino , Persona de Mediana Edad , Trasplante de Células Madre Hematopoyéticas/estadística & datos numéricos , Adulto , Enfermedad Injerto contra Huésped/prevención & control , Grupos Minoritarios/estadística & datos numéricos , Estudios de Cohortes , Antígenos HLA/inmunología , AncianoRESUMEN
BACKGROUND: Therapies for relapsed/refractory acute myeloid leukemia remain limited and outcomes poor, especially amongst patients who are ineligible for cytotoxic chemotherapy or targeted therapies. PATIENTS AND METHODS: This phase 1b trial evaluated venetoclax, a B-cell lymphoma-2 (BCL-2) inhibitor, plus cobimetinib, a MEK1/2 inhibitor, in patients with relapsed/refractory acute myeloid leukemia, ineligible for cytotoxic chemotherapy. Two-dimensional dose-escalation was performed for venetoclax dosed daily, and for cobimetinib dosed on days 1-21 of each 28-day cycle. RESULTS: Thirty patients (median [range] age: 71.5 years [60-84]) received venetoclax-cobimetinib. The most common adverse events (AEs; in ≥40.0% of patients) were diarrhea (80.0%), nausea (60.0%), vomiting (40.0%), febrile neutropenia (40.0%), and fatigue (40.0%). Overall, 66.7% and 23.3% of patients experienced AEs leading to dose modification/interruption or treatment withdrawal, respectively. The composite complete remission (CRc) rate (complete remission [CR]â¯+â¯CR with incomplete blood count recoveryâ¯+â¯CR with incomplete platelet recovery) was 15.6%; antileukemic response rate (CRcâ¯+â¯morphologic leukemia-free state/partial remission) was 18.8%. For the recommended phase 2 dose (venetoclax: 600 mg; cobimetinib: 40 mg), CRc and antileukemic response rates were both 12.5%. Failure to achieve an antileukemic response was associated with elevated baseline phosphorylated ERK and MCL-1 levels, but not BCL-xL. Baseline mutations in ≥1 signaling gene or TP53 were noted in nonresponders and emerged on treatment. Pharmacodynamic biomarkers revealed inconsistent, transient inhibition of the mitogen-activated protein kinase (MAPK) pathway. CONCLUSION: Venetoclax-cobimetinib showed limited preliminary efficacy similar to single-agent venetoclax, but with added toxicity. Our findings will inform future trials of BCL-2/MAPK pathway inhibitor combinations.