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Venous thromboembolism (VTE) is common among older individuals, but provoking factors are not identified in many cases. Patients with myeloid malignancies, especially myeloproliferative neoplasms, are at increased risk for venous thrombosis. Clonal hematopoiesis of indeterminate potential (CHIP), a precursor state to myeloid malignancies, is common among the elderly and may similarly predispose to venous thrombosis. We evaluated overall and genotype-specific associations between CHIP and prevalent and incident VTE in >400,000 samples from the UK Biobank. CHIP was modestly associated with incident VTE with a hazard ratio of 1.17 (95% confidence interval (CI) 1.09-1.3; p= 0.002) but was not significantly associated with prevalent VTE with an odds ratio of 1.02 (95% CI 0.81-1.23; p= 0.81). TET2-mutant CHIP was associated with incident VTE with a hazard ratio of 1.33 (95% CI 1.05-1.69; p= 0.02). JAK2 mutations were highly associated with both prevalent and incident VTE risk with odds ratio of 6.58 (95% CI 2.65-16.29; p= 4.7 x 10-5) and hazard ratio of 4.2 (95% CI 2.18-8.08; p= 1.7 x 10-5), respectively, consistent with the thrombophilia associated with JAK2-mutant myeloproliferative neoplasms. The association between JAK2-mutant CHIP and VTE remained significant after excluding potential undiagnosed myeloproliferative neoplasms based on laboratory parameters. Compared to heterozygous factor V Leiden and heterozygous prothrombin gene mutation, JAK2-mutant CHIP was more strongly associated with VTE but was less common. These results indicate that most individuals with CHIP do not have an altered risk of thrombosis, but that individuals with JAK2-mutant CHIP have a significantly elevated risk of VTE.
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While intensive induction chemotherapy (IC) remains the standard of care for younger patients with acute myeloid leukemia (AML), data from older patients shows that hypomethylating agents + venetoclax (HMA/VEN) can lead to durable remissions among patients with NPM1 mutations. Whether IC or HMA/VEN is superior in patients ≥60 years-old with NPM1-mutant AML is unknown. To compare IC and HMA/VEN, we performed an international, multicenter retrospective cohort study of patients with newly diagnosed, NPM1-mutant AML.We included 221 patients (147 IC, 74 HMA/VEN) with previously untreated NPM1-mutant AML. Composite complete remission (cCR; defined as CR + CR with incomplete count recovery [CRi]) rate was similar for IC and HMA/VEN (cCR: 85% vs. 74%; p=0.067). While OS was favorable with IC in unselected patients compared to HMA/VEN (24-month OS 59% [95% CI: 52-69%] vs. 38% [95% CI 27-55%]; p=0.013), it was not statistically different among patients 60-75 years-old (60% [95% CI 52-70%] vs. 44% [95% CI 29-66%]; p=0.069) and patients who received an allogeneic stem cell transplant (70% [95% CI: 58-85%] vs. 66% [95% CI: 44-100%]; p=0.56). Subgroup analyses suggested that patients with normal cytogenetics (24-month OS with IC 65% [95% 56-74%] vs. 40% [95% CI: 26-60%] with HMA/VEN; p=0.009) and without FLT3-ITD mutations might benefit from IC compared with HMA/VEN (24-month OS: 68% [95% CI: 59-79%] vs. 43% [95% CI: 29-63%]; p=0.008). In multivariable analysis, OS was not statistically different for patients treated with IC and HMA/VEN (hazard ratio for death HMA/VEN vs. IC: 0.71; 95% CI: 0.40-1.27; p=0.25).
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Protocolos de Quimioterapia Combinada Antineoplásica , Compuestos Bicíclicos Heterocíclicos con Puentes , Quimioterapia de Inducción , Isocitrato Deshidrogenasa , Leucemia Mieloide Aguda , Mutación , Sulfonamidas , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Estudios de Cohortes , Isocitrato Deshidrogenasa/genética , Isocitrato Deshidrogenasa/antagonistas & inhibidores , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Sulfonamidas/uso terapéutico , Sulfonamidas/administración & dosificaciónRESUMEN
Phosphoinositide-3-kinase-γ (PI3Kγ) is implicated as a target to repolarize tumour-associated macrophages and promote antitumour immune responses in solid cancers1-4. However, cancer cell-intrinsic roles of PI3Kγ are unclear. Here, by integrating unbiased genome-wide CRISPR interference screening with functional analyses across acute leukaemias, we define a selective dependency on the PI3Kγ complex in a high-risk subset that includes myeloid, lymphoid and dendritic lineages. This dependency is characterized by innate inflammatory signalling and activation of phosphoinositide 3-kinase regulatory subunit 5 (PIK3R5), which encodes a regulatory subunit of PI3Kγ5 and stabilizes the active enzymatic complex. We identify p21 (RAC1)-activated kinase 1 (PAK1) as a noncanonical substrate of PI3Kγ that mediates this cell-intrinsic dependency and find that dephosphorylation of PAK1 by PI3Kγ inhibition impairs mitochondrial oxidative phosphorylation. Treatment with the selective PI3Kγ inhibitor eganelisib is effective in leukaemias with activated PIK3R5. In addition, the combination of eganelisib and cytarabine prolongs survival over either agent alone, even in patient-derived leukaemia xenografts with low baseline PIK3R5 expression, as residual leukaemia cells after cytarabine treatment have elevated G protein-coupled purinergic receptor activity and PAK1 phosphorylation. Together, our study reveals a targetable dependency on PI3Kγ-PAK1 signalling that is amenable to near-term evaluation in patients with acute leukaemia.
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Fosfatidilinositol 3-Quinasa Clase Ib , Leucemia , Transducción de Señal , Quinasas p21 Activadas , Animales , Humanos , Ratones , Línea Celular , Fosfatidilinositol 3-Quinasa Clase Ib/genética , Fosfatidilinositol 3-Quinasa Clase Ib/metabolismo , Citarabina/farmacología , Citarabina/uso terapéutico , Leucemia/tratamiento farmacológico , Leucemia/enzimología , Leucemia/genética , Leucemia/metabolismo , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Fosforilación Oxidativa/efectos de los fármacos , Quinasas p21 Activadas/antagonistas & inhibidores , Quinasas p21 Activadas/metabolismo , Fosforilación , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
ABSTRACT: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) can involve skin, bone marrow (BM), central nervous system (CNS), and non-CNS extramedullary sites. Preclinical models demonstrated clonal advantage of TET2-mutated plasmacytoid dendritic cells exposed to UV radiation. However, whether sun exposure, disease characteristics, and patient survival are clinically related is unclear. We classified organ involvement in 66 patients at diagnosis as skin only (n = 19), systemic plus skin (n = 33), or systemic only (n = 14). BM involvement was absent, microscopic (<5%), or overt (≥5%). UV exposure was based on clinical and demographic data. Patients with skin only BPDCN were more frequently aged ≥75 years (47% vs 19%; P = .032) and had lower rates of complex karyotype (0 vs 32%, P = .022) and mutated NRAS (0 vs 29%, P = .044). Conversely, those without skin involvement had lower UV exposure (23% vs 59%, P = .03) and fewer TET2 mutations (33% vs 72%, P = .051). The median overall survival (OS) was 23.5, 20.4, and 17.5 months for skin only, systemic plus skin, and systemic only, respectively. Patients with no BM involvement had better OS vs overt involvement (median OS, 27.3 vs 15.0 months; P = .033) and comparable with microscopic involvement (27.3 vs 23.5 months; P = .6). Overt BM involvement remained significant for OS when adjusted for baseline characteristics and treatment received. In summary, BPDCN clinical characteristics are associated with disease genetics and survival, which together may impact prognosis and indicate informative disease subtypes for future research.
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Proteínas de Unión al ADN , Dioxigenasas , Mutación , Proteínas Proto-Oncogénicas , Humanos , Masculino , Femenino , Proteínas de Unión al ADN/genética , Proteínas Proto-Oncogénicas/genética , Anciano , Persona de Mediana Edad , Adulto , Luz Solar/efectos adversos , Células Dendríticas/metabolismo , Anciano de 80 o más Años , Neoplasias Hematológicas/mortalidad , Neoplasias Hematológicas/genética , Proteínas ras/genética , PronósticoRESUMEN
The clinical impact of molecular ontogeny in acute myeloid leukemia (AML) was defined in patients treated with intensive chemotherapy. In a cohort of 314 newly diagnosed AML patients, we evaluated whether molecular ontogeny subgroups have differential benefit of venetoclax (VEN) added to hypomethylating agents (HMA). In secondary ontogeny (n = 115), median overall survival (OS)(14.1 vs. 6.9 months, P = 0.0054), composite complete remission (cCR 61% vs. 18%, P < 0.001) and allogeneic hematopoietic stem cell transplant (alloHCT) (24% vs. 6%, P = 0.02) rates were better in patients treated with HMA + VEN vs. HMA. In contrast, in TP53 AML(n = 111) median OS (5.7 vs. 6.1, P = 0.93), cCR (33% vs. 37%, P = 0.82) and alloHCT rates (15% vs. 8%, P = 0.38) did not differ between HMA + VEN vs. HMA. The benefit of VEN addition in the secondary group was preserved after adjustment for significant clinicopathologic variables (HR 0.59 [95% CI 0.38-0.94], P = 0.025). The OS benefit of HMA + VEN in secondary ontogeny was similar in those with vs. without splicing mutations (P = 0.92). Secondary ontogeny AML highlights a group of patients whose disease is selectively responsive to VEN added to HMA and that the addition of VEN has no clinical benefit in TP53-mutated AML.
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Protocolos de Quimioterapia Combinada Antineoplásica , Compuestos Bicíclicos Heterocíclicos con Puentes , Metilación de ADN , Leucemia Mieloide Aguda , Sulfonamidas , Humanos , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Sulfonamidas/uso terapéutico , Sulfonamidas/administración & dosificación , Femenino , Persona de Mediana Edad , Masculino , Anciano , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Adulto Joven , Anciano de 80 o más Años , Mutación , Trasplante de Células Madre Hematopoyéticas , Tasa de Supervivencia , Pronóstico , Proteína p53 Supresora de Tumor/genética , Adolescente , Inducción de RemisiónRESUMEN
Molecularly defined secondary acute myeloid leukemia is associated with a prior myeloid neoplasm and confers a worse prognosis. We compared outcomes of molecularly defined secondary AML patients (n = 395) treated with daunorubicin and cytarabine (7 + 3, n = 167), liposomal daunorubicin and cytarabine (CPX-351, n = 66) or hypomethylating agents (HMA) + venetoclax (VEN) (n = 162). Median overall survival (OS) was comparable between treatment groups among patients aged >60 years. In a multivariable model HMA + VEN vs. 7 + 3 was associated with better OS (hazard ratio [HR] 0.64 [95% confidence interval (CI) 0.42-0.98, p = 0.041]), whereas CPX-351 vs. 7 + 3 was not (HR 0.79 [CI 95% 0.50-1.25, p = 0.31]). Allogeneic hematopoietic stem cell transplantation, BCOR and IDH mutations were associated with improved OS; older age, prior myeloid disease, NRAS/KRAS mutations, EZH2 mutation, and monosomal karyotype were associated with worse OS. When analyzed in each treatment separately, the IDH co-mutations benefit was seen with 7 + 3 and the detrimental effect of NRAS/KRAS co-mutations with HMA + VEN and CPX-351. In pairwise comparisons adjusted for age, HMA + VEN was associated with improved OS vs. 7 + 3 in patients with SF3B1 mutation and improved OS vs. CPX-351 in those with RNA splicing factor mutations. In molecularly defined secondary AML treatment with HMA + VEN might be preferred but could further be guided by co-mutations.
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Leucemia Mieloide Aguda , Neoplasias Primarias Secundarias , Sulfonamidas , Humanos , Quimioterapia de Inducción , Proteínas Proto-Oncogénicas p21(ras) , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Citarabina/uso terapéutico , Daunorrubicina/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Neoplasias Primarias Secundarias/etiología , Estudios RetrospectivosRESUMEN
Chronic graft-versus-host-disease (cGVHD) is divided into two subtypes: classic (absence of acute GVHD features) and overlap cGVHD ('ocGVHD'), in which both chronic and acute GVHD clinical features are present simultaneously. While worse outcomes with ocGVHD have been reported, there are few recent analyses. We performed a secondary analysis of data from the ABA2 trial (N = 185), in which detailed GVHD data were collected prospectively and systematically adjudicated. Analyses included cumulative incidence of classic versus ocGVHD, their specific organ manifestations, global disease severity scores, non-relapse mortality (NRM), disease-free survival (DFS) and overall survival (OS) in these two cGVHD subtypes. Of 92 patients who developed cGVHD, 35 were classified as ocGVHD. The 1-year cumulative incidence, organ involvement, and global severity of classic and ocGVHD were similar between ABA2 patients receiving CNI/MTX+placebo and CNI/MTX+abatacept; thus, cohorts were combined for ocGVHD evaluation. This analysis identified ocGVHD as having significantly higher severity at presentation and at maximum global severity compared to classic cGVHD. OS and DFS were significantly lower for ocGVHD versus classic cGVHD. OcGVHD is associated with increased cGVHD severity scores, and is associated with decreased OS and DFS compared to classic cGVHD, underscoring the high risks with this cGVHD subtype.
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Enfermedad Injerto contra Huésped , Humanos , Enfermedad Injerto contra Huésped/mortalidad , Masculino , Femenino , Enfermedad Crónica , Adulto , Persona de Mediana Edad , Supervivencia sin Enfermedad , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Tasa de Supervivencia , AncianoRESUMEN
Understanding how intra-tumoral immune populations coordinate to generate anti-tumor responses following therapy can guide precise treatment prioritization. We performed systematic dissection of an established adoptive cellular therapy, donor lymphocyte infusion (DLI), by analyzing 348,905 single-cell transcriptomes from 74 longitudinal bone-marrow samples of 25 patients with relapsed myeloid leukemia; a subset was evaluated by protein-based spatial analysis. In acute myelogenous leukemia (AML) responders, diverse immune cell types within the bone-marrow microenvironment (BME) were predicted to interact with a clonally expanded population of ZNF683 + GZMB + CD8+ cytotoxic T lymphocytes (CTLs) which demonstrated in vitro specificity for autologous leukemia. This population, originating predominantly from the DLI product, expanded concurrently with NK and B cells. AML nonresponder BME revealed a paucity of crosstalk and elevated TIGIT expression in CD8+ CTLs. Our study highlights recipient BME differences as a key determinant of effective anti-leukemia response and opens new opportunities to modulate cell-based leukemia-directed therapy.
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Single-cell transcriptomics has become the definitive method for classifying cell types and states, and can be augmented with genotype information to improve cell lineage identification. Due to constraints of short-read sequencing, current methods to detect natural genetic barcodes often require cumbersome primer panels and early commitment to targets. Here we devise a flexible long-read sequencing workflow and analysis pipeline, termed nanoranger, that starts from intermediate single-cell cDNA libraries to detect cell lineage-defining features, including single-nucleotide variants, fusion genes, isoforms, sequences of chimeric antigen and TCRs. Through systematic analysis of these classes of natural 'barcodes', we define the optimal targets for nanoranger, namely those loci close to the 5' end of highly expressed genes with transcript lengths shorter than 4 kB. As proof-of-concept, we apply nanoranger to longitudinal tracking of subclones of acute myeloid leukemia (AML) and describe the heterogeneous isoform landscape of thousands of marrow-infiltrating immune cells. We propose that enhanced cellular genotyping using nanoranger can improve the tracking of single-cell tumor and immune cell co-evolution.
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Secuenciación de Nucleótidos de Alto Rendimiento , Leucemia Mieloide Aguda , Humanos , Genotipo , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Fenotipo , Perfilación de la Expresión Génica/métodosRESUMEN
The continued emergence of highly pathogenic viruses, which either thwart immune- and small molecule-based therapies or lack interventions entirely, mandates alternative approaches, particularly for prompt and facile pre- and post-exposure prophylaxis. Many highly pathogenic viruses, including coronaviruses, employ the six-helix bundle heptad repeat membrane fusion mechanism to achieve infection. Although heptad-repeat-2 decoys can inhibit viral entry by blocking six-helix bundle assembly, the biophysical and pharmacologic liabilities of peptides have hindered their clinical development. Here, we develop a chemically stapled lipopeptide inhibitor of SARS-CoV-2 as proof-of-concept for the platform. We show that our lead compound blocks infection by a spectrum of SARS-CoV-2 variants, exhibits mucosal persistence upon nasal administration, demonstrates enhanced stability compared to prior analogs, and mitigates infection in hamsters. We further demonstrate that our stapled lipopeptide platform yields nanomolar inhibitors of respiratory syncytial, Ebola, and Nipah viruses by targeting heptad-repeat-1 domains, which exhibit strikingly low mutation rates, enabling on-demand therapeutic intervention to combat viral outbreaks.
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Infecciones por Coronavirus , Lipopéptidos , Humanos , Lipopéptidos/farmacología , Lipopéptidos/uso terapéutico , Lipopéptidos/química , Pandemias/prevención & controlRESUMEN
ABSTRACT: CD123, a subunit of the interleukin-3 receptor, is expressed on â¼80% of acute myeloid leukemias (AMLs). Tagraxofusp (TAG), recombinant interleukin-3 fused to a truncated diphtheria toxin payload, is a first-in-class drug targeting CD123 approved for treatment of blastic plasmacytoid dendritic cell neoplasm. We previously found that AMLs with acquired resistance to TAG were re-sensitized by the DNA hypomethylating agent azacitidine (AZA) and that TAG-exposed cells became more dependent on the antiapoptotic molecule BCL-2. Here, we report a phase 1b study in 56 adults with CD123-positive AML or high-risk myelodysplastic syndrome (MDS), first combining TAG with AZA in AML/MDS, and subsequently TAG, AZA, and the BCL-2 inhibitor venetoclax (VEN) in AML. Adverse events with 3-day TAG dosing were as expected, without indication of increased toxicity of TAG or AZA+/-VEN in combination. The recommended phase 2 dose of TAG was 12 µg/kg/day for 3 days, with 7-day AZA +/- 21-day VEN. In an expansion cohort of 26 patients (median age 71) with previously untreated European LeukemiaNet adverse-risk AML (50% TP53 mutated), triplet TAG-AZA-VEN induced response in 69% (n=18/26; 39% complete remission [CR], 19% complete remission with incomplete count recovery [CRi], 12% morphologic leukemia-free state [MLFS]). Among 13 patients with TP53 mutations, 7/13 (54%) achieved CR/CRi/MLFS (CR = 4, CRi = 2, MLFS = 1). Twelve of 17 (71%) tested responders had no flow measurable residual disease. Median overall survival and progression-free survival were 14 months (95% CI, 9.5-NA) and 8.5 months (95% CI, 5.1-NA), respectively. In summary, TAG-AZA-VEN shows encouraging safety and activity in high-risk AML, including TP53-mutated disease, supporting further clinical development of TAG combinations. The study was registered on ClinicalTrials.gov as #NCT03113643.
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Compuestos Bicíclicos Heterocíclicos con Puentes , Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Proteínas Recombinantes de Fusión , Sulfonamidas , Adulto , Anciano , Humanos , Azacitidina/uso terapéutico , Subunidad alfa del Receptor de Interleucina-3 , Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicos/genética , Proteínas Proto-Oncogénicas c-bcl-2RESUMEN
Importance: Anthracyclines treat a broad range of cancers. Basic and retrospective clinical data have suggested that use of atorvastatin may be associated with a reduction in cardiac dysfunction due to anthracycline use. Objective: To test whether atorvastatin is associated with a reduction in the proportion of patients with lymphoma receiving anthracyclines who develop cardiac dysfunction. Design, Setting, and Participants: Double-blind randomized clinical trial conducted at 9 academic medical centers in the US and Canada among 300 patients with lymphoma who were scheduled to receive anthracycline-based chemotherapy. Enrollment occurred between January 25, 2017, and September 10, 2021, with final follow-up on October 10, 2022. Interventions: Participants were randomized to receive atorvastatin, 40 mg/d (n = 150), or placebo (n = 150) for 12 months. Main Outcomes and Measures: The primary outcome was the proportion of participants with an absolute decline in left ventricular ejection fraction (LVEF) of ≥10% from prior to chemotherapy to a final value of <55% over 12 months. A secondary outcome was the proportion of participants with an absolute decline in LVEF of ≥5% from prior to chemotherapy to a final value of <55% over 12 months. Results: Of the 300 participants randomized (mean age, 50 [SD, 17] years; 142 women [47%]), 286 (95%) completed the trial. Among the entire cohort, the baseline mean LVEF was 63% (SD, 4.6%) and the follow-up LVEF was 58% (SD, 5.7%). Study drug adherence was noted in 91% of participants. At 12-month follow-up, 46 (15%) had a decline in LVEF of 10% or greater from prior to chemotherapy to a final value of less than 55%. The incidence of the primary end point was 9% (13/150) in the atorvastatin group and 22% (33/150) in the placebo group (P = .002). The odds of a 10% or greater decline in LVEF to a final value of less than 55% after anthracycline treatment was almost 3 times greater for participants randomized to placebo compared with those randomized to atorvastatin (odds ratio, 2.9; 95% CI, 1.4-6.4). Compared with placebo, atorvastatin also reduced the incidence of the secondary end point (13% vs 29%; P = .001). There were 13 adjudicated heart failure events (4%) over 24 months of follow-up. There was no difference in the rates of incident heart failure between study groups (3% with atorvastatin, 6% with placebo; P = .26). The number of serious related adverse events was low and similar between groups. Conclusions and Relevance: Among patients with lymphoma treated with anthracycline-based chemotherapy, atorvastatin reduced the incidence of cardiac dysfunction. This finding may support the use of atorvastatin in patients with lymphoma at high risk of cardiac dysfunction due to anthracycline use. Trial Registration: ClinicalTrials.gov Identifier: NCT02943590.
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Antraciclinas , Antibióticos Antineoplásicos , Atorvastatina , Fármacos Cardiovasculares , Cardiopatías , Linfoma , Femenino , Humanos , Persona de Mediana Edad , Antraciclinas/efectos adversos , Antraciclinas/uso terapéutico , Antibióticos Antineoplásicos/efectos adversos , Antibióticos Antineoplásicos/uso terapéutico , Atorvastatina/uso terapéutico , Método Doble Ciego , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/prevención & control , Estudios Retrospectivos , Volumen Sistólico , Función Ventricular Izquierda , Fármacos Cardiovasculares/uso terapéutico , Linfoma/tratamiento farmacológico , Cardiopatías/inducido químicamente , Cardiopatías/fisiopatología , Cardiopatías/prevención & control , Estudios de Seguimiento , Masculino , Adulto , AncianoRESUMEN
Adolescent and young adults (AYAs) with acute lymphoblastic leukemia (ALL) treated with asparaginase-containing pediatric regimens are commonly overweight or obese. We studied the association of body mass index (BMI) on outcomes of 388 AYAs aged 15 to 50 years treated on Dana-Farber Cancer Institute (DFCI) consortium regimens (2008-2021). BMI was normal in 207 (53.3%) and overweight/obese in 181 (46.7%). Patients who were overweight or obese experienced higher nonrelapse mortality (NRM; 4-year, 11.7% vs 2.8%, P = .006), worse event-free survival (4-year, 63% vs 77%, P = .003), and worse overall survival (OS; 4-year, 64% vs 83%, P = .0001). Because younger (aged 15-29 years) AYAs more frequently had a normal BMI (79% vs 20%, P < .0001), we conducted separate analyses in each BMI group. We found excellent OS among younger and older (30-50 years) AYAs with normal BMI (4-year OS, 83% vs 85%, P = .89). Conversely, in AYAs who were overweight/obese, worse outcomes were seen in older AYAs (4-year OS, 55% vs 73%, P = .023). Regarding toxicity, AYAs who were overweight/obese experienced higher rates of grade 3/4 hepatotoxicity and hyperglycemia (60.7% vs 42.2%, P = .0005, and 36.4% vs 24.4%, P = .014, respectively) but had comparable rates of hypertriglyceridemia (29.5% vs 24.4%, P = .29). In a multivariable analysis, higher BMI was associated with worse OS, hypertriglyceridemia was associated with improved OS, and age was not associated with OS. In conclusion, among AYAs treated on DFCI Consortium ALL regimens, elevated BMI was associated with increased toxicity, increased NRM, and decreased OS. The deleterious effect of elevated BMI was more pronounced in older AYAs.
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Hipertrigliceridemia , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Niño , Adolescente , Adulto Joven , Anciano , Índice de Masa Corporal , Supervivencia sin Enfermedad , Sobrepeso , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Obesidad/complicacionesRESUMEN
BACKGROUND: Children treated for acute lymphoblastic leukemia (ALL) receive prolonged treatment, resulting in toxicities that affect health-related quality of life (HR-QoL). Longitudinal assessment of HR-QoL allows improved understanding of experiences with ALL. PROCEDURE: Parent-proxy and child self-report HR-QoL over the first year of chemotherapy were evaluated in the context of DFCI Protocol 05-001, a phase 3 therapeutic trial for childhood ALL. HR-QoL was assessed with the Pediatric Quality-of-Life inventory (PedsQL) domains for Pain and Hurt, Procedural Anxiety, Treatment Anxiety, Emotional Functioning, General Fatigue, and Sleep/Rest Fatigue. RESULTS: Total of 281 subjects participated, with 141 contributing at least one child report and 280 at least one parent report. Children with ALL experienced impairment in HR-QoL by both patient and parent report compared to the published PedsQL reference population at each time point on each subscale. Agreement between parent and child assessment of HR-QoL impairment was high, particularly among those for whom HR-QoL was not impaired. During the consolidation phase, which included intensive asparaginase administration, multivariable models demonstrated more impairment in Treatment Anxiety and Procedural Anxiety for children treated with intramuscular asparaginase than intravenous asparaginase, but randomized groups were otherwise similar in HR-QoL. Impairments in fatigue, both General and Sleep/Rest, were evident throughout and worse during intensive asparaginase therapy. CONCLUSIONS: This report examines HR-QoL for children with ALL during treatment longitudinally by parent and patient report across multiple domains. Children with ALL demonstrated substantial impairment in HR-QoL, particularly related to fatigue during intensive consolidation therapy including asparaginase.
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Leucemia-Linfoma Linfoblástico de Células Precursoras , Calidad de Vida , Niño , Humanos , Asparaginasa/efectos adversos , Fatiga/etiología , Dolor , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/psicología , Calidad de Vida/psicologíaRESUMEN
In the ABA2 study, the T-cell costimulation blockade agent, abatacept, was safe and effective in preventing acute graft-versus-host disease (aGVHD) after unrelated-donor hematopoietic cell transplant (HCT), leading to US Food and Drug Administration approval. Here, we performed a determination of abatacept pharmacokinetics (PK), which enabled an examination of how abatacept exposure-response relationships affected clinical outcomes. We performed a population PK analysis of IV abatacept using nonlinear mixed-effect modeling and assessed the association between abatacept exposure and key transplant outcomes. We tested the association between the trough after dose 1 (Ctrough_1) and grade (GR) 2 or 4 aGVHD (GR2-4 aGVHD) through day +100. An optimal Ctrough_1 threshold was identified via recursive partitioning and classification tree analysis. This demonstrated that abatacept PK was characterized by a 2-compartment model with first-order elimination. The ABA2 dosing regimen was based on previous work targeting a steady-state abatacept trough of 10 µg/mL. However, a higher Ctrough_1 (≥39 µg/mL, attained in â¼60% of patients on ABA2) was associated with a favorable GR2-4 aGVHD risk (hazard ratio, 0.35; 95% confidence interval, 0.19-0.65; P < .001), with a Ctrough_1 <39 µg/mL associated with GR2-4 aGVHD risk indistinguishable from placebo (P = .37). Importantly, no significant association was found between Ctrough_1 and key safety indicators, including relapse, and cytomegalovirus or Epstein-Barr virus viremia. These data demonstrate that a higher abatacept Ctrough_1 (≥39 µg/mL) was associated with a favorable GR2-4 aGVHD risk, without any observed exposure-toxicity relationships. This trial was registered at www.clinicaltrials.gov as #NCT01743131.
Asunto(s)
Infecciones por Virus de Epstein-Barr , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Humanos , Abatacept/efectos adversos , Infecciones por Virus de Epstein-Barr/etiología , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Herpesvirus Humano 4RESUMEN
BACKGROUND: The role of cytoreduction prior to hematopoietic cell transplant (HCT) for patients with pediatric myelodysplastic syndrome (MDS) and related disorders remains unclear. PROCEDURE: We performed a single-center retrospective analysis of pre-transplant disease management and subsequent HCT outcome for pediatric patients with MDS and related disorders who underwent HCT between 2010 and 2020. RESULTS: Total 62 patients (median age 11 years) with idiopathic MDS (n = 16), MDS secondary to an underlying germline condition (n = 11), secondary acute myeloid leukemia (n = 9), myeloproliferative neoplasms (n = 8), and treatment-related myeloid neoplasms (n = 18) received an allogeneic HCT. Cytoreduction prior to HCT was performed in 30/62 (48%) patients; this subset of patients had higher risk disease characteristics, including a higher blast count on presentation. In the overall cohort, use of cytoreduction before HCT was associated with higher rates of relapse (cumulative incidence of relapse 24 months post HCT: 48.1% [27.5%-66.1%]) for those who received cytoreduction versus 16.6% (5.9%-32.1%) for those who did not (p = .03). There was a trend toward decreased overall survival (OS) for those patients who received cytoreduction (24 months post HCT 57.1% vs. 75.3%, respectively; p = .06). OS for patients who received cytoreduction and attained measurable residual disease (MRD) negativity prior to HCT was superior compared to those with persistent disease (24 months post HCT 63.9% [36%-81.2%] vs. 33.3% [7.8%-62.3%], respectively; p = .04). CONCLUSION: Cytoreduction did not provide survival benefit in our overall cohort, but its increased use in children with higher risk disease impacted the analysis. Patients receiving cytoreduction and achieving MRD-negative status before HCT demonstrated improved OS compared to those with persistent disease.