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Inotuzumab ozogamicin (InO) is an antibody-drug conjugate approved for the treatment of relapsed/refractory B-cell acute lymphoblastic leukemia (ALL). Several clinical trials are investigating InO in combination with low-intensity chemotherapy or other anti-ALL-targeted therapies in the salvage and frontline settings, notably in older adults who often cannot tolerate intensive chemotherapy and tend to have higher-risk disease. InO is also increasingly used to bridge patients to hematopoietic stem cell transplantation (HSCT), in sequence with chimeric antigen receptor T-cell therapy, to eliminate measurable residual disease and to prevent post-HSCT relapse. Veno-occlusive disease/sinusoidal obstruction syndrome is a potential complication of InO treatment, particularly when followed by HSCT. Herein, the authors review the historical development and current status of InO, strategies for mitigating the risk of InO-related veno-occlusive disease/sinusoidal obstruction syndrome, and future directions for InO research and clinical use.
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The effect of prior inotuzumab ozogamicin (InO) treatment on brexucabtagene autoleucel (brexu-cel) outcomes remains unclear in adults with acute lymphoblastic leukemia (ALL), particularly the influence off previous InO response and the timing of administration. We conducted a retrospective multicenter analysis of 189 patients with relapsed/refractory (r/r) ALL treated with brexu-cel. Over half of the patients received InO before brexu-cel (InO-exposed). InO-exposed patients were more heavily pretreated (p= 0.02) and frequently had active marrow disease pre-apheresis (p= 0.03). Response rate and toxicity profile following brexu-cel were comparable for InO-exposed and InO-naïve; however, consolidation therapy post brexu-cel response was utilized at a higher rate in InO-naïve patients (p= 0.005). With a median follow up of 11.4 months, InO-exposed patients had inferior progression-free survival (PFS) (p=0.013) and overall survival (OS) (p=0.006) in univariate analyses; however, prior InO exposure did not influence PFS (HR 1.20, 95%CI, 0.71-2.03) in multivariate models. When InO-exposed patients were stratified according to prior InO response, InO responders had superior PFS (p=0.002) and OS (p<0.0001) relative to InO-refractory. The timing of administering InO did not affect brexu-cel outcomes, with comparable PFS (p=0.51) and OS (p=0.86) for patients receiving InO as bridging therapy or pre-apheresis. In conclusion, while InO exposure was associated with inferior survival outcomes following brexu-cel in unadjusted analyses, these associations were no longer significant in multivariate analyses, suggesting it is unlikely that InO negatively impacts brexu-cel efficacy. Our data instead imply that InO-exposed recipients of brexu-cel tend to be higher-risk patients with intrinsic adverse leukemia biology.
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BACKGROUND: Many older adults with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) have a relapse despite having a measurable residual disease (MRD)-negative complete remission with combination chemotherapy. The addition of blinatumomab, a bispecific T-cell engager molecule that is approved for the treatment of relapsed, refractory, and MRD-positive BCP-ALL, may have efficacy in patients with MRD-negative remission. METHODS: In a phase 3 trial, we randomly assigned patients 30 to 70 years of age with BCR::ABL1-negative BCP-ALL (with :: indicating fusion) who had MRD-negative remission (defined as <0.01% leukemic cells in bone marrow as assessed on flow cytometry) after induction and intensification chemotherapy to receive four cycles of blinatumomab in addition to four cycles of consolidation chemotherapy or to receive four cycles of consolidation chemotherapy alone. The primary end point was overall survival, and relapse-free survival was a secondary end point. RESULTS: The data and safety monitoring committee reviewed the results from the third efficacy interim analysis and recommended that they be reported. Complete remission with or without full count recovery was observed in 395 of 488 enrolled patients (81%). Of the 224 patients with MRD-negative status, 112 were assigned to each group. The characteristics of the patients were balanced between the groups. At a median follow-up of 43 months, an advantage was observed in the blinatumomab group as compared with the chemotherapy-only group with regard to overall survival (at 3 years: 85% vs. 68%; hazard ratio for death, 0.41; 95% confidence interval [CI], 0.23 to 0.73; P = 0.002), and the 3-year relapse-free survival was 80% with blinatumomab and 64% with chemotherapy alone (hazard ratio for relapse or death, 0.53; 95% CI, 0.32 to 0.87). A higher incidence of neuropsychiatric events was reported in the blinatumomab group than in the chemotherapy-only group. CONCLUSIONS: The addition of blinatumomab to consolidation chemotherapy in adult patients in MRD-negative remission from BCP-ALL significantly improved overall survival. (Funded by the National Institutes of Health and others; E1910 ClinicalTrials.gov number, NCT02003222.).
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Anticuerpos Biespecíficos , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Humanos , Anticuerpos Biespecíficos/efectos adversos , Anticuerpos Biespecíficos/uso terapéutico , Anticuerpos Biespecíficos/administración & dosificación , Adulto , Persona de Mediana Edad , Masculino , Femenino , Anciano , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidad , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Quimioterapia de Consolidación , Inducción de Remisión , Supervivencia sin Enfermedad , Estimación de Kaplan-Meier , Análisis de Supervivencia , Recurrencia , Antineoplásicos/uso terapéutico , Antineoplásicos/efectos adversos , Quimioterapia de InducciónRESUMEN
Sequencing of bulk tumor populations has improved genetic classification and risk assessment of B-ALL, but does not directly examine intratumor heterogeneity or infer leukemia cellular origins. We profiled 89 B-ALL samples by single-cell RNA-seq (scRNA-seq) and compared them to a reference map of normal human B-cell development established using both functional and molecular assays. Intra-sample heterogeneity was driven by cell cycle, metabolism, differentiation, and inflammation transcriptional programs. By inference of B lineage developmental state composition, nearly all samples possessed a high abundance of pro-B cells, with variation between samples mainly driven by sub-populations. However, ZNF384- r and DUX4- r B-ALL showed composition enrichment of hematopoietic stem cells, BCR::ABL1 and KMT2A -r ALL of Early Lymphoid progenitors, MEF2D -r and TCF3::PBX1 of Pre-B cells. Enrichment of Early Lymphoid progenitors correlated with high-risk clinical features. Understanding variation in transcriptional programs and developmental states of B-ALL by scRNA-seq refines existing clinical and genomic classifications and improves prediction of treatment outcome.
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BACKGROUND: Older patients with myelodysplastic syndromes (MDS), particularly those with no or one cytopenia and no transfusion dependence, typically have an indolent course. Approximately, half of these receive the recommended diagnostic evaluation (DE) for MDS. We explored factors determining DE in these patients and its impact on subsequent treatment and outcomes. PATIENTS AND METHODS: We used 2011-2014 Medicare data to identify patients ≥66 years of age diagnosed with MDS. We used Classification and Regression Tree (CART) analysis to identify combinations of factors associated with DE and its impact on subsequent treatment. Variables examined included demographics, comorbidities, nursing home status, and investigative procedures performed. We conducted a logistic regression analysis to identify correlates associated with receipt of DE and treatment. RESULTS: Of 16 851 patients with MDS, 51% underwent DE. patients with MDS with no cytopenia (n = 3908) had the lowest uptake of DE (34.7%). Compared to patients with no cytopenia, those with any cytopenia had nearly 3 times higher odds of receiving DE [adjusted odds ratio (AOR), 2.81: 95% CI, 2.60-3.04] and the odds were higher for men than for women [AOR, 1.39: 95%CI, 1.30-1.48] and for Non-Hispanic Whites [vs. everyone else (AOR, 1.17: 95% CI, 1.06-1.29)]. The CART showed DE as the principal discriminating node, followed by the presence of any cytopenia for receiving MDS treatment. The lowest percentage of treatment was observed in patients without DE, at 14.6%. CONCLUSION: In this select older patients with MDS, we identified disparities in accurate diagnosis by demographic and clinical factors. Receipt of DE influenced subsequent treatment but not survival.
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Anemia , Síndromes Mielodisplásicos , Masculino , Humanos , Femenino , Anciano , Estados Unidos/epidemiología , Medicare , Síndromes Mielodisplásicos/terapia , Síndromes Mielodisplásicos/tratamiento farmacológico , ComorbilidadRESUMEN
Asparaginase is a key component of pediatric-inspired regimens in young adults with acute lymphoblastic leukemia (ALL). Truncation of asparaginase therapy is linked to inferior outcomes in children with ALL. However, a similar correlation in adults is lacking. Here, we studied the prevalence and risk factors associated with pegylated (PEG)-asparaginase discontinuation in young adults with ALL treated on the US intergroup Cancer and Leukemia Group B (CALGB) 10403 study and examined the prognostic impact of early discontinuation (ED) (defined as <4 of 5 or 6 planned doses) on survival outcomes. The analysis included 176 patients who achieved complete remission and initiated the delayed intensification (DI) cycle. The median number of PEG-asparaginase doses administered before DI was 5 (range, 1-6), with 57 (32%) patients with ED. The ED patients were older (median, 26 vs 23 years; P = .023). Survival was apparently lower for ED patients compared with those receiving ≥4 doses, but this finding was not statistically significant (hazard ratio [HR], 1.82; 95% confidence interval [CI], 0.97-3.43; P = .06), with corresponding 5-year overall survival (OS) rates of 66% and 80%, respectively. In patients with standard-risk ALL, the ED of PEG-asparaginase adversely influenced OS (HR, 2.3; 95% CI, 1.02-5.22; P = .04) with a trend toward inferior event-free survival (EFS) (HR, 1.84; 95% CI, 0.92-3.67; P = .08). In contrast, there was no impact of early PEG-asparaginase discontinuation on OS (P = .64) or EFS (P = .32) in patients with high-risk disease based on the presence of high-risk cytogenetics, Ph-like genotype, and/or high white blood cell count at presentation. In conclusion, early PEG-asparaginase discontinuation is common in young adults with ALL and may adversely impact survival of patients with standard-risk ALL.
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Asparaginasa , Leucemia-Linfoma Linfoblástico de Células Precursoras , Niño , Humanos , Adulto Joven , Asparaginasa/efectos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Polietilenglicoles/efectos adversos , Inducción de RemisiónRESUMEN
Novel treatment strategies are needed for the treatment of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) in older patients. This trial evaluated the feasibility and outcomes with the anti-CD19 bispecific T-cell-engaging antibody, blinatumomab, in combination with dasatinib and steroids. Patients 65 years of age or older with Ph+ or Ph-like ALL (with dasatinib-sensitive fusions/mutations) were eligible and could be newly diagnosed or relapsed/refractory. Induction therapy consisted of dasatinib/prednisone. Patients not achieving response by day 56 proceeded to blinatumomab reinduction therapy. Patients achieving response with induction or reinduction therapy proceeded to blinatumomab/dasatinib postremission therapy for 3 cycles followed by dasatinib/prednisone maintenance. All patients received central nervous system prophylaxis with intrathecal methotrexate for a total of 8 doses. Response was assessed at days 28, 56, and 84 and at additional time points based on response parameters. Measurable residual disease was assessed centrally by 8-color flow cytometry at day 28. A total of 24 eligible patients with newly diagnosed Ph+ ALL were enrolled with a median age of 73 years (range, 65-87 years). This combination was safe and feasible. With a median of 2.7 years of follow-up, 3-year overall survival and disease-free survival were 87% (95% confidence interval [CI], 64-96) and 77% (95% CI, 54-90), respectively. Although longer follow-up is needed, these results are encouraging, and future trials are building on this backbone regimen. This trial was registered at www.clinicaltrials.gov as #NCT02143414.
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Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Anciano , Anciano de 80 o más Años , Dasatinib/efectos adversos , Prednisona/uso terapéutico , Resultado del Tratamiento , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapiaAsunto(s)
Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Mutación , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/terapiaRESUMEN
In this secondary analysis of Hispanic adolescents and young adults (AYA) with acute lymphoblastic leukemia (ALL) treated on Cancer and Leukemia Group B (CALGB) 10403, we evaluated outcomes and geographic enrollment patterns relative to US population data. We used demographic, clinical, and survival data on AYAs enrolled on CALGB 10403 (N = 295, 2007-2012). Surveillance, Epidemiology, and End Results registries provided overall survival (OS) for US AYA ALL by ethnicity/race. North American Association of Cancer Registries provided AYA ALL incidence overall and proportion among Hispanics by US state. Of AYAs enrolled on CALGB 10403, 263 (89%) reported ethnicity/race: 45 (17%) Hispanic, 172 (65%) non-Hispanic White (NHW), 25 (10%) non-Hispanic Black (NHB), and 21 (8%) other. Compared with NHWs, Hispanic and NHB patients had lower household income, and Hispanic patients were more likely to harbor high-risk CRLF2 aberrations. Relative to US estimates, where Hispanic patients represented 46% of newly diagnosed AYA ALL patients and experienced inferior OS compared with NHW (P < .001), Hispanic AYAs on CALGB 10403 did as well as NHW patients (3 year OS, 75% vs 74%; P = NS). Hispanic patients also had higher rates of protocol completion (P = .05). Enrollments on CALGB 10403 differed relative to the distribution of Hispanic AYA ALL in the United States: enrollment was highest in the Midwest; t and only 15% of enrollees were from states with a high proportion of Hispanic AYA ALL patients. In summary, Hispanic patients treated on CALGB 10403 did as well as NHWs and better than population estimates. Geographical misalignment between trial sites and disease epidemiology may partially explain the lower-than-expected enrollment of Hispanic AYA ALL patients.
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Ensayos Clínicos como Asunto , Disparidades en Atención de Salud , Hispánicos o Latinos , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adolescente , Disparidades en Atención de Salud/etnología , Humanos , Incidencia , Participación del Paciente , Leucemia-Linfoma Linfoblástico de Células Precursoras/etnología , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Sistema de Registros , Estados Unidos/epidemiología , Adulto JovenRESUMEN
BACKGROUND: In relapsed/refractory acute lymphoblastic leukemia (R/R ALL), successive salvage therapies may worsen outcomes and decrease quality of life. This post hoc analysis of the phase III INO-VATE trial investigates subsequent salvage therapies and compared the time from randomization to first subsequent salvage therapy (TST) in the inotuzumab ozogamicin (InO) and standard-of-care chemotherapy (SoC) arms. PATIENTS AND METHODS: Adults (aged ≥18 years) with CD22+ R/R ALL were randomized to InO (n = 164) or SoC (n = 162) treatment. We determined TST and proportion of patients receiving subsequent salvage therapies by treatment arm and for subgroups based on transplantation status and baseline characteristics. RESULTS: In the InO versus SoC arm, a smaller proportion of patients received subsequent salvage therapy (34.1% [n = 56] vs. 56.8% [n = 92]), and TST was longer (median 19 vs. 4 months, hazard ratio 0.339, P < .0001). Similar benefits were seen with InO versus SoC irrespective of transplantation status, age, salvage phase, first remission duration, Philadelphia chromosome status, or CD22 expression. Following receipt of subsequent salvage therapy, median overall survival was 4 months, irrespective of treatment arm. CONCLUSION: Patients in the InO versus SoC arm were less likely to receive subsequent salvage therapy, and showed a clinically meaningful extension of TST irrespective of subgroup. This suggests InO treatment leads to improved outcomes by increasing the likelihood that subsequent salvage therapies and their associated adverse impacts can be delayed or avoided. PLAIN LANGUAGE SUMMARY: Available in Supplementary Materials. CLINICAL TRIAL REGISTRATION: NCT01564784.
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Leucemia-Linfoma Linfoblástico de Células Precursoras , Terapia Recuperativa , Adolescente , Adulto , Humanos , Inotuzumab Ozogamicina/farmacología , Inotuzumab Ozogamicina/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Calidad de Vida , Nivel de AtenciónRESUMEN
PURPOSE: Chemotherapy outcomes in older patients with Philadelphia (Ph) chromosome-negative B-acute lymphoblastic leukemia (ALL) are very poor. Here, we evaluated blinatumomab as induction and consolidation therapy followed by prednisone, vincristine, 6-mercaptopurine, and methotrexate (POMP) maintenance chemotherapy in this patient population. PATIENTS AND METHODS: Patients were treated at National Clinical Trial Network sites. Eligibility criteria included age ≥ 65 years and newly diagnosed Ph chromosome-negative B-ALL. Patients received blinatumomab as induction for one-two cycles until attainment of response (complete remission (CR) and CR with incomplete count recovery). Patients then received three cycles of consolidation with blinatumomab followed by 18 months of POMP maintenance chemotherapy. Eight doses of intrathecal methotrexate were administered as central nervous system prophylaxis. RESULTS: Twenty-nine eligible patients were enrolled. The median age was 75 years, and the median bone marrow blast count at diagnosis was 87%. Cytogenetic risk was poor in 10 patients (34%), and five of 14 patients (36%) tested had the Ph-like ALL gene signature. Nineteen patients (66%; 95% CI, 46 to 82) achieved CR. Kaplan-Meier 3-year disease-free survival and overall survival estimates were 37% (95% CI, 17 to 57) and 37% (95% CI, 20 to 55), respectively. CONCLUSION: Blinatumomab was well tolerated and effective in the treatment of older patients with newly diagnosed Ph chromosome-negative B-ALL, including patients with poor-risk cytogenetics. The 3-year disease-free survival and overall survival results are encouraging and suggest that this approach should be further explored.
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Anticuerpos Biespecíficos , Linfoma de Células B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Anciano , Anticuerpos Biespecíficos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Humanos , Linfoma de Células B/tratamiento farmacológico , Metotrexato , Cromosoma Filadelfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológicoRESUMEN
Uproleselan (GMI-1271) is a novel E-selectin antagonist that disrupts cell survival pathways, enhances chemotherapy response, improves survival in mouse xenograft and syngeneic models, and decreases chemotherapy toxicity in vivo. A phase 1/2 study evaluated the safety, tolerability, and antileukemic activity of uproleselan (5-20 mg/kg) with MEC (mitoxantrone, etoposide, and cytarabine) among patients with relapsed/refractory (R/R) acute myeloid leukemia (AML). Among the first 19 patients, no dose-limiting toxicities were observed. The recommended phase 2 dose (RP2D) was 10 mg/kg twice daily. An additional 47 patients with R/R AML were treated with uproleselan at the RP2D plus MEC. At the RP2D, the remission rate (complete response [CR]/CR with incomplete count recovery [CRi]) was 41% (CR, 35%), and the median overall survival (OS) was 8.8 months. In a separate cohort, 25 newly diagnosed patients age ≥60 years received uproleselan at the RP2D plus cytarabine and idarubicin (7 + 3). In these frontline patients, the CR/CRi rate was 72% (CR, 52%), and the median OS was 12.6 months. The addition of uproleselan was associated with low rates of oral mucositis. E-selectin ligand expression on leukemic blasts was higher in patients with relapsed vs primary refractory AML and in newly diagnosed older patients with high-risk cytogenetics and secondary AML. In the R/R cohort, E-selectin expression >10% was associated with a higher response rate and improved survival. The addition of uproleselan to chemotherapy was well tolerated, with high remission rates, low induction mortality, and low rates of mucositis, providing a strong rationale for phase 3 randomized confirmatory studies. This trial was registered at www.clinicaltrials.gov as #NCT02306291.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Glucolípidos/administración & dosificación , Leucemia Mieloide Aguda , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Citarabina/administración & dosificación , Citarabina/efectos adversos , Supervivencia sin Enfermedad , Etopósido/administración & dosificación , Etopósido/efectos adversos , Femenino , Glucolípidos/efectos adversos , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Mitoxantrona/administración & dosificación , Mitoxantrona/efectos adversos , Tasa de SupervivenciaRESUMEN
Natural killer (NK) cells are regulated by killer immunoglobulin-like receptor (KIR) interactions with human leukocyte antigen class I ligands. Various models of NK cell alloreactivity have been associated with outcomes after allogeneic hematopoietic cell transplant (alloHCT), but results have varied widely. We hypothesized that somatic mutations in acute myeloid leukemia (AML) in the context of KIR profiles may further refine their association with transplant outcomes. In this single-center, retrospective, observational study, 81 AML patients who underwent matched-related donor alloHCT were included. Post-HCT outcomes were assessed based on mutational status and KIR profiles with the Kaplan-Meier method and log-rank test. On multivariable analysis those with any somatic mutations and C1/C2 heterozygosity had less acute graft-versus-host disease (GvHD) (hazard ratio [HR], 0.32; 95% confidence interval [CI], 0.14-0.75; P = .009), more relapse (HR, 3.02; 95% CI, 1.30-7.01; P = .010), inferior relapse-free survival (RFS; HR, 2.22; 95% CI, 1.17-4.20; P = .014), and overall survival (OS; HR, 2.21; 95% CI, 1.17-4.20; P = .015), whereas those with a missing KIR ligand had superior RFS (HR, 0.53; 95% CI, 0.30-0.94; P = .031). The presence of a somatic mutation and donor haplotype A was also associated with less acute GvHD (HR, 0.38; 95% CI, 0.16-0.92; P = .032), more relapse (HR, 2.72; 95% CI, 1.13-6.52; P = .025), inferior RFS (HR, 2.11; 95% CI, 1.07-4.14; P = .030), and OS (HR, 2.20; 95% CI, 1.11-4.38; P = .024). Enhanced NK cell alloreactivity from more KIR activating signals (donor B haplotype) and fewer inhibitory signals (recipient missing KIR ligand or C1 or C2 homozygosity) may help mitigate the adverse prognosis associated with some AML somatic mutations. These results may have implications for improving patient risk stratification prior to transplant and optimizing donor selection.
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Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Humanos , Inmunoglobulinas , Leucemia Mieloide Aguda/genética , Mutación , Receptores KIR/genéticaRESUMEN
Although genomic alterations drive the pathogenesis of acute myeloid leukemia (AML), traditional classifications are largely based on morphology, and prototypic genetic founder lesions define only a small proportion of AML patients. The historical subdivision of primary/de novo AML and secondary AML has shown to variably correlate with genetic patterns. The combinatorial complexity and heterogeneity of AML genomic architecture may have thus far precluded genomic-based subclassification to identify distinct molecularly defined subtypes more reflective of shared pathogenesis. We integrated cytogenetic and gene sequencing data from a multicenter cohort of 6788 AML patients that were analyzed using standard and machine learning methods to generate a novel AML molecular subclassification with biologic correlates corresponding to underlying pathogenesis. Standard supervised analyses resulted in modest cross-validation accuracy when attempting to use molecular patterns to predict traditional pathomorphologic AML classifications. We performed unsupervised analysis by applying the Bayesian latent class method that identified 4 unique genomic clusters of distinct prognoses. Invariant genomic features driving each cluster were extracted and resulted in 97% cross-validation accuracy when used for genomic subclassification. Subclasses of AML defined by molecular signatures overlapped current pathomorphologic and clinically defined AML subtypes. We internally and externally validated our results and share an open-access molecular classification scheme for AML patients. Although the heterogeneity inherent in the genomic changes across nearly 7000 AML patients was too vast for traditional prediction methods, machine learning methods allowed for the definition of novel genomic AML subclasses, indicating that traditional pathomorphologic definitions may be less reflective of overlapping pathogenesis.
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Leucemia Mieloide Aguda/genética , Aprendizaje Automático , Teorema de Bayes , Citogenética , Regulación Leucémica de la Expresión Génica , Genómica , Humanos , Leucemia Mieloide Aguda/clasificación , Leucemia Mieloide Aguda/diagnóstico , Mutación , Neoplasias Primarias Secundarias/clasificación , Neoplasias Primarias Secundarias/diagnóstico , Neoplasias Primarias Secundarias/genética , Translocación GenéticaRESUMEN
Philadelphia-like (Ph-like) acute lymphoblastic leukemia (ALL) is a high-risk subset of B-cell ALL characterized by high rates of treatment failure. Unsatisfactory outcomes with frontline therapy in adults with Ph-like ALL have been observed irrespective of the employed regimen, including modern pediatric-inspired regimens. Notably, Ph-like ALL is not an uncommon entity in adults, and it's prevalence extends to older patients with B-cell ALL. As the majority of Ph-like ALL cases harbor genetic alterations in kinases and/or cytokine receptors, the integration of tyrosine kinase inhibitors in newly diagnosed patients and poor early responders with Ph-like ALL has emerged as an area of active research with several ongoing clinical trials. Furthermore, the encouraging activity of novel therapies such as inotuzumab and blinatumomab in chemo-refractory B-cell ALL has promoted an interest in introducing these agents early in Ph-like ALL management, which may lead to improved cure rates with frontline therapies, sparing more adults from undergoing early allogeneic hematopoietic cell transplantation (HCT). Finally, the high relapse rate in patients with Ph-like ALL, does not necessary correlate with early minimal residual disease (MRD) response, raising the question of consolidation with allogenic HCT in all adults with Ph-like ALL in first complete remission irrespective of MRD response.
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Trasplante de Células Madre Hematopoyéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Niño , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Recurrencia , Inducción de RemisiónRESUMEN
PURPOSE: We assessed the relationship between cluster of differentiation-22 (CD22) expression and outcomes of inotuzumab ozogamicin versus standard of care (SC) in INO-VATE (NCT01564784). PATIENTS AND METHODS: Adults with relapsed/refractory B-cell precursor CD22-positive (by local or central laboratory) acute lymphoblastic leukemia were randomized to inotuzumab ozogamicin (n = 164) or SC (n = 162). Outcomes were analyzed by baseline CD22 positivity (percentage of leukemic blasts CD22 positive, ≥90% vs. <90%) and CD22 receptor density [molecules of equivalent soluble fluorochrome (MESF), quartile analysis]. RESULTS: Most patients had high (≥90%) CD22 positivity per central laboratory. The response rate was significantly higher with inotuzumab ozogamicin versus SC. Minimal/measurable residual disease negativity, duration of remission (DoR), progression-free survival, and overall survival (OS) were significantly better with inotuzumab ozogamicin versus SC in patients with CD22 positivity ≥90%. Fewer patients had CD22 positivity <90%; for whom, response rates were higher with inotuzumab ozogamicin versus SC, but DoR and OS appeared similar. Similar trends were evident in quartile analyses of CD22 MESF and CD22 positivity per local laboratory. Among inotuzumab ozogamicin-responding patients with subsequent relapse, decrease in CD22 positivity and receptor density was evident, but not the emergence of CD22 negativity. Rates of grade ≥3 hematologic adverse events (AEs) were similar and hepatobiliary AEs rate was higher for inotuzumab ozogamicin versus SC. No apparent relationship was observed between the rates of hematologic and hepatic AEs and CD22 expression. CONCLUSIONS: Inotuzumab ozogamicin demonstrated a favorable benefit-risk profile versus SC in patients with higher and lower CD22 expression. Patients with high CD22 expression and normal cytogenetics benefited the most from inotuzumab ozogamicin therapy.
Asunto(s)
Antineoplásicos Inmunológicos/uso terapéutico , Inotuzumab Ozogamicina/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/efectos adversos , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Resistencia a Antineoplásicos , Humanos , Inotuzumab Ozogamicina/administración & dosificación , Inotuzumab Ozogamicina/efectos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiología , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Recurrencia , Retratamiento , Lectina 2 Similar a Ig de Unión al Ácido Siálico/metabolismo , Resultado del TratamientoRESUMEN
PURPOSE: TTI-621 (SIRPα-IgG1 Fc) is a novel checkpoint inhibitor that activates antitumor activity by blocking the CD47 "don't eat me" signal. This first-in-human phase I study (NCT02663518) evaluated the safety and activity of TTI-621 in relapsed/refractory (R/R) hematologic malignancies. PATIENTS AND METHODS: Patients with R/R lymphoma received escalating weekly intravenous TTI-621 to determine the maximum tolerated dose (MTD). During expansion, patients with various malignancies received weekly single-agent TTI-621 at the MTD; TTI-621 was combined with rituximab in patients with B-cell non-Hodgkin lymphoma (B-NHL) or with nivolumab in patients with Hodgkin lymphoma. The primary endpoint was the incidence/severity of adverse events (AEs). Secondary endpoint included overall response rate (ORR). RESULTS: Overall, 164 patients received TTI-621: 18 in escalation and 146 in expansion (rituximab combination, n = 35 and nivolumab combination, n = 4). On the basis of transient grade 4 thrombocytopenia, the MTD was determined as 0.2 mg/kg; 0.1 mg/kg was evaluated in combination cohorts. AEs included infusion-related reactions, thrombocytopenia, chills, and fatigue. Thrombocytopenia (20%, grade ≥3) was reversible between doses and not associated with bleeding. Transient thrombocytopenia that determined the initial MTD may not have been dose limiting. The ORR for all patients was 13%. The ORR was 29% (2/7) for diffuse large B-cell lymphoma (DLBCL) and 25% (8/32) for T-cell NHL (T-NHL) with TTI-621 monotherapy and was 21% (5/24) for DLBCL with TTI-621 plus rituximab. Further dose optimization is ongoing. CONCLUSIONS: TTI-621 was well-tolerated and demonstrated activity as monotherapy in patients with R/R B-NHL and T-NHL and combined with rituximab in patients with R/R B-NHL.
Asunto(s)
Antígeno CD47/antagonistas & inhibidores , Neoplasias Hematológicas/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inmunoglobulina G/efectos adversos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Resistencia a Antineoplásicos , Femenino , Neoplasias Hematológicas/inmunología , Humanos , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Inmunoglobulina G/administración & dosificación , Infusiones Intravenosas , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Recurrencia Local de Neoplasia/inmunología , Resultado del Tratamiento , Adulto JovenRESUMEN
Adolescents and young adults (AYAs) with acute lymphoblastic leukemia have improved outcomes when treated with pediatric-inspired regimens. CALGB 10403 was the largest prospective study to evaluate the feasibility of using a pediatric regimen in AYAs with acute lymphoblastic leukemia up to 40 years of age. This article presents the toxicity events observed in the CALGB 10403 study and compares these toxicities vs those observed among AYAs treated on the same arm of the companion Children's Oncology Group (COG) AALL0232 study. Toxicities in CALGB 10403 were similar to those observed in COG AALL0232. Some grade 3 to 4 adverse events were more often reported in CALGB 10403 compared with COG AALL0232 (hyperglycemia, hyperbilirubinemia, transaminase elevation, and febrile neutropenia). Adverse events correlated with body mass index ≥30 kg/m2 and some with increasing age. The mortality rate in CALGB 10403 was low (4%) and similar to that in the COG AALL0232 trial. A caveat to this analysis is that only 39% of CALGB 10403 patients completed all planned protocol treatment. In COG AALL0232, although 74% of patients aged <18 years completed treatment, only 57% of patients aged ≥18 years completed treatment. This scenario suggests that issues associated with age and treating physician may be a factor. Due to its improved survival rates compared with historical controls, the CALGB 10403 regimen is now a standard of care. The hope is that the rate of protocol completion will increase as more familiarity is gained with this regimen. These trials were registered at www.clinicaltrials.gov as #NCT00558519 (CALGB 10403) and #NCT00075725 (COG AALL0232).