RESUMO
BACKGROUND: Late onset non-infectious pulmonary complications (LONIPCs) following allogenic hematopoietic stem cell transplantation (allo-HSCT) confer a significant mortality risk. Lung transplantation (LTx) has the potential to provide survival benefit but the impact of prior allo-HSCT on post-LTx outcomes is not well studied. METHODS: This retrospective, single-centre cohort study assessed the post-LTx outcomes of adults with LONIPCs of allo-HSCT. Outcomes of LTx for LONIPCs were compared to propensity-score matched LTx controls (n = 38, non-HSCT) and recipients of re-LTx (n = 70) for chronic lung allograft dysfunction (CLAD). RESULTS: Nineteen patients underwent DLTx for LONIPCs of allo-HSCT between 2003 and 2019. Post-LTx survival was 50% at 5-years. Survival to 1-year post-LTx was similar to matched controls (p = 0.473). Survival, conditional on 1-year survival, was lower in the allo-HSCT cohort (p = 0.034). An increased risk of death due to infection was identified in the allo-HSCT cohort compared to matched controls (p = 0.003). Compared to re-LTx recipients, the allo-HSCT cohort had superior survival to 1-year post-LTx (p = 0.034) but conditional 1-year survival was similar (p = 0.145). CONCLUSION: This study identifies an increased risk of post-LTx mortality in recipients with previous allo-HSCT, associated with infection. It supports the hypothesis that allo-HSCT LTx recipients are relatively more immunosuppressed than patients undergoing LTx for other indications. Optimisation of post-LTx immunosuppressive and antimicrobial strategies to account for this finding should be considered.
Assuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Pulmão/métodos , Complicações Pós-Operatórias , Disfunção Primária do Enxerto/cirurgia , Pontuação de Propensão , Transplantados , Adolescente , Adulto , Biópsia , Broncoscopia , Doença Crônica , Feminino , Seguimentos , Humanos , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Disfunção Primária do Enxerto/diagnóstico , Disfunção Primária do Enxerto/etiologia , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Transplante Homólogo/efeitos adversos , Adulto JovemRESUMO
BACKGROUND: Health-related quality of life (HRQOL) in patients with chronic-phase chronic myeloid leukemia (CML) is important because of the requirement for long-term treatment. This study assessed HRQOL in bosutinib-treated patients with Philadelphia chromosome-positive CML and resistance or intolerance to 1 (chronic-phase second-line [CP2L]) or more (chronic-phase third-line [CP3L]) tyrosine kinase inhibitors who had 264 weeks or more of follow-up (ClinicalTrials.gov identifier NCT00261846). METHODS: Patient-reported HRQOL was assessed with the EuroQol 5-Dimensions Questionnaire (EQ-5D) and the Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu). RESULTS: In total, 284 and 119 patients composed the CP2L and CP3L cohorts, respectively. At treatment completion, more than 50% of the patients in the CP2L and CP3L cohorts completed the EQ-5D and FACT-Leu assessments. The EQ-5D and EQ-5D visual analog scale scores were stable in both cohorts throughout treatment. The mean FACT-Leu scores were generally stable over time but were lower in magnitude in the CP3L cohort versus the CP2L cohort. The FACT-Leu scale scores of a subset of patients with chronic diarrhea (CP2L, n = 101; CP3L, n = 30) were similar to the scores of the larger cohorts. Minimally important differences (MIDs) from baseline for the FACT-Leu scale scores were observed for the following: emotional well-being (EWB), Functional Assessment of Cancer Therapy-General (FACT-G) Total, FACT-Leu Total, and Functional Assessment of Cancer Therapy Trial Outcome Index (FACT-TOI) in the CP2L cohort and FACT-Leu Total in the CP3L cohort. Among patients with chronic diarrhea, MIDs were observed for EWB, FACT-G Total, FACT-Leu Total, and FACT-TOI in the CP2L cohort and for EWB, FACT-G Total, and FACT-Leu Total in the CP3L cohort. CONCLUSIONS: HRQOL was maintained with long-term bosutinib treatment for patients with CP2L and CP3L CML. Cancer 2018;124:587-95. © 2017 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
Assuntos
Compostos de Anilina/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Nitrilas/uso terapêutico , Medidas de Resultados Relatados pelo Paciente , Cromossomo Filadélfia , Quinolinas/uso terapêutico , Adulto , Idoso , Compostos de Anilina/efeitos adversos , Doença Crônica , Diarreia/induzido quimicamente , Feminino , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/psicologia , Masculino , Pessoa de Meia-Idade , Nitrilas/efeitos adversos , Qualidade de Vida , Quinolinas/efeitos adversosRESUMO
Chronic graft-versus-host disease (cGVHD) remains one of the most significant long-term complications after allogeneic blood and marrow transplantation. Diagnostic biomarkers for cGVHD are needed for early diagnosis and may guide identification of prognostic markers. No cGVHD biomarker has yet been validated for use in clinical practice. We evaluated both previously known markers and performed discovery-based analysis for cGVHD biomarkers in a 2 independent test sets (total of 36 cases ≤1 month from diagnosis and 31 time-matched controls with no cGVHD). On the basis of these results, 11 markers were selected and evaluated in 2 independent replication cohorts (total of 134 cGVHD cases and 154 controls). cGVHD cases and controls were evaluated for several clinical covariates, and their impact on biomarkers was identified by univariate analysis. The 2 replications sets were relatively disparate in the biomarkers they replicated. Only sBAFF and, most consistently, CXCL10 were identified as significant in both replication sets. Other markers identified as significant in only 1 replication set included intercellular adhesion molecule 1 (ICAM-1), anti-LG3, aminopeptidase N, CXCL9, endothelin-1, and gelsolin. Multivariate analysis found that all covariates evaluated affected interpretation of the biomarkers. CXCL10 had an increased significance in combination with anti-LG3 and CXCL9, or inversely with CXCR3(+)CD56(bright) natural killer (NK) cells. There was significant heterogeneity of cGVHD biomarkers in a large comprehensive evaluation of cGVHD biomarkers impacted by several covariates. Only CXCL10 strongly correlated in both replication sets. Future analyses for plasma cGVHD biomarkers will need to be performed on very large patient groups with consideration of multiple covariates.
Assuntos
Biomarcadores/sangue , Quimiocina CXCL10/metabolismo , Doença Enxerto-Hospedeiro/diagnóstico , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/patologia , Receptores CXCR3/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Doença Crônica , Feminino , Doença Enxerto-Hospedeiro/sangue , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Bosutinib is a Src/Abl tyrosine kinase inhibitor indicated for adults with newly-diagnosed Philadelphia positive chronic myeloid leukemia or with resistant/intolerant disease. We report the final results of a phase I/II study of second-line bosutinib in chronic phase chronic myeloid leukemia patients after imatinib failure (n=284). Median follow up and treatment durations were 54.8 (range 0.6-96.3) and 25.6 (0.2-96.3) months, respectively. At years 2 and 5, 54% and 40% of patients, respectively, remained on bosutinib. Cumulative major cytogenetic response and complete cytogenetic response rates (newly-attained or maintained from baseline) were 58% and 46%, respectively, by year 2 and 60% and 50% by year 5. Kaplan-Meier probability of maintaining major and complete cytogenetic response was 76% and 78%, respectively, at year 2 and 71% and 69% at year 5. Cumulative incidence of on-treatment disease progression/death was similar at years 5 (19%) and 2 (15%); Kaplan-Meier overall survival was 91% at year 2 and 84% at year 5. Of 169 patients who had discontinued bosutinib by year 5, 38 did so after year 2, most commonly for disease progression (n=11). Most adverse events initially occurred within two years. Overall, gastrointestinal events were the most common (diarrhea 86%, nausea 46%, vomiting 37%); the most common grade 3/4 toxicity was thrombocytopenia (25%). None of the 4 on-treatment deaths in years 3-5 were related to bosutinib. Bosutinib demonstrated durable efficacy and manageable toxicity through year 5 confirming its importance in the treatment of chronic phase chronic myeloid leukemia patients resistant/intolerant to prior imatinib. This trial was registered at clinicaltrials.gov identifier: 00261846.
Assuntos
Compostos de Anilina/uso terapêutico , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Nitrilas/uso terapêutico , Quinolinas/uso terapêutico , Adolescente , Adulto , Idoso , Compostos de Anilina/efeitos adversos , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Antineoplásicos/toxicidade , Seguimentos , Humanos , Mesilato de Imatinib/uso terapêutico , Leucemia Mieloide de Fase Crônica/complicações , Leucemia Mieloide de Fase Crônica/mortalidade , Pessoa de Meia-Idade , Nitrilas/efeitos adversos , Fragmentos de Peptídeos/uso terapêutico , Quinolinas/efeitos adversos , Análise de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
Randomized trials have conclusively shown higher rates of chronic graft-versus-host disease with filgrastim-stimulated apheresis peripheral blood as a donor source than unstimulated bone marrow. The Canadian Blood and Marrow Transplant Group conducted a phase 3 study of adults who received either filgrastim-stimulated apheresis peripheral blood or filgrastim-stimulated bone marrow from human leukocyte antigen-identical sibling donors. Because all donors received the identical filgrastim dosing schedule, this study allowed for a controlled evaluation of the impact of stem cell source on development of chronic graft-versus-host disease. One hundred and twenty-one evaluable filgrastim-stimulated apheresis peripheral blood and filgrastim-stimulated bone marrow patient donor products were immunologically characterized by flow cytometry and tested for their association with acute and chronic graft-versus-host disease within 2 years of transplantation. The immune populations evaluated included, regulatory T cells, central memory and effector T cells, interferon γ positive producing T cells, invariate natural killer T cells, regulatory natural killer cells, dendritic cell populations, macrophages, and activated B cells and memory B cells. When both filgrastim-stimulated apheresis peripheral blood and filgrastim-stimulated bone marrow were grouped together, a higher chronic graft-versus-host disease frequency was associated with lower proportions of CD56bright natural killer regulatory cells and interferon γ-producing T helper cells in the donor product. Lower CD56bright natural killer regulatory cells displayed differential impacts on the development of extensive chronic graft-versus-host disease between filgrastim-stimulated apheresis peripheral blood and filgrastim-stimulated bone marrow. In summary, while controlling for the potential impact of filgrastim on marrow, our studies demonstrated that CD56bright natural killer regulatory cells had a much stronger impact on filgrastim-stimulated apheresis peripheral blood than on filgrastim-stimulated bone marrow. This supports the conclusion that a lower proportion of CD56bright natural killer regulatory cells results in the high rate of chronic graft-versus-host disease seen in filgrastim-stimulated apheresis peripheral blood. clinicaltrials.gov Identifier: 00438958.
Assuntos
Antígeno CD56/metabolismo , Filgrastim/uso terapêutico , Doença Enxerto-Hospedeiro/etiologia , Mobilização de Células-Tronco Hematopoéticas , Transplante de Células-Tronco Hematopoéticas , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Adolescente , Adulto , Idoso , Biomarcadores , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Doença Crônica , Feminino , Filgrastim/farmacologia , Doença Enxerto-Hospedeiro/diagnóstico , Mobilização de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Imunofenotipagem , Interferon gama/metabolismo , Masculino , Pessoa de Meia-Idade , Irmãos , Condicionamento Pré-Transplante , Adulto JovemRESUMO
The dual SRC/ABL1 tyrosine kinase inhibitor bosutinib is indicated for adults with Ph+ chronic myeloid leukaemia (CML) resistant/intolerant to prior therapy. This analysis of an ongoing phase 1/2 study (NCT00261846) assessed effects of baseline patient characteristics on long-term efficacy and safety of bosutinib 500 mg/day in adults with imatinib (IM)-resistant (IM-R; n = 196)/IM-intolerant (IM-I; n = 90) chronic phase (CP) CML. Median treatment duration was 24·8 months (median follow-up, 43·6 months). Cumulative major cytogenetic response (MCyR) rate [95% confidence interval (CI)], was 59% (53-65%); Kaplan-Meier (KM) probability of maintaining MCyR at 4 years was 75% (66-81%). Cumulative incidence of on-treatment progression/death at 4 years was 19% (95% CI, 15-24%); KM 2-year overall survival was 91% (87-94%). Significant baseline predictors of both MCyR and complete cytogenetic response (newly attained/maintained from baseline) at 3 and 6 months included prior IM cytogenetic response, baseline MCyR, prior interferon therapy and <6 months duration from diagnosis to IM treatment initiation and no interferon treatment before IM. The most common adverse event (AE) was diarrhoea (86%). Baseline bosutinib-sensitive BCR-ABL1 mutation was the only significant predictor of grade 3/4 diarrhoea; no significant predictors were identified for liver-related AEs. Bosutinib demonstrates durable efficacy and manageable toxicity in IM-R/IM-I CP-CML patients.
Assuntos
Compostos de Anilina/uso terapêutico , Antineoplásicos/uso terapêutico , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Nitrilas/uso terapêutico , Quinolinas/uso terapêutico , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Compostos de Anilina/efeitos adversos , Antineoplásicos/efeitos adversos , Resistencia a Medicamentos Antineoplásicos , Feminino , Seguimentos , Proteínas de Fusão bcr-abl/genética , Humanos , Mesilato de Imatinib/uso terapêutico , Estimativa de Kaplan-Meier , Leucemia Mieloide de Fase Crônica/genética , Masculino , Pessoa de Meia-Idade , Mutação , Nitrilas/efeitos adversos , Quinolinas/efeitos adversos , Resultado do Tratamento , Adulto JovemRESUMO
Vascular and cardiac safety during tyrosine kinase inhibitor (TKI) therapy is an emerging issue. We evaluated vascular/cardiac toxicities associated with long-term bosutinib treatment for Philadelphia chromosome-positive (Ph+) leukemia based on treatment-emergent adverse events (TEAEs) and changes in QTc intervals and ejection fraction in two studies: a phase 1/2 study of second-/third-/fourth-line bosutinib for Ph+ leukemia resistant/intolerant to prior TKIs (N = 570) and a phase 3 study of first-line bosutinib (n = 248) versus imatinib (n = 251) in chronic phase chronic myeloid leukemia. Follow-up time was ≥48 months (both studies). Incidences of vascular/cardiac TEAEs in bosutinib-treated patients were 7%/10% overall with similar incidences observed with first-line bosutinib (5%/8%) and imatinib (4%/6%). Few patients had grade ≥3 vascular/cardiac events (4%/4%) and no individual TEAE occurred in >2% of bosutinib patients. Exposure-adjusted vascular/cardiac TEAE rates (patients with events/patient-year) were low for second-line or later bosutinib (0.037/0.050) and not significantly different between first-line bosutinib (0.015/0.024) and imatinib (0.011/0.017; P ≥ 0.267). Vascular/cardiac events were managed mainly with concomitant medications (39%/44%), bosutinib treatment interruptions (18%/21%), or dose reductions (4%/8%); discontinuations due to these events were rare (0.7%/1.0%). Based on logistic regression modelling, performance status >0 and history of vascular or cardiac disorders were prognostic of vascular/cardiac events in relapsed/refractory patients; hyperlipidemia/hypercholesterolemia and older age were prognostic of cardiac events. In newly diagnosed patients, older age was prognostic of vascular/cardiac events; history of diabetes was prognostic of vascular events. Incidences of vascular and cardiac events were low with bosutinib in the first-line and relapsed/refractory settings following long-term treatment in patients with Ph+ leukemia. Am. J. Hematol. 91:606-616, 2016. © 2016 Wiley Periodicals, Inc.
Assuntos
Compostos de Anilina/toxicidade , Cardiotoxicidade/etiologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/complicações , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Nitrilas/toxicidade , Quinolinas/toxicidade , Doenças Vasculares/etiologia , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Compostos de Anilina/uso terapêutico , Feminino , Humanos , Hipercolesterolemia , Hiperlipidemias , Mesilato de Imatinib/uso terapêutico , Masculino , Pessoa de Meia-Idade , Nitrilas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Quinolinas/uso terapêutico , Estudos Retrospectivos , Fatores de Risco , Doenças Vasculares/induzido quimicamente , Adulto JovemRESUMO
Bosutinib is an Src/Abl tyrosine kinase inhibitor (TKI) indicated for adults with Ph+ chronic myeloid leukemia (CML) resistant/intolerant to prior TKIs. This long-term update of an ongoing phase 1/2 study evaluated the efficacy and safety of third-/fourth-line bosutinib in adults with chronic phase (CP) CML. Median durations of treatment and follow-up were 8.6 (range, 0.2-87.7) months and 32.7 (0.3-93.3) months, respectively. Cumulative confirmed complete hematologic response (cCHR) and major cytogenetic response (MCyR) rates were 74% (95% CI, 65-81%) and 40% (31-50%), respectively; Kaplan-Meier (K-M) probability of maintaining cCHR or MCyR at 4 years was 63% (95% CI, 50-73%) and 69% (52-81%). Cumulative incidence of on-treatment disease progression (PD)/death at 4 years was 24% (95% CI, 17-33%); K-M 4-year overall survival was 78% (68-85%). Baseline Ph+ cells ≤35 vs. ≥95% was prognostic of MCyR and CCyR by 3 and 6 months, increased baseline basophils was prognostic of PD/death, and no prior response to second-line TKI was prognostic of death. Common adverse events included diarrhea (83%), nausea (48%), vomiting (38%), and thrombocytopenia (39%). Bosutinib demonstrates durable efficacy and a toxicity profile similar to previous bosutinib studies in CP CML patients resistant/intolerant to multiple TKIs, representing an important treatment option for patients in this setting. This trial is registered at www.clinicaltrials.gov (NCT00261846). Am. J. Hematol. 91:1206-1214, 2016. © 2016 Wiley Periodicals, Inc.
Assuntos
Compostos de Anilina/uso terapêutico , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Nitrilas/uso terapêutico , Quinolinas/uso terapêutico , Terapia de Salvação/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Compostos de Anilina/efeitos adversos , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Dasatinibe , Progressão da Doença , Humanos , Mesilato de Imatinib , Leucemia Mieloide de Fase Crônica/mortalidade , Estudos Longitudinais , Pessoa de Meia-Idade , Nitrilas/efeitos adversos , Pirimidinas , Quinolinas/efeitos adversos , Indução de Remissão , Análise de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Phenotypic overlap among the inherited bone marrow failure syndromes (IBMFSs) frequently limits the ability to establish a diagnosis based solely on clinical features. >70 IBMFS genes have been identified, which often renders genetic testing prolonged and costly. Since correct diagnosis, treatment and cancer surveillance often depend on identifying the mutated gene, strategies that enable timely genotyping are essential. METHODS: To overcome these challenges, we developed a next-generation sequencing assay to analyse a panel of 72 known IBMFS genes. Cases fulfilling the clinical diagnostic criteria of an IBMFS but without identified causal genotypes were included. RESULTS: The assay was validated by detecting 52 variants previously found by Sanger sequencing. A total of 158 patients with unknown mutations were studied. Of 75 patients with known IBMFS categories (eg, Fanconi anaemia), 59% had causal mutations. Among 83 patients with unclassified IBMFSs, we found causal mutations and established the diagnosis in 18% of the patients. The assay detected mutant genes that had not previously been reported to be associated with the patient phenotypes. In other cases, the assay led to amendments of diagnoses. In 20% of genotype cases, the results indicated a cancer surveillance programme. CONCLUSIONS: The novel assay is efficient, accurate and has a major impact on patient care.
Assuntos
Hemoglobinúria Paroxística , Análise de Sequência de DNA/métodos , Anemia Aplástica , Doenças da Medula Óssea , Transtornos da Insuficiência da Medula Óssea , Hemoglobinúria Paroxística/diagnóstico , Hemoglobinúria Paroxística/genética , Hemoglobinúria Paroxística/terapia , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Mutação , Assistência ao Paciente , Sensibilidade e EspecificidadeRESUMO
Chronic myeloid leukemia (CML) patients with the BCR-ABL T315I mutation do not benefit from therapy with currently approved tyrosine kinase inhibitors. Omacetaxine mepesuccinate is a protein synthesis inhibitor that has demonstrated activity in cells harboring the T315I mutation. This phase 2 trial assessed the efficacy of omacetaxine in CML patients with T315I and tyrosine kinase inhibitor failure. Patients received subcutaneous omacetaxine 1.25 mg/m(2) twice daily, days 1-14, every 28 days until hematologic response or a maximum of 6 cycles, and then days 1-7 every 28 days as maintenance. Results for patients treated in chronic phase are reported here. Patients (n = 62) received a median of 7 (range, 1-41) cycles. Complete hematologic response was achieved in 48 patients (77%; 95% lower confidence limit, 65%); median response duration was 9.1 months. Fourteen patients (23%; 95% lower confidence limit, 13%) achieved major cytogenetic response, including complete cytogenetic response in 10 (16%). Median progression free-survival was 7.7 months. Grade 3/4 hematologic toxicity included thrombocytopenia (76%), neutropenia (44%), and anemia (39%) and was typically manageable by dose reduction. Nonhematologic adverse events were mostly grade 1/2 and included infection (42%), diarrhea (40%), and nausea (34%). Omacetaxine may provide a safe and effective treatment for CML patients with T315I mutation. This study is registered at www.clinicaltrials.gov as NCT00375219.
Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteínas de Fusão bcr-abl/genética , Harringtoninas/administração & dosagem , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Mutação/genética , Inibidores de Proteínas Quinases/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Mepesuccinato de Omacetaxina , Humanos , Injeções Subcutâneas , Leucemia Mieloide de Fase Crônica/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Terapia de Salvação , Taxa de SobrevidaRESUMO
Tyrosine kinase inhibitor therapy with imatinib (IM), dasatinib (DAS), or nilotinib is very effective in chronic-phase chronic myeloid leukemia. Two hundred fifty-three patients with newly diagnosed chronic-phase chronic myeloid leukemia were randomized to IM 400 mg/day or DAS 100 mg/day. The proportion of patients achieving a complete cytogenetic remission rate was superior with DAS (84% vs 69%), as was the 12-month molecular response by the proportions of patients achieving > 3-log, > 4-log, and > 4.5-log reduction in BCR-ABL transcript levels. Overall and progression-free survival was similar in the 2 arms. Among patients who achieved hematologic CR, 3-year relapse-free survival was 91% with DAS and 88% with IM 400 mg. Grade 3 and 4 toxicities were most commonly hematologic, including thrombocytopenia in 18% and 8% of DAS and IM patients, respectively. DAS induced more complete cytogenetic response and deeper molecular responses after 12 months, compared with IM 400 mg, and with a median follow-up of 3.0 years there have been very few deaths, relapses, or progressions in the 2 arms. In summary, DAS compared with IM appeared to have more short-term cytogenetic and molecular response, more hematologic toxicity, and similar overall survival. This trial is registered at www.clinicaltrials.gov as NCT00070499.
Assuntos
Antineoplásicos/uso terapêutico , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Tiazóis/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Benzamidas , Dasatinibe , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Mesilato de Imatinib , Leucemia Mieloide de Fase Crônica/genética , Leucemia Mieloide de Fase Crônica/mortalidade , Masculino , Pessoa de Meia-Idade , Mutação , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Recidiva , Tiazóis/administração & dosagem , Tiazóis/efeitos adversos , Resultado do Tratamento , Adulto JovemRESUMO
Bosutinib, an orally active, Src/Abl tyrosine kinase inhibitor, has demonstrated clinical activity and acceptable tolerability in chronic phase chronic myeloid leukemia (CP CML). This updated analysis of the BELA trial assessed the safety profile and management of toxicities of bosutinib versus imatinib in adults with newly diagnosed (≤6 months) CP CML after >30 months from accrual completion. Among patients randomized to bosutinib 500 mg/d (n = 250) or imatinib 400 mg/d (n = 252), 248 and 251, respectively, received ≥1 dose of study treatment. Adverse events (AEs; any grade) with bosutinib versus imatinib were significantly more common for certain gastrointestinal events (diarrhea, 70% vs. 26%; P < 0.001; vomiting, 33% vs. 16%; P < 0.001), alanine aminotransferase (33% vs. 9%; P < 0.001) and aspartate aminotransferase (28% vs. 10%; P < 0.001) elevations, and pyrexia (19% vs. 12%; P = 0.046). AEs significantly less common with bosutinib included edema (periorbital, 2% vs. 14%; P < 0.001; peripheral, 5% vs. 12%; P = 0.006), musculoskeletal (myalgia, 5% vs. 12%; P = 0.010; muscle cramps, 5% vs. 22%; P < 0.001; bone pain, 4% vs. 11%; P = 0.003), increased creatine phosphokinase (8% vs. 20%; P < 0.001), neutropenia (13% vs. 30%; P < 0.001), and leukopenia (9% vs. 22%; P < 0.001). Between-group differences in the incidence of cardiac and vascular AEs were not significant. Diarrhea was typically transient, mostly Grade 1/2, occurring early during treatment, and was manageable with antidiarrheal medication. Despite higher rates of aminotransferase elevation with bosutinib, events were managed in most patients with dose modification and/or concomitant medication. Bosutinib had a manageable safety profile distinct from that of imatinib in patients with newly diagnosed CP CML.
Assuntos
Compostos de Anilina , Antineoplásicos , Benzamidas , Nitrilas , Piperazinas , Pirimidinas , Quinolinas , Alanina Transaminase/sangue , Compostos de Anilina/administração & dosagem , Compostos de Anilina/efeitos adversos , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Aspartato Aminotransferases/sangue , Benzamidas/administração & dosagem , Benzamidas/efeitos adversos , Diarreia/sangue , Diarreia/induzido quimicamente , Feminino , Febre/sangue , Febre/induzido quimicamente , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/sangue , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Pessoa de Meia-Idade , Cãibra Muscular/sangue , Cãibra Muscular/induzido quimicamente , Mialgia/sangue , Mialgia/induzido quimicamente , Nitrilas/administração & dosagem , Nitrilas/efeitos adversos , Dor/sangue , Dor/induzido quimicamente , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Quinolinas/administração & dosagem , Quinolinas/efeitos adversos , Vômito/sangue , Vômito/induzido quimicamenteRESUMO
Fifty-five years after publication of the first hematopoietic stem cell transplantation this technique has become an accepted treatment option for defined hematologic and non-hematologic disorders. There is considerable interest in understanding differences in its use and trends on a global level and the macro-economic factors associated with these differences. Data on the numbers of hematopoietic stem cell transplants performed in the 3-year period 2006-2008 were obtained from Worldwide Network for Blood and Marrow Transplantation member registries and from transplant centers in countries without registries. Population and macro-economic data were collected from the World Bank and from the International Monetary Fund. Transplant rates were analyzed by indication, donor type, country, and World Health Organization regional offices areas and related to selected health care indicators using single and multiple linear regression analyses. Data from a total of 146,808 patients were reported by 1,411 teams from 72 countries over five continents. The annual number of transplants increased worldwide with the highest relative increase in the Asia Pacific region. Transplant rates increased preferentially in high income countries (P=0.02), not in low or medium income countries. Allogeneic transplants increased for myelodysplasia, chronic lymphocytic leukemia, acute leukemias, and non-malignant diseases but decreased for chronic myelogenous leukemia. Autologous transplants increased for autoimmune and lymphoproliferative diseases but decreased for leukemias and solid tumors. Transplant rates (P<0.01), donor type (P<0.01) aand disease indications (P<0.01) differed significantly between countries and regions. Transplant rates were associated with Gross National Income/capita (P<0.01) but showed a wide variation of explanatory content by donor type, disease indication and World Health Organization region. Hematopoietic stem cell transplantation activity is increasing worldwide. The preferential increase in high income countries, the widening gap between low and high income countries and the significant regional differences suggest that different strategies are required in individual countries to foster hematopoietic stem cell transplantation as an efficient and cost-effective treatment modality.
Assuntos
Saúde Global/economia , Saúde Global/tendências , Transplante de Células-Tronco Hematopoéticas/economia , Transplante de Células-Tronco Hematopoéticas/tendências , Saúde Global/normas , Produto Interno Bruto/tendências , Transplante de Células-Tronco Hematopoéticas/normas , Humanos , Sistema de Registros/normas , Estudos Retrospectivos , Organização Mundial da Saúde/economiaRESUMO
BACKGROUND: We have previously shown in a pediatric Hematopoietic stem cell transplant (HSCT) population that a non-invasive oral rinse can be used to monitor engraftment, neutrophil tissue delivery and susceptibility to infection post-HSCT. METHODS: Using the same oral rinse protocol, we studied neutrophil tissue delivery kinetics and its relationship to clinical parameters and outcomes following HSCT in 29 adult patients. Oral neutrophil counts were compared to circulating neutrophil levels, oral mucositis scores and patient health status at 6 months post-HSCT. RESULTS: Neutrophils were detected on average 8.4 ± 3.4 SD days earlier in the oral tissues than in the blood circulation, enabling us to confirm successful engraftment more than one week earlier than when using blood neutrophil counts alone. As well, in this population the time-span between oral engraftment (OE) and blood engraftment (BE) was a consistent predictor of treatment outcome at 6 months following HSCT where a BE-OE of <6 days resulted in 100% of patients having a negative outcome. CONCLUSION: We conclude that monitoring the timing of neutrophil delivery to the oral tissues with a non-invasive oral rinse has the potential to allow the physician to identify those patients who are at a high risk of HSCT failure within just a few weeks of the initiation of treatment.
Assuntos
Medula Óssea/patologia , Citodiagnóstico/métodos , Transplante de Células-Tronco Hematopoéticas/métodos , Mucosa Bucal/patologia , Antissépticos Bucais/administração & dosagem , Adulto , Seguimentos , Sobrevivência de Enxerto , Nível de Saúde , Humanos , Leucemia/cirurgia , Contagem de Leucócitos , Linfoma/cirurgia , Síndromes Mielodisplásicas/cirurgia , Recidiva Local de Neoplasia/patologia , Neutrófilos/patologia , Prognóstico , Indução de Remissão , Estomatite/classificação , Estomatite/patologia , Taxa de Sobrevida , Resultado do TratamentoRESUMO
The recommended starting dose of bosutinib is 500â¯mg/day for chronic-phase (CP) or accelerated-/blast-phase Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) resistant/intolerant to prior therapy. However, some patients may require dose reductions to manage the occurrences of adverse events (AEs). Bosutinib efficacy and safety were evaluated following dose reductions in a phase I/II study of Ph+ patients with CP CML resistant/intolerant to imatinib or imatinib plus dasatinib and/or nilotinib, and those with accelerated-/blast-phase CML or acute lymphoblastic leukemia after at least imatinib treatment. In all, 570 patients with ≥4 years' follow-up were included in this analysis. Among 144 patients who dose-reduced to bosutinib 400â¯mg/day (without reduction to 300â¯mg/day), 22 (15 %) had complete cytogenetic response (CCyR) before and after reduction, 40 (28 %) initially achieved CCyR after reduction, and 4 (3 %) only had CCyR before reduction. Among 95 patients who dose-reduced to bosutinib 300â¯mg/day, 23 (24 %) had CCyR before and after reduction, 13 (14 %) initially achieved CCyR after reduction, and 3 (3 %) only had CCyR before reduction. Results were similar to matched controls who remained on 500â¯mg/day, indicating dose reductions had not substantially affected efficacy. The incidence of treatment-emergent AEs was lower after dose reductions, particularly for gastrointestinal events. The incidence of hematologic toxicities generally was similar before and after dose reduction. The management of AEs with bosutinib through dose reduction can lead to improved/maintained efficacy and better tolerability; still, approximately half of patients on treatment at year 4 maintained a dose of ≥500â¯mg/day. ClinicalTrials.gov: NCT00261846.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Redução da Medicação/métodos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Compostos de Anilina/administração & dosagem , Dasatinibe/administração & dosagem , Feminino , Seguimentos , Humanos , Mesilato de Imatinib/administração & dosagem , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Pessoa de Meia-Idade , Nitrilas/administração & dosagem , Cromossomo Filadélfia , Prognóstico , Pirimidinas/administração & dosagem , Quinolinas/administração & dosagem , Estudos Retrospectivos , Adulto JovemRESUMO
CONTEXT: Hematopoietic stem cell transplantation (HSCT) requires significant infrastructure. Little is known about HSCT use and the factors associated with it on a global level. OBJECTIVES: To determine current use of HSCT to assess differences in its application and to explore associations of macroeconomic factors with transplant rates on a global level. DESIGN, SETTING, AND PATIENTS: Retrospective survey study of patients receiving allogeneic and autologous HSCTs for 2006 collected by 1327 centers in 71 participating countries of the Worldwide Network for Blood and Marrow Transplantation. The regional areas used herein are (1) the Americas (the corresponding World Health Organization regions are North and South America); (2) Asia (Southeast Asia and the Western Pacific Region, which includes Australia and New Zealand); (3) Europe (includes Turkey and Israel); and (4) the Eastern Mediterranean and Africa. MAIN OUTCOME MEASURES: Transplant rates (number of HSCTs per 10 million inhabitants) by indication, donor type, and country; description of main differences in HSCT use; and macroeconomic factors of reporting countries associated with HSCT rates. RESULTS: There were 50 417 first HSCTs; 21 516 allogeneic (43%) and 28 901 autologous (57%). The median HSCT rates varied between regions and countries from 48.5 (range, 2.5-505.4) in the Americas, 184 (range, 0.6-488.5) in Asia, 268.9 (range, 5.7-792.1) in Europe, and 47.7 (range, 2.8-95.3) in the Eastern Mediterranean and Africa. No HSCTs were performed in countries with less than 300,000 inhabitants, smaller than 960 km(2), or having less than US $680 gross national income per capita. Use of allogeneic or autologous HSCT, unrelated or family donors for allogeneic HSCT, and proportions of disease indications varied significantly between countries and regions. In linear regression analyses, government health care expenditures (r(2) = 77.33), HSCT team density (indicates the number of transplant teams per 1 million inhabitants; r(2) = 76.28), human development index (r(2) = 74.36), and gross national income per capita (r(2) = 74.04) showed the highest associations with HSCT rates. CONCLUSION: Hematopoietic stem cell transplantation is used for a broad spectrum of indications worldwide, but most frequently in countries with higher gross national incomes, higher governmental health care expenditures, and higher team densities.
Assuntos
Transplante de Células-Tronco Hematopoéticas/estatística & dados numéricos , Coleta de Dados , Países em Desenvolvimento , Economia/estatística & dados numéricos , Gastos em Saúde/estatística & dados numéricos , Transplante de Células-Tronco Hematopoéticas/economia , Humanos , Renda , Estudos Retrospectivos , Transplante Autólogo , Transplante HomólogoRESUMO
PURPOSE: The risk of developing head and neck squamous cell carcinoma (HNSCC) in patients with graft versus host disease (GVHD) after bone marrow transplant (BMT) is well established but large series reporting outcomes are sparse. METHODS: Retrospective, single institution, study of patients with GVHD and HNSCC after BMT, between January 1, 1968, and June 30, 2016. RESULTS: In total, 25 patients were studied, of which 21 (84%) were male and 4 (16%) were female. Mean age for BMT was 41 (18-65) years. All patients developed GVHD, most common site was oral cavity (19 patients, 76%). Mean age for diagnosis of HNSCC was 52 (28-76) years. Mean time between BMT and diagnosis of HNSCC was 12 (2-13) years. The 2-year progression-free survival (PFS) was 61.4%, 5-year PFS was 56.7%. The 2-year overall survival (OS) was 82.8%, 5-year OS was 68.7%. CONCLUSION: HNSCC can develop many years after BMT in patients without the classic risk factors for head and neck cancer. The majority were seen with oral cancer and with early-stage disease likely due to active surveillance and early detection in this patient population.
Assuntos
Transplante de Medula Óssea , Neoplasias de Cabeça e Pescoço , Adulto , Idoso , Transplante de Medula Óssea/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Estudos Retrospectivos , Carcinoma de Células Escamosas de Cabeça e PescoçoRESUMO
Toll-like receptor-9 (TLR9) responsive B cells have previously been associated with the onset of extensive chronic graft-versus-host disease (cGvHD). We hypothesized that the onset of cGvHD associated with a higher level of plasma-free mitochondrial DNA (mtDNA), a putative TLR9 agonist. Plasma cell-free mtDNA levels were measured in 39 adult patients post-HSCT with and without cGvHD. mtDNA was isolated from plasma and quantified by Q-PCR amplification. We correlated B cell responsiveness to CpG-DNA, a prototypical TLR9 agonist, and previously identified cGVHD biomarkers with mtDNA levels. Free plasma mtDNA were elevated in patients post-HSCT without cGvHD compared to normal non-HSCT adults. There was a significantly higher level of free plasma mtDNA associated with the onset of cGvHD (3080 ± 1586 versus 1834 ± 1435 copies/µL; p = 0.02) compared to 6 months post-HSCT controls. Free mtDNA levels post-HSCT correlated with B cell responsiveness to CpG-DNA and known cGvHD biomarkers: CXCL10 (p = 0.003), ICAM-1 (p = 0.007), CXCL9 (p = 0.03), sCD25 (p = 0.05) and sBAFF (p = 0.05), and percentage of CD21low B cells. Plasma levels of free mtDNA are increased in cGvHD and may represent an endogenous inflammatory stimulus for TLR9 expressing B cells.