RESUMO
Traditional response criteria in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are based on bone marrow morphology and may not accurately reflect clonal tumor burden in patients treated with non-cytotoxic chemotherapy. We used next-generation sequencing of serial bone marrow samples to monitor MDS and AML tumor burden during treatment with epigenetic therapy (decitabine and panobinostat). Serial bone marrow samples (and skin as a source of normal DNA) from 25 MDS and AML patients were sequenced (exome or 285 gene panel). We observed that responders, including those in complete remission (CR), can have persistent measurable tumor burden (that is, mutations) for at least 1 year without disease progression. Using an ultrasensitive sequencing approach, we detected extremely rare mutations (equivalent to 1 heterozygous mutant cell in 2000 non-mutant cells) months to years before their expansion at disease relapse. While patients can live with persistent clonal hematopoiesis in a CR or stable disease, ultimately we find evidence that expansion of a rare subclone occurs at relapse or progression. Here we demonstrate that sequencing of serial samples provides an alternative measure of tumor burden in MDS or AML patients and augments traditional response criteria that rely on bone marrow blast percentage.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Evolução Clonal/genética , Epigênese Genética/efeitos dos fármacos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/genética , Idoso , Idoso de 80 Anos ou mais , Medula Óssea/patologia , Exoma , Feminino , Genes p53 , Sequenciamento de Nucleotídeos em Larga Escala , Inibidores de Histona Desacetilases/administração & dosagem , Humanos , Leucemia Mieloide Aguda/diagnóstico , Masculino , Pessoa de Meia-Idade , Mutação , Síndromes Mielodisplásicas/diagnóstico , Polimorfismo de Nucleotídeo Único , Indução de Remissão , Resultado do Tratamento , Carga TumoralAssuntos
Histocompatibilidade , Transplante de Células-Tronco de Sangue Periférico/métodos , Transplante Haploidêntico/métodos , Adulto , Idoso , Feminino , Antígenos HLA/análise , Humanos , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Transplante de Células-Tronco de Sangue Periférico/mortalidade , Estudos Retrospectivos , Análise de Sobrevida , Linfócitos T , Transplante Haploidêntico/mortalidade , Adulto JovemRESUMO
Allogeneic stem cell transplantation (allo-SCT) outcomes in patients with Hodgkin lymphoma (HL) remain poorly defined. We performed a meta-analysis of allo-SCT studies in HL patients. The primary endpoints were 6-month, 1-year, 2-year and 3-year relapse-free survival (RFS) and overall survival (OS). A total of 42 reports (1850 patients) was included. The pooled estimates (95% confidence interval) for 6-month, 1-year, 2-year and 3-year RFS were 77 (59-91)%, 50 (42-57)%, 37 (31-43)% and 31 (25-37)%, respectively. The corresponding numbers for OS were 83 (75-91)%, 68 (62-74)%, 58 (52-64)% and 50 (41-58)%, respectively. There was statistical heterogeneity among studies in all outcomes. In meta-regression, accrual initiation year in 2000 or later was associated with higher 6-month (P=0.012) and 1-year OS (P=0.046), and pre-SCT remission with higher 2-year OS (P=0.047) and 1-year RFS (P=0.016). In conclusion, outcomes of allo-SCT in HL have improved over time, with 5-10% lower non-relapse mortality and relapse rates, and 15-20% higher RFS and OS in studies that initiated accrual in 2000 or later compared with earlier studies. However, there is no apparent survival plateau, demonstrating the need to improve on current allo-SCT strategies in relapsed/refractory HL.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Doença de Hodgkin/mortalidade , Doença de Hodgkin/terapia , Aloenxertos , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Fatores de Risco , Taxa de SobrevidaAssuntos
Doença Enxerto-Hospedeiro/diagnóstico por imagem , Neoplasias Hematológicas , Pelve/diagnóstico por imagem , Transplante de Células-Tronco , Tomografia Computadorizada por Raios X , Doença Aguda , Adulto , Aloenxertos , Feminino , Doença Enxerto-Hospedeiro/etiologia , Neoplasias Hematológicas/diagnóstico por imagem , Neoplasias Hematológicas/terapia , Humanos , Masculino , Pessoa de Meia-IdadeAssuntos
Transplante de Células-Tronco Hematopoéticas , Neoplasias Hepáticas/cirurgia , Linfoma de Células T/cirurgia , Neoplasias Esplênicas/cirurgia , Adolescente , Adulto , Idoso , Aloenxertos , Criança , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Hepáticas/mortalidade , Linfoma de Células T/mortalidade , Masculino , Pessoa de Meia-Idade , Neoplasias Esplênicas/mortalidade , Resultado do Tratamento , Adulto JovemRESUMO
High-dose melphalan has been the standard conditioning regimen for auto-SCT in multiple myeloma (MM) for decades. A more effective conditioning regimen may induce deeper responses and longer remission duration. It is especially needed in the setting of second auto-SCT, which rarely achieves comparable results with the first auto-SCT using the same conditioning regimen. Here we conducted a phase II study to investigate the efficacy and safety of a conditioning regimen V-BEAM (bortezomib-BEAM) before second auto-SCT for multiple myeloma. Ten patients were enrolled from September 2012 to May 2013. The CR rate at day +100 after auto-SCT was 75%; all except for one patient remained in remission after a median follow-up of 6 months. Three patients developed Clostridium difficile infection. Two patients died within the first 30 days of auto-SCT from neutropenic colitis and overwhelming sepsis, respectively. Due to the high rate of morbidity and mortality, the study was terminated after 10 patients. In summary, although the conditioning regimen V-BEAM before second auto-SCT for MM provided promising responses, it was associated with unexpected treatment-related toxicity and should not be investigated further without modifications.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Ácidos Borônicos , Mieloma Múltiplo , Pirazinas , Transplante de Células-Tronco , Condicionamento Pré-Transplante , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Autoenxertos , Ácidos Borônicos/administração & dosagem , Ácidos Borônicos/efeitos adversos , Bortezomib , Carmustina/administração & dosagem , Carmustina/efeitos adversos , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Feminino , Seguimentos , Humanos , Masculino , Melfalan/administração & dosagem , Melfalan/efeitos adversos , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/terapia , Podofilotoxina/administração & dosagem , Podofilotoxina/efeitos adversos , Pirazinas/administração & dosagem , Pirazinas/efeitos adversos , Condicionamento Pré-Transplante/efeitos adversos , Condicionamento Pré-Transplante/métodosAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Azacitidina/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Humanos , Lenalidomida , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Indução de Remissão , Talidomida/administração & dosagem , Talidomida/análogos & derivados , Adulto JovemRESUMO
BACKGROUND: Cytomegalovirus (CMV) infection is an important cause of morbidity and mortality after allogeneic hematopoietic stem cell transplant (HSCT). This pilot prospective randomized clinical trial compares valganciclovir (VGV) to ganciclovir (GCV) as pre-emptive therapy for CMV viremia in the post-allogeneic HSCT population. METHODS: Patients undergoing allogeneic HSCT who were at risk for CMV viremia were monitored post HSCT by weekly quantitative whole blood polymerase chain reaction. Pre-emptive therapy was delayed until the viral load (VL) was >10,000 copies/mL once, or >5000 copies/mL twice. Patients were randomized to either GCV 5 mg/kg twice a day (b.i.d.) for 7 days followed by daily GCV 5 mg/kg for up to 21 days, or VGV 900 mg b.i.d. for 7 days followed by 900 mg daily for up to 21 days. The primary endpoint was clearance of viremia (VL <5000 copies/mL) within 28 days of initiation of therapy. RESULT: In total, 37 patients were enrolled; 19 patients received treatment with VGV and 18 patients received treatment with GCV. The VGV was not inferior in efficacy to GCV as pre-emptive therapy, with rates of viral clearance at 28 days of 89.5% and 83%, respectively (P-value for non-inferiority = 0.030). Toxicities were similar between the 2 arms. No patients developed CMV disease. CONCLUSIONS: In this trial, the rates of clearance of viremia appear to be similar with VGV and GCV.
Assuntos
Antivirais/uso terapêutico , Infecções por Citomegalovirus/prevenção & controle , Ganciclovir/análogos & derivados , Ganciclovir/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Viremia/prevenção & controle , Administração Oral , Adolescente , Adulto , Antivirais/administração & dosagem , Citomegalovirus/efeitos dos fármacos , Infecções por Citomegalovirus/virologia , Relação Dose-Resposta a Droga , Feminino , Ganciclovir/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Reação em Cadeia da Polimerase , Estudos Prospectivos , Transplante Homólogo , Valganciclovir , Carga Viral/efeitos dos fármacos , Viremia/virologia , Adulto JovemRESUMO
Currently, granulocyte colony stimulating factor (G-CSF) remains the standard mobilizing agent for peripheral blood stem cell (PBSC) donors, allowing the safe collection of adequate PBSCs from the vast majority of donors. However, G-CSF mobilization can be associated with some significant side effects and requires a multi-day dosing regimen. The other cytokine approved for stem cell mobilization, granulocyte-macrophage colony stimulating factor (GM-CSF), alters graft composition and may reduce the development of graft-versus-host disease, but a significant minority of donors fails to provide sufficient CD34+ cells with GM-CSF and some experience unacceptable toxicity. AMD3100 is a promising new mobilizing agent, which may have several advantages over G-CSF for donor mobilization. As it is a direct antagonist of the interaction between the chemokine stromal-derived factor-1 and its receptor CXCR4, AMD3100 mobilizes PBSCs within hours rather than days. It is also well tolerated, with no significant side effects reported in any of the clinical trials to date. Studies of autologous and allogeneic transplantation of AMD3100 mobilized grafts have demonstrated prompt and stable engraftment. Here, we review the current state of stem cell mobilization in normal donors and discuss novel strategies for donor stem cell mobilization.