RESUMO
Historically, progress in leukemia research has been slow, but it has accelerated recently as a result of understanding the pathophysiology of leukemias and implementing more effective and targeted therapies. This review summarizes the progress across leukemia subsets and projects the potential cure of most leukemias in the next decade.
Assuntos
Leucemia/classificação , Leucemia/terapia , Antineoplásicos/uso terapêutico , Intervalo Livre de Doença , Humanos , Leucemia/genética , Padrão de Cuidado , Transplante de Células-Tronco , Resultado do TratamentoRESUMO
BACKGROUND: The prognosis is poor for patients who have relapsed-refractory acute myelogenous leukemia (AML). Most published reports analyzed results from therapies in first-salvage AML or in studies that were conducted before 2000. Several novel agents and strategies are being tested for potential approval as treatment for patients with relapsed-refractory AML in second salvage. Therefore, it is important to establish the historic results of anti-AML therapies in this setting in the modern era. The objective of the current study was to analyze the results from second salvage therapies in patients with AML since 2000 with regard to response and survival. METHODS: In total, 673 patients who received second salvage therapies for AML since 2000 were analyzed. Their median age was 60 years (range, 18-89 years). Salvage therapy consisted of cytarabine-based regimens in 267 patients, noncytarabine combinations in 37, hypomethylating agent-based regimens in 136, and phase 1 and 2 single agents in 233. RESULTS: Eighty-six of the 673 patients (13%) achieved a complete response (CR) or a CR with low platelet count (CRp). The median duration of CR-CRp was 7.2 months. The median survival was 4.4 months (95% confidence interval, 4.0-4.8 months), and the 1-year survival rate was 16% (95% confidence interval, 14%-19%). Multivariate analysis identified the following as independent adverse factors for achievement of CR-CRp: platelets < 50 × 109 /L (P < .001), complex karyotype with ≥3 chromosomal abnormalities (P = .02), regimens that did not include cytarabine or hypomethylating agents (P = .014), and no prior CR lasting ≥12 months with frontline or salvage 1 therapies (P < .001). The independent adverse factors associated with worse survival were age ≥60 years (P = .01), platelets < 50 × 109 /L (P = .02), peripheral blasts ≥ 20% (P = .03), albumin ≤ 3 g/dL (P = .04), and complex karyotype (P = .003). The authors also applied and validated, in the current population, the 2 multivariate-derived prognostic models for CR and survival developed in their previous study of 594 patients who received treatment for second salvage AML from the previous 2 decades. CONCLUSIONS: This large-scale analysis establishes the modern historic results of second salvage therapy in AML and validates the prognostic models associated with outcome. These data could be used to analyze the differential benefits of current or future investigational strategies under evaluation in this setting and for the purpose of potential approval of new agents in the United States and the world. Cancer 2018;124:2534-40. © 2018 American Cancer Society.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Indução de Remissão/métodos , Terapia de Salvação/métodos , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Ensaios Clínicos como Assunto , Citarabina/farmacologia , Citarabina/uso terapêutico , Metilação de DNA/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Cariótipo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Prognóstico , Retratamento/métodos , Análise de Sobrevida , Taxa de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
Accurate identification of patients likely to achieve long-progression-free survival (PFS) after chemoimmunotherapy is essential given the availability of less toxic alternatives, such as ibrutinib. Fludarabine, cyclophosphamide, and rituximab (FCR) achieved a high response rate, but continued relapses were seen in initial reports. We reviewed the original 300 patient phase 2 FCR study to identify long-term disease-free survivors. Minimal residual disease (MRD) was assessed posttreatment by a polymerase chain reaction-based ligase chain reaction assay (sensitivity 0.01%). At the median follow-up of 12.8 years, PFS was 30.9% (median PFS, 6.4 years). The 12.8-year PFS was 53.9% for patients with mutated immunoglobulin heavy chain variable (IGHV) gene (IGHV-M) and 8.7% for patients with unmutated IGHV (IGHV-UM). 50.7% of patients with IGHV-M achieved MRD-negativity posttreatment; of these, PFS was 79.8% at 12.8 years. A plateau was seen on the PFS curve in patients with IGHV-M, with no relapses beyond 10.4 years in 42 patients (total follow-up 105.4 patient-years). On multivariable analysis, IGHV-UM (hazard ratio, 3.37 [2.18-5.21]; P < .001) and del(17p) by conventional karyotyping (hazard ratio, 7.96 [1.02-61.92]; P = .048) were significantly associated with inferior PFS. Fifteen patients with IGHV-M had 4-color MRD flow cytometry (sensitivity 0.01%) performed in peripheral blood, at a median of 12.8 years posttreatment (range, 9.5-14.7). All were MRD-negative. The high rate of very long-term PFS in patients with IGHV-M after FCR argues for the continued use of chemoimmunotherapy in this patient subgroup outside clinical trials; alternative strategies may be preferred in patients with IGHV-UM, to limit long-term toxicity.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cadeias Pesadas de Imunoglobulinas/genética , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/genética , Mutação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Causas de Morte , Ciclofosfamida/administração & dosagem , Feminino , Humanos , Incidência , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasia Residual , Segunda Neoplasia Primária/epidemiologia , Segunda Neoplasia Primária/etiologia , Segunda Neoplasia Primária/mortalidade , Prognóstico , Recidiva , Indução de Remissão , Retratamento , Rituximab/administração & dosagem , Análise de Sobrevida , Resultado do Tratamento , Vidarabina/administração & dosagem , Vidarabina/análogos & derivados , Adulto JovemRESUMO
Studies of the leukemias in the laboratory and in the clinic have generated many new concepts and therapies that will undoubtedly continue to be rapidly applied to the other forms of systemic cancer, particularly the concept of narrowly targeted personalized therapy that has proven so effective in CML. It seems likely that other subtypes of leukemia will eventually approach the success achieved with APL, CML, and pediatric ALL.
Assuntos
Antineoplásicos/história , Leucemia/história , Antineoplásicos/uso terapêutico , História do Século XX , História do Século XXI , Humanos , Leucemia/tratamento farmacológico , Editoração/história , Editoração/estatística & dados numéricos , Taxa de Sobrevida , Resultado do TratamentoRESUMO
Allogeneic granulocyte transfusion has evolved into a viable therapeutic option for immunocompromised severely neutropenic leukemic patients and those with hematopoietic stem cell transplant with life-threatening bacterial and fungal infections. The collection of larger cell doses of granulocyte concentrates (GCs) has been facilitated by the stimulation of donors with granulocyte colony stimulating factor (G-CSF) and dexamethasone. The synergistic effect of G-CSF and dexamethasone has allowed the collection of larger cell doses of GCs and its use has increased steadily. This has allowed us to split the high-yield GC products and facilitated distribution of the split GC products to a second or third patient who needs GCs but lacks donors. The main objective of this article was to present our rationale for splitting GC products and how the split GC units were transfused to multiple patients. We believe that split GCs are as equally effective as unsplit GCs and that multiple patients benefit from splitting GCs.
Assuntos
Dexametasona/farmacologia , Fator Estimulador de Colônias de Granulócitos/farmacologia , Granulócitos/efeitos dos fármacos , Leucaférese/métodos , Transfusão de Leucócitos/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Anti-Inflamatórios/farmacologia , Doadores de Sangue/estatística & dados numéricos , Feminino , Granulócitos/citologia , Granulócitos/transplante , Neoplasias Hematológicas/terapia , Humanos , Estimativa de Kaplan-Meier , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemAssuntos
Neoplasias Hematológicas/patologia , Hematologia , Humanos , Oncologia , Sociedades MédicasAssuntos
Antineoplásicos/história , Pesquisa Biomédica/história , Neoplasias/história , Ensaios Clínicos Controlados Aleatórios como Assunto/história , Antineoplásicos/uso terapêutico , Institutos de Câncer/história , Quimioterapia Adjuvante/história , Esquema de Medicação , História do Século XX , História do Século XXI , Doença de Hodgkin/história , Humanos , Quimioterapia de Indução , Leucemia/história , Linfoma não Hodgkin/história , National Cancer Institute (U.S.)/história , Neoplasias/tratamento farmacológico , Estados UnidosRESUMO
We conducted a phase 1 study of an anti-CD33 immunotoxin, humanized monoclonal antibody M195 conjugated to recombinant gelonin (HUM-195/rGEL), in patients with relapsed, refractory myeloid leukemias. Twenty-eight patients received the construct intravenously at four dose levels (12, 18, 28 and 40 mg/m(2) per course) in a "3+3" study design. The dose-limiting toxicity was infusion-related allergic reaction including hypoxia and hypotension. The 28 mg/m(2) total dose was considered the maximally tolerated dose. Four patients developed a reduction in peripheral blood blasts of at least 50%. Three patients treated with the 10, 12 and 28 mg/m(2) doses showed a 38-50% reduction in bone marrow blasts. There was normalization of platelets in one patient treated with 40 mg/m(2). Pharmacokinetic analysis demonstrated that the highest blood levels achieved were 200-300 ng/mL which cleared with a half-life of â¼20 hours. Antigenicity was low with one patient at the 12 mg/m(2) dose and one patient at the 18 mg/m(2) dose (2/23, <10%) developing antibodies to the recombinant gelonin component after 28 days. We concluded that HUM-195/rGel can be safely administered in a multi-dose cycle to patients with advanced myeloid malignancies and warrants further investigation.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Imunotoxinas/uso terapêutico , Leucemia Mieloide/tratamento farmacológico , Leucemia Mieloide/patologia , Proteínas Inativadoras de Ribossomos Tipo 1/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacologia , Antineoplásicos/farmacologia , Feminino , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Imunotoxinas/imunologia , Imunotoxinas/farmacologia , Leucemia Mieloide/imunologia , Masculino , Pessoa de Meia-Idade , Proteínas Inativadoras de Ribossomos Tipo 1/imunologia , Proteínas Inativadoras de Ribossomos Tipo 1/farmacologia , Resultado do TratamentoRESUMO
The advances in leukemia therapy which occurred during one professional lifetime of the author is described, and forms the basis for projecting the probable progress which will occur in a subsequent professional lifetime. These advances in leukemia therapy have rapidly found application to 'solid tumors,' suggesting that the road to cancer control will be led by discoveries made in leukemia biology, treatment, and prevention.
Assuntos
Leucemia/história , Leucemia/terapia , Oncologia/história , Criança , História do Século XIX , História do Século XX , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/história , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapiaRESUMO
Arsenic trioxide (ATO) is an inorganic arsenic derivative that is very effective against acute promyelocytic leukemia. However, organic arsenic derivatives (OAD) have a more favorable toxicity profile than ATO. We herein characterized dipropil-S-glycerol arsenic (GMZ27), a novel OAD. GMZ27 had potent antiproliferative activity against human acute myeloid leukemia (AML) cell lines that was higher than that of ATO. In contrast to ATO, GMZ27 only marginally induced maturation of leukemia cells and had no effect on the cell cycle. The anti-leukemia activity of GMZ27 against AML cells was independent of the presence of the PML-RARα fusion protein. GMZ27 dissipates mitochondrial transmembrane potential, and induces cleavage of caspase 9 and activation of caspase 3 without altering the expression levels of (BCL-2), BAX and BCL-xl. GMZ27 induces the formation of intracellular superoxide, a reactive oxygen species (ROS) which plays a major role in the antileukemia activity of this OAD. In addition to ROS generation, GMZ27 concomitantly reduces intracellular glutathione which markedly weakens the cellular antioxidant capacity, thus enhancing the detrimental intracellular effects of ROS production. These results indicate that GMZ27 induces apoptosis in AML cells in a PML-RARα-independent fashion, through the induction of ROS production. This activity provides the rationale for the testing of GMZ27 in patients with AML.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Arsenicais/farmacologia , Leucemia Mielomonocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/tratamento farmacológico , Proteínas de Fusão Oncogênica/biossíntese , Animais , Apoptose/fisiologia , Trióxido de Arsênio , Caspase 9/metabolismo , Ciclo Celular/efeitos dos fármacos , Processos de Crescimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Ativação Enzimática/efeitos dos fármacos , Feminino , Células HL-60 , Humanos , Leucemia Mielomonocítica Aguda/metabolismo , Leucemia Mielomonocítica Aguda/patologia , Leucemia Promielocítica Aguda/metabolismo , Leucemia Promielocítica Aguda/patologia , Camundongos , Óxidos/farmacologia , Oxigênio/metabolismoRESUMO
BACKGROUND: Activating mutations in RAS are frequently present in patients with acute myeloid leukemia (AML), but their overall prognostic impact is not clear. METHODS: A retrospective analysis was performed to establish the clinical characteristics of patients with RAS-mutated (RAS(mut) ) AML, to analyze their outcome by therapy, and to describe the proteomic profile of RAS(mut) compared with wild-type RAS (RAS(WT) ) AML. RESULTS: Of 609 patients with newly diagnosed AML, 11% had RAS(mut) . Compared with RAS(WT) , patients with RAS(mut) AML were younger (median age, 54 years vs 63 years; P = .001), had a higher white blood cell count (16K mm(-3) vs 4K mm(-3) ; P < 0.001) and bone marrow blast percentage (56% vs 42%; P = .01) at diagnosis, and were less likely to have an antecedent hematologic disorder (36% vs 50%; P = .03). The inv(16) karyotype was overrepresented in patients with RAS(mut) and the -5 and/or -7 karyotype was underrepresented. RAS mutations were found to have no prognostic impact on overall survival or disease-free survival overall or within cytogenetic subgroups. There was a suggestion that patients with RAS(mut) benefited from cytarabine (AraC)-based therapy. Proteomic analysis revealed simultaneous upregulation of the RAS-Raf-MAP kinase and phosphoinositide 3-kinase (PI3K) signaling pathways in patients with RAS(mut) . CONCLUSIONS: RAS mutations in AML may delineate a subset of patients who benefit from AraC-based therapy and who may be amenable to treatment with inhibitors of RAS and PI3K signaling pathways.
Assuntos
Citarabina/uso terapêutico , Genes ras , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Mutação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Intervalo Livre de Doença , Feminino , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/metabolismo , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteômica , Indução de Remissão , Estudos Retrospectivos , Transdução de Sinais , Adulto Jovem , Proteínas ras/metabolismoRESUMO
BACKGROUND: This article gives the status of clinical cancer research in the 1950's-1960's and tells the story of the development and conduct of the 6-mercaptopurine (6-MP) versus placebo clinical trial in acute leukemia through the initiation, design, conduct and analysis stages, with emphasis on the ethical aspects of randomizing patients to 6-MP or placebo when in remission. PURPOSE: The specific objective was to compare the lengths of remission for patients receiving 6-MP or placebo after achieving complete or partial remission from steroid treatment. METHODS: A randomized, double-blind, placebo controlled sequential study was conducted in which patients were paired by remission status at each of the eleven institutions participating in the study, and randomized to 6-MP or placebo within each pair of patients. A preference for 6-MP or placebo was recorded depending on which patient in the pair had the longer remission. The preferences were plotted according to a restricted sequential procedure devised by Peter Armitage and, depending on which boundary of the design was crossed, a statistically significant difference could be declared favoring 6-MP, placebo or no preference. CONCLUSIONS: The trial established the efficacy of 6-MP for maintaining longer remissions in acute leukemia and led to the concept of 'adjuvant chemotherapy', namely that patients with minimal disease have a substantially better response to chemotherapy than patients with advanced disease, a concept that has been followed in many other forms of cancer. Statistically, the fact that many patients were still in remission when the study was stopped (i.e. the length of remission data for these patients was 'right censored') led to the development of a generalized Wilcoxon test and was an important influence on Cox's development of the proportional hazards model. The trial had an innovative design in the early 1960's and has been an important influence on subsequent clinical research in cancer and statistical research in survival analysis.
Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Mercaptopurina/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Antimetabólitos Antineoplásicos/metabolismo , Método Duplo-Cego , Humanos , Mercaptopurina/metabolismo , Avaliação de Resultados em Cuidados de Saúde , Placebos , Modelos de Riscos Proporcionais , Indução de RemissãoRESUMO
The treatment of anemia and thrombocytopenia with allogeneic cell transfusions is an effective and well-developed technology. However, leukocyte replacement transfusion has been frustrated by the physiology of the leukocytes. To achieve effective leukocyte replacement, the continuous-flow centrifugal blood cell separator was developed, and it soon proved to be an important instrument for separation, collection, and transfusion of all the components of the blood. Thus, the continuous-flow centrifugal blood cell separator has become an important instrument in the science of blood collection and transfusion.
Assuntos
Separação Celular/instrumentação , Transfusão de Leucócitos/história , Transferência Adotiva/métodos , Separação Celular/história , Tamanho Celular , Centrifugação/história , Centrifugação/instrumentação , Desenho de Equipamento , Etiocolanolona/uso terapêutico , Granulócitos/transplante , Granulócitos/ultraestrutura , Mobilização de Células-Tronco Hematopoéticas , História do Século XX , Humanos , Derivados de Hidroxietil Amido/uso terapêutico , Hospedeiro Imunocomprometido , Infecções/terapia , Leucemia Mielogênica Crônica BCR-ABL Positiva/sangue , Leucemia Mielogênica Crônica BCR-ABL Positiva/imunologia , Transfusão de Leucócitos/instrumentação , Transfusão de Leucócitos/métodos , Linfócitos/ultraestrutura , Maryland , Substitutos do Plasma/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Reologia , TexasRESUMO
Peripheral blood stem cell transplantation (PBSCT) is the most common transplantation procedure performed in medicine. Its clinical introduction in 1986 replaced BM as a stem-cell source to approximately 100% in the autologous and to approximately 75% in the allogeneic transplantation setting. This historical overview provides a brief insight into the discovery of circulating hematopoietic stem cells in the early 1960s, the development of apheresis technology, the discovery of hematopoietic growth factors and small molecule CXCR4 antagonist for stem- cell mobilization, and in vivo experimental transplantation studies that eventually led to clinical PBSCT. Also mentioned are the controversies surrounding the engraftment potential of circulating stem cells before acceptance as a clinical modality. Clinical trials comparing the outcome of PBSCT with BM transplantation, registry data analyses, and the role of the National Marrow Donor Program (NMDP) in promoting unrelated blood stem-cell donation are addressed.
Assuntos
Transplante de Células-Tronco de Sangue Periférico/métodos , Transplante de Células-Tronco de Sangue Periférico/tendências , Animais , Remoção de Componentes Sanguíneos/métodos , Fatores de Crescimento de Células Hematopoéticas/fisiologia , Mobilização de Células-Tronco Hematopoéticas/métodos , Humanos , Modelos Biológicos , Células-Tronco/citologia , Células-Tronco/fisiologia , Fatores de Tempo , Falha de TratamentoRESUMO
We previously identified LDOC1 as one of the most significantly differentially expressed genes in untreated chronic lymphocytic leukemia (CLL) patients with respect to the somatic mutation status of the immunoglobulin heavy-chain variable region genes. However, little is known about the normal function of LDOC1, its contribution to the pathophysiology of CLL, or its prognostic significance. In this study, we have investigated LDOC1 mRNA expression in a large cohort of untreated CLL patients, as well as in normal peripheral blood B-cell (NBC) subsets and primary B-cell lymphoma samples. We have confirmed that LDOC1 is dramatically down-regulated in mutated CLL cases compared with unmutated cases, and have identified a new splice variant, LDOC1S. We show that LDOC1 is expressed in NBC subsets (naive > memory), suggesting that it may play a role in normal B-cell development. It is also expressed in primary B-cell lymphoma samples, in which its expression is associated with somatic mutation status. In CLL, we show that high levels of LDOC1 correlate with biomarkers of poor prognosis, including cytogenetic markers, unmutated somatic mutation status, and ZAP70 expression. Finally, we demonstrate that LDOC1 mRNA expression is an excellent predictor of overall survival in untreated CLL patients.