RESUMO
The emergence of ABL point mutations is the most frequent cause for imatinib resistance in chronic myelogenous leukemia (CML) patients and can occur during any phase of the disease; however, their clinical impact remains controversial. In this study, we retrospectively analyzed the predictive impact of 94 BCR-ABL kinase domain mutations (18 T315I, 26 P-loop, 50 in other sites) found in 89 imatinib-resistant CML patients. At imatinib onset, 64% of patients (57/89) were in chronic phase (CP), 24% (21/89) in accelerated phase (AP) and 12% (11/89) in blastic phase (BP). T315I and P-loop mutations were preferentially discovered in accelerated phase of BP CML, and other types of mutations in CP (P=0.003). With a median follow-up of 39.2 months (6.3-67.2), since imatinib initiation, overall survival (OS) was significantly worse for P-loop (28.3 months) and for T315I (12.6 months), and not reached for other mutations (P=0.0004). For CP only, multivariate analysis demonstrated a worse OS for P-loop mutations (P=0.014), and a worse progression-free survival (PFS) for T315I mutations (P=0.014). Therefore, P-loop and T315I mutations selectively impair the outcome of imatinib-resistant CML patients, in contrast to other mutations, which may benefit from dose escalation of imatinib, able to improve or stabilize disease response.
Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Proteínas de Fusão bcr-abl/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Piperazinas/uso terapêutico , Mutação Puntual , Pirimidinas/uso terapêutico , Adolescente , Adulto , Idoso , Benzamidas , Análise Mutacional de DNA , Relação Dose-Resposta a Droga , Feminino , França , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do TratamentoRESUMO
INTRODUCTION: Hypercalcemia frequently occurs in the course of Adult T-cell leukemia/lymphoma (ATLL). We report the first case of acute pancreatitis revealing ATLL. EXEGESIS: A 41-year-old woman, without medical history, presented with acute pancreatitis. Physical examination found recent loss of weight, hepatosplenomegaly and generalised lymphoadenopathy. Biochemical tests showed severe hypercalcemia and the peripheral white blood cell count revealed an atypical lymphocytosis. ATLL was diagnosed by immunophenotypic and morphological analysis of circulating lymphocytes, bone marrow and lymphatic node biopsy. Level of serum parathyroid hormone-related protein was not increased. We discuss the mechanism of hypercalcemia in this context. CONCLUSION: In spite of the high prevalence of hypercalcemia in ATLL, acute pancreatitis revealing this pathology is an exceptional condition.
Assuntos
Hipercalcemia/complicações , Hipercalcemia/etiologia , Leucemia-Linfoma de Células T do Adulto/complicações , Leucemia-Linfoma de Células T do Adulto/diagnóstico , Pancreatite/etiologia , Doença Aguda , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Humanos , Hipercalcemia/diagnóstico , Hipercalcemia/terapia , Leucemia-Linfoma de Células T do Adulto/tratamento farmacológico , Pancreatite/diagnóstico , Pancreatite/terapia , Indução de RemissãoRESUMO
The outcome of adult patients with Philadelphia chromosome-negative acute lymphoblastic leukemia (Ph- ALL) relapsing after pediatric-inspired front-line therapy is ill known. Here 229 relapsing Ph- ALL younger adults (18-63 years) treated within the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL)-2003/-2005 trials were considered. Salvage regimens consisted of potentially curative therapies in 194 cases, low-intensity therapies in 21, allogeneic stem cell transplant (allo-SCT) in 6 and best supportive care in 8. Overall, 77 patients received allo-SCT after relapse. The median follow-up was 3.1 years. A second complete remission (CR2) was achieved in 121 patients (53%). In multivariate analysis, only younger age <45 years (P=0.008) and CR1 duration ⩾18 months (P=0.009) predicted CR2. Overall survival (OS) at 2 and 5 years was 19.3% (14-24%) and 13.3% (8-18%), respectively. In CR2 patients, disease-free survival (DFS) at 2 and 5 years was 29.0% (21-38%) and 25% (17-33%). In multivariate analysis, CR1 duration ⩾18 months and allo-SCT after relapse were associated with longer DFS (P<0.009 and P=0.004, respectively) and longer OS (P=0.004 and P<0.0001, respectively). In conclusion, although younger adults relapsing after pediatric-inspired ALL therapies retain a poor outcome, some of them may be cured if CR1 duration ⩾18 months and if allo-SCT can be performed in CR2. New therapies are definitely needed for these patients.
Assuntos
Mesilato de Imatinib/administração & dosagem , Leucemia Mieloide Crônica Atípica BCR-ABL Negativa/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Rituximab/administração & dosagem , Adolescente , Adulto , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Leucemia Mieloide Crônica Atípica BCR-ABL Negativa/patologia , Masculino , Pessoa de Meia-Idade , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Indução de Remissão , Transplante Homólogo , Resultado do Tratamento , Adulto JovemAssuntos
Herpesvirus Humano 4/metabolismo , Medula Renal/virologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Fígado/virologia , Transtornos Linfoproliferativos/virologia , Piperazinas/efeitos adversos , Pirimidinas/efeitos adversos , Baço/virologia , Antineoplásicos/efeitos adversos , Benzamidas , Proliferação de Células , Feminino , Humanos , Mesilato de Imatinib , Hibridização in Situ Fluorescente , Transtornos Linfoproliferativos/induzido quimicamente , Transtornos Linfoproliferativos/metabolismo , Pessoa de Meia-Idade , Recidiva , Translocação GenéticaRESUMO
The mTORC1 signaling pathway is constitutively activated in almost all acute myelogenous leukemia (AML) patients. We conducted a phase Ib trial combining RAD001 (everolimus), an allosteric inhibitor of mTORC1, and conventional chemotherapy, in AML patients under 65 years of age at first relapse (clinical trial NCT 01074086). Increasing doses of RAD001 from 10-70 mg were administrated orally on days 1 and 7 (d1 and d7) of a 3+7 daunorubicin+cytarabine conventional induction chemotherapy regimen. Twenty-eight patients were enrolled in this trial. The treatment was well tolerated with <10% toxicity, mainly involving the gastrointestinal tract and lungs. In this phase Ib trial, the RAD001 maximum tolerated dose was not reached at 70 mg. Sixty-eight percent of patients achieved CR, of which 14 received a double induction. Eight subsequently were intensified with allogeneic-stem cell transplant. Strong plasma inhibition of P-p70S6K was observed after RAD001 administration, still detectable at d7 (d7)at the 70 mg dosage. CR rates in patients with RAD001 areas under or above the curve median were 53% versus 85%. A 70 mg dose of RAD001 at d1 and d7 of an induction chemotherapy regimen for AML has acceptable toxicity and may improve treatment.