Higher doses of the anthracycline daunorubicin during induction therapy for acute myeloid leukemia (AML) have been shown to improve remission rates and survival. We hypothesized that improvements in outcomes in adult AML may be further achieved by increased anthracycline dose during consolidation therapy. Patients and MethodsPatients with AML in complete remission after induction therapy were randomly assigned to receive two cycles of consolidation therapy with cytarabine 100 mg/m 2 daily for 5 days, etoposide 75 mg/m 2 daily for 5 days, and idarubicin 9 mg/m 2 daily for either 2 or 3 days (standard and intensive arms, respectively). The primary end point was leukemia-free survival (LFS). ResultsTwo hundred ninety-three patients 16 to 60 years of age, excluding those with core binding factor AML and acute promyelocytic leukemia, were randomly assigned to treatment groups (146 to the standard arm and 147 to the intensive arm). Both groups were balanced for age, karyotypic risk, and FLT3-internal tandem duplication and NPM1 gene mutations. One hundred twenty patients in the standard arm (82%) and 95 patients in the intensive arm (65%) completed planned consolidation (P , .001). Durations of severe neutropenia and thrombocytopenia were prolonged in the intensive arm, but there were no differences in serious nonhematological toxicities. With a median follow-up of 5.3 years (range, 0.6 to 9.9 years), there was a statistically significant improvement in LFS in the intensive arm compared with the standard arm (3-year LFS, 47% [95% CI, 40% to 56%] v 35% [95% CI, 28% to 44%]; P = .045). At 5 years, the overall survival rate was 57% in the intensive arm and 47% in the standard arm (P = .092). There was no evidence of selective benefit of intensive consolidation within the cytogenetic or FLT3-internal tandem duplication and NPM1 gene mutation subgroups. ConclusionAn increased cumulative dose of idarubicin during consolidation therapy for adult AML resulted in improved LFS, without increased nonhematologic toxicity. J Clin Oncol 35:1678-1685. © 2017 by American Society of Clinical Oncology INTRODUCTIONAnthracyclines are one of the major classes of drugs active against acute myeloid leukemia (AML).1 Daunorubicin used at 45 mg/m 2 daily for 3 days is an integral component of the 7 + 3 regimen, which, with various modifications, has been the standard induction regimen for AML for more than three decades.2 Increased daunorubicin dosage from 45 to 50 mg/m 2 to 90 mg/m 2 daily for 3 days during induction therapy for AML has been shown in three studies to improve remission rates and survival in some patient subgroups, although another trial showed no benefit of 90 mg/m 2 compared with 60 mg/m 2 , with the caveat that the lower-dose arm received a median cumulative total of 330 mg/m 2 daunorubicin. [3][4][5][6][7] Another anthracycline widely used for AML induction is idarubicin. Several randomized trials have now been conducted comparing idarubicin 12 mg/m 2 daily for 3 days with daunorubicin 45 to 50 mg/m 2 in the same schedule, ...
Background. Patients with lymphoma who have experienced a first relapse or progression and have disease deemed sensitive to salvage chemotherapy nevertheless have a high likelihood of having a second relapse. To decrease the likelihood of a second relapse after high-dose therapy (HDT) and autologous stem cell transplantation (ASCT), interferon (IFN) ␣-2b was given in a prospective randomized international trial. Methods. In this trial, 221 patients with varying histologic diagnoses (8 small lymphocytic, 37 follicular, 9 mantle, 90 diffuse large B-cell, 20 peripheral T-cell, 3 high-grade B-cell non-Hodgkin lymphoma, and 54 Hodgkin lymphoma) were randomly assigned to receive no further treatment (arm A: 117 patients) or IFN␣-2b, 3 MU three times weekly, for 18 months (arm B: 104 patients). Results. In arm B, 21 patients (20%) did not receive IFN␣-2b because of early progression or absence of hematologic recovery, 29 patients (28%) completed the 18 months of treatment, and 54 patients (52%) interrupted treatment because of progression (23%) or toxicity (29%). Event-free survival and overall survival were not different between the two arms on an intent-to-treat analysis and also if analysis was restricted to patients who were alive and had not experienced disease progression three months after transplantation. The study was not sufficiently powered to evaluate effects in histologic subtypes. Conclusion. In this trial, post-autograft IFN␣-2b did not improve outcomes in a heterogeneous group of patients with lymphoma.
Nonalcoholic fatty liver disease (NAFLD) has been associated with a condition known as the dysmetabolic iron overload syndrome, but the frequency and severity of iron overload in NAFLD is not well described. There is emerging evidence that mild to moderate excess hepatic iron can aggravate the risk of progression of NAFLD to nonalcoholic steatohepatitis and eventually cirrhosis. Mechanisms are postulated to be via reactive oxygen species, inflammatory cytokines, lipid oxidation, and oxidative stress. The aim of this review is to assess the evidence for true hepatic iron overload in NAFLD, to discuss the pathogenesis by which excess iron may be toxic, and to critically evaluate the studies designed to deplete iron by regular venesection. In brief, the studies are inconclusive due to heterogeneity in eligibility criteria, sample size, randomization, hepatic iron measurement, serial histological endpoints, target ferritin levels, length of venesection, and degree of confounding lifestyle intervention. We propose a trial designed to overcome the limitations of these studies.
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