Cytarabine plays a pivotal role in the treatment of patients with acute myeloid leukemia (AML). Most centers use 7 to 10 days of cytarabine at a daily dose of 100 to 200 mg/m(2) for remission ...induction. Consensus has not been reached on the benefit of higher dosages of cytarabine.
The European Organisation for Research and Treatment of Cancer (EORTC) and Gruppo Italiano Malattie Ematologiche dell' Adulto (GIMEMA) Leukemia Groups conducted a randomized trial (AML-12; Combination Chemotherapy, Stem Cell Transplant and Interleukin-2 in Treating Patients With Acute Myeloid Leukemia) in 1,942 newly diagnosed patients with AML, age 15 to 60 years, comparing remission induction treatment containing daunorubicin, etoposide, and either standard-dose (SD) cytarabine (100 mg/m(2) per day by continuous infusion for 10 days) or high-dose (HD) cytarabine (3,000 mg/m(2) every 12 hours by 3-hour infusion on days 1, 3, 5, and 7). Patients in complete remission (CR) received a single consolidation cycle containing daunorubicin and intermediate-dose cytarabine (500 mg/m(2) every 12 hours for 6 days). Subsequently, a stem-cell transplantation was planned. The primary end point was survival.
At a median follow-up of 6 years, overall survival was 38.7% for patients randomly assigned to SD cytarabine and 42.5% for those randomly assigned to HD cytarabine (log-rank test P = .06; multivariable analysis P = .009). For patients younger than age 46 years, survival was 43.3% and 51.9%, respectively (P = .009; multivariable analysis P = .003), and for patients age 46 to 60 years, survival was 33.9% and 32.9%, respectively (P = .91). CR rates were 72.0% and 78.7%, respectively (P < .001) and were 75.6% and 82.4% for patients younger than age 46 years (P = .01) and 68.3% and 74.8% for patients age 46 years and older (P = .03). Patients of all ages with very-bad-risk cytogenetic abnormalities and/or FLT3-ITD (internal tandem duplication) mutation, or with secondary AML benefitted from HD cytarabine.
HD cytarabine produces higher remission and survival rates than SD cytarabine, especially in patients younger than age 46 years.
Although induction chemotherapy results in remission in many older patients with acute myeloid leukemia (AML), relapse is common and overall survival is poor.
We conducted a phase 3, randomized, ...double-blind, placebo-controlled trial of the oral formulation of azacitidine (CC-486, a hypomethylating agent that is not bioequivalent to injectable azacitidine), as maintenance therapy in patients with AML who were in first remission after intensive chemotherapy. Patients who were 55 years of age or older, were in complete remission with or without complete blood count recovery, and were not candidates for hematopoietic stem-cell transplantation were randomly assigned to receive CC-486 (300 mg) or placebo once daily for 14 days per 28-day cycle. The primary end point was overall survival. Secondary end points included relapse-free survival and health-related quality of life.
A total of 472 patients underwent randomization; 238 were assigned to the CC-486 group and 234 were assigned to the placebo group. The median age was 68 years (range, 55 to 86). Median overall survival from the time of randomization was significantly longer with CC-486 than with placebo (24.7 months and 14.8 months, respectively; P<0.001). Median relapse-free survival was also significantly longer with CC-486 than with placebo (10.2 months and 4.8 months, respectively; P<0.001). Benefits of CC-486 with respect to overall and relapse-free survival were shown in most subgroups defined according to baseline characteristics. The most common adverse events in both groups were grade 1 or 2 gastrointestinal events. Common grade 3 or 4 adverse events were neutropenia (in 41% of patients in the CC-486 group and 24% of patients in the placebo group) and thrombocytopenia (in 22% and 21%, respectively). Overall health-related quality of life was preserved during CC-486 treatment.
CC-486 maintenance therapy was associated with significantly longer overall and relapse-free survival than placebo among older patients with AML who were in remission after chemotherapy. Side effects were mainly gastrointestinal symptoms and neutropenia. Quality-of-life measures were maintained throughout treatment. (Supported by Celgene; QUAZAR AML-001 ClinicalTrials.gov number, NCT01757535.).
Summary Background Isavuconazole is a novel triazole with broad-spectrum antifungal activity. The SECURE trial assessed efficacy and safety of isavuconazole versus voriconazole in patients with ...invasive mould disease. Methods This was a phase 3, double-blind, global multicentre, comparative-group study. Patients with suspected invasive mould disease were randomised in a 1:1 ratio using an interactive voice–web response system, stratified by geographical region, allogeneic haemopoietic stem cell transplantation, and active malignant disease at baseline, to receive isavuconazonium sulfate 372 mg (prodrug; equivalent to 200 mg isavuconazole; intravenously three times a day on days 1 and 2, then either intravenously or orally once daily) or voriconazole (6 mg/kg intravenously twice daily on day 1, 4 mg/kg intravenously twice daily on day 2, then intravenously 4 mg/kg twice daily or orally 200 mg twice daily from day 3 onwards). We tested non-inferiority of the primary efficacy endpoint of all-cause mortality from first dose of study drug to day 42 in patients who received at least one dose of the study drug (intention-to-treat ITT population) using a 10% non-inferiority margin. Safety was assessed in patients who received the first dose of study drug. This study is registered with ClinicalTrials.gov , number NCT00412893. Findings 527 adult patients were randomly assigned (258 received study medication per group) between March 7, 2007, and March 28, 2013. All-cause mortality from first dose of study drug to day 42 for the ITT population was 19% with isavuconazole (48 patients) and 20% with voriconazole (52 patients), with an adjusted treatment difference of −1·0% (95% CI −7·8 to 5·7). Because the upper bound of the 95% CI (5·7%) did not exceed 10%, non-inferiority was shown. Most patients (247 96% receiving isavuconazole and 255 98% receiving voriconazole) had treatment-emergent adverse events (p=0·122); the most common were gastrointestinal disorders (174 68% vs 180 69%) and infections and infestations (152 59% vs 158 61%). Proportions of patients with treatment-emergent adverse events by system organ class were similar overall. However, isavuconazole-treated patients had a lower frequency of hepatobiliary disorders (23 9% vs 42 16%; p=0·016), eye disorders (39 15% vs 69 27%; p=0·002), and skin or subcutaneous tissue disorders (86 33% vs 110 42%; p=0·037). Drug-related adverse events were reported in 109 (42%) patients receiving isavuconazole and 155 (60%) receiving voriconazole (p<0·001). Interpretation Isavuconazole was non-inferior to voriconazole for the primary treatment of suspected invasive mould disease. Isavuconazole was well tolerated compared with voriconazole, with fewer study-drug-related adverse events. Our results support the use of isavuconazole for the primary treatment of patients with invasive mould disease. Funding Astellas Pharma Global Development, Basilea Pharmaceutica International.
Within the myelodysplastic syndrome (MDS) work package of the European LeukemiaNet, an Expert Panel was selected according to the framework elements of the National Institutes of Health Consensus ...Development Program. A systematic review of the literature was performed that included indexed original papers, indexed reviews and educational papers, and abstracts of conference proceedings. Guidelines were developed on the basis of a list of patient- and therapy-oriented questions, and recommendations were formulated and ranked according to the supporting level of evidence. MDSs should be classified according to the 2008 World Health Organization criteria. An accurate risk assessment requires the evaluation of not only disease-related factors but also of those related to extrahematologic comorbidity. The assessment of individual risk enables the identification of fit patients with a poor prognosis who are candidates for up-front intensive treatments, primarily allogeneic stem cell transplantation. A high proportion of MDS patients are not eligible for potentially curative treatment because of advanced age and/or clinically relevant comorbidities and poor performance status. In these patients, the therapeutic intervention is aimed at preventing cytopenia-related morbidity and preserving quality of life. A number of new agents are being developed for which the available evidence is not sufficient to recommend routine use. The inclusion of patients into prospective clinical trials is strongly recommended.
To compare low-dose decitabine to best supportive care (BSC) in higher-risk patients with myelodysplastic syndrome (MDS) age 60 years or older and ineligible for intensive chemotherapy.
Two-hundred ...thirty-three patients (median age, 70 years; range, 60 to 90 years) were enrolled; 53% had poor-risk cytogenetics, and the median MDS duration at random assignment was 3 months. Primary end point was overall survival (OS). Decitabine (15 mg/m(2)) was given intravenously over 4 hours three times a day for 3 days in 6-week cycles.
OS prolongation with decitabine versus BSC was not statistically significant (median OS, 10.1 v 8.5 months, respectively; hazard ratio HR, 0.88; 95% CI, 0.66 to 1.17; two-sided, log-rank P = .38). Progression-free survival (PFS), but not acute myeloid leukemia (AML) -free survival (AMLFS), was significantly prolonged with decitabine versus BSC (median PFS, 6.6 v 3.0 months, respectively; HR, 0.68; 95% CI, 0.52 to 0.88; P = .004; median AMLFS, 8.8 v 6.1 months, respectively; HR, 0.85; 95% CI, 0.64 to 1.12; P = .24). AML transformation was significantly (P = .036) reduced at 1 year (from 33% with BSC to 22% with decitabine). Multivariate analyses indicated that patients with short MDS duration had worse outcomes. Best responses with decitabine versus BSC, respectively, were as follows: complete response (13% v 0%), partial response (6% v 0%), hematologic improvement (15% v 2%), stable disease (14% v 22%), progressive disease (29% v 68%), hypoplasia (14% v 0%), and inevaluable (8% v 8%). Grade 3 to 4 febrile neutropenia occurred in 25% of patients on decitabine versus 7% of patients on BSC; grade 3 to 4 infections occurred in 57% and 52% of patients on decitabine and BSC, respectively. Decitabine treatment was associated with improvements in patient-reported quality-of-life (QOL) parameters.
Decitabine administered in 6-week cycles is active in older patients with higher-risk MDS, resulting in improvements of OS and AMLFS (nonsignificant), of PFS and AML transformation (significant), and of QOL. Short MDS duration was an independent adverse prognosticator.
Overcoming graft-versus-host disease (GvHD) without increasing relapse and severe infections is a major challenge after allogeneic hematopoietic stem-cell transplantation (HSCT). ATIR101 is a ...haploidentical, naïve cell-enriched T-cell product, depleted of recipient-alloreactive T cells to minimize the risk of GvHD and provide graft-versus-infection and -leukemia activity. Safety and efficacy of ATIR101 administered after T-cell-depleted haploidentical HSCT (TCD-haplo + ATIR101) without posttransplant immunosuppressors were evaluated in a Phase 2, multicenter study of 23 patients with acute leukemia and compared with an observational cohort undergoing TCD-haplo alone (n = 35), matched unrelated donor (MUD; n = 64), mismatched unrelated donor (MMUD; n = 37), and umbilical cord blood (UCB; n = 22) HSCT. The primary endpoint, 6-month non-relapse mortality (NRM), was 13% with TCD-haplo + ATIR101. One year post HSCT, TCD-haplo + ATIR101 resulted in lower NRM versus TCD-haplo alone (P = 0.008). GvHD-free, relapse-free survival (GRFS) was higher with TCD-haplo + ATIR101 versus MMUD and UCB (both P < 0.03; 1-year rates: 56.5%, 27.0%, and 22.7%, respectively) and was not statistically different from MUD (1 year: 40.6%). ATIR101 grafts with high third-party reactivity were associated with fewer clinically relevant viral infections. Results suggest that haploidentical, selective donor-cell depletion may eliminate requirements for posttransplant immunosuppressors without increasing GvHD risk, with similar GRFS to MUD. Following these results, a randomized Phase 3 trial versus posttransplant cyclophosphamide had been initiated.
Myelodysplastic syndromes and acute myeloid leukemia exemplify the complexity of treatment allocation in older patients as options range from best supportive care, non-intensive treatment (e.g. ...hypomethylating agents) to intensive chemotherapy/hematopoietic cell transplantation. Novel metrics for non-disease variables are urgently needed to help define the best treatment for each older patient. We investigated the feasibility and prognostic value of geriatric/quality of life assessments aside from established disease-specific variables in 195 patients aged 60 years or over with myelodysplastic syndromes/acute myeloid leukemia. These patients were grouped according to treatment intensity and assessed. Assessment consisted of eight instruments evaluating activities of daily living, depression, mental functioning, mobility, comorbidities, Karnofsky Index and quality of life. Patients with a median age of 71 years (range 60-87 years) with myelodysplastic syndromes (n=63) or acute myeloid leukemia (n=132) were treated either with best supportive care (n=47), hypomethylating agents (n=73) or intensive chemotherapy/hematopoietic cell transplantation (n=75). After selection of variables, pathological activities of daily living and quality of life/fatigue remained highly predictive for overall survival in the entire patient group beyond disease-related risk factors adverse cytogenetics and blast count of 20% or over. In 107 patients treated non-intensively activities of daily living of less than 100 (hazard ratio, HR 2.94), Karnofsky Index below 80 (HR 2.34) and quality of life/'fatigue' of 50 or over (HR 1.77) were significant prognosticators. Summation of adverse features revealed a high risk of death (HR 9.36). In-depth evaluation of older patients prior to individual treatment allocation is feasible and provides additional information to standard assessment. Patients aged 60 years or over with newly diagnosed myelodysplastic syndromes/acute myeloid leukemia and impairments in activities of daily living, Karnofsky Index below 80%, quality of life/'fatigue' of 50 or over, are likely to have poor outcomes.
Del(5q) myelodysplastic syndromes defined by the International Prognostic Scoring System as low- or intermediate-1-risk (lower-risk) are considered to have an indolent course; however, recent data ...have identified a subgroup of these patients with more aggressive disease and poorer outcomes. Using deep sequencing technology, we previously demonstrated that 18% of patients with lower-risk del(5q) myelodysplastic syndromes carry TP53 mutated subclones rendering them at higher risk of progression. In this study, bone marrow biopsies from 85 patients treated with lenalidomide in the MDS-004 clinical trial were retrospectively assessed for p53 expression by immunohistochemistry in association with outcome. Strong p53 expression in ≥ 1% of bone marrow progenitor cells, observed in 35% (30 of 85) of patients, was significantly associated with higher acute myeloid leukemia risk (P=0.0006), shorter overall survival (P=0.0175), and a lower cytogenetic response rate (P=0.009), but not with achievement or duration of 26-week transfusion independence response. In a multivariate analysis, p53-positive immunohistochemistry was the strongest independent predictor of transformation to acute myeloid leukemia (P=0.0035). Pyrosequencing analysis of laser-microdissected cells with strong p53 expression confirmed the TP53 mutation, whereas cells with moderate expression predominantly had wild-type p53. This study validates p53 immunohistochemistry as a strong and clinically useful predictive tool in patients with lower-risk del(5q) myelodysplastic syndromes. This study was based on data from the MDS 004 trial (clinicaltrials.gov identifier: NCT00179621).
PDF
