Invasive fungal disease (IFD) is a significant cause of morbidity and mortality in patients undergoing treatment for acute leukemia (AL). Antifungal prophylactic strategies are associated with significant toxicities and cost. We performed a retrospective study of the incidence and risk factors for IFD among patients newly diagnosed with and treated for AL between January 1, 2004 and July 1, 2006. Patient follow up concluded January 1, 2007. Among 231 patients with newly diagnosed AL, 31 (13.4%) developed IFD by the end of follow up, 24 (10.4%) of whom developed IFD within the first 100 days after diagnosis of AL. The cumulative probability of developing IFD was 5.9% by 30 days and 11.1% at 100 days after AL diagnosis. Patients who had persistent leukemia after an initial course of induction chemotherapy were significantly more likely to develop IFD than those who did not have evidence of persistent leukemia (14/65 (21.5%) vs. 15/148 (10.1%), P = 0.03). In a time‐dependent Cox model, the adjusted hazard ratio for developing IFD within the first 100 days of AL diagnosis based on the number of days of neutropenia in that period was 4.85 (95% confidence interval: 1.52, 15.4). Those patients with more days of neutropenia in the first 100 days after AL diagnosis, such as those who did not achieve remission after a first course of induction chemotherapy, were more likely to develop IFD. Am. J. Hematol., 2010. © 2010 Wiley‐Liss, Inc.

A B S T R A C T PurposeTo determine the efficacy and toxicity of the combination of sorafenib, cytarabine, and idarubicin in patients with acute myeloid leukemia (AML) younger than age 65 years. Patients and MethodsIn the phase I part of the study, 10 patients with relapsed AML were treated with escalating doses of sorafenib with chemotherapy to establish the feasibility of the combination. We then treated 51 patients (median age, 53 years; range, 18 to 65 years) who had previously untreated AML with cytarabine at 1.5 g/m 2 by continuous intravenous (IV) infusion daily for 4 days (3 days if Ͼ 60 years of age), idarubicin at 12 mg/m 2 IV daily for 3 days, and sorafenib at 400 mg orally twice daily for 7 days. ResultsOverall, 38 (75%) patients have achieved a complete remission (CR), including 14 (93%) of 15 patients with mutated FMS-like tyrosine kinase-3 (FLT3; the 15th patient had complete remission with incomplete platelet recovery [CRp]) and 24 (66%) of 36 patients with FLT3 wild-type (WT) disease (three additional FLT3-WT patients had CRp). FLT3-mutated patients were more likely to achieve a CR than FLT3-WT patients (P ϭ .033). With a median follow-up of 54 weeks (range, 8 to 87 weeks), the probability of survival at 1 year is 74%. Among the FLT3-mutated patients, 10 have relapsed and five remain in CR with a median follow-up of 62 weeks (range, 10 to 76 weeks). Plasma inhibitory assay demonstrated an on-target effect on FLT3 kinase activity. ConclusionSorafenib can be safely combined with chemotherapy, produces a high CR rate in FLT3-mutated patients, and inhibits FLT3 signaling.

The pathophysiology of IDH mutations in tumorigenesis is increasingly described, yet the prognostic significance of IDH1 and IDH2 mutations in AML remains controversial. The primary objective of this study was to define the natural history and prognosis of patients with AML and IDH1 or IDH2 mutations and provide historical survival expectations. A total of 826 patients treated from 2010 to 2014 at a single institution were evaluated, including 167 patients (20%) with AML and IDH1 or IDH2 mutations. Median age was 62 years (range 18–92). There were 59 IDH1-R132, 83 IDH2-R140, and 23 IDH2-R172 mutations. Clinicopathologic characteristics associated with IDH-mutations included older age, less frequent therapy-related status, and increased incidence of intermediate-risk cytogenetics, FLT3-ITD mutations, and NPM1 mutations. Remission rates (CR/CRi) by AML treatment status were: induction, 68%; Salvage-1 (S1), 42%; and Salvage-2 and beyond (S2+), 27%. No difference in response was identified by IDH mutation status. Similarly, overall survival (OS) was not dependent on IDH status within any cohort. The median OS was 15.4 months in induction, 8.7 months in S1, and 4.8 months in S2+. This analysis defines the clinical outcome associated with IDH-mutations in both the front-line and salvage AML treatment settings, and confirms that response rate and OS for both IDH-mutated and IDH wild-type AML patients is comparable. This provides contemporary data to be used for comparison with results of novel investigational (e.g., selective IDH inhibitor) strategies.

The combination of all--retinoic acid (ATRA) plus arsenic trioxide (ATO) has been shown to be superior to ATRA plus chemotherapy in the treatment of standard-risk patients with newly diagnosed acute promyelocytic leukemia (APL). A recent study demonstrated the efficacy of this regimen with added gemtuzumab ozogamicin (GO) in high-risk patients. We examined the long-term outcome of patients with newly diagnosed APL treated at our institution on 3 consecutive prospective clinical trials, using the combination of ATRA and ATO, with or without GO. For induction, all patients received ATRA (45 mg/m daily) and ATO (0.15 mg/kg daily) with a dose of GO (9 mg/m on day 1) added to high-risk patients (white blood cell count, >10 × 10/L), as well as low-risk patients who experienced leukocytosis during induction. Once in complete remission, patients received 4 cycles of ATRA plus ATO consolidation. One hundred eighty-seven patients, including 54 with high-risk and 133 with low-risk disease, have been treated. The complete remission rate was 96% (52 of 54 in high-risk and 127 of 133 in low-risk patients). Induction mortality was 4%, with only 7 relapses. Among low-risk patients, 60 patients (45%) required either GO or idarubicin for leukocytosis. Median duration of follow-up was 47.6 months. The 5-year event-free, disease-free, and overall survival rates are 85%, 96%, and 88%, respectively. Late hematological relapses beyond 1 year occurred in 3 patients. Fourteen deaths occurred beyond 1 year; 12 were related to other causes. This study confirms the durability of responses with this regimen.

We reviewed the outcome of 671 patients 65 years of age or older with newly diagnosed acute myeloid leukemia (AML) treated at our institution between 2000 and 2010 with intensive chemotherapy (n ‫؍‬ 557) or azacitidine-or decitabinebased therapy (n ‫؍‬ 114). Both groups were balanced according to cytogenetics and performance status. The complete response rates with chemotherapy and epigenetic therapy were 42% and 28%, respectively (P ‫؍‬ .001), and the 8-week mortality 18% and 11%, respectively (P ‫؍‬ .075). Two-year relapse-free survival rates (28% vs 39%, P ‫؍‬ .843) and median survival (6.7 vs 6.5 months, P ‫؍‬ .413) were similar in the 2 groups. Multivariate analysis identified older age, adverse cytogenetics, poor performance status, elevated creatinine, peripheral blood and BM blasts, and hemoglobin, but not type of AML therapy, as independent prognostic factors for survival. No outcome differences were observed according to cytogenetics, FLT3 mutational status, age, or performance status by therapy type. Decitabine was associated with improved median overall survival compared with azacitidine (5.5 vs 8.8 months, respectively, P ‫؍‬ .03). Survival after failure of intensive chemotherapy, azacitidine, or decitabine was more favorable in patients who had previously received decitabine (1.1 vs 0.9 vs 3.1 months, respectively, P ‫؍‬ .109). The results of the present study show that epigenetic therapy is associated with similar survival rates as intensive chemotherapy in older patients with newly diagnosed AML. The studies reviewed are registered at www.clinicaltrials