ALBERT

Description: This study was coordinated by the ECOG-ACRIN Cancer Research Group (Robert L. Comis, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported in part by Public Health Service Grants CA180794, CA180820, CA180795, CA180791, CA189859, CA180790, CA180853, and from the National Cancer Institute, National Institutes of Health and the Department of Health and Human Services. Its content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute. Background: Relapse after achieving a complete remission (CR) in AML portends for a poor prognosis and allogeneic transplant after achieving a second remission is the only chance for cure. Patients who undergo a transplant have a 30-40% chance of long term survival. This is a follow-up of a report published 10 years ago (Rowe JM, ASH 2005, abstract 546) and includes contemporary studies and longer follow-up. The study examines the long term overall survival (OS) of AML patients who relapsed after achieving first CR in 9 successive ECOG-ACRIN trials for newly-diagnosed AML patients (E3483, E3489, PC486, E3993, E4995, E1490, E3997, E1900 and E3999) from March 1984 to November 2008. Methods: OS was defined as time from first relapse to death from any cause. Kaplan-Meier estimates were used to estimate the event-time distributions for OS. Multivariate model stratified on protocol and treatment were used to examine whether the following factors are prognostic for OS from relapse: age, gender, cytogenetic risk, ECOG performance status, WBC, platelets, hemoglobin, marrow blasts, peripheral blasts, and duration of CR. All P values were based on 2-sided tests. Results: A total of 3160 patients were enrolled in the 9 studies. The median follow-up on patients still alive was 10.0 years. Among those 3160 patients enrolled, 1864 (58.9%) achieved first CR of which 1086 (58.2%) had documented relapse. The median age at diagnosis of the relapsed patients was 50 (range: 16-84) and 50.6% were males. Fifty percent of the patients had reliable cytogenetic results. Of those, 13.5% had favorable cytogenetics, 55.8% - intermediate and 30.6% had unfavorable baseline results. The median OS from relapse was 0.5 years. The 2- and 5-year OS were 16(±1)% and 10(±1)%, respectively. This is true in even the most contemporary studies (E1900 and E3999) with median OS of 0.6 and 0.4 years, respectively. By age stratification (〈 or ≥ 55), 5-year OS was 13(±1)% and 5(±1)%, respectively (figure 1). Among patients

Description: Abstract 2481 Purpose: Cancer-associated IDH mutations produce the metabolite 2-hydroxyglutarate (2HG), but the clinical utility of serum 2HG measurements has not been previously established. We studied whether 2HG measurements in AML patients correlate with the presence of IDH mutations and whether diagnostic or remission 2HG measurements predict survival. Patients and Methods: Serum samples from 223 previously untreated adults (≤ 60 years of age) with de novo AML from the Eastern Cooperative Oncology Group E1900 clinical trial (62 IDH mutated, 161 IDH wild-type) were analyzed for 2HG concentration by reverse-phase liquid chromatography coupled to mass spectrometry (GC-MS). Results: Pretreatment 2HG levels ranged from 10 to 30000 ng/ml and were significantly elevated in IDH-mutant samples (median 3004.1 ng/ml), as compared to the wild-type cohort (median 61.2 ng/ml) (p 〈 0.0005). 2HG levels did not differ among the specific IDH1 or IDH2 allelic variants. In ROC analysis, a discriminatory level of 700 ng/ml segregated patients with and without IDH mutations with 86.9% sensitivity and 90.7% specificity. On repeat mutational analysis of 13 IDH wild-type samples with 2HG levels 〉700 ng/ml, IDH mutations were identified in nine samples, most often at low allele burden. IDH mutant patients with 2HG levels ≤ 200 ng/ml at complete remission experienced improved overall survival compared to those with higher 2HG levels (HR 3.5, p = 0.02) (Figure 1). Conclusion: We establish a firm association between IDH mutations and elevated serum 2HG concentration in AML. These data confirm that peripheral blood measurement of an oncometabolite provides useful diagnostic and prognostic information for cancer therapy, and furthermore can inform patient selection of IDH mutant targeted therapies. Disclosures: Levine: Agios Pharmaceuticals: Research Funding. Straley:Agios Pharmaceuticals: Employment. Yen:Agios Pharmaceuticals: Employment. Agresta:Agios Pharmaceuticals: Employment. Carroll:Agios Pharmaceuticals: Research Funding.