Phase II study of the oral MEK inhibitor selumetinib in advanced acute myelogenous leukemia: a University of Chicago phase II consortium trial.

PURPOSE: The clinical relevance of targeting the RAS/RAF/MEK/ERK pathway, activated in 70% to 80% of patients with acute myelogenous leukemia (AML), is unknown. EXPERIMENTAL DESIGN: Selumetinib is an oral small-molecule inhibitor of MAP-ERK kinase (MEK)-1/2. Forty-seven patients with relapsed/refractory AML or 60 years old or more with untreated AML were enrolled on a phase II study. Patients were stratified by FLT3 ITD mutation status. The primary endpoint was response rate (complete, partial, and minor). Leukemia cells were analyzed for extracellular signal-regulated kinase (ERK) and mTOR phosphorylation. RESULTS: Common drug-related toxicities were grade 1-2 diarrhea, fatigue, nausea, vomiting, and skin rash. In the FLT3 wild-type cohort, six of 36 (17%) patients had a response [one partial response, three minor responses, two unconfirmed minor responses (uMR)]. No patient with FLT3 ITD responded. NRAS and KRAS mutations were detected in 7% and 2% of patients, respectively. The sole patient with KRAS mutation had uMR with hematologic improvement in platelets. Baseline p-ERK activation was observed in 85% of patients analyzed but did not correlate with a response. A single-nucleotide polymorphism (SNP) rs3733542 in exon 18 of the KIT gene was detected in significantly higher number of patients with response/stable disease compared with nonresponders (60% vs. 23%; P = 0.027). CONCLUSIONS: Selumetinib is associated with modest single-agent antileukemic activity in advanced AML. However, given its favorable toxicity profile, combination with drugs that target other signaling pathways in AML should be considered. The potential association of SNP rs3733542 in exon 18 of the KIT gene with antileukemic activity of selumetinib is intriguing, but will require validation in larger trials.

Treatment-influenced associations of PML-RARα mutations, FLT3 mutations, and additional chromosome abnormalities in relapsed acute promyelocytic leukemia.

Mutations in the all-trans retinoic acid (ATRA)-targeted ligand binding domain of PML-RARα (PRα/LBD+) have been implicated in the passive selection of ATRA-resistant acute promyelocytic leukemia clones leading to disease relapse. Among 45 relapse patients from the ATRA/chemotherapy arm of intergroup protocol C9710, 18 patients harbored PRα/LBD+ (40%), 7 of whom (39%) relapsed Off-ATRA selection pressure, suggesting a possible active role of PRα/LBD+. Of 41 relapse patients coanalyzed, 15 (37%) had FMS-related tyrosine kinase 3 internal tandem duplication mutations (FLT3-ITD+), which were differentially associated with PRα/LBD+ depending on ATRA treatment status at relapse: positively, On-ATRA; negatively, Off-ATRA. Thirteen of 21 patients (62%) had additional chromosome abnormalities (ACAs); all coanalyzed PRα/LBD mutant patients who relapsed off-ATRA (n = 5) had associated ACA. After relapse Off-ATRA, ACA and FLT3-ITD+ were negatively associated and were oppositely associated with presenting white blood count and PML-RARα type: ACA, low, L-isoform; FLT3-ITD+, high, S-isoform. These exploratory results suggest that differing PRα/LBD+ activities may interact with FLT3-ITD+ or ACA, that FLT3-ITD+ and ACA are associated with different intrinsic disease progression pathways manifest at relapse Off-ATRA, and that these different pathways may be short-circuited by ATRA-selectable defects at relapse On-ATRA. ACA and certain PRα/LBD+ were also associated with reduced postrelapse survival.

Detection of minimal residual disease following induction immunochemotherapy predicts progression free survival in mantle cell lymphoma: final results of CALGB 59909.

BACKGROUND: In the present study, the prognostic impact of minimal residual disease during treatment on time to progression and overall survival was analyzed prospectively in patients with mantle cell lymphoma treated on the Cancer and Leukemia Group B 59909 clinical trial. DESIGN AND METHODS: Peripheral blood and bone marrow samples were collected during different phases of the Cancer and Leukemia Group B 59909 study for minimal residual disease analysis. Minimal residual disease status was determined by quantitative polymerase chain reaction of IgH and/or BCL-1/JH gene rearrangement. Correlation of minimal residual disease status with time to progression and overall survival was determined. In multivariable analysis, minimal residual disease, and other risk factors were correlated with time to progression. RESULTS: Thirty-nine patients had evaluable, sequential peripheral blood and bone marrow samples for minimal residual disease analysis. Using peripheral blood monitoring, 18 of 39 (46%) achieved molecular remission following induction therapy. The molecular remission rate increased from 46 to 74% after one course of intensification therapy. Twelve of 21 minimal residual disease positive patients (57%) progressed within three years of follow up compared to 4 of 18 (22%) molecular remission patients (P=0.049). Detection of minimal residual disease following induction therapy predicted disease progression with a hazard ratio of 3.7 (P=0.016). The 3-year probability of time to progression among those who were in molecular remission after induction chemotherapy was 82% compared to 48% in patients with detectable minimal residual disease. The prediction of time to progression by post-induction minimal residual disease was independent of other prognostic factors in multivariable analysis. CONCLUSIONS: Detection of minimal residual disease following induction immunochemotherapy was an independent predictor of time to progression following immunochemotherapy and autologous stem cell transplantation for mantle cell lymphoma.