Abstract
Introduction: Acute myeloid leukemia (AML) is a heterogeneous disorder such that each patient exhibits a unique pattern of mutations. Nevertheless, standard treatment approaches are largely used for all patients with the exception of those with the PML-RARA translocation or FLT3 mutations. We are conducting a feasibility study, "Individualized Treatment for Relapsed/Refractory Acute Leukemia Based on Chemosensitivity and Genomics/Gene Expression Data" (NCT02551718). This abstract summarizes the results in the AML patients.
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Methods: The primary objective of this trial is to test the feasibility of rapidly assessing patient cells using a high throughput assay for in vitro drug sensitivity with individual drugs and drug combinations and mutation profiling by next generation sequencing (NGS) of 194 genes (MyAML) to enable prompt initiation of optimal therapy. The secondary objective is to evaluate the response to the chosen therapy. The eligibility criteria include diagnosis of acute leukemia, age ≥ 3, relapsed after or refractory to 2 prior lines of therapy, ECOG ≤ 3, and adequate organ function. The high throughput screen (HTS) is performed at a core facility under CLIA. The custom Oncopanel1 contains 160 drugs and drug combinations, including FDA approved and investigational agents, targeted agents including kinase, mTOR, proteasome, HDAC and other inhibitors, and chemotherapy drugs including alkylators, purine analogs, topoisomerase inhibitors and others. Patient blood or marrow samples enriched for leukemia cells are analyzed for survival after a 72-hour exposure to 8 customized drug concentrations spanning 4 logs in duplicate in 384 well plates adherent to matrix protein. DNA and RNA are isolated from the same enriched cell fractions for NGS (MyAML) and RNAseq. MyAML analyzes genes at high depth, including breakpoint hotspot loci with optimized detection of large insertion and deletions and other structural variants found in AML.
Results: Fourteen patients signed consent, and 11 AML patients were enrolled in the study to date. Seven patients had unfavorable and 4 intermediate cytogenetic risk. Four were primary refractory, 5 had antecedent hematologic disorder. The average number of prior regimens was 4 (range 2 to 6). Six patients had relapsed within ≤3 months after allogeneic transplant, prior to enrollment on this study. HTS results were obtained within an average of 5.5 days; mutation testing was obtained within an average of 13 days (range 9-17), return time after receipt at MyAML was on average 8 (range 7-12) days. Drug regimens were chosen within 1-2 weeks from testing. For 2 patients, treatment start was delayed by about one month to allow recovery from toxicity from prior therapy. For the other patients, treatment was initiated on average 7.8, median 8 (range 4-11) days from start of testing. Of 7 patients treated so far, the median overall survival was 171 days, range 70 to >289 days.
Regimens chosen based on HTS results, mutation analysis, and ability to obtain FDA approved drugs off label included: bortezomib (B)/daunorubicin/cytarabine, romidepsin, B/azacitidine (Aza), B/idarubicin (2 patients),cladribine, omacetaxine (HHT) then HHT/cytarabine, B/Aza/sorafenib, gemcitabine, bortezomib, sorafenib. Mutation analysis revealed previously unknown potential targets in those patients, including ABL kinase, FLT3 ITD in 2 patients, and FLT3 TKD mutations that led to choice of treatment with imatinib, sorafenib, and investigational Flt3 inhibitor for 4 patients, respectively. Other potentially targetable mutations identified included IDH1/2, NRAS, KRAS, KIT, TP53, WT1, and others (Table).
None of these very heavily pre-treated patients obtained a complete remission, but 3 remain alive > 1 yr post early relapse after allogeneic transplant. One patient's marrow exhibited decline in blasts from 82% to 24%, and all patients exhibited a decline in circulating blasts with the chosen treatments.
Conclusion: This trial has proven that application of rapid molecular and functional screening to choice of treatment for patients with advanced acute myeloid leukemia is feasible. Direct comparison of this precision medicine approach to results obtained with standard trials is planned. These data and the responses and correlation with gene expression data will contribute to a future algorithm to optimize precision medicine approaches to leukemia therapy.
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Disclosures
Becker: JW Pharmaceutical: Research Funding; Millennium: Research Funding; Glycomimetics: Research Funding; Pfizer: Other: Scientific Steering Committee for a post marketing study; Amgen: Research Funding; CVS Caremark: Other: Accordant Health Services Medical Advisory Board; Abbvie: Research Funding; Invivoscribe: Honoraria. Patay:Invivoscribe, Inc: Consultancy. Carson:Invivoscribe, Inc: Employment. Radich:Novartis: Consultancy, Other: laboratory contract; Bristol-MyersSquibb: Consultancy; TwinStrand: Consultancy; ARIAD: Consultancy; Pfizer: Consultancy.
Dasatinib response in acute myeloid leukemia is correlated with FLT3/ITD, PTPN11 mutations and a unique gene expression signature
