Abstract 3409: MSK-IMPACT Heme: Validation and clinical experience of a comprehensive molecular profiling platform for hematologic malignancies

Abstract

Background: As the repertoire of molecular targeted therapies for hematologic malignancies continues to expand, so too does the opportunity for molecular profiling to inform treatment decisions. While mutations in certain genes, such as JAK2, MPL, MYD88 and BRAF have diagnostic utility, others such as FLT3, NPM1, IDH1, IDH2, DNMT3A, KIT and CEBPA have prognostic value. Here, we present the development and clinical experience of MSK-IMPACT Heme (Integrated Mutation Profiling of Actionable Cancer Targets for Hematologic malignancies), a comprehensive molecular profiling platform, utilizing hybridization capture and high coverage next generation sequencing of paired tumor and normal tissues. Methods: We designed custom DNA probes corresponding to all exons of 400 key oncogenes and tumor suppressor genes implicated in hematologic malignancies, including all genes that are targetable by approved and experimental therapies being investigated in clinical trials at our institution. The accuracy, precision, and sensitivity of MSK-IMPACT Heme was assessed on a validation set of 113 unique tumor samples with known SNVs and indels previously confirmed by orthogonal methods. We implemented a custom analysis pipeline to integrate the analysis of any number of normal samples with a given tumor and provide a reliable assessment of somatic alterations, even in post-transplant chimeric patients. The selection of matched nail, saliva, and/or blood tissue was determined at the time of test initiation as indicated by patient diagnosis and transplant history. The ability to detect somatic copy number alterations was demonstrated with samples previously characterized by SNP array platforms. Results: We sequenced 821 tumor samples, from 759 patients that represented over 50 tumor types to a mean depth of 758X. 429 patients were male (56.5%) and 20 cases were post allogeneic stem cell transplantation. The most common tumor types sequenced were Follicular lymphoma (11.9%), DLBCL (11.3%), and AML (11.0%). We identified 4,935 mutations from 732 samples. The most commonly altered genes were TP53, KMT2D, and CREBBP. Implementation of the MSK-IMPACT Heme workflow enabled the characterization of complex tumor specimens, including sorted cells and tumor samples from post-transplant chimeric patients. The joint utilization of matched patient and donor normal tissues enabled differentiation between somatic alterations and both host and donor derived common polymorphisms. Conclusions: The MSK-IMPACT Heme assay provides molecular profiling of hematologic malignancies with high accuracy and sensitivity. Paired analysis of tumors and patient and/or donor matched normal tissue samples enables the unambiguous detection of somatic alterations and the ability apply these data towards tumor classification, risk assessment, prognosis, disease monitoring, and treatment optimization. Citation Format: Ryan N. Ptashkin, Ryma Benayed, John Ziegler, Anoop Balakrishnan Rema, Justyna Sadowska, Iwona Kiecka, Caleb Ho, JinJuan Yao, Christine Moung, Kseniya Petrova-Drus, Khedoudja Nafa, Connie Batlevi, Martin Tallman, Ross Levine, Sergio Giralt, Anas Younes, Marc Ladanyi, Mike Berger, Ahmet Zehir, Maria E. Arcila. MSK-IMPACT Heme: Validation and clinical experience of a comprehensive molecular profiling platform for hematologic malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3409.

Successful treatment and integrated genomic analysis of an infant with FIP1L1-RARA fusion–associated myeloid neoplasm

“…A final diagnosis of FIP1L1-RARA fusion–associated myeloid neoplasm was assigned, with a differential diagnosis of variant APL vs an overlap myelodysplastic/myeloproliferative neoplasm (MDS/MPN) within the spectrum of JMML. Next-generation sequencing-based mutational profiling (MSK-IMPACT Heme) 12 targeting 400 genes altered in hematological malignancies was performed with a paired matched normal sample and revealed a somatic MAP2K2 p.R231L mutation (23.5% allele frequency).…”

Lenalidomide-associated B-cell ALL: clinical and pathologic correlates and sensitivity to lenalidomide withdrawal

“…Paired tumor (bone marrow [BM] or blood) and normal samples from MSK patients were analyzed using MSK IMPACT-Heme (13 patients) where possible; 8 the FoundationOne Heme platform (Foundation Medicine, Cambridge, MA) for DNA and targeted RNA sequencing (RNA-seq) was used for profiling in 3 patients, including 1 who also had MSK IMPACT-Heme data. In 2 MSK patients who did not have one of these comprehensive profiling studies performed, targeted sequencing was performed using a next-generation sequencing (NGS) platform panel comprised genes frequently mutated in myeloid neoplasms (RainDance Technologies ThunderBolts Myeloid Panel).…”

Molecular predictors of immunophenotypic measurable residual disease clearance in acute myeloid leukemia

“…If both were available, data from BMA were used preferentially (for details see Supplemental Methods). 15,16 …”