The Diagnostic Utility of Mutational Analysis in Patients with Suspected Myeloid Neoplasms, a Single Institution Experience
Authors: Macklis Jason , Shammo Jamile M. , Buckingham Lela , Venugopal Parameswaran 
Published: October 2019

Abstract
Introduction
Molecular abnormalities in primary myeloid diseases have been well described. Some of these molecular alterations are nearly pathognomonic for specific diseases such as JAK2 V617F and CALR, whereas others are more generally associated with myeloid disorders, though they may have prognostic significance. Commercially available panel testing screen for multiple genetic alterations simultaneously and are used increasingly for diagnostic and prognostic purposes. We sought to evaluate the clinical utility of panel testing in primary myeloid disorders and to evaluate the impact on diagnosis and management.
Methods
Patients who presented to the MDS/MPN clinic between February, 2015 and May, 2016 were included in the study if a Genoptix Myeloid Molecular Panel (MMP) was submitted and resulted. The MMP tests for 40 recurrently mutated genes in myeloid malignancies using next generation sequencing. It includes genes involved with RNA splicing, epigenetics, transcription factors, cohesion complex, activated signaling, and others. Primary diagnosis (if determined), and rationale for testing (diagnostic, diagnosis in question, or prognostic) at the time the test was ordered was recorded. Charts were reviewed to determine if a diagnosis was made or if there was a change in diagnosis, prognosis, or management as a result of the MMP.
Results
40 patients had a resulted MMP. The primary diagnoses at presentation were: ICUS (8), MDS (18), MF (7), CMML (2), MPN-U (2), MDS/MPN (1), and multiple diagnoses (2). Of the 40 patients that were evaluated, 35 patients had at least one reported mutation. 5 MMPs (12.5%) resulted in a change in diagnosis. 2 patients diagnosed with MPN-U at presentation were found to carry CSF3R mutation consistent with a diagnosis of chronic neutrophilic leukemia. 3 additional patients had an original diagnosis of MDS with fibrosis; however, 2 of these patients had a MPL mutation and third had a CALR mutation consistent with myelofibrosis. Of prognostic significance, 5 of the 18 patients with MDS (27.8%) were found to harbor TP53 mutations. Of these, 4 (22.2%) patients were previously classified as having low risk disease by IPSS, 2 (11.1%) of which had deletion 5q as their only cytogenetic abnormality. Altogether, 8 (20%) patients had a drastic change in diagnosis or prognosis. In 4 (10%) patients, this resulted in a change in management as follows: of the 2 patients that had a diagnosis of CNL, 1 was enrolled on a clinical trial involving a JAK2 inhibitor; 1 of the 2 patients with a history of MDS changed to MF by the identification of a CALR mutation was treated with a JAK2 inhibitor; and 2 of the patients with low risk MDS were referred for transplant evaluation due to the presence of a TP53 mutation where transplant would otherwise not be indicated.
Conclusions:
In this small series, we find that the MMP can aid in making an accurate diagnosis and has prognostic significance particularly in the following patient populations: MDS with fibrosis, MPN-U, and young patients with low-risk MDS who may benefit from closer monitoring and early referral for transplant evaluation. Confirmation of these observations merits prospective evaluation for a larger number of patients.

Disclosures
Shammo: novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; incyte: Consultancy, Honoraria, Research Funding, Speakers Bureau; alexion: Consultancy, Honoraria, Research Funding, Speakers Bureau.