Does Occurrence of Other Malignancy after Essential Thrombocythemia and Polycythemia Vera Influence Their Rate of Transformation to Myelofibrosis?
Authors: Masarova Lucia , Daver Naval , Pemmaraju Naveen , Bose Prithviraj , Pierce Sherry , Cortes Jorge E. , Kantarjian Hagop M , Verstovsek Srdan 
Published: November 2019

Abstract
Introduction: Other malignancies (OM) were reported to be increased in patients with essential thrombocythemia "ET" and polycythemia vera "PV". However, the effect of coexistent OM on the rate of disease transformation to myelofibrosis "MF" is unknown.
Objective: To determine the occurrence of OM in patients with ET and PV and their influence on transformation rate to overt MF.
Methods: Fisher's exact test, and Mann-Whitney test were used to compare categorical and continuous variable, respectively. Control group without OM matched for age, MPN diagnosis type and year was created to compare transformation rates, expressed by Kaplan-Meier curve and Log rank test.
Results: We perform a retrospective chart review for 783 patients referred to our institution between years 1960 - 2013 with diagnosis of Philadelphia-negative myeloproliferative neoplasm "MPN", of which 256 had ET, 165 PV and 362 post ET- or post PV- MF. Overall, 107 (13.7%) patients had OM prior to MF transformation, accounting for total of 125 cases. See table for OM types and distribution. In total, 9 patients had more than 1 OM with the most common being prostatic carcinoma (n=6), melanoma (n=4) and renal cell carcinoma (n=2). Relapsed/refractory OM were noticed in 15 patients, 3 of these had recurrence only prior MPN. None of alive patients with refractory OM experienced progression after MF transformation. Median age at diagnosis of MPN and OM (59 and 62 years), median age at the time of first event (OM or MPN; 51 and 53 years), and male to female ratio (1:1) were similar. Time to secondary OM was shorter than time to secondary MPN (6.5 vs 9 years, p>0.05). After median follow up of 30 months (range, 1-150), 49 (46%) patients had died. Eleven (23%) patients died because of OM progression, most commonly due to lung carcinoma and melanoma. No MPN related deaths were observed, however, 2 patients progressed to acute leukemia. Median overall survival "OS" for MPN was 160 months (range, 1-240) and was not different for patients with and without MF (212 and 173 months; p>0.05). No significant differences were detected between patients with and without MF in terms of age at the time of MPN diagnosis, gender, MPN characteristics (cytogenetic, molecular mutations) or time between OM and MPN. However, patients who transformed to MF were older at the time of OM (53 vs 59 years, p= 0.041, 95% CI: 1.2-11.7). Similarly, within a group of MF, patients with OM prior to MPN were younger at the time of OM (53 vs 62 years, p<0.001, 95%CI 5.0-23.5) and older at the time of MPN (67 vs 55 years, p=0.001, 95%CI 8.3-19.4) that patients who had OM after previous MPN. Overall time to transformation to MF was similar between ET and PV, and between studied cohort and control group (6 years, range 0.5-29, p>0.05, chi square 1.14). However, patients who developed OM after MPN had longer time to transformation (14 years, range 1-36, p=0.011, HR 1.9, 95%CI of 1.3 -4.4), which remained significant when control group was added, p=0.024 [Fig.]
Conclusions: OM diagnosed after ET or PV does not seem to influence rate of disease transformation to MF.
Table. ET/PV, n=421 ET/PV -> MF, n= 362 OM characteristics OM prior MPN, n OM after MPN, n OM prior MPN, n OM after MPN, n No. of patients with OM 29 26 19 33 No. of OM 30 26 26 43 Breast 5 4 ( 1*) 2 (1*) 3 Female reproductive 5 1 4 Prostate 7 1 6 (1*) 14 (1*) Gastrointestinal tract 2 4 6 3 Genitourinary tract 3 (1*) 4 2 Lungs 1 3 (3*) Melanoma 3 (1*) 2 4 9 (1*) Soft tissue 1 2 (1*) 1 Thyroid 3 2 (1*) 1 2 Head and neck 1 (1*) Hematologic malignancy 3 5 (1*) 6 (1*) (*) stands for relapsed or refractory disease

Disclosures
Pemmaraju: Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Cortes:Pfizer: Consultancy, Research Funding; Teva: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; ARIAD Pharmaceuticals Inc.: Consultancy, Research Funding.