Study of the Relation Between the Time Course of the JAK2V617F Allele Burden and the Clinical Evolution in Patients with Myeloproliferative Neoplasms (MPN); A Single Center Study
Authors: Sobas Marta Anna , Pérez-Encinas Manuel , Quinteiro Celsa , González Teresa , Suaréz Sandra , Alonso Natalia , Díaz José , Bendaña Angeles , González Marta Sonia , Bello Jose-Luis 
Published: April 2020

Abstract
Introduction: The JAK2V617F mutation is frequent in MPN, however its clinical implication is still in debate. There are few publications that analyze changes in JAK2V617F allele burden.
Methods: We performed a single centre study on 65 patients (19 polycythemia vera (PV), 42 essential thrombocythemia (ET) and 4 primary myelofibrosis (PMF)) all of them with at least two JAK2V617F determination separated by minimum 12 months. The JAK2 mutation was determinated in DNA from peripheral blood granulocytes (in 3 cases from bone marrow smear) by MutaScreenTMKit (IPSOGEN).
Results: The mean follow-up period was 26 months (range 12–176). In 42/65 (64.6%) patients JAK2 mutation was positive and in 24/42 (57%) changes in JAK2V617F allele burden (&gt;10%) were observed. Interestingly, in 7/18 (39%) patients who showed an increase of JAK2V617F allele burden progression was observed. In this group, one case of PMF with initial increase of JAK2V617F allele burden during transformation to acute myeloid leukemia (AML) and posterior decrease after transformation* and one case of ET with an increase during transformation to myelofibrosis (MF) and posterior conversion to JAK2V617F negativity after allo-HSCT** were observed (table1). 36/42 (85.7%) of JAK2V617F positive patients were under cytoreductive treatment: 30 with hydroxyurea (HDU), 1 anagrelide (ANA) and 5 mixed. There was no decrease of JAK2-V617F allele burden in patients without cytoreductive treatment. Data of patients with HDU treatment are presented in table 2. 3/5 of patients with mixed cytoreduction showed an increase of JAK2V617F allele burden: all of them presented bad clinical control but no data of progression were observed. None of JAK2V617F negative patients (n=23: 1 PV, 2 PMF, 20 ET) became positive for the mutation with the mean follow-up period of 19.37 months. There were no cases of transformation in this group of patients.
Conclusions: According to our study, JAK2V617F allele burden can change during the follow-up. Increase (or stability) of JAK2V617F allele burden are more frequent in transformation from ET to PV or MF; in cases of progression to AML we can observe decrease, stability or initial increase with posterior decrease of JAK2V617F allele burden. Decrease of JAK2 allele burden can be related to cytoreductive treatment. Increase of JAK2V61F in patients with cytoreductive treatment can be related to transformation or bad clinical control. More prospective studies are needed to conclude whether changes in JAK2-V617F allele burden could be useful to predict transformation of MPN patients.
Table1. Changes of JAK2V617F allele burden and clinical evolution in JAK2V617F positive patients.
JAK2 Clinical evolution (N=42) STABILITY PROGRESSION DECREASE 6/42 (14%) 5 1 [1 PV-AML] STABILITY 18/42 (33%) 15 3 [1 PV-MF; 1 ET-MF; 1 ET-AML] INCREASE 18/42 (43%) 11 7 [3 ET-PV; 3 ET-MF (one case with posterior allo-HSCT**); 1 PMF-AML*]
Table2. Changes of JAK2V617F allele burden in JAK2V617F positive patients with HDU and no cytoreductive treatment.
Treatment JAK2V617F: changes of allele burden DECREASE STABILITY INCREASE Untreated - 4 2 [ET-PV] HDU newly started 2 5 [PV-MF and ET-AML after 14 and 7 years of treatment respectively] 7 [2 ET-PV; PMF-AML*] HDU already treated 3 [PV-AML] 7 6 [3 ET-MF (one case with posterior allo-HSCT**)]