The Impact of Driver Mutations of JAK2, Calr, or MPL in Patients with Myelofibrosis Undergoing Hemopoietic Stem Cell Transplantation

Introduction. The vast majority of patients with primary myelofibrosis (PMF) have been shown to carry driver mutations of JAK2, CALR (calreticulin gene) or MPL ì, and these molecular leasions may impact the clinical course of the disease. In a recent paper (Blood 2014;124:1062) patients with CALR mutation, had a lower risk of developing anemia, thrombocytopenia, marked leukocytosis, thrombosis and showed better overall survival, than either JAK2 -mutant or triple-negative patients.

Aim of the study. The aim of the present study was to assess whether CALR exon 9 mutation, conferred a survival advantage in MF patients undergoing a hemopoietic stem cell transplant (HSCT).

Patients. All patients were selected for transplant by two authors (AB and GB) and grafted in Genova.

Patients are outlined in 2 groups: 15 with CALR mutation and 31 with wild-type CALR; the latter included 21 patients with JAK2 (V617F), 7 patients with MPL mutation and 3 patients triple negative. There were no significant differences, between the 2 groups in terms of DIPSS, spleen size, circulating CD34+ cell count, donor type, year of HSCT and conditioning regimens.

Mutation status. Granulocyte JAK2 (V617F) mutation status and mutant allele burden were assessed using a quantitative polymerase chain reaction (qPCR)-based allelic discrimination assay on a Rotor-Gene 6000 real-time analyzer (Qiagen), as previously described.^1,2 Patients without JAK2 (V617F) were evaluated for MPL exon 10 mutations using a high-resolution melt (HRM) assay or Sanger sequencing.^3,4 Patients with nonmutated JAK2 and MPL were studied for CALR exon 9 mutations as reported in our original paper or by Sanger sequencing, as described elsewhere.⁴

Results. With a median follow up of over 500 days for both groups, we could find no significant differences in CALR -mutated patients as compared to the remaining ones: transplant related mortality (26% vs 29%, respectively); relapse (20% vs 39%, p=0.2), relapse related death (20% vs 22%) and survival (47% vs 52%, p=0.7).

When dissecting the patients with wild-type CALR, we could indeed see a survival advantage for the small number of MPL -mutated patients (n=7): when these were compared against all the others (n=39), again with similar disease and transplant characteristics, survival was 86% vs 44% (p=0.04) and relapse 14% vs 36% (p=0.2). In multivariate analysis, DIPPS was the only predictor of survival.

Conclusions. These data suggests that CALR mutation does not confer a survival advantage in PMF patients undergoing an allogeneic HSCT. MPL mutation, on the other hand, though present in a very small number of patients, may be worth investigating further in a larger number of patients.