Validation of the differential prognostic impact of type 1/type 1-like versus type 2/type 2-like CALR mutations in myelofibrosis

The discovery of mutations in calreticulin ( CALR ) in patients with primary myelofibrosis (PMF) 1 , 2 prompted a reappraisal of the clinical correlates and prognostic impact of the so-called driver mutations that include JAK2 V617F, MPL W515L/K/A and CALR in ~60%, 5–10% and 20–25% of patients, respectively. As compared with their JAK2 V617F counterpart, PMF patients harboring CALR mutations showed younger age, higher platelet and lower hemoglobin and leukocyte counts. The cumulative incidence of anemia, leukocytosis and thrombocytopenia was significantly lower in CALR -mutated patients who were also less likely to be red cell transfusion-dependent; 3 , 4 in addition, they had significantly longer large splenomegaly-free survival compared with the other genotypes as well as patients lacking the three driver mutations (triple-negative (TN) patients). 3 , 4 Interestingly, spliceosome mutations were significantly less represented in CALR- mutated patients; however, no additional molecular or cytogenetic correlate was highlighted. 3 These data suggested a milder disease in patients harboring the CALR mutation, and conceivably the presence of CALR mutation was associated with better overall survival (OS) when compared with JAK2 V617F- and MPL W515-mutated patients, and particularly TN patients. 3 , 4 In multivariable analysis, CALR mutations had a favorable impact on survival that was independent of International Prognostic Scoring System (IPSS), Dinamic IPSS (DIPSS) 4 or DIPSS-plus risk stratification, 3 and also of ASXL1 mutation, known for its dismal impact on survival in PMF. 5 At this regard, we found that DIPSS-plus-independent OS was significantly longer in CALR -mutated/ ASXL1 -unmutated compared with CALR -unmutated/ ASXL1 -mutated patients. 6