MILAN—Two new studies appear to confirm the prognostic significance of CALR mutations in patients with primary myelofibrosis (PMF).
One study showed that PMF patients with mutated CALR had prolonged overall survival (OS) compared to patients with wild-type CALR. And additional subclonal mutations did not impair the positive impact of CALR mutations.
Another study suggested that indels in exon 9 of CALR are founding driver mutations in PMF. These mutations are independent predictors of clinical course, disease progression, and OS.
Both studies were presented at the 19th Congress of the European Hematology Association (EHA).
Paola Guglielmelli, MD, PhD, of the University of Florence in Italy, presented data on CALR mutations in the context of additional mutations (abstract S1355).
And Elisa Rumi, MD, of the University of Pavia in Italy, presented information on mutated CALR and other founding driver mutations in PMF (abstract S1356).
CALR & other subclonal mutations in PMF
To investigate the prognostic role of CALR mutations in relation to additional subclonal mutations, Dr Guglielmelli and her colleagues analyzed 274 samples from PMF patients.
The team genotyped the samples for mutations in 11 genes: JAK2, CALR, MPL, EZH2, ASXL1, SRSF2, IDH1, IDH2, CBL, TET2, and DNMT3A.
Two hundred and fifty-six patients (93.4%) presented with at least 1 somatic mutation, and 104 (38%) presented with at least 2.
The median follow-up was 3.8 years (range, 0.52-29.20 years). Among all patients, the median OS was 12.2 years (range, 5.6-18.8 years). Eighty-four patients died (30.7%), 44 (16.1%) of them due to leukemia.
The presence of CALR mutations was associated with better OS, independent of IPSS and molecular risk categories (hazard ratio [HR] 0.51, P=0.03). But CALR mutations did not impact the risk of progression to acute leukemia.
Among patients with a low- to intermediate-1-risk IPSS score, those with CALR mutations lived a median of 27.7 years, and those without lived a median of 21.7 years (HR 0.4, P=0.02). Among patients with intermediate-2 to high risk, those with CALR mutations lived a median of 4.2 years, and those without lived a median of 2.6 years (HR=0.5, P=0.09).
Among patients with high molecular risk, those with CALR mutations lived a median of 17.7 years, and those without lived a median of 4.3 years, (HR=0.3, P=0.008). High molecular risk was defined as at least 1 mutation in ASXL1, EZH2, SRSF2, or IDH1/2.
Among patients in the low-molecular-risk group, those with CALR mutations lived a median of 27.7 years, and those without lived a median of 21.7 years (HR=0.6, P=0.048).
Dr Guglielmelli said these results confirm the association between CALR mutation and favorable outcomes in PMF. They also show that additional subclonal mutations do not impair the positive impact of CALR mutation, thereby reinforcing the idea that CALR-mutated PMF is a distinct entity in terms of prognosis.
Founding driver mutations in PMF
In another presentation at the EHA Congress, Dr Rumi presented data on founding driver mutations in PMF. She and her colleagues analyzed 617 PMF patients, screening them for JAK2 V617F mutations, indels of CALR exon 9, and MPL exon 10 mutations.
The researchers assessed the impact of these mutations on thrombosis, progression to leukemia, and OS.
Their analysis suggested CALR-mutated PMF patients have a lower risk of thrombosis than JAK2-mutated patients (P=0.021). And this difference retained significance after adjusting for age.
Triple-negative PMF patients had a higher risk of leukemic evolution than CALR-mutated patients (P=0.016) and JAK2-mutated patients (P=0.043).
After adjusting for age, the risk remained significantly higher in triple-negative patients compared to JAK2-mutated patients (P=0.04) and retained borderline significance compared to CALR-mutated patients (P=0.052).
Patients with CALR-mutated PMF had a better OS than JAK2-mutated patients (P<0.001), MPL-mutated patients (P=0.009), and triple-negative patients (P<0.001).
In a multivariate analysis, CALR-mutated patients maintained a better OS than JAK2-mutated patients (P=0.019) and triple-negative patients (P<0.001).
Based on these results, Dr Rumi concluded that mutations in JAK2, CALR, and MPL are independent predictors of clinical course, disease progression, and OS in PMF. So screening patients for these mutations can likely improve upon the risk stratification provided by IPSS.
