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Outcomes in primary myelofibrosis varied greatly based on mutation status
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Driver mutations of JAK2, MPL and the calreticulin gene further divided primary myelofibrosis into distinct subtypes, and outcomes such as disease progression and OS varied considerably between each group of patients, according to study results.
Although JAK2 and MPL mutation testing has significantly simplified the diagnosis of primary myelofibrosis, the genomic landscape has become more complicated in recent years, researchers wrote.
“In 2013, somatic mutations of CALR, the gene encoding calreticulin, have been found in 20% to 25% of patients with essential thrombocythemia or primary myelofibrosis,” Elisa Rumi, MD, of the department of molecular medicine at University of Pavia in Italy, and colleagues wrote. “Like JAK2 and MPL mutations, somatic mutations of CALR behave as driver mutations responsible for the myeloproliferative phenotype.”
Rumi and colleagues performed mutational analysis in 617 patients with primary myelofibrosis to assess the effect of driver mutations of JAK2, CALR or MPL on clinical course, leukemic transformation and survival.
Researchers identified the JAK2 V617F mutation in 64.7% (n=399) of the cohort, the CALR exon 9 indel in 22.7% (n=140) of the cohort, and the MPL W515 mutation in 4% (n=25) of the cohort. They determined 8.6% (n=53) of the cohort exhibited nonmutated JAK2, CALR and MPL, otherwise known as triple-negative primary myelofibrosis.
Results showed patients with a CALR mutation exhibited a lower risk for developing anemia, marked leukocytosis and thrombocytopenia compared with other subtypes. These patients also had a lower risk for thrombosis compared with patients who harbored JAK2 V617F mutations.
However, researchers observed that triple-negative patients experienced higher incidence of leukemic transformation compared with patients who harbored CALR or JAK2 mutations.
Rumi and colleagues reported median OS of 17.7 years for patients with CALR mutations, 9.2 years for patients with JAK2 mutations, 9.1 years for patients with MPL mutations and 3.2 years for triple-negative patients.
Multivariate analyses indicated that patients with CALR mutations experienced longer OS than patients with JAK2 mutations or those with triple-negative primary myelofibrosis.
“The remarkable differences in clinical course and outcomes observed among the diverse genetic subtypes suggest that, in spite of similar clinical features, the disease biology varies considerably according to the different genetic lesions,” Rumi and colleagues wrote. “The findings of this study provide a proof of concept that a genetic classification of primary myelofibrosis is not only feasible but also highly relevant to clinical decision-making as regards diagnostic approach and prognostication. In addition, they indicate that primary myelofibrosis genotypes should now be considered [when] designing clinical trials on the use of novel drugs for treatment of primary myelofibrosis.”
Perspective
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Ramon Tiu, MD
Molecular mutations of specific genes have provided insight into the pathogenesis of several myeloid neoplasms. These genetic mutations can be helpful in diagnosis and prognosis, and sometimes as predictive biomarkers for specific pharmacologic therapies. The ultimate goal is that they may help provide mechanistic clues that also can lead to targeted therapies specific to patients who harbor a specific genetic defect and may lead to better response rates and, potentially, cures.
In myelofibrosis (MF), genetic mutations in JAK2 are found in 50% to 60% of patients, and mutations in MPL genes are found in 5% to 10% of patients. Their primary use is for diagnosis, although some studies suggest that they may be prognostically important as well. Thus, the genetic mutational landscape of the remaining 50% of patients with MF and essential thrombocythemia (ET) patients who were genetically unaccounted for subsequently became the primary area of interest. It led to the coining of the term “triple-negative MF” to initially refer to MF patients who are wild-type for JAK2 exon 14, JAK2 exon 12 and MPL, first used by our group in 2012 (Tabarroki A. Abstract #3805. Presented at: ASH Annual Meeting; Dec. 8-11, 2012; Atlanta).
Two independent groups identified recurrent mutations in the calreticulin (CALR) gene in these triple-negative MF and ET patients and constitute 50% of triple-negative ET and MF, respectively. Aside from being important diagnostically, the presence of mutations in CALR is associated with better survival outcomes.
The study by Rumi and colleagues confirms many of the clinical observations made by Klampfl and colleagues, as well as Nangalia and colleagues. This study represents a large cohort of patients from two major hematology centers in Italy and one center in Spain. They found that patients who harbor the CALR mutation have decreased risk for the development of anemia, thrombocytopenia and marked leukocytosis. They also have better OS and are independent predictors of better outcomes. Patients with ET or MF who are wild-type for JAK2, MPL and CALR are now called “triple-negative MF or ET,” a group of patients who have poor outcomes.
These findings have several clinical and research implications. They suggest that the design of future prognostic scoring systems — and maybe even pharmacologic or hematopoietic cell transplantation clinical trials for MF — must take into account CALR molecular mutational status. Specific studies intended to study disease mechanisms in CALR -mutant cases will be very important, and the poor outcomes seen in patients who are currently labelled as triple-negative MF must be investigated for additional mutations or pathogenetic mechanisms that may explain their more aggressive disease phenotype.
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