The discovery of mutations in exon 9 of the calreticulin (CALR) gene in the majority of cases of JAK2 wild-type essential thrombocythemia (ET) and primary myelofibrosis (PMF) came out of left field.1,2 This breakthrough dominated the landscape of myeloproliferative neoplasms (MPN) in 2014 and imbued investigators with a similar scholarly frenzy that followed the identification of JAK2 V617F in 2005.
CALR is a highly conserved protein with pleiotropic roles related to its distribution in the endosplasmic reticulum and cytosol, and on the cell surface. In cellular assays, transfection of mutant CALR leads to hyperactivation of the JAK-STAT pathway – a functional relationship that was unanticipated.2 The segregation of CALR mutations with cases of ET, PMF, and less frequently, refractory anemia with ring sideroblasts (RARS-T) is consistent with Dr. Alessandro Vannucchi and colleagues’ observation that CALR immunostaining primarily highlights megakaryocytes in marrow specimens from patients with these diagnoses.3 Together with the detection of mutant CALR in hematopoietic stem cells,1 these data define CALR-mutated MPNs as stem cell–derived neoplasms with aberrant and preferential expansion of the megakaryocyte lineage. A retroviral mouse model of mutant CALR phenocopies human disease and should be a useful platform for evaluating new treatments.4
What is the profile of the “typical” MPN patient with a CALR mutation? Compared with ET patients with JAK2 or MPL mutations, CALR-mutated ET patients are more commonly male, and they exhibit lower white blood cell and hemoglobin levels, higher platelet counts, a lower risk of thrombosis, but no clear difference in overall survival or transformation to myelofibrosis (MF).5,6 In PMF, carrying a CALR mutation is associated with better survival compared to patients with JAK2 or MPL mutations.2 However, Dr. Ayalew Tefferi and colleagues have shown that in PMF, the prognostic benefit of CALR mutations may be limited to type 1 (52-base pair [bp]) or type 1–like CALR variants; patients with type 2 (5-bp insertion) or type 2–like CALR variants exhibit comparably worse survival, which is comparable with that of PMF patients with JAK2 V617F.7 So-called triple-negative patients (nonmutated JAK2, CALR, and MPL) carry a poor prognosis and demonstrate a high rate of leukemic transformation.8
While CALR is a clonal marker that can provide diagnostic clarity in cases of ambiguous thrombocytosis, it does not have a bearing on therapeutic decisions in established cases of ET or PMF. For example, mutation of CALR does not affect the international prognostic score for predicting the risk of thrombosis in ET.9 Similarly, MF patients with mutant CALR exhibit responsiveness to JAK inhibitor therapy.10 For the individual patient, the prognostic import of mutated CALR needs to be weighed in the context of refined genetic-based scoring systems that layer additional prognostic information such as karyotype and other molecular abnormalities (especially poor-risk mutations in ASXL1, EZH2, SRSF2, IDH 1/2) on top of the clinical and laboratory variables that comprise the DIPSS-PLUS prognostic score. Such dynamic prognostic schemes are particularly relevant to decision making about hematopoietic stem cell transplantation.
At the end of 2014, the ASH annual meeting featured an eclectic mix of novel agents for MPNs. Current JAK inhibitors, which are type I inhibitors, only bind to the active conformation of the JAK2 kinase. These agents effectively reduce splenomegaly and symptom burden in patients with MF but exhibit modest effects on the MPN clone. Most MF patients exhibit disease persistence that has been attributed to transactivation of JAK2 by JAK family kinase members JAK1 and TYK2.11 The laboratory of Dr. Ross Levine at Memorial Sloan Kettering Cancer Center presented preclinical data on the type II JAK inhibitor NVP-CHZ868, which binds the inactive conformation of JAK2.12 The drug showed impressive activity in JAK inhibitor persistent cells as well as murine models of MF and polycythemia vera. These data portend a wave of promising second-generation JAK inhibitors in MF.
Follow-up pilot data were presented at the ASH annual meeting on the telomerase inhibitor imetelstat. The agent elicited partial or complete remissions in seven (21%) of 33 patients with intermediate-2/high risk MF.13 All patients with complete remission experienced reversal of bone marrow fibrosis, and three of them exhibited a complete molecular response. High-grade myelosuppression and treatment-emergent grade 1/2 liver function abnormalities were common, and will certainly guide dosing considerations for the upcoming phase II trial. Phase I/II data were presented on antifibrotics as well as inhibitors of histone deacetylase and the PI3 kinase and hedgehog signaling pathways. Time will tell whether any of these approaches prove useful in MF as monotherapy or in combination with JAK inhibitors. A satisfying bookend to the year in MPNs was the U.S. Food and Drug Administration approval of ruxolitinib for patients with polycythemia vera who have a resistance to, or intolerance of hydroxyurea. Approval was based on the randomized, phase III RESPONSE trial, in which ruxolitinib was found to be superior to best available care in achieving durable hematocrit control and spleen volume reduction.14
