Calreticulin Mutations Can Worsen Survival Outcomes in Ruxolitinib-Treated Patients With Myelofibrosis

Patients with myelofibrosis (MF) who harbor calreticulin (CALR) mutations begin treatment with ruxolitinib presenting severe disease with a longer median time from diagnosis, with inferior spleen responses and lower rates of symptom responses observed at 6-months, according to study results published in Annals of Hematology.¹

CALR mutations in patients with myelofibrosis being treated with ruxolitinib can lead to worsened outcomes. | Image Credit: © rost9 | stock.adobe.com

CALR mutations can be found in around 20% of patients with primary and post-essential thrombocythemia (ET) MF. Patients who harbor CALR mutations often present with distinct clinical features compared with Janus kinase (JAK)2-mutated patients. Typically, they feature lower levels of hemoglobin and white blood cells, present at younger age, and are associated with better survival rates.^1,2

Ruxolitinib (Jakfafi; Incyte) is a targeted therapeutic option for patients with MF that has shown efficacy regardless of the driver mutation in patients. However, new therapies continue to be developed that specifically target CALR, necessitating further research on therapies that are currently standard in CALR-positive patients, according to the investigators.^1,3

The study authors reported the outcomes of a sub-analysis of the RUX-MF clinical trial, documenting 135 patients with CALR mutation who received ruxolitinib in a real-world setting. The analysis was performed with major considerations, including that the younger age of CALR-mutated patients compared with JAK2-mutated patients may influence survival outcomes, and that younger patients are eligible for allogeneic stem cell transplantation, which the investigators noted could meaningfully impact the treatment algorithm.¹

In total, 786 patients from the RUX-MF trial were JAK2-mutated, while 135 had a CALR mutation. Only 78 CALR-mutated patients were evaluable, in which their mutation was type 1-like in 66.7% of the population, while 30.8% had type 2-like mutation. At the beginning of ruxolitinib initiation, CALR-mutated patients were younger, had higher percentages of peripheral blasts, and lower median hemoglobin levels compared with JAK2-mutated patients.¹

Responses to ruxolitinib and patient outcomes according to mutation type were reported at 6 months. There were no major differences in spleen responses (CALR: 21.4%; JAK2: 25.7%), and there were comparable rates of treatment-emergent anemia (CALR: 35.7%; JAK2: 30.4%) and both overall and treatment-emergent thrombocytopenia. However, symptoms response was significantly lower in CALR-mutated patients (56.1% vs 66.7%), and overall anemia rates (60.3% vs 50.3%) were higher in this population compared with JAK2-mutated participants.¹

Across the 135 patients with CALR mutation, there were no factors associated with spleen or symptom response. Notably, factors correlated with worse survival included hemoglobin below 10 g/dL and a high burden of symptoms. In the subgroup of 72 CALR-mutated patients who began ruxolitinib over 2 years following diagnosis, anemia (HR: 1.92; 95% CI, 1.02-3.79) and the use of a reduced ruxolitinib initiation dose (HR: 2.29; 95% CI, 1.15-4.56) were associated with poor overall survival.¹

Survival outcomes of various other subgroups were examined. In patients who were transplant-eligible (523), overall survival (OS) rates at 3 and 5 years was 79.7% and 63.7% for CALR-mutated patients and 81.5% and 69.1% for JAK2-mutated patients, respectively. For patients who were of older age (398), OS rates at 3 and 5 years were 62.8% and 35.5% for CALR-mutated patients and 54.4% and 36.2% for JAK2-mutated patients, respectively.¹

Not only do these data reveal that CALR-mutated patients present with a more severe clinical burden when starting ruxolitinib, but the investigators observed a greater worsening of clinical and laboratory features between diagnosis and ruxolitinib start in CALR-mutated patients compared with JAK2-mutated patients. They note that the prolonged time to beginning ruxolitinib—perhaps due to patients harboring a more indolent nature of MF—had a major impact on the worsened outcomes for patients with CALR. Overall, despite previous research to the contrary, these investigators “failed to confirm” that patients with CALR have more prolonged survival during ruxolitinib therapy.^1,2

“CALR-mutated patients may require more innovative therapeutic interventions to achieve optimal outcomes,” the study investigators concluded. “This further emphasizes the necessity of exploring alternative or adjunctive therapies tailored specifically for CALR-mutated individuals.”¹

REFERENCES

1. Palandri F, Branzanti F, Morsia E, et al. Impact of calreticulin mutations on treatment and survival outcomes in myelofibrosis during ruxolitinib therapy. Ann Hematol. 2025. doi:10.1007/s00277-025-06204-5

2. Klampfl T, Gisslinger H, Harutyunyan AS, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med. 2013;369(25):2379-2390. doi:10.1056/NEJMoa1311347

3. Arakelians S. Myelofibrosis treatment options: A guide for pharmacists. Pharmacy Times. Published January 2, 2025. Accessed January 28, 2025. https://www.pharmacytimes.com/view/myelofibrosis-treatment-options-a-guide-for-pharmacists