What is the recommended treatment approach for a patient with CALR‑positive primary myelofibrosis?

Treatment of CALR-Positive Primary Myelofibrosis

Treatment decisions for CALR-positive primary myelofibrosis should be based on risk stratification using DIPSS-plus or molecular prognostic models, with allogeneic stem cell transplantation reserved for high-risk disease and JAK2 inhibitors (ruxolitinib, fedratinib, or pacritinib) used for symptomatic intermediate-2 or high-risk patients with splenomegaly. 1, 2

Risk Stratification and Prognostic Significance

CALR-positive myelofibrosis represents a molecularly favorable subgroup with superior survival compared to JAK2-mutated or triple-negative disease. 3

• CALR(+)ASXL1(-) patients have the longest median survival at 10.4 years, compared to 2.3 years for CALR(-)ASXL1(+) patients (HR 5.9; 95% CI 3.5-10.0). 3
• CALR Type 1/Type 1-like mutations confer improved overall survival compared to CALR Type 2 or JAK2 V617F mutations. 1
• The CALR/ASXL1 mutation-based prognostic model is DIPSS-plus independent (P<0.0001) and effectively identifies patients with dramatically different survival outcomes. 3
• CALR-positive patients typically present younger, with higher platelet counts, less pronounced splenomegaly, and fewer constitutional symptoms compared to JAK2-mutated patients. 4, 5

Treatment Algorithm Based on Risk Category

Low and Very Low Risk (MIPSSv2)

Observation alone is the recommended approach for patients with low or very low-risk disease (estimated 10-year survival 56%-92%). 2

• These patients do not require immediate cytoreductive therapy unless symptomatic. 1
• Regular monitoring for disease progression is appropriate. 1

Intermediate-1 Risk

Allogeneic hematopoietic stem cell transplantation (AHSCT) should be considered in carefully selected intermediate-1 risk patients who present with refractory transfusion-dependent anemia, peripheral blood blasts >2%, adverse cytogenetics, or high-risk mutations (ASXL1, SRSF2, U2AF1-Q157). 1, 2

• For symptomatic patients not eligible for transplant, ruxolitinib is recommended for highly symptomatic splenomegaly. 1
• The transplant procedure should be performed in a controlled setting. 1

Intermediate-2 and High Risk

AHSCT is the preferred treatment of choice for intermediate-2 and high-risk disease (estimated 10-year survival 0-13%), as it remains the only curative modality. 1, 2, 4

• For patients ineligible for transplant, JAK2 inhibitors are first-line therapy for splenomegaly and constitutional symptoms. 1, 2

JAK2 Inhibitor Therapy

First-Line JAK2 Inhibitor Selection

Ruxolitinib is the recommended first-line JAK2 inhibitor for patients with intermediate-2 or high-risk myelofibrosis presenting with splenomegaly. 1, 2

• Ruxolitinib achieves spleen volume reduction ≥35% in a significant proportion of patients. 6
• Symptom response requires ≥50% reduction in MPN-SAF Total Symptom Score, though responses <50% may be clinically meaningful and justify continued use. 1

Second-Line Options After Ruxolitinib Failure

Fedratinib is FDA-approved for patients failing treatment with ruxolitinib. 2

• In the JAKARTA trial, 37% of patients achieved ≥35% spleen volume reduction at end of Cycle 6 with fedratinib 400 mg daily versus 1% with placebo (p<0.0001). 6
• 40% of patients achieved ≥50% reduction in Total Symptom Score versus 9% with placebo (p<0.0001). 6
• Median duration of spleen response was 18.2 months. 6

Pacritinib is FDA-approved specifically for patients with platelet counts <50 × 10⁹/L. 2

Emerging Option

Momelotinib has shown erythropoietic benefits in addition to spleen and symptom responses and is poised for FDA approval. 2

Management of Specific Complications

Anemia Management

Drug therapy for anemia includes erythropoiesis-stimulating agents, danazol, or other supportive measures, as JAK2 inhibitors can worsen anemia. 1, 2

• Dose-limiting anemia is an on-target effect of ruxolitinib because erythropoiesis depends on JAK-STAT signaling. 1

Splenomegaly Refractory to Medical Therapy

Splenectomy should be considered for drug-refractory splenomegaly. 2

Extramedullary Hematopoiesis

Involved field radiotherapy is recommended for non-hepatosplenic extramedullary hematopoiesis and extremity bone pain. 2

Critical Prognostic Mutations to Assess

Beyond CALR status, testing for ASXL1, SRSF2, and U2AF1-Q157 mutations is essential as these predict inferior survival. 1, 2

• RAS/CBL mutations predict resistance to ruxolitinib therapy and should be assessed before initiating treatment. 2
• Very high-risk cytogenetic abnormalities include -7, inv(3), i(17q), +21, +19, 12p-, and 11q-. 1

Common Clinical Pitfalls

Do not assume all CALR-positive patients have favorable prognosis—the presence of concurrent ASXL1 mutation significantly worsens outcomes (median survival 5.8 years for CALR(+)ASXL1(+) versus 10.4 years for CALR(+)ASXL1(-)). 3

Triple-negative status (absence of JAK2, CALR, and MPL mutations) confers particularly poor prognosis with shorter overall survival (HR 7.0; 95% CI 1.6-31.1) and leukemia-free survival (HR 6.3; 95% CI 1.8-22.0). 5

CALR Type 2 mutations may have inferior outcomes compared to Type 1 mutations, warranting closer monitoring. 7