What is the recommended treatment for an adult with primary myelofibrosis, CALR‑mutated, intermediate‑1 risk by the Dynamic International Prognostic Scoring System, without life‑threatening cytopenias?

Treatment of CALR-Mutated DIPSS Intermediate-1 Risk Myelofibrosis

For CALR-mutated primary myelofibrosis with DIPSS intermediate-1 risk and no life-threatening cytopenias, observation with close monitoring is the recommended approach, as these patients have a favorable prognosis with median survival exceeding 10 years, particularly if ASXL1-negative. 1, 2

Prognostic Context Guiding Treatment Decisions

Your patient occupies a uniquely favorable prognostic niche that fundamentally shapes management:

• CALR-positive, ASXL1-negative patients demonstrate the longest overall survival in myelofibrosis (median 10.4 years), making aggressive intervention unnecessary in the absence of symptoms 1, 2
• The intermediate-1 DIPSS risk category itself carries a median survival of approximately 6.5 years, but the CALR mutation status significantly improves this prognosis 3
• Molecular assessment for ASXL1 mutation is specifically recommended for therapeutic decisions in intermediate-1 risk patients, as ASXL1 positivity would substantially worsen prognosis and potentially warrant consideration of allogeneic stem cell transplant 1

Recommended Management Strategy

Observation Approach

• Observation alone is advised for patients without high-risk mutations and intermediate-1 risk disease 4
• This recommendation is based on the excellent survival outcomes in CALR-mutated disease and the lack of disease-modifying potential of currently available JAK2 inhibitors 5, 4
• JAK2 inhibitors have not demonstrated the ability to induce complete remissions, significantly affect mutant allele burden, or modify the natural history of disease 3

Essential Molecular Testing

Before finalizing the observation strategy, ASXL1 mutation status must be determined 1:

• If ASXL1-negative: Continue observation with routine monitoring
• If ASXL1-positive: The patient moves into a higher molecular risk category (median survival 5.8 years) and should be evaluated for allogeneic hematopoietic stem cell transplant, which is the only curative therapy 1, 4, 2

Monitoring Protocol

Regular monitoring every 3-6 months is recommended to assess for disease progression 6:

• Monitor for worsening cytopenias
• Assess for increasing blast percentage
• Evaluate for development of transfusion dependency (which predicts median survival <5 years) 6
• Monitor for symptomatic splenomegaly or constitutional symptoms

When to Initiate Treatment

Treatment should be initiated only when specific indications develop 5, 4:

Indications for JAK2 Inhibitor Therapy

• Symptomatic splenomegaly: Ruxolitinib, fedratinib, or pacritinib (if platelets <50 × 10⁹/L) 5, 4
• Constitutional symptoms: Ruxolitinib is the preferred agent 4
• Momelotinib may be considered if anemia develops, as it has shown erythropoietic benefits in addition to spleen and symptom responses 7, 5

Indications for Anemia-Directed Therapy

If symptomatic anemia develops without other indications for JAK inhibitors 4:

• Androgens
• Prednisone
• Thalidomide
• Danazol

Indications for Allogeneic Stem Cell Transplant

Transplant should be considered if 1, 4:

• ASXL1 mutation is present (moving patient to higher molecular risk)
• Disease progresses to intermediate-2 or high-risk category
• Additional high-risk mutations are detected (SRSF2, U2AF1-Q157) 4

Critical Pitfalls to Avoid

• Do not initiate JAK2 inhibitor therapy in asymptomatic patients: These agents are purely palliative and do not modify disease course 5, 4, 3
• Do not skip ASXL1 testing: This mutation is DIPSS-plus independent and specifically recommended for therapeutic decisions in intermediate-1 risk patients 1
• Do not overlook transfusion dependency: Development of transfusion need identifies patients with dramatically shortened survival (<5 years) and warrants treatment escalation 6
• Do not delay transplant evaluation if high-risk mutations emerge: Allogeneic stem cell transplant is the only curative option and should be pursued in appropriate candidates with adverse molecular features 4