What is myelofibrosis and how does it impact stem cell transplant outcomes in patients with intermediate to high-risk disease?

Understanding Myelofibrosis and Its Impact on Stem Cell Transplantation

Allogeneic stem cell transplantation (alloSCT) is the only potentially curative treatment for myelofibrosis but carries substantial treatment-related mortality (approximately 30% at 1 year with conventional conditioning), making patient selection and timing critical for optimizing survival outcomes. 1

What is Myelofibrosis?

Myelofibrosis is a clonal myeloproliferative neoplasm characterized by progressive bone marrow fibrosis, splenomegaly, constitutional symptoms (night sweats, weight loss, fever), and cytopenias. 2, 3 The disease results from ineffective hematopoiesis with extramedullary blood cell production occurring in the spleen and liver. 1 Common molecular drivers include JAK2V617F, CALR, and MPL mutations, though the disease pathogenesis is multifactorial involving both clonal proliferation and microenvironmental changes. 1, 3

How Myelofibrosis Affects Stem Cell Transplant Outcomes

Transplant Candidacy and Risk Stratification

Allogeneic transplantation should be reserved for intermediate-2 and high-risk patients (DIPSS-Plus score 4-6, IPSS ≥3) whose expected median survival without transplant is less than 5 years. 1 This recommendation is based on the risk-benefit analysis showing that:

• Conventional-intensity conditioning alloSCT has approximately 30% 1-year treatment-related mortality with 50% overall survival at 1 year 1
• Reduced-intensity conditioning alloSCT achieves 45% 5-year median survival with similar rates of treatment-related and relapse-related deaths 1
• Non-transplant intermediate/high-risk patients have 1-year survival of 71-95% and 3-year survival of 55-77%, making the transplant risk justifiable only when expected survival is substantially shorter 1

Disease-Specific Factors Affecting Transplant Outcomes

Bone marrow fibrosis itself adversely impacts transplant outcomes by correlating with higher relapse rates and delayed engraftment. 1 Additional factors that worsen transplant prognosis include:

• Thrombocytopenia ≤50,000/μL - indicates impending leukemic transformation and warrants immediate transplant evaluation 1
• Complex cytogenetics - particularly in intermediate-1 risk patients, this upgrades them to transplant candidates 1
• High-risk molecular mutations - NRAS, DNMT3A, JAK2, and TP53 mutations predict worse post-transplant outcomes 1
• High mutation burden - ≥10 mutations or ≥4 mutated epigenetic regulatory genes increase post-transplant relapse risk 1

Timing Considerations

For intermediate-1 risk patients (DIPSS 1-2, IPSS=1), transplant should be deferred unless additional high-risk features emerge, including low platelets, complex cytogenetics, or progressive disease. 1 Dynamic reassessment every 3-6 months is essential to detect:

• Rapidly increasing white blood cell counts (>10,000 increase within ≤3 months) 1
• Rising blast percentages in blood or marrow 1
• Clonal evolution on cytogenetic studies 1
• Worsening cytopenias 1

Pre-Transplant Management Challenges

Splenomegaly presents a significant peri-transplant challenge, with splenectomy carrying 5-10% perioperative mortality and 50% complication rates in myelofibrosis patients. 1 Complications include surgical bleeding, thrombosis, subphrenic abscess, accelerated hepatomegaly, and extreme thrombocytosis. 1, 4 When splenectomy is necessary before transplant, prophylactic measures include:

• Cytoreduction to maintain platelets <400,000/μL 1, 4
• Immediate postoperative therapeutic anticoagulation with LMWH 4
• Lifelong antibiotic prophylaxis (penicillin or erythromycin) to prevent overwhelming post-splenectomy infection 4

Post-Transplant Monitoring

JAK2V617F allele burden monitoring post-transplant is useful for predicting relapse and should be incorporated into routine surveillance. 1 Additional monitoring parameters include cytogenetics, spleen size, blood counts, leukoerythroblastosis, LDH, circulating CD34+ cells, and bone marrow morphology/fibrosis. 1

Critical Pitfalls to Avoid

Do not proceed with transplant in low-risk patients (DIPSS=0, IPSS=0) as their median survival exceeds 10 years and transplant-related mortality outweighs potential benefit. 1 These patients should receive observation or JAK inhibitor therapy if symptomatic. 1

Blast-phase transformation (≥20% blasts) requires induction chemotherapy or hypomethylating agents before transplant, though complete remission is not mandatory if disease reverts to chronic phase. 1 Blast-phase disease has median survival of only 6 months without aggressive intervention. 1

Patient selection must account for age, performance status, major comorbidities, and caregiver availability - not just disease risk scores - as these factors significantly impact transplant-related mortality. 1