What are the steps of allogeneic hematopoietic stem‑cell transplantation for a patient with intermediate‑2 or high‑risk myelofibrosis being evaluated for curative therapy?

Allogeneic Hematopoietic Stem Cell Transplantation for Intermediate-2 or High-Risk Myelofibrosis

For patients with intermediate-2 or high-risk myelofibrosis, allogeneic hematopoietic stem cell transplantation (allo-HSCT) should be pursued as the only curative therapy, with transplant-eligible patients proceeding directly to transplantation as soon as possible, preferably without disease-modifying treatment to maximize the chance of reaching transplant. 1

Patient Selection and Transplant Candidacy Assessment

Transplant eligibility determination is based on multiple factors that predict tolerability and outcomes 1:

• Age: Generally considered for patients <70 years, though reduced-intensity conditioning (RIC) has enabled successful transplantation in patients 60-70 years old 2, 3
• Performance status: Must be adequate to tolerate the procedure 1
• Comorbidity burden: Major comorbid conditions must be assessed using validated scoring systems 1
• Psychosocial factors: Patient preference and availability of caregiver support are essential 1

Risk stratification using DIPSS-Plus is preferred for determining transplant candidacy 1:

• Intermediate-2 risk: DIPSS-Plus score 4-6, median survival 30-37 months, 21-24% transformation to AML at 48 months 1
• High-risk: DIPSS-Plus score ≥4, median survival 17-18 months, 48-52% transformation to AML at 48 months 1

Molecular risk assessment should include next-generation sequencing to identify higher-risk mutations (ASXL1, EZH2, SRSF2, IDH1/2) that may influence transplant timing 1, 2, 4

Pre-Transplant Evaluation and Management

Baseline Assessment

Complete disease staging must be performed before proceeding 1:

• Bone marrow aspirate and biopsy with cytology, histology, flow cytometry
• Conventional cytogenetics and fluorescence in situ hybridization
• Comprehensive molecular testing including JAK2, CALR, MPL mutations
• Assessment of peripheral blood and bone marrow blast percentage
• Evaluation of splenomegaly and extramedullary disease

Splenomegaly Management

Splenectomy considerations prior to transplant 5:

• Indicated for symptomatic portal hypertension, drug-refractory marked splenomegaly, or established transfusion-dependent anemia
• Carries 5-10% perioperative mortality and approximately 50% complication rate
• Requires good performance status and absence of disseminated intravascular coagulation

Ruxolitinib use pre-transplant remains controversial 1:

• May be used as bridging therapy to reduce splenomegaly and improve symptoms
• Can decrease marrow blasts to acceptable levels if needed
• Should not delay transplant in high-risk patients

Blast Phase Management

For patients with elevated blasts (10-19% accelerated phase or ≥20% blast phase) 1:

• Induce remission with hypomethylating agents (azacitidine or decitabine) or intensive induction chemotherapy
• Complete remission is not required before transplantation if disease reverts to chronic phase 5
• Proceed to transplant as consolidation therapy

Donor Selection

Donor hierarchy for optimal outcomes 1, 4, 6:

1. HLA-matched sibling donor (MSD): Preferred first choice
2. Matched unrelated donor (MUD): Acceptable alternative with high-resolution HLA typing (≥9/10 loci matched)
3. Haploidentical donor (HID): Increasingly used option for patients without matched donors
4. Cord blood transplant (CBT): Alternative source when other options unavailable

Conditioning Regimen Selection

Reduced-intensity conditioning (RIC) is preferred over myeloablative conditioning (MAC) for most patients 2, 4, 6:

• RIC shows superior outcomes when adjusted for age
• Decreases transplant-related mortality (TRM)
• Enables successful transplantation in older patients (60-70 years)
• Typical regimens include fludarabine-based combinations with busulfan (dose-adjusted to target levels) or melphalan

Conditioning modifications that have improved outcomes 3:

• Omission of high-dose total body irradiation
• Busulfan dose adjustment to achieve defined target levels
• Use of fludarabine instead of cyclophosphamide for immunosuppression
• Addition of melphalan in some protocols
• Incorporation of antithymocyte globulin for GVHD prophylaxis

Stem Cell Source

Peripheral blood stem cells are the most commonly used source 4, 6:

• Faster engraftment compared to bone marrow
• Higher risk of chronic GVHD but potentially stronger graft-versus-tumor effect

Post-Transplant Monitoring and Management

Disease Monitoring

Molecular surveillance is critical for early relapse detection 1, 5, 4:

• Monitor JAK2V617F allele burden post-transplant to predict relapse
• Serial assessment of driver mutations using next-generation sequencing
• Peripheral blood monitoring increasingly used alongside bone marrow assessments

Donor chimerism monitoring should be performed regularly to detect mixed chimerism or declining donor engraftment 4

Response Assessment

Disease activity monitoring includes 5:

• Spleen size assessment
• Complete blood counts
• Peripheral blood leukoerythroblastosis
• Serum lactate dehydrogenase levels
• Circulating CD34+ cells
• Bone marrow morphology and fibrosis grading

Relapse Management

Early intervention for relapse 4:

• Aggressive monitoring of driver mutations
• Early cellular therapy (donor lymphocyte infusions)
• Consider ruxolitinib for symptomatic relapse

Expected Outcomes

Transplant outcomes for intermediate-2 and high-risk patients 5, 2:

• Cure rate: 40-70%
• Treatment-related mortality at 1 year: approximately 30%
• 5-year survival rates vary based on risk stratification and transplant-specific factors

Common pitfalls to avoid:

• Delaying transplant for disease-modifying therapy in high-risk patients reduces the chance of reaching transplantation 1
• Inadequate molecular risk assessment may miss opportunities for earlier transplant in molecularly high-risk patients 1, 2
• Using myeloablative conditioning in older patients increases TRM without survival benefit 2, 3