What is the recommended protocol for a haploidentical (half-matched) transplant in a patient with Fanconi anemia?

Protocol for Haploidentical Transplantation in Fanconi Anemia

For haploidentical transplantation in Fanconi anemia patients, the recommended protocol is the FluCyATG regimen consisting of fludarabine 150 mg/m², cyclophosphamide 5-20 mg/kg/day × 4 days, and rabbit ATG 10 mg/kg, with or without low-dose TBI. 1

Conditioning Regimen

The conditioning regimen must be modified for Fanconi anemia patients due to their inherent DNA repair defects and hypersensitivity to alkylating agents and radiation:

• Fludarabine: 150 mg/m² total dose (30 mg/m²/day for 5 days)
• Cyclophosphamide: Reduced dose of 5-20 mg/kg/day × 4 days (significantly lower than standard doses used in other conditions)
• Anti-thymocyte globulin (rabbit): 10 mg/kg total dose
• Total Body Irradiation (optional): Low-dose (200 cGy) may be considered

This reduced-intensity conditioning is critical as Fanconi anemia patients cannot tolerate standard myeloablative regimens due to their DNA repair defects.

Donor Selection

For haploidentical donors, select in the following order of preference:

1. Children
2. Male siblings
3. Father
4. Siblings with non-inherited maternal antigen (NIMA)
5. Siblings with non-inherited paternal antigen (NIPA)
6. Mother
7. Other collateral relatives

Important considerations:

• Avoid donors with donor-specific anti-HLA antibodies (DSAs) with MFI > 10,000
• Prefer ABO and CMV IgG serological status compatibility
• Consider KIR ligand matching in haploidentical setting

GVHD Prophylaxis

Post-transplant cyclophosphamide (PT-CY) has shown promising results in haploidentical transplants for Fanconi anemia:

• PT-CY: 25 mg/kg/day on days +3 and +4 (total dose 50 mg/kg) 2, 3
• Cyclosporine: Starting day +5
• Mycophenolate mofetil: Starting day +5

Recent evidence suggests that adding rabbit ATG to the regimen reduces rates of severe GVHD while maintaining engraftment 2.

Stem Cell Source

Bone marrow is the preferred stem cell source for haploidentical transplantation in Fanconi anemia. G-CSF mobilized bone marrow with a target mononuclear cell count of 6 × 10⁸/kg recipient weight is recommended.

Monitoring and Supportive Care

1. Pre-transplant evaluation:

   • Complete blood count with differential
   • Bone marrow aspiration and biopsy
   • HLA typing (high-resolution)
   • Viral serology (CMV, EBV, HSV, VZV)
   • Organ function assessment

2. Post-transplant monitoring:

   • Daily CBC and electrolytes during hospitalization
   • CMV monitoring (weekly for first 100 days)
   • Chimerism studies at days +30, +60, +100, +180, +365
   • Bone marrow evaluation at day +30 and +100

3. Supportive care:

   • Antimicrobial prophylaxis (bacterial, fungal, viral)
   • Aggressive hydration during cyclophosphamide administration
   • MESNA for hemorrhagic cystitis prevention
   • Blood product support as needed

Potential Complications and Management

1. Hemorrhagic cystitis: Occurs in approximately 50% of patients 2

   • Prevention: Hyperhydration and MESNA during cyclophosphamide
   • Treatment: Continuous bladder irrigation if severe

2. CMV reactivation: Occurs in approximately 75% of patients 2

   • Preemptive therapy based on PCR monitoring

3. Graft failure: More common with reduced-intensity conditioning

   • Consider second transplant with modified conditioning if primary graft failure occurs

Outcomes and Prognosis

Recent studies using haploidentical transplantation with PT-CY for Fanconi anemia have reported:

• One-year overall survival of approximately 73% 2
• Better outcomes when r-ATG is included in the conditioning regimen
• Lower rates of severe GVHD with r-ATG inclusion
• Full donor chimerism in surviving patients

Important Considerations

1. Timing is critical: HSCT should be performed before progression to MDS or leukemia and before multiple transfusions 1

2. Dose adjustment: Due to DNA repair defects, Fanconi anemia patients require significantly reduced doses of alkylating agents compared to standard transplant protocols

3. Comorbidities: Pre-existing comorbidities significantly impact survival; early transplant referral is associated with better outcomes 2, 3

4. Post-transplant monitoring: Long-term follow-up for secondary malignancies is essential, particularly for head and neck squamous cell carcinoma

This protocol has shown promising results in improving engraftment while minimizing toxicity in this challenging patient population.