Chemotherapy-Only Preparative Regimen for Alternative Donor Hematopoietic Cell Transplantation for Patients with Fanconi Anemia (FA): Results of a Multi-Institutional Study

Objective:
This multi-institutional study was designed to optimize outcomes of alternative donor HCT in patients with FA without using total body irradiation (TBI). TBI was replaced by busulfan (BU) (to reduce the risk of secondary solid tumors) and BU dose was reduced after first 25 patients to find the lowest acceptable BU dose.

Methods:
45 patients were transplanted from June 2009 to May 2014. These included patients with prior transfusions, androgen use and myelosdysplastic syndrome.  Patient demographics, disease and donor characteristics are described in Table 1.

Preparative regimen included: BU (BU) 0.8-1.0 mg/Kg/dose IV (first 25 patients) and 0.6-0.8 mg/kg/dose Q 12H (next 20 patients) x 4 doses, cyclophosphamide (10mg/kg/dose), fludarabine (35mg/m2/dose) and rabbit ATG(2.5mg/kg/dose) daily x 4 days. BU doses were adjusted based on pharmacokinetics of the first dose. All grafts were T-cell depleted using the CliniMacs CD34 columns (Miltenyi). GvHD prophylaxis was cyclosporine.

Results:
43 patients engrafted. One patient had late graft failure and one had early relapse of MDS. See Table 2 for detailed results and transplant outcomes. One patient (#3) developed sinusoidal obstruction syndrome of liver. However, after reducing the BU goal level, no further SOS observed.

36 of the 45 patients are alive. Causes of death included infection (n=5), multi-organ failure (n=3), and severe pulmonary hypertension (n=1). One year probability of overall and disease free survival for the entire cohort was 79.2% (+/-6.2%) and 76.7 (+/-6.5%) respectively (Fig 1). OS for patients <10 years of age transplanted for marrow failure was 91.3 % (+/-5.9%) similar to that reported for historical matched sibling donor HCT outcomes.

Conclusion:
This chemotherapy only preparative regimen leads to excellent outcomes in patients undergoing alternative donor HCT for FA, comparable to historical TBI-based protocols, while avoiding short and (to date) long-term toxicity associated with radiation.

Table 1. Patient demographics

Characteristics	Number/Median (Range)
Median age in years	8.2 (4.3-44)
<10 years of age	27
≥10 years of age	18
Gender
- Males	20
- Females	25
Severe Single Lineage      Cytopenia	5
Severe Aplastic Anemia	29
Myelodysplastic Syndrome	11
- Low grade	7
- High grade	4
Donor type
Matched Unrelated (8/8 match)	25
Mismatched Unrelated (7/8 match)	14
Mismatched Related (4/8, 5/8, 6/8 match)	5
Phenotypically Matched Related (8/8)	1
Follow-up in months, Median and Range	21.3 (2.6 - 61)

                                                                                                                                                                                                                                                 Table 2. Patient outcomes

Characteristic	Number/Median (range)
Days to Neutrophil engraftment	9 (7-15)
Days to Platelet engraftment	16 (11-230)
Complication
Oral mucositis	23
Hyperbilirubinemia	10
Hypertension	12
Sinusoidal obstruction syndrome          (SOS)*	1
Infections (number of patients)	26
- Bacterial	11
- Viral	21
- Fungal	3
GVHD              Acute GVHD
- Acute Gr I-II	4
- Acute Gr III-IV	0
Chronic GVHD
- Chronic, limited	3
- Chronic, extensive	0