Hematopoietic Cell Transplantation in Fanconi Anemia Patients with Biallelic BRCA2 Mutations.

Fanconi anemia patients with biallelic BRCA2 mutations have an exceptionally high risk of developing hematological malignancies, Wilms tumors and medulloblastoma at a very young age. We report on the hematopoietic cell transplant (HCT) results of 6 patients from 4 kindreds, all of whom have biallelic BRCA2 mutations. Two patients (800/2 and 984/2) were found to have a Wilms tumor at time of work-up for HCT despite normal previous renal ultrasounds. One was a stage 1 favorable histology, the second a stage II poorly differentiated tumor with diffuse anaplasia. In each case, the patient underwent nephrectomy and proceeded to HCT 3 weeks later. All unrelated or mismatched related donor marrow grafts were T cell depleted either by elutriation in patient 632/1, or CD34 selection with Isolex in the remaining cases. Five of 6 patients achieved neutrophil engraftment. Only one patient developed severe regimen related toxicity and one patient GVHD. Two of 6 patients are alive and well after HCT, both whom had T-cell ALL, which is uncommon in FA patients. Patient and Transplant Characteristics | Kindred, IFAR No. | Age/Gender | Clinical Hx | Donor | Preparative Rx | Day to ANC>500 | Toxicity, GVHD | Outcome | |:----------------- | ---------- | ------------------------------------------------------------------------------------------------ | -------------- | --------------------------------------- | ------------------ | ---------------------- | ------------------------------------------------------ | | 1, 632/1 | 3.7 yr/F | AML at 36 mo, chemotherapy refractory | 6/6 URD BM x 2 | CY, TBI, ATG, CSA, MP; CY, ATG, MP, CSA | graft failure; +31 | None | AML relapse after both HCT, died day +76 after 2nd HCT | | 1, 632/2 | 1.9 yr/F | AML at 21 mo, chemotherapy refractory | 6/6 MSD BM | CY, TBI, FLU, ATG, CSA, MP | Engrafted | None | AML relapse, died day +288 | | 2, 800/1 | 1.8 yr/M | AML at 11 mo, chemotherapy refractory | 6/6 URD TCD BM | CY, TBI, ATG, CSA, MP | +11 | Grade II aGVHD | AML relapse day +110, died day +124 | | 2, 800/2 | 0.8 yr/M | Neutropenia at 5 mo, Wilms tumor at 9 mo | 6/6 URD TCD BM | CY, TBI, FLU, ATG, CSA, MP | +9 | Resp and renal failure | Died day +60 from pulmonary hemorrhage | | 3, 900/1 | 4.9 yr/M | T cell ALL at 5.2 yr, CR after chemotherapy | 5/6 Mat TCD BM | BU, CY, FLU, ATG, CSA, MP | +10 | None | Alive and well 19 mo after HCT | | 4, 900/2 | 6.7 yr/F | T cell ALL at 4.9 yr, remission with chemotherapy, relapse with AML 17 mo later, Wilms at 6.6 yr | 6/6 URD UCB | BU, CY, FLU, ATG, CSA, MP | +13 | None | Alive and well 3 mo after HCT | In summary, HCT has limited effectiveness after the onset of leukemia in patients with Fanconi anemia. While these patients have tolerated chemoradiotherapy well in most cases, refractoriness of the leukemia is the principle obstacle to success. Therefore, patients with biallelic BRCA2 mutations should be screened for solid tumors and referred for HCT as soon as possible, prior to the onset of leukemia. In addition, these patients require routine screening for solid tumors after HCT, the incidence of which remains to be determined.