Fertility Outcomes after Allogeneic Hematopoietic Stem Cell Transplants Conditioned with Busulfan 4 Mg/Kg and Cyclophosphamide 200 Mg/Kg to Treat Severe Aplastic Anemia

Hematopoietic stem cell transplantation (HCT) is a standard treatment for young patients with Severe Aplastic Anemia and an available matched sibling donor. Conditioning regimens frequently use high-dose cyclophosphamide. A second conditioning agent is frequently associated when transplanting patients with multiple prior transfusions to decrease the risk of primary or secondary graft failure. Low dose oral Busulfan has been used in our country for many years, but the impact of this therapy on fertility has never been evaluated. The objective of this study is to retrospectively evaluate fertility in patients with Severe Aplastic Anemia who underwent allogeneic HCT with Busulfan 4 mg/Kg and Cyclophosphamide 200 mg/Kg. Methods: Retrospective chart review. Patients without appropriate information in the hospital charts were called, asked about pregnancy, and scheduled a regular appointment at the HCT service.  All patients had related allogeneic bone marrow grafts from matched sibling donors, received the same conditioning therapy, and GVHD prophylaxis based on Cyclosporine and Methotrexate. Results: A total of 29 consecutive patients underwent HCT between 1991 and 2014, were alive, and had the information on fertility. The patients had a median age of 22 years at the time of transplant (range 6-36) and were followed after transplant for 2 to 24 years (median 14 years). Twenty-two were male and seven were female.  Among the 7 females, 3 had documented ovarian failure; other 3 have tried to become pregnant and all of them did, having 2 normal children and 2 abortions. The patients reported no congenital anomaly. Twenty-two men were contacted: 12 had testosterone levels drawn, and it was low in only one man. Among the 12/22 men who wanted to make their wives pregnant, only one was not successful. The 11 male patients fathered 19 children (between 1 and 3 children per male patient). Conclusions: Very low dose Busulfan associated to Cyclophosphamide seems to have an important adverse impact on ovarian function: half of the females developed gonadal failure, while only one out of 22 men had low testosterone levels. In patients with normal gonadal function, pregnancy seems to be normal with 21 normal babies being born from 2/3 females and 11/ 12 man after the transplant.  Since the relatively high rate of gonadal failure in females may be also secondary to high dose Cyclophosphamide, novel conditioning regimens are still desired for women with Severe Aplastic Anemia who still have the desire to get pregnant.

Table 1: Fertility Outcomes after Busufan 4 mg/Kg and Cyclophosphamide 200 mg/Kg

	Female	Male
	N = 7	N = 22
Gonadal failure	3/7	1/12
Have tried to become pregnant	3/7	12/22
Failed to become pregnant/ father a child	3/7	1/12
Number of pregnant patients/ partners	3	11
Number of children	2	19