Successful Pregnancy After Allogeneic Bone Marrow Transplantation Followed by Ovarian Tissue Autograft in a Sickle Cell Patient.

Abstract

4482 One major drawback of myeloablative allogeneic stem cell transplantation is the near 100% risk of profound fertility impairment leading to early menopause and sterility in most female patients. This toxic effect is especially critical in patients without malignant disease, i.e hemoglobinopathies or other inherited diseases. Cryopreservation of ovarian tissue with subsequent autotransplantation is an emerging procedure to preserve the fertility of young patients with a high risk of premature ovarian failure resulting from radiotherapy or chemotherapy for cancer. We report the restoration of ovarian activity and pregnancy with live birth after an orthotopic transplantation of frozen/thawed ovarian tissue in a 23 year old female patient given a transplant for sickle cell disease. In spring 2005, the patient of S/S hemoglobin genotype experienced a central nervous system stroke with unilateral central retinal artery occlusion. Monthly exchange transfusions were started from then and a pretransplant procedure was undertaken with a 10/10 matched sibling male donor who was heterozygous for HbS. In autumn 2005, biopsy samples of ovarian tissue were cryopreserved prior to conditioning. The patient received a conditioning regimen with IV busulfan (12.8 mg/kg total dose), cyclophosphamide (200 mg/kg total dose) and antilymphocyte globulin (15 mg/kg total dose) followed by allogeneic bone marrow transplantation (BMT). A stable 100% donor chimerism was obtained from D60.The patient developed grade II acute GVHD treated by steroids, then followed by limited chronic GVHD treated by a combination of mycophenolate-mofetil and ciclosporin. The treatment was tapered and stopped 7 months after BMT. After BMT, the patient presented clinical menopause with amenorrhoea and hot flushes due to premature ovarian failure. FSH and LH concentrations rose to menopausal levels. Hormone replacement therapy with oestro-progestogens was started 6 months after BMT and was maintained until ovarian function restoration after ovarian transplantation. In spring 2008, as the patient had been menopausal for 2.5 years as a result of the conditioning chemotherapy, an orthotopic autotransplantation of ovarian cortex was performed. The cortical fragments were grafted according to the following procedure: a first laparoscopy was performed to create a peritoneal windows between the right iliac vessels and an ovarian window in the remaining left ovary with the aim of further inducing angiogenesis. One thawed strip of ovarian cortex was cut in fragments, that were fixed in the ovarian incision and deposited in the peritoneal window. Three days later, a second laparoscopy was performed and three thawed cortical strips were fixed into the left ovary and one into the peritoneal window. Ovarian function recovery was evaluated by hormonal levels and follicular development was observed by ultrasound. The patient conceived spontaneously in a natural cycle in autumn 2008, and delivered a healthy female child in June 2009. This first case report of pregnancy and delivery after ovarian autograft in a patient treated by allogeneic BMT suggests that cryopreservation of ovarian tissue should be offered prior to SCT not only to women of childbearing age but also to prepubertal patients, as primordial follicles are already present in the post natal ovaries. This technique still deserves further investigations in leukemias but appears safe in non malignant diseases. Time line of treatment Disclosures: No relevant conflicts of interest to declare.

Has the time come to implement gene therapy for sickle cell disease?

“…A plasmid is used for insertion. At the present time this appears to be the most promising technology [5].…”

“…The conditioning process invariably leads to loss of oocytes in the ovary with resulting infertility. Roux and collogues [5] cryopreserved ovarian tissue then transplanted it two years after the bone marrow transplant. Aperitoneal window was created adjacent to the iliac vessels by laparoscopy, and a slice of the frozen ovary was placed there.…”

“…Aperitoneal window was created adjacent to the iliac vessels by laparoscopy, and a slice of the frozen ovary was placed there. The patient spontaneously conceived, had an uneventful pregnancy and was delivered of a child at term [5].…”