Non-Myeloablative Conditioning Regimen (NMCR) for Allogeneic Bone Marrow Transplantation (BMT) in Patients with Severe Aplastic Anemia (SAA).

Allogeneic bone marrow transplantation is a curative form of therapy for patients (pts) with acquired severe aplastic anemia. Current preparative therapies are associated with early and late sequelae such as organ injury, and secondary tumors. Recent studies showed that BMT following reduced-intensity or NMCR may result in long-term survival for a fraction of pts with hematologic malignancies (Giralt, Biol. Blood Marrow Transplant, 13:884, 2007). However, with the exception of BMT for pts With Fanconi’s anemia, little is known about using NMCR for patients with non-malignant disorders. We report the use of NMCR in patients with SAA. Patients and Methods: Four female pts ages 6–12 years, diagnosed with SAA, had allogeneic BMT from an HLA-identical sibling (SIB) (Pts #1 and #2) or a matched unrelated donor (MUD) (pts #3 and #4). The reasons to offer NMCR were: delay in results of chromosome fragility studies (Pt #1), abnormal pulmonary function (Pt #2), history of recent life threatening infection (Pt #3), and failure to respond to immunosuppressive therapy (Pt #4). The NMCR consisted of fludarabine (FLU) (30 mg/m2 x 4), low dose cyclophosphamide (LDC) (5 mg/kg x 4) and rabbit antithymocyte globulin (rATG) (1.5 mg/kg x 4) in patients with SIB donor and FLU, LDC, at a higher dose of 15 mg/kg x 4), rATG and a single fraction of total body irradiation at 200 cGy in patients with a MUD donor. Supportive care, prophylactic anti-microbial therapy, and treatment for prevention of aGvHD were given according to the institution standard guidelines. Results: The NMCR was well tolerated in all 4 patients. Pts #1 and #2 who had a SIB BMT had no transplant-related toxicities, including mucositis or alopecia. Toxicities in the MUD BMT patients included mild mucositis and partial alpecia in both pts. Pt#3 had reactivation od Enterobacter cloacae sepsis with typhlitis and later CMV viremia. Myeloid and platelet engraftment were uneventful in pts #1, #2, and #4. The recovery of peripheral blood counts was slow in Pt #3 following typhlitis and CMV viremia. Myeloid engraftment occurred on day +19 (range 15–33 days). The median time to a platelet count >20,000 unsupported by transfusion was day +33, (range 12–76 days). Periodic engraftmen anlyses using short tandem repeat (STR) by PCRT continue to show full donor chimerism in all 4 pts. There were no signs for acute or chronic graft-vs-host disease (aGvHD or chGvHD, respectively) in pts with SIB BMT. Both patients continue to do well with a fully recovered hematopoietic system 17 months and 42 months post transplant. There were no aGVHD.or chGVHD in Pt#3. Pt #4 had aGVHD of the skin, clinical grade II, which responded well to immunosuppressive therapy. Both MUD BMT pts are well 5 and 3 months post-transplant, respectively, with partial hematopoietic recovery in Pt #3 and normal counts in Pt #4. Conclusion: This data suggests that a non-myeloablative, immunosuppressive regimen is sufficient to provide a stable engraftment in the patients with SAA. This approach may be associated with decreased transplant-related, short- and long-term, toxicities. A larger study is needed to fully evaluate the outcome and the toxicity associated with this conditioning.