Treatment of Hepatitis-Associated Aplastic Anemia with High Dose Cyclophosphamide.

OBJECTIVE: Demonstrate that high dose cyclophosphamide (CY) induces durable hematologic remissions in patients with hepatitis-associated aplastic anemia (HAA). INTRODUCTION: HAA is a rare variant of aplastic anemia that accounts for 5% of cases. The hepatitis is seronegative and most often spontaneously resolves. The aplastic anemia that follows presents within a few months after the onset of hepatitis and is often fatal. The one other study that investigated treatment for HAA used antithymocyte globulin and cyclosporine, which induced remissions in 7 of 10 patients, with up to one year of follow-up. In that study, there were 3 deaths related to treatment failure and 1 relapse. High dose CY has induced durable remissions in severe aplastic anemia (SAA) and other autoimmune diseases, and we hypothesized that it could induce durable remissions in HAA as well. METHODS: Five patients (ages 6–17 years) with HAA and without a matched sibling BMT option were treated with CY (50 mg/kg/day IV x 4 days) plus mesna. Serology/PCR for HAV, HBV, HCV, EBV, and CMV were negative. All patients met criteria for very severe aplastic anemia pretreatment: bone marrow cellularity <25%, ANC <200/μL platelet count <20,000/μL, absolute reticulocyte count <60,000/μL. Infection prophylaxis consisted of trimethoprim/sulfamethoxazole, G-CSF, and fluconazole. RESULTS: All patients were transfusion dependent for erythrocytes and platelets prior to high dose CY. Other baseline and current values are shown in Table I. Four patients demonstrated hematopoietic recovery. Median time to ANC>500/μL was 51 days (range 44–369). Median time to transfusion independence for erythrocytes and platelets was 109 (range 57–679) and 160 (range 48–679) days, respectively. The 4 patients with hematopoietic responses are in remission up to 6 years after treatment without further immune suppression beyond high dose CY. Patient 2 met criteria for autoimmune hepatitis (AIH), and her AIH remains in remission, as well. Patient 5 had no hematopoietic response and died 3 months after BMT of multi-organ failure. CONCLUSIONS: High dose CY induced durable remissions in hepatitis-associated aplastic anemia in 4 of 5 patients based on follow-up from 1–6 years. Treatment failure led to one death in this series. The remission of HAA and AIH in one patient suggests that high dose CY may be an alternative and effective treatment for AIH, which is a disease characterized by long-term dependence on immunosuppression and recurrent relapses. Table I: Pre-Treatment and Current Patient Characteristics Age/Sex Follow Up ANC (cells/μL) ALT (U/L) Hgb (g/dL) Platelets (1000/μL) Nadir/Current Peak/Current Current Current * ANA titer >1:640 and anti-smooth muscle Ab titer 1:40. † Had no hematologic response and proceeded to unrelated BMT after 5 months 17/F 6 y 138 / 3430 1832 / 16 11.1 99 9/F* 2 y 178 / 2500 1186 / 11 13 140 14/M 16 mo 0 / 2380 2800 / 31 13.7 98 6/F 13 mo 0 / 669 2213 / 21 13.9 37 16/F 5 mo † 0 / † 3051 / † † †