Severe aplastic anemia (SAA) is a life-threatening disorder characterized by pancytopenia and a hypocellular bone marrow. As most patients lack a histocompatible donor, the majority of patients are treated with immunosuppressive therapy (IST) with horse anti-thymocyte globulin plus cyclosporine (h-ATG/CsA). The current limitations of IST in SAA are: 1) most responses are not complete; 2) 1/3 of patients are refractory to initial h-ATG/CsA; 3) hematologic relapses occur in 30–35% of responders following initial response ATG/CsA; 4) and clonal evolution is observed in about 15% of patients at 10 years after first therapy (Scheinberg and Young 2012). Efforts to improve initial IST in treatment-naïve patients with the addition of mycophenolate mofetil and sirolimus to standard h-ATG/CsA or use of lymphocytotoxic agents such as rabbit ATG or alemtuzumab have not yielded better outcomes when compared to standard h-ATG/CsA (Scheinberg and Young 2012). Cyclophosphamide (Cy) has been proposed as an alternative IST regimen to h-ATG/CsA. A pilot and single institution phase II study suggested that high dose Cy (200 mg/kg) yielded similar results to that observed for h-ATG/CsA but with fewer relapses and clonal evolutions (Brodsky, Chen et al. 2010). However, in a randomized study at NHLBI comparing high dose Cy (200 mg/kg) and h-ATG/CsA in treatment-naïve patients excess toxicity and deaths from invasive fungal infections were observed in the Cy arm, which led to the discontinuation of this regimen (Tisdale, Dunn et al. 2000). In a recent Chinese protocol introduced by Dr. Zhang (Institute of Hematology & Blood Disease Hospital, China), lower doses of Cy (30 mg/kg/d * 4 days, 120 mg/kg total) plus CsA, were reported to achieve similar results as with high-dose Cy at 200 mg/kg with reduced toxicity (Kojima, Nakao et al. 2011). Because of the marked improvement in survival in SAA, especially among patients who did not respond to IST, likely due at least in part to improved antifungal drugs (Valdez, Scheinberg et al. 2011), we considered it reasonable to investigate “moderate” dose Cy + CsA as proposed by the Chinese as first line in SAA. The main objective was to assess the safety and efficacy of Cy at 120 mg/kg + low dose CsA, at doses aimed to achieve plasma levels of 100 – 200 mg/L, in treatment-naïve SAA, and the primary hematologic endpoint was response, defined as no longer meeting criteria for SAA, at 6 months. The study was designed to show an increase in complete response rate > 30%, in our experience a surrogate for fewer late events. Prophylactic voriconazole was administered with target levels between 1 – 5.5 ug/L, with ciprofloxacin and Bactrim. From October 2010 to April 2012, 22 patients were accrued. Toxicity from Cy + CsA was considerable and in some cases unexpected, with absolute neutrophil levels of 0/uL universal regardless of pre-therapy blood counts. Granulocyte transfusions were required in 5 participants for uncontrolled infections, and to date 5 patients have died, all from infections. Confirmed fungal infections were documented in 4 participants. In 10 patients with a pre-treatment ANC > 500/uL, 5 remained with severe neutropenia at 6 months as salvage therapies were being sought. In a companion protocol using Cy at 60 mg/kg + fludarabine at 125 mg/m2, neutropenia was also prolonged and severe in a patient leading to pulmonary murcomycosis and need for frequent granulocyte transfusions. In total 9 patients responded to “moderate” dose Cy (120 mg/kg total dose) + CsA, with 4 complete and 5 partial responders. In the relative short follow-up period, cytogenetic abnormalities have been observed in 4 patients: 1 to monosomy 7, 1 del20q, 1 trisomy 15, and 1 del7q. We conclude that Cy at 120 mg/kg + CsA, while capable of producing meaningful hematologic responses in some cases, results in significant toxicity, despite maximum prophylactic and intensive supportive care. The regimen led to very prolonged hospitalizations and frequent bacterial and fungal infections. Hematologic relapses with a higher than expected number of clonal evolution events were observed in our cohort. Due to the high toxicity of Cy (120 mg/kg) + CsA, without likelihood of benefit from decreased relapse and clonal evolution, both protocols using “moderate” dose Cy were terminated by our data and safety monitoring board. Although Cy has activity in SAA, its toxicity is not justified when far less toxic alternatives, such as h-ATG, are available.
Off Label Use: Cyclophosphamide in aplastic anemia.
Asterisk with author names denotes non-ASH members.