Cyclophosphamide Plus Cyclosporine in Treatment-Naive Severe Aplastic Anemia

Severe aplastic anemia (SAA) is a life-threatening bone marrow failure disorder characterized by pancytopenia and a hypocellular bone marrow. Allogeneic hematopoietic stem cell transplantation (HSCT) offers the opportunity for cure in 70 percent of patients, but most patients are not suitable candidates for this treatment modality due to advanced age, comorbidities or lack of a histocompatible donor. For these patients, comparable long-term survival is attainable with immunosuppressive treatment (IST) with anti-thymocyte globulin (ATG) and cyclosporine (CsA). However, approximately 1/3 of patients do not show blood count improvement after ATG/CsA and are considered to have refractory disease. Furthermore, analysis of our own extensive clinical data suggests that poor blood count responses to a single course of ATG (non-robust responders), even when transfusion-independence is achieved, predicts a markedly worse prognosis compared to those who achieve a robust hematologic improvement (protocol 90-H-0146).

The current limitations of IST in SAA are: 1) the majority of the responses observed following initial h-ATG/CsA are partial with only a few patients achieving normal blood counts; 2) 1/3 of patients are refractory to initial h-ATG/CsA; 3) hematologic relapses occur in 35 percent of responders following initial response to h-ATG/CsA; 4) among relapsed patients chronic use of CsA is not infrequent which often leads to toxicities from the long term exposure to this drug (especially in older patients); 5) and clonal evolution is still observed in 10-15 percent of patients. Efforts to improve initial IST in treatment-naive patients with the addition of mycophenolate mofetil and sirolimus to standard h-ATG/CsA or use of lymphocytotoxic agents such as r-ATG/CsA or alemtuzumab have not yielded the expected better outcomes when compared to standard h-ATG/CsA (protocols 00-H-0032, 03-H-0193, and 06-H-0034). Because the majority of SAA patients in the US and worldwide are treated with IST due to lack of an human leukocyte antigen (HLA)-matched donor or inaccessibility to transplant, novel regimens are needed to overcome the current limitations of IST in SAA. Towards the goal of addressing these limitations we are proposing a regimen of cyclophosphamide (Cy) plus low dose CsA.

Cy has been proposed by the investigators at Johns Hopkins as an alternative IST regimen to h-ATG/CsA. In a pilot study, high dose Cy (200 mg/kg) yielded similar results to that observed for h-ATG/CsA. In a randomized study, at National Institute of Heart, Lung, and BIood (NHLBI), comparing high dose Cy (200 mg/kg) and h-ATG/CsA in treatment-na(SqrRoot) ve patients (protocol 97-H-0117), excess toxicity and deaths from invasive fungal infections were observed in the Cy arm which led to the discontinuation of this regimen. Recently reported long-term results from Johns Hopkins of 44 treatment-naive patients who received high dose Cy (200 mg/kg) as sole therapy for SAA showed that a greater number of complete responses were observed with few instances of relapse and clonal evolution noted with Cy when compared to h-ATG/CsA (historical comparison). In an accompanying editorial, the incidence of invasive fungal infections in this cohort were highlighted. Of note, antifungal prophylaxis against Aspergillus sp, the deadliest culprit when neutropenia is severe and prolonged, was not employed in the Hopkins high dose Cy protocol. In the Chinese experience, data presented in a recent meeting in Japan showed that lower doses of Cy (120 mg/kg) plus CsA achieved similar results reported by the Hopkins investigators with reduced toxicity. These data suggest that Cy has activity in SAA and could be a viable alternative to standard h-ATG/CsA if the immediate toxicities associated to prolonged neutropenia could be overcome.

In recent years we have observed a marked improvement in survival in our SAA patients especially among those who are non-responders to IST where pancytopenia remain persistent for months. A detailed analysis (shown in Section 2.4 Scientific and Clinical Justification of Protocol) showed that better antifungal supportive care in recent years contributed to a reduction of infection-related mortality in the months following IST among non-responders, who remain persistently neutropenic. This observation suggests that nowadays patients can be better supported through periods of neutropenia due to improved antifungal supportive care with agents that are better tolerated (compared to deoxycholate amphotericin B), retain a broad-spectrum of activity (especially against Aspergillus sp), and can be administered orally as an outpatient.

The fact that about one-third of initial refractory patients respond to retreatment and that late complications (relapse and clonal evolution) occur in about 40-50 percent of cases suggest that initial IST with h-ATG/CsA has important limitations. Therefore, we propose to investigate Cy + CsA as initial therapy in SAA. Our intention is not to recapitulate the high dose Cy regimen initially proposed by Hopkins (200 mg/kg) but instead, investigate lower doses proposed by the Chinese (120 mg/kg) in addition to low dose CsA (target therapeutic level 100 200 microg/L). The ability to better support patients during periods of neutropenia with better antifungals should allow for the immediate toxicity to be overcome and assess the activity of Cy in SAA.

The main objective of this study is to assess the safety and efficacy of Cy 120 mg/kg + low dose CsA (100 200 microg/L) in treatment-naive SAA. The primary endpoint will be hematologic response, defined as no longer meeting criteria for SAA, at 6 months. Secondary endpoints are relapse, robustness of hematologic recovery at 6 months, response at 3 months and 12 months, survival, clonal evolution to paroxysmal nocturnal hemoglobinuria (PNH), myelodysplasia and acute leukemia. The primary endpoint will be changes in absolute neutrophil count, platelet count, and reticulocyte count at 6 months. Secondary endpoints will include time to relapse, changes in cytogenetics, and time to death.