High dose cyclophosphamide leads to durable remissions in the majority of patients with severe aplastic anemia. The results from over 100 SAA patients treated with high dose cyclophosphamide have been reported in the medical literature with roughly 3/4 of the patients from Johns Hopkins. These data demonstrate that the response rate in treatment naïve patients is 70% with the majority of responders achieving a complete remission (normalization of peripheral blood counts). Relapse and secondary clonal disorders (PNH and MDS) may occur; however, these appear to be rare events. Overall and event-free survival are less in patients with refractory severe aplastic anemia and the risk of fungal infections is increased; however, durable remission have been described in roughly 25% of patients.
These data suggest that high-dose cyclophosphamide should be considered, along with the accepted standard of HSCT and ATG/CSA, as treatment considerations for severe aplastic anemia. Each therapy has inherent advantages and disadvantages (), yet the early mortality (within 6 months of treatment) for all three is 10 –15% and the 5-year survival roughly 80%. The ideal therapy for SAA would be available to all patients, have a low toxicity profile, restore normal hematopoiesis without dependency on long term medical therapy (drug-free remission) and eliminate the risk for late clonal disorders such as PNH and MDS. Thus, treatment decisions must be based on both early toxicity and late complications from the disease. Allogeneic HSCT from a matched sibling remains the most appropriate therapy for children and young adults with SAA; it restores hematopoiesis in less than 4 weeks and cures the disease in more than 80% of cases.(33
) Relapse and secondary clonal disorders are rare following allogeneic HSCT for SAA. For patients who are not suitable candidate for HSCT both ATG/CSA and high dose cyclophosphamide are reasonable options. Both have response rates of 70%. Our phase II data suggests that the relapse rate and the risk for secondary clonal disorders may be lower following high dose cyclophosphamide than with ATG/CSA, but this will need to be tested in randomized controlled clinical trials.
Treatment for Severe Aplastic Anemia
Our data also suggest that high dose cyclophosphamide is also effective in treating other severe refractory autoimmune diseases. Many investigators have questioned the safety of this approach, largely out of concern for the potential of protracted low blood counts that could lead to unacceptable morbidity and mortality(10
). In this report of 140 patients receiving high-dose cyclophosphamide for autoimmune diseases, hematopoietic recovery was not delayed by the omission of autologous stem cell rescue. The median of 9 days with an absolute neutrophil count below 0.5 × 109
/L and 13 days to transfusion independence is similar to that seen after autologous stem cell rescue. Febrile neutropenia occurred in less than 50% of patients and the median number of days in the hospital was 6.The treatment-related mortality of 0.7% in this group of heavily pretreated, refractory autoimmune disease patients also compares favorably to the 5% and 2% transplant-related mortalities reported by the EBMT and the Northwestern Group (11
), respectively. The EBMT found that 100 day transplant-related mortality varied by underlying disease. Specifically, they reported a 2% transplant related mortality in patients with multiple sclerosis, 6% in scleroderma, 11% in lupus and 1% for rheumatoid arthritis. We observed no treatment-related mortality in the lupus (n = 40) or multiple sclerosis patients (n = 47).
The overall response rate to high-dose cyclophosphamide was 94%, with 46% of patients still in remission at the time of this report. The median duration of response was 15 months, but remissions lasting five years or more occurred in more than 20% of patients. These results are comparable to the 5 year overall survival of 85% and progression-free survival of 43% after HSCT reported by the EBMT. We used a rigorous definition of relapse --worsening disease activity from the point of improvement (not baseline) and/or a requirement of an increase in dose or administration of a new immunosuppressive medication. Thus, many of our patients classified as relapsed have not had progression of their disease from baseline. The durability of response after high-dose cyclophosphamide seemed to depend upon the underlying autoimmune disease. More patients with autoimmune hemolytic anemia and multiple sclerosis achieved a durable response than did patients with pemphigus or lupus. However, since the number of patients with each individual disease is small, and most were refractory to other treatments, it is unclear whether this is truly a difference in activity against individual diseases or whether this reflects severity of the disease at the time of treatment.
Selection of patients with severe autoimmune diseases for high dose cyclophosphamide treatment has been better defined by this series. Our data suggest that high dose cyclophosphamide is not superior to monthly pulse dose cyclophosphamide and we do not recommend the use of high dose cyclophosphamide as front-line therapy in SLE. Nevertheless, high-dose cyclophosphamide can be effective salvage therapy for patients with refractory SLE, especially those with neurologic manifestations. Additional clinical trials of high dose cyclophosphamide are needed in order to determine whether this therapy should be more widely used for multiple sclerosis. Our data suggests that high dose cyclophosphamide is most effective for patients with relapsing-remitting disease and an EDSS of less than 6.5.
Eliminating stem cell rescue after high dose cyclophosphamide shortens the duration of the procedure by several weeks, and this, coupled with no requirement for stem cell mobilization, collection, and cryopreservation, should also reduce the cost of the procedure. Moreover, avoiding stem cell infusion eliminates the potential of reinfusing autoreactive lymphocytes with the autograft. Mobilized peripheral blood products usually contain at least 109 CD3+ T cells, and current CD34 selection techniques deplete T cells by only three to four logs, which may be insufficient to eliminate autoreactive clones that could reestablish disease. Recently, it has been suggested that the process of HSCT induces fundamental changes to the immune system that induce long term tolerance; however, it is unclear that cryopreserved hematopoietic stem cells are superior to the endogenous stem cells that lead to hematologic recovery after high-dose cyclophosphamide at “resetting” the immune system.
Although both autologous HSCT and high-dose cyclophosphamide without stem cell rescue generate meaningful clinical benefit for patients with advanced/refractory autoimmune diseases, neither is curative for most such patients. The safety and relative ease of delivery of high-dose cyclophosphamide without stem cell rescue may allow this approach to be utilized earlier in autoimmune disease patients, potentially improving effectiveness in these diseases. A randomized trial of high-dose cyclophosphamide versus standard therapy in patients with relapsing-remitting MS is under development, and should help define the ultimate potential of this approach in autoimmunity.