“Rebooting” the immune system with cyclophosphamide: Taking risks for a “cure”?

There is an increasing number of treatment options for neuroimmunological disorders including myasthenia gravis (MG), although there are few prospective randomized placebo controlled trials to prove that some of these therapies are truly effective. However, in some disorders, particularly in MG, there is little doubt that patients doing poorly on one therapeutic regimen may improve, sometimes dramatically, with the addition or substitution of another treatment. Despite the number of treatment possibilities, there remain patients who either do not respond to any of the therapies or have unacceptable side effects. It therefore is appropriate that the search for other therapeutic modalities continues. The provocative report by Drs Drachman, Jones, and Brodsky in this issue offers an alternative approach, an attempt to completely destroy the mature and differentiated immune system with high-dose cyclophosphamide (CPM). Referred to as “rebooting” the immune system, the protocol takes advantage of the resistance of stem cells to CPM, because they do not have the enzyme aldehyde dehydrogenase. The survival of the stem cells means that bone marrow transplant is not necessary, and the hope is that the immune system that develops from these stem cells will not be characterized by the same autoimmune response that was present before the treatment. Although the results described are exciting and generate enthusiasm, we would urge clinicians who treat patients with MG, as well as other autoimmune/immunopathologically mediated diseases of the nervous system, to remain cautious and await the results of further investigations and reports before adapting this therapy, even for patients with significant disability and/or side effects from their current therapy. There are many questions that remain unanswered about the safety and effectiveness of this therapy. It is not clear whether this is truly a “rebooting” that might provide a “cure,” or whether this is just more potent immunosuppression with a longer remission or better therapeutic outcome, which, in and of itself, might still offer important advantages for selected patients. In either case, the question that must be answered is whether the anticipated therapeutic response is strong enough to warrant the inherent risks. How does this approach compare with less aggressive immune therapy? Until these questions are answered, it will be very difficult to determine which patients should be considered for this form of therapy. Some information is available to begin to answer some of these concerns. “Rebooting” has been used by Brodsky’s group for other autoimmune disorders. The largest experience has been with aplastic anemia, but they also have reported a series of eight patients with a variety of autoimmune diseases including rheumatoid arthritis, systemic lupus, autoimmune hemolytic anemia, and one case of chronic inflammatory demyelinating polyneuropathy (CIDP). They reported that five of the eight patients achieved complete remission and two achieved partial remission that was sustained for up to 21 months. However, two patients died; one patient, treated for autoimmune hemolytic anemia, who went into remission from that disorder, died of immune thrombocytopenic purpura 16 months after the “rebooting” therapy, and another patient with immune thrombocytopenic purpura died of her disease after 8 months. Their experience with 19 patients with aplastic anemia shows an impressive response rate, but 3 patients died, 2 of fungal infections and 1 of an intracerebral hemorrhage. The authors note that this mortality rate compares favorably with the mortality rate for aplastic anemia when conventional therapy is utilized. However, this treatment-related mortality rate would not compare so well with the mortality rate for MG, even for those patients with severe disease. Concern for the morbidity from this therapy was raised by Tisdale and colleagues. A randomized trial of 31 patients with aplastic anemia, comparing high-dose CPM and cyclosporin with antithymocyte globulin and cyclosporin was stopped early because of 3 deaths in the 15 CPM-treated patients, all occurring within 6 weeks of treatment and all of fungal infections. Three other CPM-treated patients developed severe fungal infections but survived. None of the antithymocyte globulin–treated patients developed fungal infections, but one died 5 months after treatment because of refractory disease. Although the authors argue that the cyclosporin should not have increased the risk for the fungal infections, it is difficult to compare these results with those of Brodsky and colleagues who do not include cyclosporin in their regimen. In a similar way, it