High-Dose Chemotherapy in Patients With Severe Autoimmune Disease

abstract & commentary

Synopsis: High-dose cyclophosphamide (50 mg/kg for 4 consecutive days) without stem cell rescue was administered to eight patients with advanced autoimmune disease refractory to conventional approaches. Seven patients improved markedly, five achieved complete remission, and two achieved partial remission. Four of the patients remain in a sustained complete remission for 3-21 months of follow-up. The high-dose treatment was well-tolerated and there were no treatment-related deaths. The median times to a neutrophil count of 0.5 x 109 cells/L and platelet transfusion independence were 17 and 16 days, respectively. High-dose cyclophosphamide without stem cell rescue may be a useful clinical approach for selected patients with severe autoimmune disease.

Source: Brodsky RA, et al. Ann Intern Med 1998; 129:1031-1035.

The management of severe autoimmune dis-eases remains a challenge. When standard approaches fail, clinicians are left with a variety of experimental approaches. Among these are low and high doses of agents more commonly used by oncologists, including antimetabolites and alkylating agents. In the current report, clinical investigators from Johns Hopkins and Hahnemann Universities treated eight patients with severe, refractory autoimmune disease with high-dose cyclophosphamide (50 mg/kg for 4 days), without stem cell rescue. All of the patients tolerated the therapy well without nonhematological life-threatening toxicity. Cytopenias occurred in all patients but there were no treatment-related deaths. Patients received G-CSF (5 mcg/kg) six days after the last dose of cyclophosphamide and daily until the white blood count reached 109 cells/L. The median time to resolution of neutropenia was 17 days and the median time that platelet transfusions were required was 16 days.

Five patients achieved complete remissions from their severe autoimmune disease and four of these remained in remission for 3-21 months at time of publication. Two patients achieved durable partial remissions, continuing to improve at 14 and 19 months of follow-up. Thus, Brodsky and colleagues suggest that high-dose cyclophosphamide (without stem cell rescue) might become a useful clinical approach for patients with refractory autoimmune diseases.


Treatment of refractory autoimmune disease remains problematic. In laboratory animals with experimental autoimmune disease, high-dose chemotherapy followed by syngeneic bone marrow transplantation has been shown to be highly effective.1,2 However, high-dose therapy followed by autologous transplant in selected patients with advanced autoimmune disease has not been uniformly successful.3,4 When high-dose therapy has failed, it has been speculated that relapses have occurred due to the failure of the high-dose therapy to eradicate the autoaggressive population of lymphocytes, the reinfusion of the autoaggressive lymphocytes with the autograft, or the reinitiation of the disease because of persistent challenge from the autoantigen.3,4

The last of these three hypotheses is difficult to address experimentally; however, therapy can be intensified and can be given without reinfusion of autologous hematopoietic cells. If such an approach were successful, one would be less concerned about antigen persistenct. Brodsky et al have shown that the great majority of patients with aplastic anemia achieve a sustained and gratifying response (complete remission) after high-dose cyclophosphamide treatment without stem cell reconstitution.5 The success of this approach bodes well for the application of the technique to autoimmune disease because the pathogenesis of aplastic anemia in as many as 80% of adults with this disorder involves autoimmune mechanisms with marrow stem cells as targets.6

Brodsky et al point out that hematopoietic stem cells express high levels of aldehyde dehydrogenase, an enzyme responsible for cellular resistance to cyclophosphamide.7 A theoretical rationale exists for the use of cyclophosphamide based upon a presumed favorable therapeutic index, with marrow stem cells resistant, but autoimmune lymphocytes sensitive to this drug.

In this preliminary report, it is difficult not to get excited about the findings. All eight patients had advanced and debilitating diseases (rheumatoid arthritis, lupus erythematosus, chronic inflammatory demyelinating polyneuropathy, severe hemolytic anemia, Evan’s syndrome, and immune thrombocytopenia). All had been refractory to standard approaches, and all but one had a gratifying response to the high-dose chemotherapy. Clearly, this approach warrants additional investigation.

Certainly, any successful treatment of patients with these difficult and complex refractory autoimmune diseases will be met with great enthusiasm. However, some rheumatologists may not be fully apprised of the great risks associated with high-dose chemotherapy, with or without stem cell rescue, and others may be overly concerned about the potential toxicities. The decades of experience of the bone marrow transplanters who discovered and developed preventive approaches and treatments for toxicities from cyclophosphamide or similar drugs represent one of the triumphs of modern oncology and need not be repeated. In fact, rheumatologists and oncologists might best work together on these patients when further trials are conducted to confirm the impressive efficacy suggested in this preliminary report.


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    3. Euler HH, et al. Blood 1996;88:3621-3625.

    4. Snowden JA, et al. Br J Haematol 1997;99:9-22.

    5. Brodsky RA, et al. Blood 1996;87:491-494.

    6. Young NS, et al. Ann Intern Med 1997;126:166-168.

    7. Gordon MY, et al. Leuk Res 1985;9:1017-1021.