title: High-dose cyclophosphamide without stem cell rescue in 207 patients with aplastic anemia and other autoimmune diseases.
abstract: High-dose cyclophosphamide has long been used as an anticancer agent, a conditioning regimen for hematopoietic stem cell transplantation, and a potent immunosuppressive agent in autoimmune diseases including aplastic anemia. High-dose cyclophosphamide is highly toxic to lymphocytes but spares hematopoietic stem cells because of their abundant levels of aldehyde dehydrogenase, the major mechanism of cyclophosphamide inactivation. High-dose cyclophosphamide therapy induces durable remissions in most patients with acquired aplastic anemia. Moreover, high-dose cyclophosphamide without hematopoietic stem cell rescue has shown activity in a variety of other severe autoimmune diseases. Here we review the history of cyclophosphamide as it applies to aplastic anemia and other autoimmune diseases. We include historical data from early patients treated for aplastic anemia as well as data from 140 patients from an observational retrospective study in a single tertiary care hospital. This latter component was designed to assess the safety and efficacy of high-dose cyclophosphamide therapy without stem cell rescue in patients with refractory autoimmune diseases. We analyzed the 140 patients with severe, progressive autoimmune diseases treated. All patients discussed here received cyclophosphamide, 50 mg/kg per day for 4 consecutive days. Response, relapse, and overall survival were measured. Response was defined as a decrease in disease activity in conjunction with a decrease or elimination of immune-modulating drugs. Relapse was defined as worsening disease activity and/or a requirement for an increase in dose of, or administration of new, immunosuppressive medications. Hematologic recovery occurred in all patients. The overall response rate was 94%, and 44% of those patients remained progression free with a median follow-up of 36 months (range, 1-120 mo) for the 140 patients analyzed together. The overall actuarial and event-free survival across all diseases at 60 months was 90.7% and 20.6%, respectively. High-dose cyclophosphamide without stem cell rescue is well tolerated and induces a high rate of remission in severe autoimmune diseases.
authors.affiliation: From Division of Hematology (AED, RJJ, RAB), Division of Rheumatology (MP, FW), Division of Neurology (DBD, ERH), Division of Oncology Biostatistics (JK, HLT), Division of Dermatology (GA), Department of Medicine; and Department of Oncology and Department of Pediatrics (DML), The Johns Hopkins University School of Medicine, Baltimore, Maryland; and Biogen-Idec (DK), Cambridge, Massachusetts.
authors.forename: Amy E
authors.initials: AE
authors.lastname: DeZern
authors.forename: Michelle
authors.initials: M
authors.lastname: Petri
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Drachman
authors.forename: Doug
authors.initials: D
authors.lastname: Kerr
authors.forename: Edward R
authors.initials: ER
authors.lastname: Hammond
authors.forename: Jeanne
authors.initials: J
authors.lastname: Kowalski
authors.forename: Hua-Ling
authors.initials: HL
authors.lastname: Tsai
authors.forename: David M
authors.initials: DM
authors.lastname: Loeb
authors.forename: Grant
authors.initials: G
authors.lastname: Anhalt
authors.forename: Fredrick
authors.initials: F
authors.lastname: Wigley
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Jones
authors.forename: Robert A
authors.initials: RA
authors.lastname: Brodsky
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000741:Anemia, Aplastic / Q000188:drug therapy*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001327:Autoimmune Diseases / Q000188:drug therapy*; D002648:Child; D002675:Child, Preschool; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D007223:Infant; D008297:Male; D008875:Middle Aged; D012008:Recurrence; D016019:Survival Analysis; D013997:Time Factors; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D003520:Cyclophosphamide