Robert A. Brodsky, MD; Lyle L. Sensenbrenner, MD; B. Douglas Smith, MD; Donna Dorr, RN; Phillip J. Seaman, PA-C; Shing M. Lee, ScM; Judith E. Karp, MD; Isadore Brodsky, MD; and Richard J. Jones, MD

Background:  Severe aplastic anemia is a life-threatening bone marrow failure disorder. High-dose cyclophosphamide therapy followed by allogeneic bone marrow transplantation cures the disease. However, it requires a suitable donor and carries the risk for graft-versus-host disease. A small pilot study demonstrated that high-dose cyclophosphamide therapy without bone marrow transplantation leads to durable, treatment-free complete remission.

Objective:  To confirm the safety and efficacy of high-dose cyclophosphamide therapy alone in patients with severe aplastic anemia.

Design:  Uncontrolled clinical trial.

Setting:  Three tertiary care hospitals.

Patients:  19 patients with untreated severe aplastic anemia.

Intervention:  Cyclophosphamide, 50 mg/kg of body weight per day for 4 consecutive days.

Measurements:  Probability of response and overall survival were measured. Complete remission was defined as normal blood count for age and sex. Partial remission was defined as independence from transfusion and an absolute neutrophil count greater than 0.5 × 10⁹ cells/L without growth factor support. Nonresponders were patients who remained transfusion dependent or died. Relapse was defined as no longer meeting criteria for partial or complete remission.

Results:  The median time to an absolute neutrophil count of 0.5 × 10⁹ cells/L was 49 days. The probability of survival was 84% (95% CI, 59% to 95%) at 24 months. The probability of achieving treatment-free remission was 73% (CI, 51% to 91%) at 24 months, and the probability of achieving complete remission was 65% (CI, 39% to 89%) at 50 months. No responding patients have had relapse or have developed secondary clonal disorders.

Conclusions:  High-dose cyclophosphamide therapy without bone marrow transplantation produces durable treatment-free remission in severe aplastic anemia. This approach deserves further study in patients with severe aplastic anemia who are not suitable candidates for allogeneic bone marrow transplantation.

From the Johns Hopkins Oncology Center and the Greenbaum Cancer Center, University of Maryland, Baltimore, Maryland; and MCP Hahnemann University, Philadelphia, Pennsylvania.

Acknowledgment: The authors thank the physicians, nurses, and support staff of the Johns Hopkins University Bone Marrow Transplant Team, MCP Hahnemann University, and the Greenbaum Cancer Center for their excellent patient care.

Grant Support: In part by grant CA70970 from the National Institutes of Health. Dr. R. Brodsky is a Leukemia and Lymphoma Society Clinical Research Scholar and The Thomas E. Sandefur Jr. Fellow in Stem Cell Research.

Request for Single Reprints: Robert A. Brodsky, MD, Johns Hopkins Oncology Center, Bunting-Blaustein Cancer Research Building, Room 242, 1650 Orleans Street, Baltimore, MD 21231; e-mail, rbrodsky@jhmi.edu.

Current Author Addresses: Dr. R. Brodsky, Dr. Smith, Ms. Dorr, Mr. Seaman, and Dr. Jones: Johns Hopkins Oncology Center, Bunting-Blaustein Cancer Research Building, Room 242, 1650 Orleans Street, Baltimore MD 21231.

Dr. Sensenbrenner: 1613 Camden Avenue, Salisbury, MD 21801-7010.

Ms. Lee: Johns Hopkins Oncology Center, Oncology Biostatistics, 550 North Broadway, Suite 1103, Baltimore, MD 21205.

Dr. I. Brodsky: MCP Hahnemann University, Broad and Vine Streets, Mailstop 412, Philadelphia, PA 19102.

Dr. Karp: Greenbaum Cancer Center, University of Maryland School of Medicine, 22 South Greene Street, Room S9D15, Baltimore, MD 21201-1544.

Author Contributions: Conception and design: R.A. Brodsky, L.L. Sensenbrenner, R.J. Jones.

Analysis and interpretation of the data: R.A. Brodsky, B.D. Smith, J.E. Karp, I. Brodsky, R.J. Jones.

Drafting of the article: R.A. Brodsky.

Critical revision of the article for important intellectual content: L.L. Sensenbrenner, B.D. Smith, R.J. Jones.

Final approval of the article: R.A. Brodsky, R.J. Jones.

Provision of study materials or patients: R.A. Brodsky, J.E. Karp, I. Brodsky.

Statistical expertise: S.M. Lee.

Obtaining of funding: R.A. Brodsky, R.J. Jones.

Administrative, technical, or logistic support: B.D. Smith, D. Dorr, P.J. Seaman.

Collection and assembly of data: R.A. Brodsky, B.D. Smith, D. Dorr, P.J. Seaman.

Keywords: Anemia, aplastic; Cyclophosphamide; Dose-response relationship, drug; Bone marrow transplantation; Graft vs host disease