Fludarabine-Based Conditioning for Marrow Transplantation from Unrelated Donors in Severe Aplastic Anemia: Early Results of a Cyclophosphamide Dose Deescalation Study Show Life-Threatening Adverse Events at Predefined Cyclophosphamide Dose Levels

• Published in: Biology of blood and marrow transplantation Vol. 18; no. 7; pp. 1007 - 1011
• Main Authors: Tolar, Jakub, Deeg, H. Joachim, Arai, Sally, Horwitz, Mitchell, Antin, Joseph H, McCarty, John M, Adams, Roberta H, Ewell, Marian, Leifer, Eric S, Gersten, Iris D, Carter, Shelly L, Horowitz, Mary M, Nakamura, Ryotaro, Pulsipher, Michael A, DiFronzo, Nancy L, Confer, Dennis L, Eapen, Mary, Anderlini, Paolo
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2012
• Subjects: Acute Disease; Adolescent; Adult; Aged; Anemia, Aplastic - mortality; Anemia, Aplastic - therapy; Antilymphocyte Serum - administration & dosage; Antilymphocyte Serum - adverse effects; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antithymocyte globulin; Bone Marrow Transplantation; Child; Cyclophosphamide - administration & dosage; Cyclophosphamide - adverse effects; Drug Administration Schedule; Drug Dosage Calculations; Female; Hematology, Oncology and Palliative Medicine; Humans; Male; Matched unrelated donor; Middle Aged; Stem cell transplantation; Survival Rate; Transplantation Conditioning; Unrelated Donors; Vidarabine - administration & dosage; Vidarabine - adverse effects; Vidarabine - analogs & derivatives; Whole-Body Irradiation - adverse effects; Bone marrow transplantation; Stem cell transplantation; Antithymocyte globulin; Matched unrelated donor
• ISSN: 1083-8791; 1523-6536
• DOI: 10.1016/j.bbmt.2012.04.014

Excessive adverse events were encountered in a Phase I/II study of cyclophosphamide (CY) dose deescalation in a fludarabine-based conditioning regimen for bone marrow transplantation from unrelated donors in patients with severe aplastic anemia. All patients received fixed doses of antithymocyte globulin, fludarabine, and low-dose total body irradiation. The starting CY dose was 150 mg/kg, with deescalation to 100 mg/kg, 50 mg/kg, or 0 mg/kg. CY dose level 0 mg/kg was closed due to graft failure in 3 of 3 patients. CY dose level 150 mg/kg was closed due to excessive organ toxicity (n = 6) or viral pneumonia (n = 1), resulting in the death of 7 of 14 patients. CY dose levels 50 and 100 mg/kg remain open. Thus, CY at doses of 150 mg/kg in combination with total body irradiation (2 Gy), fludarabine (120 mg/m2 ), and antithymocyte globulin was associated with excessive organ toxicity.