title: Long-term interleukin-3 and intensive immunosuppression in the treatment of aplastic anemia.
abstract: We have assessed in a phase I/II clinical study the tolerability and efficacy of long-term application of recombinant human interleukin-3 (rh-IL-3) in combination with antithymocyte globulin (ATG) and cyclosporin A (CSA) in 13 patients with aplastic anemia who were refractory to or relapsed after previous immunosuppressive treatment. Four cohorts of three patients were consecutively enrolled so that they received rh-IL-3 on days 9, 6, 3 and 1 after start of ATG/CSA treatment. Yeast-derived recombinant human IL-3 was administered by daily subcutaneous injection until day 90 at a dosage of 250 micrograms/m2. Long-term application of rh-IL-3 was well tolerated. The combination of rh-IL-3 with immunosuppression did not modify the known toxicities of ATG and CSA. Incidence and severity of rh-IL-3-related adverse events was less than in other phase I/II trials of rh-IL-3 as single-agent therapy. One might speculate that co-medication with CSA alleviates rh-IL-3-induced side effects. Three of eight patients with refractory AA and all four patients with relapsed AA responded to the combined treatment within four months. The median time to response was 91.5 days. There was evidence for an rh-IL-3-dependent response in two patients. Long-term rh-IL-3 did not cause stem cell exhaustion. One patient died early during the course of the study from EBV-driven lymphoproliferative disease. Two patients developed acute myeloid leukemia 4 and 22 months after cessation of rh-IL-3. In conclusion, long-term rh-IL-3 in combination with immunosuppression is well tolerated. The response rate to the combined treatment in refractory and relapsed AA was high. Recombinant human IL-3-dependent responses suggest efficacy. A prospective randomized trial comparing immunosuppression alone versus a combination with rh-IL-3 is warranted.
authors.affiliation: Department of Internal Medicine III, University of Ulm, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Raghavachar
authors.forename: A
authors.initials: A
authors.lastname: Ganser
authors.forename: M
authors.initials: M
authors.lastname: Freund
authors.forename: H
authors.initials: H
authors.lastname: Heimpel
authors.forename: F
authors.initials: F
authors.lastname: Herrmann
authors.forename: H
authors.initials: H
authors.lastname: Schrezenmeier
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000741:Anemia, Aplastic / Q000097:blood / Q000628:therapy*; D000961:Antilymphocyte Serum / Q000009:adverse effects / Q000627:therapeutic use*; D003114:Colony-Forming Units Assay; D016572:Cyclosporine / Q000009:adverse effects / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007165:Immunosuppression Therapy / Q000009:adverse effects / Q000379:methods; D007377:Interleukin-3 / Q000009:adverse effects / Q000627:therapeutic use*; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D009504:Neutrophils; D018579:Patient Selection; D010976:Platelet Count; D011994:Recombinant Proteins / Q000009:adverse effects / Q000627:therapeutic use; D017701:Reticulocyte Count; D013997:Time Factors
chemical_list: D000961:Antilymphocyte Serum; D007377:Interleukin-3; D011994:Recombinant Proteins; D016572:Cyclosporine