title: Effect of combination therapy with all-trans-retinoic acid and recombinant human granulocyte colony-stimulating factor in patients with myelodysplastic syndromes.
abstract: Since all-trans retinoic acid (ATRA) and granulocyte colony-stimulating factor (G-CSF) not only enhance proliferation and differentiation of normal myeloid cells but also synergistically promote the differentiation of myeloid leukemic blast cells in vitro, we have started a pilot study of combined treatment with ATRA and G-CSF in patients with myelodysplastic syndrome, to analyze the effect of these drugs on hematopoietic differentiation. ATRA was given at 45 mg/m2/day p.o. from week 1-12 and G-CSF at 5 micrograms/kg/day s.c. from week 5-12 with dose modifications according to the absolute neutrophil counts (ANC). A total of 15 patients, predominantly with refractory anemia, were treated. During initial ATRA therapy, a bilineage response with increases of both ANC and platelet counts occurred in three patients. During combined ATRA/G-CSF therapy, ANC increased in all patients, and platelets increased in three out of 14 evaluable patients. An increase in hemoglobin concentration and a decrease in transfusion requirements occurred in one patient each. In the bone marrow, the myeloid-to-erythroid ratio increased during ATRA treatment and remained increased during concomitant G-CSF administration, while the maturation index of myeloid cells increased only in response to ATRA therapy, but returned to baseline during ATRA/G-CSF treatment. Cytogenetic analysis demonstrated persistence of the abnormal clones in all patients. The number of circulating progenitor cells CFU-GM increased in all patients studied. Serum concentrations of the soluble TNF receptor and IL-2 receptor both increased, while TNF-alpha--already elevated prior to therapy--and soluble ICAM-1 concentrations did not significantly change. Adverse effects included dermatitis and cheilosis in most patients, and a drop in platelet counts related to G-CSF in one patient. The pilot study demonstrates that the combination treatment with ATRA/G-CSF is well tolerated, leading to normalization of ANC in most, and improvement of platelets and red blood cells in a subgroup of patients.
authors.affiliation: Department of Hematology, University of Frankfurt, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Ganser
authors.forename: G
authors.initials: G
authors.lastname: Seipelt
authors.forename: W
authors.initials: W
authors.lastname: Verbeek
authors.forename: O G
authors.initials: OG
authors.lastname: Ottmann
authors.forename: A
authors.initials: A
authors.lastname: Maurer
authors.forename: K
authors.initials: K
authors.lastname: Kolbe
authors.forename: U
authors.initials: U
authors.lastname: Hess
authors.forename: S
authors.initials: S
authors.lastname: Elsner
authors.forename: R
authors.initials: R
authors.lastname: Reutzel
authors.forename: B
authors.initials: B
authors.lastname: Wörmann
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000753:Anemia, Refractory / Q000097:blood / Q000628:therapy*; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology; D016207:Cytokines / Q000097:blood; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D009504:Neutrophils; D010865:Pilot Projects; D010976:Platelet Count; D014212:Tretinoin / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D016207:Cytokines; D016179:Granulocyte Colony-Stimulating Factor; D014212:Tretinoin