A PILOT-STUDY OF ISOTRETINOIN IN THE TREATMENT OF JUVENILE CHRONIC MYELOGENOUS LEUKEMIA

Background. Juvenile chronic myelogenous leukemia (CML) is a rare myel oproliferative disease of infants and young children for which there i s no effective therapy other than allogeneic bone marrow transplantati on. In vitro, isotretinoin (13-cis-retinoic acid) attenuates both the spontaneous proliferation of leukemic peripheral-blood progenitor cell s (granulocyte-macrophage colony-forming units) and their selective hy persensitivity to granulocyte-macrophage colony-stimulating factor (GM -CSF). We conducted a pilot study to evaluate the clinical efficacy of isotretinoin in juvenile CML. Methods. To be eligible the patients ha d to have newly diagnosed untreated disease, leukocytosis with monocyt osis, marrow with less than 25 percent blasts, hepatosplenomegaly, no chromosomal abnormalities, and negative viral cultures and antibody ti ters. Isotretinoin was administered orally in single daily doses of 10 0 mg per square meter of body-surface area. When possible, patients su bsequently underwent bone marrow transplantation. Results. Ten childre n (median age, 10 months) were enrolled in the study. In all 10 there was spontaneous colony formation of leukemic progenitor cells in vitro . In the eight patients tested there was hypersensitivity to GMCSF. Th e only toxic effect of isotretinoin therapy was cheilitis in two patie nts. Four children had disease progression. Two children had complete responses to isotretinoin (normalization of the white-cell count and d isappearance of organomegaly), three had partial responses (more than a 50 percent reduction in the white-cell count and degree of organomeg aly), and one had a minimal response (more than a 50 percent reduction in the white-cell count, but a 26 to 50 percent reduction in the degr ee of organomegaly). The median duration of response was 37 months (ra nge, 6 to 83). Three of the four children who had a complete or partia l response and who did not undergo bone marrow transplantation were al ive 36 to 83 months after the diagnosis of juvenile CML. The spontaneo us colony formation in vitro was reduced in samples from the five pati ents in whom this factor was reassessed during treatment. There was al so a reduction in the hypersensitivity of leukemic progenitor cells to GM-CSF in the two patients retested. Conclusions. Isotretinoin can in duce durable clinical and laboratory responses in patients with juveni le CML.