isotretinoin and Leukemia--Myelogenous--Chronic--BCR-ABL-Positive

Juvenile chronic myelogenous leukemia (CML) is a rare myeloproliferative disease of infants and young children for which there is no effective therapy other than allogeneic bone marrow transplantation. In vitro, isotretinoin (13-cis-retinoic acid) attenuates both the spontaneous proliferation of leukemic peripheral-blood progenitor cells (granulocyte-macrophage colony-forming units) and their selective hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF). We conducted a pilot study to evaluate the clinical efficacy of isotretinoin in juvenile CML.. To be eligible the patients had to have newly diagnosed untreated disease, leukocytosis with monocytosis, marrow with less than 25 percent blasts, hepatosplenomegaly, no chromosomal abnormalities, and negative viral cultures and antibody titers. Isotretinoin was administered orally in single daily doses of 100 mg per square meter of body-surface area. When possible, patients subsequently underwent bone marrow transplantation.. Ten children (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 GM-CSF. The only toxic effect of isotretinoin therapy was cheilitis in two patients. Four children had disease progression. Two children had complete responses to isotretinoin (normalization of the white-cell count and disappearance of organomegaly), three had partial responses (more than a 50 percent reduction in the white-cell count and degree of organomegaly), 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 degree of organomegaly). The median duration of response was 37 months (range, 6 to 83). Three of the four children who had a complete or partial response and who did not undergo bone marrow transplantation were alive 36 to 83 months after the diagnosis of juvenile CML. The spontaneous colony formation in vitro was reduced in samples from the five patients in whom this factor was reassessed during treatment. There was also a reduction in the hypersensitivity of leukemic progenitor cells to GM-CSF in the two patients retested.. Isotretinoin can induce durable clinical and laboratory responses in patients with juvenile CML.

Topics: Child, Preschool; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Infant; Isotretinoin; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Pilot Projects; Prospective Studies

The treatment of CML with IFN alpha is limited due to resistance against this substance. Recent studies with different cells than chronic myelogenous leukemic cells revealed a synergistic effect of a combined use of Retinoids (RA) and IFN alpha. The purpose of the study was to detect possible interactions of IFN alpha and RA in CML considering also the effect of the BCR-ABL gene-product. Therefore, we investigated three CML cell lines in their proliferation after incubation with IFN alpha and Retinoids alone and in combination. We measured low susceptibility to IFN alpha but a marked influence of the Retinoids. In combination, the growth inhibition was enhanced potentially in response to an increased efficacy of IFN alpha. Even solely, ineffective concentrations of both substances lead to decreased proliferation.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cell Division; Drug Synergism; Humans; In Vitro Techniques; Interferon-alpha; Isotretinoin; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Thymidine; Tretinoin; Tumor Cells, Cultured

We have characterized a new human cell line AP-217, derived from the peripheral blood of a patient with chronic myeloid leukemia in blastic crisis. The analysis of cell surface antigens and ploidy showed that AP-217 was an erythro-megakaryocytic cell line. The effects of inducers of differentiation were studied and focused on retinoic acid (RA). Uninduced AP-217 cells produced a low level of hemoglobin (Hb) that showed a moderate but significant dose-dependent increase after 13 cis-RA induction (four times above the control at 10(-5) M). To outline this effect, AP-217 cells were cloned at limiting dilution. A subclone (clone 2) was isolated which expressed glycophorin A on 12% of cells, and showed a marked sensitivity to RA. After a 4 day induction with increasing concentrations of RA (1-10 x 10(-6) M) Hb production by clone 2 cells was enhanced 12 times over the control at the highest concentration (10(-5) M). No effect of RA on the Hb production of K-562 and HEL was observed. This increased Hb production occurred simultaneously with a growth inhibition in clonogenic cultures (20% reduction) associated with a drastic reduction of the colony size. Moreover, we demonstrated the expression of mRNA for the beta globin gene in clone 2 and AP-217-cells. This is the first report of a positive effect of RA on the erythroid differentiation of a human leukemic cell line.

Topics: Adult; Antigens, Surface; Blotting, Northern; Cell Differentiation; Cell Division; Cloning, Molecular; Erythrocytes; Globins; Hemoglobins; Humans; Isotretinoin; Karyotyping; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Megakaryocytes; Polymerase Chain Reaction; Tumor Cells, Cultured

Topics: Antibodies, Monoclonal; Antineoplastic Agents; Drugs, Investigational; Humans; Isotretinoin; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Neoplasms; Tolonium Chloride; Vinblastine; Vinorelbine

Topics: Child; Humans; Infant; Isotretinoin; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Treatment Outcome

Topics: Child; Humans; Isotretinoin; Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Systemic retinoids are used in the management of chronic cutaneous conditions and life-threatening dermatoses. Unfortunately, drug-induced hypertriglyceridemia may necessitate either dose reduction or discontinuation of therapy. The purpose of this article is to describe the successful management of isotretinoin-induced hypertriglyceridemia with gemfibrozil in a leukemia patient. Sequential serum chemistries were performed prior to, during, and following treatment with a systemic retinoid and a lipid-regulating agent. A prompt and sustained normalization of fasting triglycerides occurred following the initiation of gemfibrozil in a patient with isotretinoin-induced hypertriglyceridemia. When retinoids are being used in the management of serious conditions, the initiation of therapy with gemfibrozil to reduce the elevated triglycerides may be appropriate in those patients with retinoid-induced hypertriglyceridemia.

Topics: Acne Vulgaris; Adult; Combined Modality Therapy; Cytarabine; Gemfibrozil; Humans; Hydroxyurea; Hypertriglyceridemia; Immunologic Factors; Incidence; Isotretinoin; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male