tretinoin and Anemia--Refractory

Refractory anemias and the myelodysplastic syndromes are a group of hematopoietic stem cell disorders characterized by ineffective and dysplastic hematopoiesis, leading to persistent peripheral cytopenias. Patients also have an increased risk of transformation to acute myelogenous leukemia. Since defective cellular maturation is the central pathogenetic feature, improved differentiation may result in correction of neutropenia and thrombocytopenia. Clinical trials using retinoic acid and vitamin D3 analogues are not satisfactory and only small numbers of patients may benefit from receiving them. In view of the absence of other effective treatment, future studies should be directed to the combined use of differentiating agents with hematopoietic growth factors and to the identification of new compounds with greater differentiating ability and less toxicity.

Topics: Adult; Aged; Aged, 80 and over; Anemia, Refractory; Animals; Cholecalciferol; Female; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Tretinoin

To explore therapeutic efficacy of androgens and low dose all-trans retinoic acid (ATRA) for myelodysplastic syndrome (MDS) patients, 55 patients of MDS were observed, including 41 cases of refractory anemia (RA), 11 cases of refractory anemia with excess of blasts (RAEB), 2 cases of refractory anemia with excess of blasts in transformation (RAEB-t) and 1 case of chronic myeloic-monocytic leukemia (CMML). These patients received danazol (600 mg/day) or stanazol (6 mg/day) and ATRA (10 mg/day) for at least 3 months. The results showed that according to MDS international working group response criteria, at the end of three months,complete remission (CR) was seen in 1 patient, partial remission (PR) was found in 2 patients. Hematologic improvement: major response (MaR) were seen in 15 patients, minor response (MiR) were seen in 4 patients. The total response rate was 35.8%. In conclusion, danazol or stanazol in combination with low dose ATRA are partialy effective in therapy for patients with low-risk myelodysplastic syndrome.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Androgens; Anemia, Refractory; Anemia, Refractory, with Excess of Blasts; Antineoplastic Agents; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Treatment Outcome; Tretinoin

Used as single agents, ATRA, G-CSF, and IFN-alpha have shown a moderate benefit in patients with low-risk MDS, with a response rate of 10%. The aim of the present study was to evaluate the efficacy of a combination of these agents. The effect on hemoglobin (Hb), platelets, and absolute neutrophil count (ANC), as well as on transfusion frequency, was examined in 25 patients with MDS (11 RA, four RARS, eight RAEB, two CMML). The median age was 61 years (range 44-81), and the male/female ratio was 14/11. Treatment consisted of ATRA at 25 mg/m2/day p.o. for months 1, 3, 5, 7, 9, and 11, IFN-alpha at 1.5 MIU twice a week s.c. for 52 weeks, and, in patients with initial ANC <500/microl, G-CSF at 100-480 microg daily s.c. according to the degree of ANC. The duration of therapy was scheduled for 12 months. Two patients achieved ongoing CR (+19 months; +16 months), one patient with RA after 3 months and one with CMML after 7 months of treatment. In all patients, the mean ANC increased significantly from 1400+/-200/microl before the start of therapy to 3500+/-600/microl at the end of treatment (p=0.025). In two patients an increase of Hb was observed, and one patient ceased to require transfusions. In an additional patient with RA and 5q-syndrome, the platelet count normalized following administration of ATRA/IFN-alpha, increasing from 89,000/microl to 293,000/microl. The eight RAEB patients were nonresponders. We conclude that therapy with ATRA, IFNalpha, and G-CSF is effective in approximately 35% of low-risk MDS patients (in this study: six of 17) and may induce complete remission in individual cases.

Topics: Adult; Aged; Aged, 80 and over; Anemia, Refractory; Anemia, Refractory, with Excess of Blasts; Drug Therapy, Combination; Female; Granulocyte Colony-Stimulating Factor; Humans; Interferon-alpha; Leukemia, Myelomonocytic, Chronic; Leukocyte Count; Male; Middle Aged; Myelodysplastic Syndromes; Neutrophils; Remission Induction; Tretinoin

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.

Topics: Adult; Aged; Aged, 80 and over; Anemia, Refractory; Bone Marrow; Cytokines; Drug Administration Schedule; Drug Therapy, Combination; Female; Granulocyte Colony-Stimulating Factor; Humans; Leukocyte Count; Male; Middle Aged; Neutrophils; Pilot Projects; Platelet Count; Tretinoin

We investigated the efficacy and safety of a combination regimen in 63 patients with primary refractory anemia (RA). The daily treatment protocol comprised all-trans retinoic acid (ATRA) (30 mg/m(2)), calcitriol (0.1 microg/m(2)), and androgen (stanozolol 3mg/m(2), or danazol 300 mg/m(2)) in three separate doses for eight consecutive weeks. Hematologic improvement was observed in 43 (68.3%) patients. The treatment administered was generally well tolerated, with no severe regimen-related toxicity. The overall survival rates at 3 and 5 years were 68.72% and 53.18%, respectively. These results indicate that this combination regimen is an effective and well-tolerated treatment for patients with RA.

Topics: Adolescent; Adult; Aged; Androgens; Anemia, Refractory; Calcitriol; Child; Child, Preschool; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Female; Follow-Up Studies; Humans; Kaplan-Meier Estimate; Male; Maximum Tolerated Dose; Middle Aged; Pilot Projects; Retrospective Studies; Survival Rate; Treatment Outcome; Tretinoin

This study was aimed to examine whether a combination of all-trans retinoic acid (ATRA), 1, 25-dihydroxyvitamin D(3) and androgen possesses the therapeutic value for the MDS-refractory anemia (MDS-RA), and to analyze the mechanisms in detail. 62 cases receiving a scheme of combination of ATRA, 1, 25-dihydroxyvitamin D(3) and androgen (group A) were monitored. The remaining 33 cases (group B) were provided with vitamin supplementation, chalybeate drugs, and one or two of the combination. Bone marrow aspiration and biopsy were performed for collecting the specimens at the baseline and afterwards. The conditions of the patients were monitored by means of weekly complete blood counts and the monthly examination, including toxicity test, physical examination, electrocardiography, and biochemistry panel. The results showed that after treating for 8 weeks in group A, 4 out of 62 patients showed complete remission and 12 patients showed partial remission according to the defined response criteria, and 43 patients (69.35%) showed hematological improvement (HI). The further treatment for 16 out of 62 patients (25.81%), 13 failures (10 deaths, 2 RAEB and 1 RAEB-T) and 3 transformations (M(2), M(3), M(5)) with a median survival interval of 26.25 months, were observed and interrupted for some reasons. However, partial remission was observed only in 3 patients in group B, and HI amounted to 51.51%. Furthermore, the disease progression was observed in 12 out of 33 patients (36.36%) with a median survival interval of 16 months, 9 failures (including 6 deaths, 2 RAEB and 1 RAEB-T) and 3 transformations (M(2), M(3), M(4)). The overall ratios of survival for 3 and 5 years in group A, which received the combination, reached to 69.24% and 53.72% respectively, in comparison with 52.23% and 31.34% in the patients of group B (log-rank, P = 0.016). The following requirements, if were met, would be significant for prognosis: the combination regiment, no transformation, children, no complication, female, 90-120 g/L of hemoglobin concentration, normal cellular bone marrow and uni-cytopenias (P < 0.05). Moreover, Cox regression showed that therapy, transformation and age are all the independent factors (P < 0.05). It is concluded that the combination of above mentioned 3 drugs may be effective and safe treatment for the patients with MDS-RA. Its relevant mechanisms can be involved in the combination, that elicits a wide range of pharmacological effects, such as differentiation, anti-

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Androgens; Anemia, Refractory; Blood Cell Count; Calcitriol; Child; Child, Preschool; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Retrospective Studies; Survival Analysis; Time Factors; Treatment Outcome; Tretinoin

IFN alpha alone or in combination with retinoids or haematopoietic growth factors has been used to treat patients with early MDS because of its properties as a differentiation inducing agent. We investigated whether treatment of patients with refractory anemia (RA) with IFN alpha (1.5x10(6) IU twice a week) and intermittent all-trans retinoic acid (ATRA, 25 mg/m2/d) influences in-vitro megakaryocytic (MK) proliferation and differentiation stimulated by PEG-rHuMGDF. Low-density non-adherent bone marrow (BM) cells from 8 patients with RA were assayed prior to any treatment other than supportive and after a period of 6 months of treatment. MK development was assayed in suspension cultures in the presence of PEG-rHuMGDF and SCF for 7 d using morphological criteria and flow cytometric analysis of CD42b (GP1b) positive cells. BM-cells from 10 healthy individuals served as control. Following stimulation with PEG-rHuMGDF 23+/-7% and 16+/-4% of control cells were CD42b positive after 5 and 7 d of cultures, respectively. In cultures of cells from MDS patients prior to treatment 8+/-2% and 7+/-3% of cells were CD42b+ on days 5 and 7. In the course of IFN alpha treatment cultures of all BM samples from these MDS patients revealed a significant reduction of MK precursor cells (3+/-2%, CD42b+, p=0.03 and 0.04). In conclusion, treatment with TFN alpha and ATRA did not result in improved megakaryocytopoiesis as assessed by in-vitro cultures. On the contrary, low-dose IFN alpha appears to suppress cell proliferation as well as MK development.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anemia, Refractory; Antigens, CD; Antineoplastic Agents; CD24 Antigen; Cell Differentiation; Cell Division; Cells, Cultured; Drug Therapy, Combination; Female; Humans; Injections, Subcutaneous; Interferon-alpha; Male; Megakaryocytes; Membrane Glycoproteins; Middle Aged; Tretinoin

Topics: Anemia, Refractory; Anemia, Refractory, with Excess of Blasts; Cell Differentiation; Hematopoietic Stem Cells; Humans; Leukocyte Count; Neutrophils; Tretinoin

Eighteen patients with myelodysplastic syndrome received 13-cis-retinoic acid (1.0-mg/kg/day starting dose with 0.5-mg/kg increment escalations) in a phase I-II trial. Two partial responses involving the erythroid series were observed in four patients with primary refractory anemia with ring sideroblasts. One of two patients with chronic myelomonocytic leukemia also achieved a partial response. No other responses were found in the remaining patients, which included eight with refractory anemia with excess blasts. In six patients drug toxicity necessitated termination of the trial. Four patients had unexpected drug-induced thrombocytopenia; three of these had low platelet counts before treatment. Two of the six patients had other toxic effects. Further studies are warranted to evaluate the effectiveness of 13-cis-retinoic acid in patients with refractory anemia with ring sideroblasts and chronic myelomonocytic leukemia. At moderate doses significant toxic effects, including thrombocytopenia, are not uncommon.

Topics: Anemia, Refractory; Blood Cell Count; Drug Evaluation; Erythropoiesis; Hematopoietic Stem Cells; Hemoglobins; Humans; Isotretinoin; Leukemia, Myeloid; Myelodysplastic Syndromes; Thrombocytopenia; Tretinoin