1-arabinofuranosylcytosine-5--stearylphosphate and Anemia--Refractory--with-Excess-of-Blasts

We evaluated a combination chemotherapy with cytarabine ocfosfate (SPAC), low dose etoposide and G-CSF for the treatment of high-risk MDS (RAEB, RAEBt). Seven patients with high-risk MDS were treated with a daily combination, 200 mg/day SPAC p.o., 50 mg/day etoposide p.o. and 75 micrograms/day G-CSF s.c. One patient achieved complete response, 2 achieved good response and one patient minor response. Although all of the patients developed severe marrow hypoplasia after chemotherapy, the nonhematologic adverse effects were mild enough to be tolerated. This combination chemotherapy should be useful in the clinical management of patients with high-risk MDS.

Topics: Aged; Anemia, Refractory, with Excess of Blasts; Antineoplastic Combined Chemotherapy Protocols; Arabinonucleotides; Bone Marrow; Cytidine Monophosphate; Etoposide; Female; Granulocyte Colony-Stimulating Factor; Humans; Male; Middle Aged; Pilot Projects; Risk

Topics: Administration, Oral; Aged; Anemia, Refractory, with Excess of Blasts; Arabinonucleotides; Cytidine Monophosphate; Granulocyte Colony-Stimulating Factor; Humans; Injections, Subcutaneous; Male; Prodrugs; Remission Induction

A 55-year-old female presented with sore throat and slight fever. The patient was admitted to our hospital on December 13, 1993. Full blood count showed hemoglobin 10.7 g/dl, white cell count 960/microliters (neutrophils 14%, lymphocytes 82%, blasts 2%) and platelets 13,000/microliters. Bone marrow examination showed hypocellularity with 4.5% of myeloblast positive for peroxidase. The bone marrow specimens on Dec. 20 showed 15.5% of myeloblasts, some of which had Auer rods. These findings led to the diagnosis of refractory anemia with excess myeloblast in transformation (RAEB-T) of French-American-British Cooperative Group. The patient was transfused and treated with cytarabine ocfosfate (SP-AC) (100 mg tid) and 6-mercaptopurine (50 mg tid) for 14 days. During chemotherapy she complained of nausea and anorexia, but they were managed easily with medication. On Feb. 7, 1994, forty-two days after the start of administration, peripheral blood and bone marrow aspirate were compatible with a complete remission. Although complete remission was sustained with courses of chemotherapy for 4 months, relapse occurred and the patient died of septicemia on August 29, 1994 after induction failure. Observation suggested that oral SPAC in combination with 6-mercaptopurine had a good antileukemic effect on the myelodysplastic syndrome. However, the duration response was short, and further improvement of the therapy is needed.

Topics: Administration, Oral; Anemia, Refractory, with Excess of Blasts; Antineoplastic Combined Chemotherapy Protocols; Arabinonucleotides; Cytidine Monophosphate; Female; Humans; Mercaptopurine; Middle Aged; Remission Induction

A 58-year-old female was diagnosed as myelodysplastic syndrome (MDS) [refractory anemia with excess of blasts (RAEB)]. Although melphalan was administered, no response was obtained in the peripheral blood. Sixteen months after diagnosis, she developed RAEB in transformation (RAEB-t), and then overt leukemia. White blood cell (WBC) count elevated to 28,600/microliters with 34% of blasts. She was administered cytarabine ocfosfate (200 mg-->300 mg/day) orally, resulting in decrease of WBC count and blasts in peripheral blood. The drug has been given for 11 months, and her hematological data have now remained stable in RAEB. Cytarabine ocfosfate might be a useful drug for the treatment of high risk MDS such as RAEB and RAEB-t.

Topics: Acute Disease; Administration, Oral; Anemia, Refractory, with Excess of Blasts; Antineoplastic Agents; Arabinonucleotides; Cytidine Monophosphate; Female; Humans; Leukemia; Middle Aged

1-beta-D-Arabinofuranosylcytosine-5'-stearylphosphate (cytarabine ocfosfate, stearyl-ara-CMP) is a newly synthesized 5'-alkylphosphate derivative of 1-beta-D-arabinofuranosylcytosine (ara-C), which is lipophilic, resistant to inactivation by deamination, and orally active. Pharmacology of this drug was studied in patients with hematological malignancies. The concentrations of stearyl-ara-CMP, ara-C (its active metabolite), and 1-beta-D-arabinofuranosyluracil (ara-U, its inactive metabolite) were determined by radioimmunoassay. When six patients received a single p.o. dose of the drug (500 mg/m2), stearyl-ara-CMP, ara-C, and ara-U could be detected in the plasma for at least 72 h afterwards. The plasma disappearance curve of stearyl-ara-CMP corresponded to a one-compartment open model with first-order absorption kinetics. The peak plasma level (Cmax) was 322 +/- 218 nM, and the predicted time to reach Cmax (Tmax) was 6.5 +/- 4.5 h, while the elimination half-life (t1/2) was very long (32.0 +/- 8.4 h). The plasma ara-C level increased slowly to a Cmax of 26.3 +/- 12.7 nM (Tmax, 13.3 +/- 4.7 h) after stearyl-ara-CMP administration. This level was quite low compared with that achieved by low-dose s.c. ara-C therapy, but ara-C persisted longer in the plasma in the former case, and the area under the curve was similar for both regimens. For ara-U, the Cmax, Tmax, and t1/2 were 483 +/- 315 nM, 23.6 +/- 4.0 h, and 19.6 +/- 5.3 h, respectively. No stearyl-ara-CMP was detected in the urine, and only 8.0% of the administered dose was excreted as ara-C and ara-U within 72 h. The stearyl-ara-CMP concentration in the cerebrospinal fluid was below the limit of detection in three patients without meningeal involvement at 6 h. During clinical use of stearyl-ara-CMP, macrocytic anemia was observed, and some patients also developed megaloblastic change of their erythroblasts, suggesting a mild and persistent cytostatic effect. In conclusion, p.o. therapy with stearyl-ara-CMP achieved prolonged maintenance of the plasma drug level. Thus, the drug released a very low dose of ara-C over a long period in plasma and tissues and had a prolonged mild antineoplastic effect in patients with hematological malignancies.

Topics: Acute Disease; Adult; Aged; Anemia, Refractory, with Excess of Blasts; Antineoplastic Agents; Arabinonucleotides; Cytidine Monophosphate; Female; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid; Male; Middle Aged; Polycythemia Vera