1-arabinofuranosylcytosine-5--stearylphosphate and Myelodysplastic-Syndromes

Cytarabune ocfosfate (SPAC) is rapidly transformed into cytarabine (ara-C) when orally administered. The pharmacokinetics of SPAC was studied in six patients with acute non-lymphocytic leukemia (ANLL) and/or myelodysplastic syndromes (MDS) after oral administration of SPAC at 100 to 400 mg/day for 14 days. Plasma ara-C concentrations reached a plateau in 48 to 96 hours after initiation of SPAC administration, remained at this or a little higher level until one day after its termination and were less than 1 ng/ml 8 days after the termination. From all of pharmacokinetic data, the oral administration of SPAC at 150 to 300 mg/m2/day was pharmacokinetically concluded to be comparable to the continuous infusion of ara-C at 20 mg/m2/day. All of the patients could receive SPAC for 14 days. SPAC is considered to be useful for consolidation or maintenance chemotherapy of ANLL or MDS outpatients who are unable to undergo intensive chemotherapy.

Topics: Administration, Oral; Aged; Antineoplastic Agents; Arabinonucleotides; Cytarabine; Cytidine Monophosphate; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Myelodysplastic Syndromes; Time Factors

Cytarabine ocfosfate (SPAC) was administered orally to 19 patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). SPAC was administered at doses of 200-300 mg/day for more than 14 days with granulocyte colony-stimulating factor (G-CSF). Four of the 12 patients with AML and 1 of the 7 patients with MDS achieved complete remission (CR) after one cycle of SPAC treatment. Especially, 3 of the 6 patients with newly diagnosed AML achieved CR. Major side effects of SPAC were myelosuppression and tolerable gastrointestinal disorders. The treatment with SPAC is a therapeutic option in elderly patients or patients with organ failure.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Arabinonucleotides; Cytidine Monophosphate; Drug Therapy, Combination; Female; Granulocyte Colony-Stimulating Factor; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Myelodysplastic Syndromes

1-beta-D-Arabinofuranosylcytosine-5'-stearylphosphate (fosteabine) was administered orally to patients with myelodysplastic syndromes (MDS); refractory anemia with excess of blasts (RAEB), RAEB in transformation, acute leukemia derived from RAEB and chronic myelomonocytic leukemia, in an early phase II study in a multi-institutional study. Among 62 evaluable patients, 2 patients achieved a complete remission, 6 a good response and 8 partial response by daily oral administration of 100-200 mg of fosteabine. The overall response rate was 25.8%. The response rates were almost the same among the four subtypes of MDS. Responses were reached 2-23 weeks (median, 8 weeks) after the start of therapy and continued for 3-50 weeks (median, 10 weeks). Major side effects were myelosuppression and gastrointestinal toxicities. In spite of the disadvantages, such as unpredictable absorption, this newly developed orally administrable cytarabine analogue will be a useful drug in the treatment of MDS.

Topics: Adult; Aged; Aged, 80 and over; Arabinonucleotides; Cytidine Monophosphate; Dose-Response Relationship, Drug; Drug Evaluation; Female; Humans; Male; Middle Aged; Myelodysplastic Syndromes

Phase I study of YNK01 (1-beta-D-arabinofuranosylcytosine-5'-stearylphosphate), a derivative of cytosine arabinoside (Ara-C), was conducted by cooperative study groups between January 1986 and June 1987. The dosage for the single and 5-day oral administration ranged 50 to 1,200 and 100 to 900 mg/body/day, respectively. The main adverse effects were myelo-suppression and gastrointestinal toxicities such as nausea, vomiting, anorexia and diarrhea. In the single administration, the maximum tolerated dose (MTD) could not be determined, however, in the 5-day schedule MTD was considered to be 700 to 900 mg/body/day, and the dose limiting factor to be thrombocytopenia. After the single administration (800 mg/body/day) of YNK01, the plasma concentration of Ara-C, an active metabolite of YNK01, was 3.43 ng/ml (Cmax) at 24 hrs. and 0.82 ng/ml at 72 hrs. During the 5-day administration for 300 mg/body/day and 500 mg/body/day, the Ara-C concentration changed from 2.3 to 4.1 ng/ml, and from 1.5 to 11.9 ng/ml respectively, and sustained almost the same concentration as to during the administration period until the 2nd day after the completion of the administration.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anorexia; Antineoplastic Agents; Arabinonucleotides; Cytidine Monophosphate; Diarrhea; Drug Administration Schedule; Drug Evaluation; Female; Humans; Leukemia, Myeloid, Acute; Lung Neoplasms; Male; Middle Aged; Myelodysplastic Syndromes; Nausea; Vomiting

Phase II study of YNK01 (1-beta-D-arabinofuranosylcytosine-5'-stearylphosphate), a derivative of cytosine arabinoside, on hematological malignancies was conducted by multi-institutional cooperative group. YNK01 was administered orally at dose of 100-300 mg/body/day for more than 2 weeks. The number of registered and evaluated patients were 211 and 156, respectively. Of 23 patients with acute myelogeneous leukemia (AML), 2 complete response (CR), one partial response (PR) were observed (CR + PR: 13.0%). Hypoplastic leukemia (1/4: 25%), acute unclassified leukemia (1/1: 100%). Of 45 patients with MDS, 2CRs, 6 good response (GR) and 5PRs were observed (CR + PR: 28.9%). AML developing after a prior history of MDS (5/17: 29.4%), CML-BC (2/9: 22.2%). Of 19 patients with CML, 9 achieved CR, 3 achieved PR (63.2%). Of 11 patients with polycythemia vera, 4 achieved CR, 5 achieved PR (81.8%). Of 6 patients with essential thrombocytosis, 2 achieved CR, one achieved PR (50%). The major adverse effects included gastrointestinal toxicities such as nausea, vomiting, anorexia, diarrhea, and elevation of GOT and GPT which were tolerable and reversible. This study indicates that YNK01 is a useful agent against acute leukemia and MDS, especially RAEB, RAEB in T, CMMoL.

Topics: Acute Disease; Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Arabinonucleotides; Cytidine Monophosphate; Drug Administration Schedule; Drug Evaluation; Female; Humans; Japan; Leukemia; Male; Middle Aged; Myelodysplastic Syndromes; Nausea; Remission Induction; Vomiting

Elderly acute myeloid leukemia (AML) patients and patients with higher-risk myelodysplastic syndromes (MDS) have a much poorer prognosis than younger patients despite intensive chemotherapy.. Ten patients with higher-risk MDS and 12 patients with AML over 65 years of age were enrolled into this study and received oral induction therapy with cytarabine ocfosfate and etoposide.. The therapy response rates were 60% in the MDS group and 41.7% in the AML group. The difference in overall survival among MDS and AML patients was not statistically significant. The difference in the median survival times of the responsive and nonresponsive groups, which included MDS and AML patients, was statistically significant (790 and 174 days, respectively).. Based on a comparison of the data of this therapy in elderly higher-risk MDS patients versus elderly AML patients, we conclude that this therapy is well tolerated and can be cost-effective and useful for higher-risk MDS in elderly patients.

Topics: Administration, Oral; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Arabinonucleotides; Cytidine Monophosphate; Disease-Free Survival; Etoposide; Female; Humans; Kaplan-Meier Estimate; Leukemia, Myeloid, Acute; Male; Myelodysplastic Syndromes; Treatment Outcome

Five cases of myelodysplastic syndrome were treated with cytarabine ocfosfate. Ocfosfate (100-200 mg) was orally administered for 14 days with 14 days' interval. Etoposide was combined in one case, and nartograstim was added in two cases. Two of the five cases achieved remission, one case having complete remission, and another case showing a good response. Their remission durations were 141 and 112 days, respectively. Further improvement of therapy is needed to achieve a higher remission rate and a longer remission duration.

Topics: Administration, Oral; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Arabinonucleotides; Cytidine Monophosphate; Etoposide; Female; Granulocyte Colony-Stimulating Factor; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Remission Induction

Plasma concentration of cytosine arabinoside (Ara-C) was determined in elderly patients with myelodysplastic syndromes or acute myelocytic leukemia who were treated with subcutaneous injection of Ara-C (Ara-C s.c.; 10 mg/m2/12 hr, 14-21 days), continuous drip infusion of Ara-C (Ara-C d.i.v.; 20 mg/m2/day, 24 hr 14 days) and/or oral administration of cytarabine ocfosfate (SPAC) (SPAC p.o.; 100 mg-300 mg/body/day, 14 days) by radioimmunoassay. In the Ara-C s.c. patients, the peak plasma level (Cmax) of Ara-C was 103 ng/ml and the time to reach Cmax was 15 min. The elimination half-like (t1/2) was 25 min and no accumulation was detected after 14 days of consecutive Ara-C s.c. administrations. In the SPAC p.o. patients, Cmax of Ara-C was 3-8 ng/ml and it took 3-5 days to reach Cmax. The plasma concentration level of Ara-C remains almost at the Cmax level during the SPAC p.o. administration and it remained higher than 0.32 ng/ml for as long as 15 days after the end of administration. In a Ara-C d.i.v. patient, plasma level of Ara-C was detected 4-7 ng/ml during the administration (day 7 through day 14). In all patients bone marrow suppression was observed after chemotherapy regardless of regimen, and there was no significant difference between nadir peripheral cell blood counts of Ara-C s.c. patients and SPAC p.o. patients.

Topics: Administration, Oral; Aged; Aged, 80 and over; Antineoplastic Agents; Arabinonucleotides; Cytarabine; Cytidine Monophosphate; Female; Humans; Infusions, Intravenous; Injections, Subcutaneous; Leukemia, Myeloid, Acute; Male; Myelodysplastic Syndromes

A 65-year-old female with acute myelomonocytic leukemia (AMMoL) developed from myelodysplastic syndrome (MDS), successfully treated with cytarabine ocfosfate (SPAC) is reported. Ubenimex, calcitriol and corticosteroid had a minor effect on her MDS. Since she had severe anemia and congestive heart failure on developing leukemia, she was treated with oral administration of SPAC, a cytidine deaminase resistant derivative of Ara-C. After the second course of SPAC (200 mg/day, for 14-28 days), marked erythroid bursts were found and she entered complete remission. The samplings of SPAC and its metabolites of SPAC were investigated in 2 cases including this case, but there seemed to be no relation between their content and effects. In AML patients, especially in cases developed from MDS, SPAC might be useful because it can be given orally even in an outpatient.

Topics: Aged; Antineoplastic Agents; Arabinonucleotides; Cytidine Monophosphate; Drug Administration Schedule; Female; Humans; Leukemia, Myelomonocytic, Acute; Myelodysplastic Syndromes; Remission Induction

A 42-year-old man was admitted to our hospital because of pancytopenia in April 1992. A diagnosis of refractory anemia was made. The karyotype was normal male type on the initial study. Subcutaneous administration of granulocyte colony-stimulating factor (G-CSF) initially increased the peripheral neutrophil count, bat in January 1993, although blast cells did not increase, neutrophils had decreased in spite of the continuation of G-CSF administration. Chromosome analysis showed 46XY, +Y, -7 at this point. By adding 50 mg of cytarabine ocfosfate (SPAC) daily, the peripheral neutrophil count again rose dramatically. However, anemia, thrombocytopenia and the chromosomal abnormality were unchanged. These results indicate that SPAC may upregulate the effect of G-CSF on granulopoiesis in patients with myelodysplastic syndrome.

Topics: Adult; Arabinonucleotides; Chromosomes, Human, Pair 7; Cytidine Monophosphate; Drug Resistance; Granulocyte Colony-Stimulating Factor; Humans; Karyotyping; Leukocyte Count; Male; Monosomy; Myelodysplastic Syndromes

Topics: Aged; Antineoplastic Agents; Arabinonucleotides; Cytidine Monophosphate; Humans; Male; Myelodysplastic Syndromes; Remission Induction

Topics: Adult; Aged; Antineoplastic Agents; Arabinonucleotides; Chronic Disease; Cytidine Monophosphate; Drug Evaluation; Female; Humans; Leukemia; Male; Middle Aged; Multiple Myeloma; Myelodysplastic Syndromes; Remission Induction

Topics: Aged; Antineoplastic Agents; Arabinonucleotides; Cytidine Monophosphate; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Remission Induction

Topics: Acute Disease; Antineoplastic Agents; Arabinonucleotides; Cytidine Monophosphate; Cytosine Nucleotides; Drug Evaluation; Humans; Leukemia; Myelodysplastic Syndromes