1-arabinofuranosylcytosine-5--stearylphosphate and Leukemia--Myeloid--Acute

Twenty-one acute myeloid leukemia (AML) patients were enrolled and received oral induction therapy with cytarabine ocfosfate (SPAC) and etoposide (EP). The median age was 69 years (range: 33-86). There were 11 patients with de novo AML and 10 AML cases that had evolved from myelodysplastic syndromes. Seventeen patients had abnormal karyotypes including eight complex abnormalities, various complications, and 7 of 21 had a poor performance status (PS) with Eastern Cooperative Oncology Group (ECOG) scores of 3-4. All patients completed induction therapy without severe adverse events. Seven achieved complete remission (CR), and two achieved partial remission (PR). Uni- and multivariate analyses demonstrated a positive and significant correlation between the results of therapy (CR +/- PR) and overall survival. The plasma concentrations of cytosine arabinoside (ara-C) in some cases were higher than those previously reported, indicating the accumulation of ara-C with increasing numbers of days of SPAC administration. We conclude that this therapy is well tolerated and useful for refractory and elderly AML patients.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Arabinonucleotides; Cytidine Monophosphate; Etoposide; Female; Humans; Kaplan-Meier Estimate; Leukemia, Myeloid, Acute; Male; Middle Aged; Neoplasm Recurrence, Local

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

Ara-CMP-Stearate (1-beta-D-arabinofuranosylcytosine-5'-stearylphosphate, YNK 01, Fosteabine) is the orally applicable prodrug of cytosine-arabinoside (Ara-C). During a phase I study in patients with advanced low-grade non-Hodgkin lymphomas or acute myeloid leukemia, the pharmacokinetic parameters of Ara-CMP-Stearate (kindly provided by ASTA Medica, Frankfurt, Germany) were determined by HPLC analysis. Seventy-two hours after a first starting dose which served for the determination of baseline pharmacokinetic parameters, Ara-CMP-Stearate was administered over 14 days by daily oral application. Ara-CMP-Stearate was started at a dose of 100 mg/day and was escalated in subsequent patients to 200 mg/day and 300 mg/day. Plasma and urine concentrations of Ara-CMP-Stearate, Ara-C and Ara-U were measured during the initial treatment phase and within 72 h after the end of the 14-day treatment cycle. So far six patients have been treated with 100 mg/day, three with 200 mg/day and another six with 300 mg/day. One patient was treated consecutively with 100 mg, 300 mg and 600 mg. Fitting the results of the plasma concentration measurements of Ara-CMP-Stearate to a one-compartment model, the following pharmacokinetic parameters were obtained (average and variation coefficient VC). Ara-CMP-Stearate dose-independent parameters: lag time = 1.04 h (0.57); tmax = 5.72 h (0.30); t1/2 = 9.4 h (0.36). Dose-dependent parameters: at 100 mg: AUC = 1099 ng/h/ml (0.31); concentration(max) = 53.8 ng/ml (0.28); at 200 mg: AUC = 2753 ng/h/ml (0.32); concentration(max) = 154.8 ng/ml (0.46); at 300 mg: AUC = 2940 ng/h/ml (0.66); concentration(max) = 160.0 ng/ml (0.59). The long lag time and late tmax can be explained by resorption in the distal part of the small intestine. No Ara-CMP-Stearate was detected in urine samples (limit of detection = 500 pg/ml). Pharmacokinetic parameters of Ara-C following Ara-CMP-Stearate application showed the following characteristics: t1/2 = 24.3 h (0.39); AUC (100 mg) = 262 ng/h/ml (0.93); AUC (200 mg) = 502 ng/h/ml (0.87); AUC (300 mg) = 898 ng/h/ml (1.07). Since Ara-CMP-Stearate causes intravascular hemolysis after intravenous administration, it was not possible to determine its bioavailability by comparing the AUC after oral and i.v. application. Instead, the renal elimination of Ara-U, as the main metabolite of Ara-C was measured during the first 72-h period and after the last application.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Administration, Oral; Antineoplastic Agents; Arabinofuranosyluracil; Arabinonucleotides; Cytarabine; Cytidine Monophosphate; Dose-Response Relationship, Drug; Half-Life; Humans; Leukemia, Myeloid, Acute; Lymphoma, Non-Hodgkin; Statistics, Nonparametric

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

The prognosis of relapsed acute myeloid leukemia (AML) in elderly patients is dismal, even if the AML exhibits a good prognostic karyotype, such as inv(16)(p13.1q22). We present a 72-year-old female with AML with inv(16)(p13.1q22) who suffered five episodes of relapse with temporary complete remission. Maintenance chemotherapy with oral cytarabine ocfosfate hydrate eventually produced persistent molecular complete remission of her AML that had not been induced by conventional regimens including intensive chemotherapy and low dose cytarabine therapy. The high level of tolerability to oral cytarabine ocfosfate hydrate may offer elderly patients with this type of AML a good chance for a cure.

Topics: Aged; Antineoplastic Agents; Arabinonucleotides; Chromosome Inversion; Chromosomes, Human, Pair 16; Cytidine Monophosphate; Female; Humans; Leukemia, Myeloid, Acute; Neoplasm Recurrence, Local; Remission Induction

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

Topics: Adult; Aged; Antiemetics; Antineoplastic Agents; Arabinonucleotides; Cytidine Monophosphate; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Nausea; Ondansetron; Quality of Life

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 67-year-old man presented with acute myelogenous leukemia (M2). Peripheral blood examination revealed a leukocyte count of 1,700/mu l with 1% myeloblasts, and bone marrow aspiration showed 42.6% myeloblasts with Auer bodies. Culture of his marrow cells at diagnosis showed that granulocyte colony-stimulating factor (G-CSF) promoted cell proliferation, while all-trans retinoic acid (ATRA) inhibited the proliferative effect of G-CSF and induced differentiation. Combination therapy with G-CSF, ATRA, and low-dose cytotoxic drugs achieved complete remission without severe marrow suppression.

Topics: Aged; Antineoplastic Agents; Arabinonucleotides; Bone Marrow; Cyclophosphamide; Cytidine Monophosphate; Drug Therapy, Combination; Granulocyte Colony-Stimulating Factor; Humans; Immunosuppressive Agents; Leukemia, Myeloid, Acute; Male; Tretinoin

A case of therapy-related acute non-lymphocytic leukemia (t-ANLL) in a 70-year-old female patient is reported. An operation for lung cancer was performed in February 1991, and she was treated with etoposide (VP-16), a topoisomerase II inhibitor. Nineteen months after the start of chemotherapy, she complained of palpitations, and anemia and thrombocytopenia developed. The myelogram revealed 41.2% leukemic cells, and a diagnosis of t-ANLL induced by VP-16 was made. The karyotype of bone marrow cells showed 46, XX, t(7;11) (p13;p15), 16p+. She obtained complete remission (CR) by treatment with low dose cytosine arabinoside (Ara-C) and cytarabine ocfosfate (SPAC). Karyotype with t-ANLL induced by alkylate agents frequently shows unbalanced abnormalities. The difference of cytogenetic findings suggest the difference of mechanisms. Detailed chromosomal analysis make clear the oncogenesis of t-ANLL. It is reported that the prognosis of patients with t-ANLL treated by conventional chemotherapy is poor. Considering that elderly cases of acute leukemia have a lower probability of achieving CR than non-elderly cases, because of complications and side effects of chemotherapy such as bone marrow suppression, treatment with low dose Ara-C and SPAC is thought to be indicated in elderly patients with t-ANLL.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Arabinonucleotides; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 7; Cytarabine; Cytidine Monophosphate; Female; Humans; Leukemia, Myeloid, Acute; Neoplasms, Second Primary; Remission Induction; Translocation, Genetic

A 77-year-old female with left hemiplegia caused by cerebral infarction and with mild senile dementia was admitted for further examination of hematological abnormalities. She was diagnosed as acute myelogenous leukemia (AML-M5a) according to French-American-British classification. Since intensive combination chemotherapy seemed difficult, she was treated with oral administration of cytarabine ocfosfate (200 mg/day, for 14 days), a cytidine deaminase-resistant derivative of Ara-C, resulting in complete remission. Major side effects were nausea, vomiting and appetite loss, but their incidences were reduced tolerably when cytarabine ocfosfate was given just before sleeping. Cytarabine ocfosfate might be useful to treat AML in elderly patients having certain complications such as cerebrovascular disease.

Topics: Administration, Oral; Aged; Antineoplastic Agents; Arabinonucleotides; Cerebral Infarction; Cytidine Monophosphate; Dementia, Vascular; Female; Humans; Leukemia, Myeloid, Acute; Remission Induction