1-arabinofuranosylcytosine-5--stearylphosphate and Leukemia--Myelogenous--Chronic--BCR-ABL-Positive

In interferon-alpha (IFN) treated chronic phase chronic myeloid leukaemia (CML) patients, survival depends on individual risk profile and achievement of a complete haematological response (CHR) and a major cytogenetic response (MCR) (< 35% Philadelphia-chromosome-positive metaphases). The highest cytogenetic response rates have been achieved with the combination of IFN and low-dose sc. AraC (10 mg daily to 10-20 mg/m2 for 10-14 days/month). Whether the higher cytogenetic response rates are also associated with a significant improvement of survival still remains controversial. The different results obtained from large randomised and observational trials may be due to the numbers of patients enrolled, distribution of risk profiles and the treatment schedule, which is influenced greatly by the haematological and gastrointestinal toxicity of AraC. An oral formulation (YNK01), which is lipophilic and resistant to deamination, is currently under investigation. Clinically, it has similar activity, but toxicity leads to discontinuation of treatment in a considerable proportion of patients. The clinical benefits may therefore be outweighed by the dose-limiting toxicity for both application forms. Combinations with other drugs, e.g., STI571 or homoharringtonine, have shown promising early results in vitro and in vivo.

Topics: Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Arabinonucleotides; Clinical Trials as Topic; Cytarabine; Cytidine Monophosphate; Drug Administration Schedule; Guidelines as Topic; Humans; Interferons; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Survival Analysis

Treatment with interferon and subcutaneous cytarabine produces superior cytogenetic responses in chronic myeloid leukaemia (CML) than treatment with interferon alone, but at the expense of greater toxicity. Cytarabine ocfosfate (YNK01) is an oral precursor of cytarabine that may overcome some of the inconvenience and toxicities associated with subcutaneous cytarabine administration.. We studied the efficacy and tolerability of combination therapy with interferon-alpha-2b and YNK01 in patients with newly diagnosed, untreated CML. Forty patients were treated with interferon-alpha-2b (5 MU/m2/day) plus monthly courses of YNK01 (600 mg/day for 10 days) for 1 year.. The 6-month complete haematological response rate was 63% and the 1-year major cytogenetic response rate was 30%, with 10% of cytogenetic responses being complete. With a median follow-up of 57 months, the estimated 5-year overall survival was 86% (95% confidence interval 70% to 94%). Treatment tolerability was poor, with toxicity leading to discontinuation of one or both drugs in 60% of cases. The median daily dose of interferon alpha-2b was 7.75 MU and the median dose of YNK01 was 600 mg/day for each 10-day treatment cycle.. Interferon-alpha-2b and YNK01 produce cytogenetic responses comparable to those achieved with interferon-alpha-2b and parenteral cytarabine, although toxicity was excessive. Alternate dosing strategies may enhance the tolerability of YNK01.

Topics: Administration, Oral; Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Arabinonucleotides; Cytidine Monophosphate; Drug Administration Schedule; Female; Humans; Injections, Subcutaneous; Interferon alpha-2; Interferon-alpha; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Middle Aged; Recombinant Proteins; Treatment Outcome

Cytarabine ocfosfate (YNK01) is a prodrug analogue of cytarabine which is resistant to systemic deamination after oral administration. Following initial studies indicating significant anti-tumour activity of YNK01 a phase II trial was initiated in order to assess the tolerability and efficacy of a combination of this agent with interferon alpha-2b (IFN-alpha2b) in recently diagnosed chronic phase CML patients (n = 98). The treatment was subdivided into cycles consisting of 4 weeks of continuous administration of IFN-alpha-2b (3 MU/m(2)/day 1st week and then 5 MU/m(2)/day) and 14 days of oral YNK01 (600 mg/day 1st cycle). At the end of each cycle the dose of YNK01 was adjusted according to the blood count observed during the previous 4 weeks. The median time from diagnosis to inclusion in the trial was 2 months (range 6 days to 7.5 months). At 12 weeks, 62 patients (63%; 95% CI, 54-73) achieved a complete hematological response. At 24 weeks, of 98 patients, two achieved a complete cytogenetic response, 14 a partial response (16% major cytogenetic response rate; 95% CI, 9-24) and 34 a minor response; 19 patients were not evaluable for cytogenetic response. During the trial, 20 patients progressed to accelerated (6) or blastic phases (14). The median time to progression was 15 months (range 2-38 months). At 3 years the overall survival was 79% (95% CI, 70-88). Although the complete hematological response rate compared favorably with the 40% response rate previously obtained with the subcutaneous formulation of Ara-c, the cytogenetic response rate was less than expected. Most of the patients experienced side-effects and all permanently stopped YNK01. Although the combination seems attractive the initial dose of 600 mg per day is probably too high and should be reconsidered in further trials.

Topics: Administration, Oral; Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Arabinonucleotides; Cytidine Monophosphate; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Interferon alpha-2; Interferon-alpha; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Chronic-Phase; Male; Middle Aged; Prognosis; Recombinant Proteins; Risk Factors; Survival Rate

Subcutaneous Ara-C plus interferon (IFN) produces more cytogenetic responses than IFN in chronic myeloid leukemia (CML) but a greater toxicity. The objective of this study was to determine the efficacy and tolerance of IFN plus oral Ara-C ocfosfate (YNK-01) in IFN-resistant CML patients.. A phase II pilot study was conducted in 19 CML patients primarily resistant or with minimal cytogenetic response to IFN. Patients were scheduled to receive 6 monthly 14-day cycles of YNK-01 (500 mg/day), with progressive escalation if tolerated, in addition to IFN. Cytogenetic assessment was performed thereafter.. Of the first 7 patients, 5 had severe hematologic and 5 moderate gastrointestinal toxicity; IFN was reduced in 6, YNK-01 in 5, and treatment discontinued in 2; hematologic response was achieved in 2 of the 5 evaluable patients. In the following 4 patients the Ara-C was reduced to 300 mg: 2 had severe hematologic and 2 moderate gastrointestinal toxicity; IFN and Ara-C were reduced in 2 patients and treatment discontinued in 2 due to progression or toxicity; the other 2 achieved a minor cytogenetic response, progressing in one to a major response after 6 more cycles. In 8 patients the starting Ara-C dose was 200 mg: 5 had moderate-severe hematologic and 5 mild gastrointestinal toxicity; IFN was reduced in 5, Ara-C in 1, and treatment discontinued in 1; Ara-C was increased in 7 cases; hematologic response was obtained in 4 patients, 2 of whom attained a minor and 1 a major cytogenetic response.. These results provide background for future studies aimed at ascertaining the role of oral Ara-C combined with IFN or STI571 in newly diagnosed CML.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Arabinonucleotides; Cytidine Monophosphate; Cytogenetic Analysis; Drug Resistance, Neoplasm; Female; Humans; Interferon-alpha; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Middle Aged; Pilot Projects; Treatment Outcome

The efficacy of continuous oral cytarabine ocfosfate (YNK01) (300 mg/day) in combination with interferon alpha (IFNalpha, 5x10(6) IU/day) was evaluated in patients with advanced chronic myelogenous leukemia, who previously failed to respond to IFNalpha-based therapies. Dose escalations up to 900 mg YNK01 were allowed in patients who failed to respond. In view of our results, four patients developed a complete hematological response after YNK01 was started. Among those who initially responded to YNK01, one complete cytogenetic response was achieved 18 months later. Although the data are preliminary, this is the first study showing that continuous administration of YNK01 along with IFNalpha is effective in patients with advanced chronic myelogenous leukemia.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Arabinonucleotides; Cytidine Monophosphate; Humans; Interferon alpha-2; Interferon-alpha; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Middle Aged; Pilot Projects; Recombinant Proteins; Treatment Outcome

A 65-yr-old man developed increasing dyspnea and fulminant respiratory failure 48 h after introduction of hydroxyurea, oral cytarabine ocfosfate (YNK01) and interferon-alpha for treatment of Philadelphia chromosome-positive chronic myelogenous leukemia. The chest radiograph showed bilateral patchy infiltrates while computed tomography revealed multiple bullas, ground glass opacities, and patchy consolidations with possible cavitation. Bronchoscopic examination was normal and microbiological tests performed on all biologic fluids were negative. The patient did not respond to multiple antibiotic treatment and corticosteroid administration and died of progressive respiratory failure 5 d after chemotherapy introduction. The postmortem lung examination was consistent with the diagnosis of bronchiolitis obliterans organizing pneumonia (BOOP).

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Arabinonucleotides; Cryptogenic Organizing Pneumonia; Cytidine Monophosphate; Fatal Outcome; Humans; Hydroxyurea; Interferon-alpha; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Lung; Male; Radiography, Thoracic; Tomography, X-Ray Computed

We report a case of chronic myelogenous leukemia (CML) in which the bone marrow achieved cytogenetic complete remission (CCR) achieved by treatment with interferon-alpha and oral cytarabine ocfosfate after extramedullary blast crisis. A 51-year-old Japanese man diagnosed with CML was treated with interferon-alpha. Two months later; lymph node swellings developed in his neck and inguinal regions. Lymph node biopsy revealed the infiltration of blast cells showing bcr-abl fusion signal by fluorescence in situ hybridization analysis. Bone marrow aspiration and cytogenetic analysis demonstrated that his bone marrow was still in the chronic phase, with minor cytogenetic response. Continuing interferon-alpha for 6 months in combination with oral cytarabine ocfosfate resulted in the disappearance of the neck lymph node swellings followed by CCR in the bone marrow. However, rapid reenlargement of the neck and inguinal lymph nodes was noted 2 months after CCR despite maintaining medullary remission with major cytogenetic response. Finally, medullary crisis was noted 13 months from the initial development of the extramedullary crisis. This case suggests that interferon-alpha plus cytarabine ocfosfate therapy may be of benefit in the treatment of extramedullary blast crisis of CML.

Topics: Antineoplastic Combined Chemotherapy Protocols; Arabinonucleotides; Blast Crisis; Bone Marrow; Cytidine Monophosphate; Cytogenetic Analysis; Humans; Interferon-alpha; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Middle Aged; Remission Induction

Recombinant(R) interferon alpha (r-IFN-alpha) has been shown to be an effective drug for chronic myeloid leukaemia (CML). However, higher response rates can be achieved using cytarabine along with r-IFN-alpha. YNK01 is a derivative of cytosine arabinoside for oral administration. So far, the only published experience with continuous YNK01 was in advanced CML (10 cases). We have performed a pilot study to evaluate the efficacy and toxicity of the combined therapy r-IFN-alpha and daily oral YNK01 in patients with newly diagnosed Ph+ CML. Ten previously untreated patients were included in the study. Among those patients evaluable for cytogenetic response, 87% (seven out of eight) reached a major cytogenetic response with four reaching complete cytogenetic response (50%). The most significant side-effects were gastrointestinal. Macrocytic anaemia was observed in three patients. In conclusion, continuous oral administration of YNK01 in combination with IFN-alpha is safe and can result in high-cytogenetic response rates.

Topics: Adolescent; Adult; Aged; Arabinonucleotides; Cytidine Monophosphate; Female; Humans; Immunosuppressive Agents; Interferon alpha-2; Interferon-alpha; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Chronic-Phase; Male; Middle Aged; Pilot Projects; Recombinant Proteins; Treatment Outcome

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