Results of a phase II trial of a combination of oral cytarabine ocfosfate (YNK01) and interferon alpha-2b for the treatment of chronic myelogenous leukemia patients in chronic phase.

Abstract

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.

• Authors: F Maloisel, A Guerci, D Guyotat, N Ifrah, M Michallet, J Reiffers, G Tertain, M Blanc, F Bauduer, J Brière, J F Abgrall, B Pegourie-Bandelier, E Solary, N Cambier, D Coso, J P Vilque, M Delain, J L Harousseau, P Rousselot, K Belhadj, P Morice, J Attal, M Chabin, C Chastang, J Guilhot, F Guilhot, France Intergroupe des Leucémies Myéloïdes Chroniques
• Journal: Leukemia (Leukemia) Vol. 16 Issue 4 Pg. 573-80 (Apr 2002) ISSN: 0887-6924 [Print] England
• PMID: 11960335 (Publication Type: Clinical Trial, Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Arabinonucleotides
• Interferon alpha-2
• Interferon-alpha
• Recombinant Proteins
• 1-arabinofuranosylcytosine-5'-stearylphosphate
• Cytidine Monophosphate

Topics

• Administration, Oral
• Adolescent
• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Arabinonucleotides (administration & dosage)
• Cytidine Monophosphate (administration & dosage, analogs & derivatives)
• Dose-Response Relationship, Drug
• Female
• Follow-Up Studies
• Humans
• Interferon alpha-2
• Interferon-alpha (administration & dosage)
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy, mortality, pathology)
• Leukemia, Myeloid, Chronic-Phase (drug therapy, mortality, pathology)
• Male
• Middle Aged
• Prognosis
• Recombinant Proteins
• Risk Factors
• Survival Rate