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.
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.
Maloisel
F
F
Division of Hematology, University Hospital of Strasbourg, France.
Guerci
A
A
Guyotat
D
D
Ifrah
N
N
Michallet
M
M
Reiffers
J
J
Tertain
G
G
Blanc
M
M
Bauduer
F
F
Brière
J
J
Abgrall
J F
JF
Pegourie-Bandelier
B
B
Solary
E
E
Cambier
N
N
Coso
D
D
Vilque
J P
JP
Delain
M
M
Harousseau
J L
JL
Rousselot
P
P
Belhadj
K
K
Morice
P
P
Attal
J
J
Chabin
M
M
Chastang
C
C
Guilhot
J
J
Guilhot
F
F
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001088:Arabinonucleotides / Q000008:administration & dosage; D003568:Cytidine Monophosphate / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D015466:Leukemia, Myeloid, Chronic-Phase / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011994:Recombinant Proteins; D012307:Risk Factors; D015996:Survival Rate
D001088:Arabinonucleotides; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; C061162:1-arabinofuranosylcytosine-5'-stearylphosphate; D003568:Cytidine Monophosphate