Results of triple therapy with interferon-alpha, cytarabine, and homoharringtonine, and the impact of adding imatinib to the treatment sequence in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in early chronic phase.
BACKGROUND
Before the discovery of imatinib mesylate, a Bcr-Abl selective tyrosine kinase inhibitor, three agents, interferon-alpha (IFN-alpha), cytarabine (ara-C), and homoharringtonine (HHT), had demonstrated activity against Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia (CML) as single agents and in couplet combinations. The goals of the current study were to evaluate the efficacy of the triple combination regimen with IFN-alpha, ara-C, and HHT in newly diagnosed Ph-positive CML and to assess the impact of the added sequential therapy with imatinib on overall prognosis.


METHODS
Ninety patients with Ph-positive CML in early chronic phase received the triple regimen. Therapy consisted of 5 million units (MU)/m(2) IFN-alpha subcutaneously (s.c. daily, ara-C 10 mg s.c. daily, and HHT 2.5 mg/m(2) by continuous infusion over 24 hours daily x 5 every month. After a median duration of 16.5 months of therapy, 78 patients had their therapy changed to 400 mg orally administered imatinib daily.


RESULTS
With the triple regimen, 85 patients (94%) achieved complete hematologic response and 67 patients (74%) had a cytogenetic response (Ph suppression to < or = 90%) which was complete (Ph 0%) in 20 patients (22%) and major in 42 patients (46%). Myelosuppression was significant, resulting in considerable reductions in the dose schedules. After 12 months of therapy, the median IFN-alpha dose was 1.6 MU/m(2) daily, the median ara-C dose was 1.85 mg daily, and the median number of HHT days was 2 every month. Only three patients developed blastic phase while receiving the triple regimen. With the change to imatinib therapy, currently 57 patients (63%) are in complete cytogenetic response and 69 patients (76%) in major cytogenetic response. With a median follow-up time of 46 months for the total study group, the estimated 5-year survival rate was 88%, and only 8 patients (9%) to date have developed blastic phase.


CONCLUSIONS
The sequence of IFN-alpha, ara-C, and HHT followed by imatinib (imposed by the discovery of the latter drug) resulted in an estimated 5-year survival rate of 88%. This finding suggests that imatinib combination regimens may improve the prognosis in CML.
O'Brien
Susan
S
Department of Leukemia, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Giles
Francis
F
Talpaz
Moshe
M
Cortes
Jorge
J
Rios
Mary Beth
MB
Shan
Jianqin
J
Thomas
Deborah
D
Andreeff
Michael
M
Kornblau
Steven
S
Faderl
Stefan
S
Garcia-Manero
Guillermo
G
White
Kevin
K
Mallard
Susie
S
Freireich
Emil
E
Kantarjian
Hagop M
HM
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001549:Benzamides; D003561:Cytarabine / Q000008:administration & dosage; D004334:Drug Administration Schedule; D005260:Female; D006248:Harringtonines / Q000008:administration & dosage; D000077863:Homoharringtonine; D006801:Humans; D000068877:Imatinib Mesylate; D007262:Infusions, Intravenous; D007279:Injections, Subcutaneous; D016898:Interferon-alpha / Q000008:administration & dosage; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage; D016019:Survival Analysis; D016896:Treatment Outcome
D001549:Benzamides; D006248:Harringtonines; D016898:Interferon-alpha; D010879:Piperazines; D011743:Pyrimidines; D003561:Cytarabine; D000077863:Homoharringtonine; D000068877:Imatinib Mesylate