Imatinib in combination with cytarabine for the treatment of Philadelphia-positive chronic myelogenous leukemia chronic-phase patients: rationale and design of phase I/II trials.
Imatinib (Gleevec) (formerly STI571) has been shown to selectively inhibit the tyrosine kinase domain of the oncogenic BCR-ABL fusion protein of chronic myelogenous leukemia (CML) cells. In recent phase I and II studies testing this new compound in patients who had failed to respond to interferon (IFN), hematological and cytogenetic responses were reported in most of those with chronic-phase CML. However, in some patients resistance has been associated with a single amino acid substitution in a threonine residue of the Abl kinase domain. In vitro studies examining the effects of imatinib plus cytarabine (Ara-C) using CML cell lines and colony-forming assays of CML patient samples have shown synergistic antiproliferative effects of this combination. Thus several groups decided to investigate this new combination with the hypothesis that cell resistance would be less frequent. The CML French Group performed a phase II trial to determine the safety and tolerability of a combination of imatinib and Ara-C for previously untreated patients with chronic-phase CML. Treatment was administered on 28-day cycles for 12 months. Patients were treated continuously with imatinib orally at a dose of 400 mg daily. Ara-C was given on days 14 to 28 of each cycle at an initial dose of 20 mg/m(2)/d via subcutaneous injection, hydroxyurea (HU) being stopped at least 7 days before imatinib. Recently, the Dutch group decided to explore a combination of high-dose Ara-C with imatinib in patients in chronic-phase CML. Preliminary results are encouraging. However, a long follow-up is required before concluding that these strategies will overcome cell resistance.
Guilhot
François
F
Department of Oncology-Hematology and Cell Therapy, CHU la Milétrie, Poitiers, France.
Gardembas
Martine
M
Rousselot
Philippe
P
Tulliez
Michel
M
Vigier
Magda
M
Buzyn
Agnès
A
Rigal-Huguet
Françoise
F
Legros
Laurence
L
Michallet
Mauricette
M
Berthou
Christian
C
Najman
Albert
A
Maloisel
Frederic
F
Mahon
François-Xavier
FX
Facon
Thierry
T
Berthaud
Patrice
P
Guilhot
Joëlle
J
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001549:Benzamides; D002985:Clinical Protocols; D002986:Clinical Trials as Topic; D003561:Cytarabine / Q000627:therapeutic use*; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D010879:Piperazines / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*
D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D003561:Cytarabine; D000068877:Imatinib Mesylate