Phase I trial with escalating doses of idarubicin and multidrug resistance reversal by short-course cyclosporin A, sequential high-dose cytosine arabinoside, and granulocyte colony-stimulating factor for adult patients with refractory acute leukemia.
OBJECTIVE
Patients with refractory acute myeloid or lymphoid leukemia (AML, ALL) were treated with a high-dose regimen comprising idarubicin (IDR) plus short-course cyclosporin A (CsA) as multidrug resistance type-1 (MDR1) blocking agent. The principal aim was to define the maximum tolerated dose (MTD) of IDR, which is reported to be a less MDR1-sensitive anthracycline. The short CsA infusion was patterned after the results of a previous in vitro study.


METHODS
This was a phase I trial, in which eligible patients received high-dose cytarabine (HDAC) 3 g/m(2)/bd on days 1, 2 and 8, 9, and IDR 12.5-20 mg/m(2)/d on days 3 and 10, with increments of 2.5 mg/m(2)/d from the baseline per treatment group. Intravenous CsA infusion started 4 hours before IDR and lasted 12 hours. Recombinant granulocyte colony-stimulating factor (G-CSF) was added from day 11. IDR MTD was evaluated through analysis of regimen-related toxicity (RRT).


RESULTS
Eighteen patients were treated (16 AML, 2 ALL; MDR1+: 8/8 studied). Overall response rate was 61%. Toxicity was severe but manageable up to an IDR dose of 17.5 mg/m(2)/d, while grade 4 RRT developed with IDR 20 mg/m(2)/d. High-grade toxicity, not strictly regimen-related, was sometimes observed at lower IDR concentrations in patients with unresolved complications from prior extensive treatments. In keeping, the complete response (CR) rate was 92% (11/12) for patients with an ECOG performance score <2 compared to 0% (0/6) in the others (p=0.000). Apart from that, induction of markedly hypocellular, leukemia-free bone marrow on day 11 was associated with achievement of CR (13 evaluable: CR 8/10 vs 0/3, p=0.035).


CONCLUSIONS
IDR at 17.5 mg/m(2)/d (x2) can be associated with short-course CsA and HDAC for the management of refractory acute leukemias. While this regimen could deserve testing in a larger phase II trial, to document activity in MDR1+ disease, it remains important to select the most suitable patients in order to avoid the occurrence of life-threatening cumulative toxicity.
Bassan
Renato
R
Department of Hematology, Ospedali Riuniti, largo Barozzi 1, 24100 Bergamo, Italy. basbas@virgilio.it
Lerede
Teresa
T
Borleri
Gianmaria
G
Chiodini
Barbara
B
Rossi
Andrea
A
Buelli
Maurizio
M
Rambaldi
Alessandro
A
Viero
Piera
P
Barbui
Tiziano
T
D000208:Acute Disease; D000328:Adult; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000633:toxicity; D016572:Cyclosporine / Q000008:administration & dosage; D003561:Cytarabine / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage; D006801:Humans; D015255:Idarubicin / Q000008:administration & dosage; D007938:Leukemia / Q000188:drug therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D016879:Salvage Therapy; D016896:Treatment Outcome
D000903:Antibiotics, Antineoplastic; D003561:Cytarabine; D016179:Granulocyte Colony-Stimulating Factor; D016572:Cyclosporine; D015255:Idarubicin