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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.
Haematologica. 2002 Mar; 87(3):257-63.H

Abstract

BACKGROUND AND OBJECTIVES

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.

DESIGN AND 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).

INTERPRETATION AND 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.

Authors+Show Affiliations

Department of Hematology, Ospedali Riuniti, largo Barozzi 1, 24100 Bergamo, Italy. basbas@virgilio.itNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Clinical Trial
Clinical Trial, Phase I
Journal Article

Language

eng

PubMed ID

11869937

Citation

Bassan, Renato, et al. "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." Haematologica, vol. 87, no. 3, 2002, pp. 257-63.
Bassan R, Lerede T, Borleri G, et al. 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. Haematologica. 2002;87(3):257-63.
Bassan, R., Lerede, T., Borleri, G., Chiodini, B., Rossi, A., Buelli, M., Rambaldi, A., Viero, P., & Barbui, T. (2002). 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. Haematologica, 87(3), 257-63.
Bassan R, et al. 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. Haematologica. 2002;87(3):257-63. PubMed PMID: 11869937.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Bassan,Renato, AU - Lerede,Teresa, AU - Borleri,Gianmaria, AU - Chiodini,Barbara, AU - Rossi,Andrea, AU - Buelli,Maurizio, AU - Rambaldi,Alessandro, AU - Viero,Piera, AU - Barbui,Tiziano, PY - 2002/3/1/pubmed PY - 2002/5/25/medline PY - 2002/3/1/entrez SP - 257 EP - 63 JF - Haematologica JO - Haematologica VL - 87 IS - 3 N2 - BACKGROUND AND OBJECTIVES: 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. DESIGN AND 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). INTERPRETATION AND 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. SN - 0390-6078 UR - https://www.unboundmedicine.com/medline/citation/11869937/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_ L2 - https://medlineplus.gov/leukemia.html DB - PRIME DP - Unbound Medicine ER -