Prolonged administration of all-trans retinoic acid in combination with intensive chemotherapy and G-CSF for adult acute myelogenous leukemia: single-centre pilot study in different risk groups.

INTRODUCTION: An exploratory trial was conducted to evaluate toxicity and potential therapeutic role of all trans-retinoic acid (ATRA) given long-term together with chemotherapy and G-CSF to adult patients with acute myelogenous leukemia (AML). MATERIALS AND METHODS: ATRA was administered orally at 45 mg/m(2)/day on days 1-14 and 25 mg/m(2)/day on days 15-28 of two standard cycles (idarubicin, etoposide, cytarabine, G-CSF) and of up to three high-dose courses (cytarabine, G-CSF). The results obtained in 19 patients enrolled in the ATRA trial were compared with those from 29 comparable cases treated with the same schedule without ATRA, according to patient risk class and an in vitro study. RESULTS: ATRA was administered for a median of 52 days to the patients selected for study who achieved a remission. ATRA-related toxicity was mostly non-severe apart from high incidence of headache in conjunction with high-dose cytarabine. Complete remission (CR) rate after cycle 1 (54%), kinetics of hematological recovery, postremission treatment realization, disease-free survival (DFS 37.5% at three years) and overall survival (30% at three years) were not different between ATRA-treated and untreated patients. The only significant prognostic factor was the patient risk class, as defined by cytogenetics and other clinical criteria: DFS rate was 57% at three years in standard-risk cases compared to only 19% in the high-risk group, with no influx by ATRA in either category. The in vitro study, in patients with a definite clinical response, failed to document any inhibitory or pro-apoptotic effect of ATRA on AML blast cells. CONCLUSION: As a consequence to these results, the pilot ATRA phase was closed. This study does not suggest a significant role for the present ATRA schedule as an adjunct to standard antileukemic therapy in adult AML.

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.

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.