P-glycoprotein inhibition using valspodar (PSC-833) does not improve outcomes for patients younger than age 60 years with newly diagnosed acute myeloid leukemia: Cancer and Leukemia Group B study 19808

Abstract

Cancer and Leukemia Group B 19808 (CALGB 19808) is the only randomized trial of a second-generation P-glycoprotein (Pgp) modulator in untreated patients with acute myeloid leukemia (AML) younger than age 60 years. We randomly assigned 302 patients to receive induction chemotherapy regimens consisting of cytosine arabinoside (Ara-C; A), daunorubicin (D), and etoposide (E), without (ADE) or with (ADEP) PSC-833 (P). The incidence of complete remission was 75% with both regimens. Reversible grade 3 and 4 liver and mucosal toxicities were significantly more common with ADEP. Therapy-related mortality was 7% and did not differ by induction arm. Excess cardiotoxicity was not seen with high doses of D in ADE. The median disease-free survival was 1.34 years in the ADE arm and 1.09 years in the ADEP arm (P = .74, log-rank test); the median overall survival was 1.86 years in the ADE arm and 1.69 years in the ADEP arm (P = .82). There was no evidence of a treatment difference within any identifiable patient subgroup. Inhibition of Pgp-mediated drug efflux by PSC-833 did not improve clinical outcomes in younger patients with untreated AML. This trial was registered at www.clinicaltrials.gov as #NCT00006363.

Figures

Figure 1

CONSORT flow sheet. The first 302 patients enrolled were randomly assigned between ADE and ADEP. After the unavailability of PSC-833, all subsequent patients received induction chemotherapy with ADE. All 302 patients randomly assigned are included in the analysis, as required by the ITT principle. The flow sheet outlines the therapies received by patients in CR. BMT indicates bone marrow transplantation.

Figure 2

DFS of randomly assigned patients. The estimated probability of DFS for all 227 patients randomly assigned who achieved a CR is shown according to the assigned treatment regimen.

Figure 3

OS of patients randomly assigned patients. The estimated probability of OS for all 302 patients randomly assigned is shown according to the assigned treatment regimen.

Figure 4

DFS by ELN risk category. The estimated probability of DFS for the 189 patients randomly assigned who achieved a CR and for whom the ELN risk category is known is shown according to risk category. ELN risk categories have been adapted as described in the text.

Figure 5

OS by ELN risk category. The estimated probability of OS for the 249 patients randomly assigned for whom the ELN risk category is known is shown according to risk category. ELN risk categories have been adapted as described in the text.

Figure 6

Forest plots of DFS and OS models in subgroups of patients. Estimated hazard ratios (ADEP vs ADE) and the 95% CIs from a fitted proportional hazards regression model are provided for each category. Estimated hazard ratios less than 1 favor ADEP, whereas those greater than 1 favor ADE.