Randomized, phase 2 trial of low-dose cytarabine with or without volasertib in AML patients not suitable for induction therapy

Abstract

Treatment outcomes for older patients with acute myeloid leukemia (AML) have remained dismal. This randomized, phase 2 trial in AML patients not considered suitable for intensive induction therapy compared low-dose cytarabine (LDAC) with or without volasertib, a highly potent and selective inhibitor of polo-like kinases. Eighty-seven patients (median age 75 years) received LDAC 20 mg twice daily subcutaneously days 1-10 or LDAC + volasertib 350 mg IV days 1 + 15 every 4 weeks. Response rate (complete remission and complete remission with incomplete blood count recovery) was higher for LDAC + volasertib vs LDAC (31.0% vs 13.3%; odds ratio, 2.91; P = .052). Responses in the LDAC + volasertib arm were observed across all genetic groups, including 5 of 14 patients with adverse cytogenetics. Median event-free survival was significantly prolonged by LDAC + volasertib compared with LDAC (5.6 vs 2.3 months; hazard ratio, 0.57; 95% confidence interval, 0.35-0.92; P = .021); median overall survival was 8.0 vs 5.2 months, respectively (hazard ratio, 0.63; 95% confidence interval, 0.40-1.00; P = .047). LDAC + volasertib led to an increased frequency of adverse events that was most pronounced for neutropenic fever/infections and gastrointestinal events; there was no increase in the death rate at days 60 + 90. This study was registered at www.clinicaltrials.gov as #NCT00804856.

Figure 1

Kaplan-Meier survival estimates according to randomization. (A) Median EFS times for patients who received LDAC (n = 45) and LDAC + volasertib (n = 42) were 2.3 and 5.6 months, respectively (HR, 0.57; 95% CI, 0.35-0.92; P = .021); 1-year EFS was 14.6% and 29.0%. (B) Median RFS times were 10.0 and 18.5 months for LDAC (n = 6) and LDAC + volasertib (n = 13), respectively. (C) Median OS times for patients who received LDAC (n = 45) and LDAC + volasertib (n = 42) were 5.2 and 8.0 months, respectively (HR, 0.63; 95% CI, 0.40-1.00; P = .047); 1-year OS was 22.2% and 36.8%. Database snapshot November 7, 2013. NR, not reported.

Figure 2

OS estimates according to randomization and ELN genetic group. (A) Favorable and intermediate I/II groups. Median OS times for patients who received LDAC (n = 28) and LDAC + volasertib (n = 22) were 7.8 and 9.8 months, respectively (HR, 0.54; 95% CI 0.29-1.02). (B) Adverse group. Median OS times for patients who received LDAC (n = 14) and LDAC + volasertib (n = 14) were 3.3 and 5.9 months, respectively (HR, 0.63; 95% CI, 0.29-1.40). Database snapshot November 7, 2013.