Subgroup analysis of the phase III VALOR study – vosaroxin/cytarabine in ≥ 60 years old patients with refractory/early relapsed acute myeloid leukemia

In a recent issue of Haematologica, Farhad Ravandi, University of Texas MD Anderson Cancer Center, Houston, TX, USA, and colleagues, published the results of a subgroup analysis of the randomized phase III VALOR study (NCT01191801). This study evaluated the safety and efficacy of vosaroxin, a first-in-class anticancer quinolone derivative that intercalates DNA and inhibits topoisomerase II, plus cytarabine (vos/cyt) versus placebo plus cytarabine (pla/cyt), for the treatment of patients ≥ 60 years of age with refractory/early relapsed (Ref/eRel) acute myeloid leukemia (AML).

Vosaroxin (90 mg/m² cycle 1 [70 mg/m² subsequent cycles]) was administered in 361 patients by short intravenous infusion on days 1 and 4, in combination with cytarabine (1 g/m² IV over 2 hours on days 1–5). In the control arm, placebo plus cytarabine was administered. A median of one treatment cycle was administered (range, 1–4) in both cohorts. Median age was 68 years (range, 60–78).

Key data is given as vos/cyt arm vs pla/cyt arm:

Efficacy

• Complete remission (CR) rate: 25.8% (47/182; 95% CI, 19.6–32.8) vs 10.4% (19/182; 95% CI, 6.4–15.8), P = 0.0001
• Overall response rate (ORR): 34.1% vs 12.6%, P < 0.0001
• Median overall survival (OS): 6.5 months (95% CI, 4.4–7.8) vs 3.9 months (95% CI, 3.3–5.2), HR = 0.69 (95% CI, 0.55–0.86), P = 0.0009
• Median leukemia-free survival (LFS): 9.7 months (95% CI, 5.8–NE) vs 5.5 months (95% CI, 2.3–8.3), HR = 0.50 (95% CI, 0.25–0.99), P = 0.0424
• Median event-free survival (EFS): 1.7 months (95% CI, 1.5–2.3) vs 1.3 months (95% CI, 1.2–1.4), HR = 0.59 (95% CI, 0.47–0.74), P < 0.0001
• Post-treatment transplantation rates were similar in the two cohorts
  • CR rates in transplanted patients: 48.4% (15/31) vs 32.3% (10/31)
  • 100-day mortality rate after transplant: 19.4% (6/31) vs 25.8% (8/31)
  • Median OS in transplanted patients: 18.3 months (95% CI, 11.9–NE) vs 9.9 months (95% CI, 7.7–12.2), HR = 0.46 (95% CI, 0.25–0.86), P = 0.0125

Safety

• Serious adverse events (SAEs): 53.8% vs 32.4%
• SAEs leading to death: 15.9% vs 11.2%
• The most common AEs and SAEs in both treatment arms: myelosuppression, infections, and gastrointestinal (GI) toxicities
• Grade ≥ 3 febrile neutropenia: 40.7% vs 29.1%
• Grade ≥ 3 hematologic events occurred with similar frequency in both arms: thrombocytopenia (23.1% vs 26.8%), anemia (22.5% vs 25.7%), and neutropenia (17.6% vs 16.2%)

The authors concluded that “this analysis demonstrated that vos/cyt produced clinically meaningful improvements in response and survival compared with pla/cyt in patients ≥ 60 years old with Ref/eRel AML, without increasing early mortality. The AE profile of vos/cyt in older patients was consistent with the AE profile of the overall VALOR population reported previously. Rates of SAEs were higher in the vos/cyt arm compared with the pla/cyt arm, though this would be expected with the addition of a second cytotoxic agent and has been observed in other trials of cytarabine combination regimens compared to cytarabine alone.”