Adding vosaroxin to cytarabine suggests survival benefit in aggressive acute myeloid leukemia

Results of the phase III VALOR trial demonstrate that the combination of vosaroxin and cytarabine is associated with a non-significant, longer overall survival (OS) as compared to cytarabine alone in patients with relapsed or treatment-resistant acute myeloid leukemia (AML). Moreover, adding vosaroxin to cytarabine almost doubled the complete response rates as compared to cytarabine alone. Interestingly, the benefit of vosaroxin was particularly visible in older patients, who experienced manageable added toxicity. The VALOR results represent one of the largest datasets available in this setting. As such, these data suggest the use of this combination as a new option for salvage therapy in patients with relapsed or refractory AML.

Despite 40 years of intense clinical research, treatment options for patients with relapsed or refractory AML are scarce. The chemotherapeutic agent cytarabine has been used since the 1960s either alone or in combination with other agents to treat aggressive AML. However, these cytarabine-based treatment approaches are associated with substantial toxicity and are ineffective in many patients. Vosaroxin is a first-in-class, anticancer quinolone derivative that is active in AML. Preclinical data indicate that vosaroxin is minimally metabolized and has activity independent of p53 status. VALOR is a phase 3, randomized, double-blind, placebo-controlled trial comparing the combination of vosaroxin with cytarabine to placebo plus cytarabine in 711 patients with relapsed/refractory AML.

Patients in the study were randomized 1:1 to receive cytarabine (1 g/m2 IV over 2 hours on days 1-5) plus either vosaroxin (90 mg/m2 IV over 10 min d 1 and 4; 70 mg/m2 in subsequent cycles) (N= 356) or placebo (N= 355). Up to 2 induction and 2 consolidation cycles were administered. Eligible patients had refractory disease (persistent disease after induction, or first complete remission < 90 days) or were in first relapse (early relapse: first complete remission of 90 days to 12 months; late relapse: first complete remission of 12 to 24 months). Patients in the study had received 1-2 cycles of prior induction chemotherapy including at least 1 cycle of anthracycline and cytarabine.

At the final analysis, patients treated with vosaroxin achieved a longer OS as compared to those treated with placebo (7.5 vs. 6.1 months). However, this difference did not reach statistical significance (p=0.06). When censoring for transplantation, however, the survival benefit with vosaroxin was statistically significant (7.0 vs. 5.3 months HR[95%CI]: 0.81[0.67-0.97]; p= 0.02). Overall, 29.5% of the patients underwent an allogeneic stem cell transplant and the transplant rates were comparable between the 2 treatment arms (30.1% with vosaroxin-cytarabine and 29.0% with placebo-cytarabine). Predefined subgroup analyses showed that the OS benefit was greatest in patients aged 60 years or older (7.1 vs. 5.0 months; HR: 0.75; p= 0.003) and in patients with an early relapse (6.7 vs. 5.2 months; HR: 0.77; p= 0.04). Patients who received vosaroxin were also more likely to achieve complete responses to the treatment (30.1% vs. 16.3% with placebo; p< 0.00001). The rate of all-cause mortality at 30 and 60 days was similar in both arms at 7.9% and 19.7% in the vosaroxin arm and 6.7% and 19.4% with placebo.

The most common serious adverse events in both arms were febrile neutropenia (11.3% with vosaroxin-cytarabine vs. 7.4% with placebo-cytarabine), sepsis (8.7% vs. 4.3%), pneumonia (7.6% vs. 4.9%), bacteremia (8.5% vs. 2.9%) and stomatitis (3.4% vs. 1.4%). In summary, adding vosaroxin to cytarabine resulted in a prolonged OS and higher CR rates in patients with relapsed, or refractory AML without increased early mortality. Of note, the overall clinical benefit in association with vosaroxin may be underestimated in the primary OS analysis due to the confounding effect of high transplant rates, a known methodological limitation of AML trials. This is particularly the case in younger patients. The vosaroxin-containing therapy had an acceptable toxicity. As such, these data support the potential use of this combination as a new option for salvage therapy in patients with relapsed or refractory AML.

Reference

Ravandi F, Ritchie E, Sayar H, et al. Improved Survival in Patients with First Relapsed or Refractory Acute Myeloid Leukemia (AML) Treated with Vosaroxin Plus Cytarabine Versus Placebo Plus Cytarabine: Results of a Phase 3Double-Blind Randomized Controlled Multinational Study (VALOR). Presented at ASH 2014; Abstract #LBA6.