Vosaroxin Does Not Boost AML Overall Survival

Although salvage therapy with vosaroxin plus cytarabine does not significantly improve overall survival compared with placebo plus cytarabine, specific subgroups may benefit

medwireNews: Patients with refractory or relapsed acute myeloid leukaemia (AML) derive no significant overall survival (OS) benefit from the addition of vosaroxin to cytarabine , show the results of a placebo-controlled phase III trial.

But a prespecified secondary analysis stratified by factors such as age and time to relapse did show a significant OS improvement favouring the anticancer quinolone derivative, which suggests that boosting cytarabine with vosaroxin may be clinically beneficial for “some patients”, say the investigators.

Moreover, the addition of vosaroxin to cytarabine did not increase early mortality, they note in The Lancet Oncology, which commentator Martin Bornhäuser, from Technische Universität in Dresden, Germany, says in an accompanying piece is “encouraging” in light of previous studies in this setting that have reported excess toxicity of combined salvage regimens, outweighing survival benefits.

The phase III double-blind VALOR trial comprised 711 AML patients with refractory or relapsed disease who had previously received no more than two cycles of induction therapy with an anthracycline or anthracenedione plus cytarabine.

Median OS was comparable for the 356 patients randomly assigned to receive intravenous vosaroxin 90 mg/m2 in the first cycle and 70 mg/m2 in subsequent cycles on days 1 and 4 plus cytarabine 1 g/m2 on days 1 to 5 and for the 355 patients who were given placebo plus cytarabine, at 7.5 and 6.1 months, respectively.

However, the difference between treatment arms became significant in an analysis that stratified by randomisation factors, including age and disease status (refractory, first relapse between 90 days and 12 months or between 12 and 24 months), with patients aged 60 years or older (7.1 vs 5.0 months) and those with early relapse (6.7 vs 5.2 months) benefitting the most from vosaroxin addition.

Complete remission was attained by 30% of patients in the vosaroxin group, which was significantly higher than the 16% rate observed in the placebo group. And again the greatest between-group difference was in patients aged 60 years or more, with complete remission achieved by 32% of vosaroxin-treated patients and 14% of those given placebo.

Although the trial was not powered to detect differences in treatment effect by subgroup, Farhad Ravandi, from MD Anderson Cancer Center in Houston, Texas, USA, and team suggest that the combination of vosaroxin and cytarabine “could be a treatment option for salvage therapy in patients aged 60 years or older”.

All-cause mortality at 30 days and at 60 days was similar in the vosaroxin and placebo arms. But deaths and serious adverse events attributed to the study drug were more frequent in the vosaroxin than in the placebo arm.

Adverse events of grade 3 or more that occurred more frequently in the vosaroxin than in the placebo group included febrile neutropenia (47 vs 33%), neutropenia (19 vs 14%), stomatitis (15 vs 3%), hypokalaemia (15 vs 6%), bacteraemia (12 vs 5%), sepsis (12 vs 5%) and pneumonia (11 vs 7%)

Commending the authors for their “large and informative study”, Martin Bornhäuser writes that “[t]he next steps should include trials in patients with newly diagnosed acute myeloid leukaemia with prespecified subgroup analyses of cytogenetically and molecularly defined subcategories.

“Potentially, a comparison with anthracyclines combined with cytarabine as first-line therapy would be warranted, since higher doses of anthracyclines have been shown to be effective in subgroups of patients, but may render patients at risk for increased toxic effects.”


Ravandi F, Ritchie EK, Sayar H,et al.Vosaroxin plus cytarabine versus placebo plus cytarabine in patients with first relapsed or refractory acute myeloid leukaemia (VALOR): a randomised, controlled, double-blind, multinational, phase 3 study. Lancet Oncol 2015; Advance online publication 30 July. doi: http://dx.doi.org/10.1016/S1470-2045(15)00201-6

Bornhäuser M. Vosaroxin in acute myeloid leukaemia. Lancet Oncol 2015; Advance online publication 30 July . doi: http://dx.doi.org/10.1016/S1470-2045(15)00165-5

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