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Vosaroxin may improve outcomes for older patients with relapsed, refractory AML
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The addition of vosaroxin to cytarabine provided clinical benefit to certain patients with first relapsed or refractory acute myeloid leukemia, according to the results of a randomized, controlled phase 3 study.
However, researchers observed no significant difference in OS between patients who received vosaroxin (Quinprezo, Sunesis Pharmaceuticals) and placebo.
“The prognosis for patients with relapsed or refractory AML is poor; median survival is less than 1 year,” Farhad Ravandi, MD, professor of medicine in the department of leukemia at The University of Texas MD Anderson Cancer Center, and colleagues wrote. “High-dose cytarabine monotherapy or cytarabine-based combination regimens are often used as salvage therapy with limited efficacy. In a recent randomized trial, salvage chemotherapy with the investigator’s choice of one of seven commonly used regimens (including high-dose cytarabine) produced complete remission in 12% of patients with a median survival of 3.3 months, with no significant difference between regimens.”
Farhad Ravandi
Ravandi and colleagues initiated the international, double blind VALOR trial to investigate the safety and efficacy of vosaroxin — a first-in-class anticancer quinolone derivative — plus cytarabine in patients with relapsed or refractory AML.
The trial included 711 patients aged 18 years or older who either had refractory AML or were in their first relapse after receiving one or two previous cycles of induction chemotherapy, including at least one cycle of anthracycline or anthracenedione plus cytarabine.
The researchers randomly assigned 356 patients to receive IV vosaroxin (90 mg/m2 on days 1 and 4 in the first cycle; 70 mg/m2 in subsequent cycles) plus IV cytarabine (1 g/m2 on days 1-5). The other 355 patients received cytarabine plus placebo.
OS served as the primary efficacy endpoint. All-cause mortality at 30 days and 60 days served as the primary safety endpoint.
The final safety analysis included data from 705 patients (vosaroxin, n = 355; placebo, n = 350) who received a first induction cycle.
At the final analysis, researchers observed longer median OS among patients assigned vosaroxin (7.5 months vs. 6.1 months; HR = 0.87; 95% CI, 0.73-1.02).
In a pre-specified secondary analysis stratified by randomization factors, patients aged 60 years or older (HR = 0.75; 95% CI, 0.62-0.92) and those with early relapse (HR = 0.77; 95% CI, 0.59-1) appeared to derive a particular OS benefit.
A greater percentage of patients assigned vosaroxin achieved complete remission (30% vs. 16%; P < .0001). However, researchers reported similar rates of 30-day mortality (8% vs. 7%) and 60-day mortality (20% vs. 19%) in both groups.
A pre-specified analysis showed that, among patients aged 60 years or older, those assigned vosaroxin plus cytarabine experienced a significantly greater response rate (32% vs. 14%; P < .0001) than those assigned cytarabine and placebo.
Thirty percent of patients (n = 210) underwent allogeneic hematopoietic stem cell transplantation following the study. A similar percentage of patients in both groups underwent HSCT (30% vs. 29%).
Treatment-related deaths at any time occurred in 6% (n = 20) of patients assigned vosaroxin and 2% (n = 8) of patients assigned placebo.
A higher percentage of serious adverse events occurred among patients assigned vosaroxin (33% vs. 17%). Grade 3 or higher adverse events reported more frequently in the vosaroxin group included febrile neutropenia (47% vs. 33%), neutropenia (19% vs. 14%), stomatitis (15% vs. 3%), hypokalemia (15% vs. 6%), bacteremia (12% vs. 5%), sepsis (12% vs. 5%) and pneumonia (11% vs. 7%).
“Our study represents one of the largest datasets available in the relapsed or refractory AML setting,” Ravandi and colleagues concluded. “Although there was no significant difference in the primary endpoint between groups, a pre-specified secondary analysis stratified by randomization factors suggests that the addition of vosaroxin to cytarabine might be of clinical benefit to some patients with relapsed or refractory AML.
“The toxicity reported with the addition of vosaroxin is acceptable in view of the benefits conferred,” the researchers wrote. “Our findings suggest that this combination could be a treatment option for salvage therapy in patients aged 60 years or older.”
Randomized trials of patients with relapsed or refractory AML are difficult for several reasons, Martin Bornhäuser, PhD, head of Stem Cell Lab Dresden in Germany, wrote in an accompanying editorial. They include the heterogeneity of patient populations with regard to prior treatments and responsiveness.
“The outcome of such a trial is mainly affected by the frequency with which a clinician refers patients to allogeneic transplantation and the associated availability of a matched sibling or unrelated donor,” Bornhäuser wrote. “Additionally, the biology of the underlying disease is likely to be very different between primary diagnosis and relapsed or refractory disease.”
The benefit of vosaroxin likely will remain confined to certain appropriately selected patients, Bornhäuser said.
“AML is a very heterogeneous disease that is unlikely to respond in a uniform pattern to a non-targeted therapeutic approach,” Bornhäuser wrote. “Vosaroxin will probably take a place in future therapeutic algorithms. The drug is unlikely to become a one-size-fits-all treatment, as cytarabine and anthracyclines have been for decades, but more likely a combination partner for somewhat more targeted approaches in well-defined subgroups.” – by Cameron Kelsall
Disclosure: Sunesis Pharmaceuticals funded this study. Ravandi reports grants and personal fees from Sunesis. Please see the full study for a list of all other researchers’ relevant financial disclosures. Bornhäuser reports personal fees from Jazz Pharmaceuticals and Merck.
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