Addition of Vosaroxin to Cytarabine Demonstrates Antileukemic Activity in Relapsed or Refractory Acute Myeloid Leukemia
In a phase Ib/II study of patients with relapsed or refractory acute myeloid leukemia (AML), the addition of vosaroxin to cytarabine demonstrated antileukemic activity and an acceptable risk-benefit profile, according to a study by Lancet et al in Haematologica. Based on the findings from this study, a phase III study has been initiated.
Patients with relapsed or refractory AML generally have poor outcomes, and studies have shown median survival rates of less than 1 year. One of the major issues facing oncologists is that there is no consensus standard-of-care regimen. Several cytarabine-based combination induction regimens have been investigated in the relapsed/refractory setting, often incorporating topoisomerase II inhibitors such as anthracyclines (daunorubicin, idarubicin), anthracenediones (mitoxantrone), or epipodophyllotoxins (etoposide). These agents have demonstrated limited efficacy, particularly in older adults.
Thus, the investigators conducted a phase Ib/II study of vosaroxin, in combination with cytarabine, in patients with relapsed or refractory AML. In contrast to classic topoisomerase II agents, the anticancer activity of vosaroxin results exclusively from intercalation of DNA and inhibition of topoisomerase II. The investigators hypothesized that the characteristics of vosaroxin may provide a more favorable risk-benefit profile than other commonly used agents, such as anthracyclines.
Study Details
In total, 108 patients received at least one dose of vosaroxin and/or cytarabine. Vosaroxin was administered on a day 1, 4 dosing schedule. Patients were enrolled sequentially in two successive cohorts to either schedule A (56 patients) or schedule B (52 patients). Patients in schedule A received 10 to 90 mg/m2 of vosaroxin in 10-minute infusions on days 1 and 4 and cytarabine 400 mg/m2/d in 24-hour continuous infusions on days 1 to 5. Patients in schedule B received 70 to 90 mg/m2 of vosaroxin plus 1 g/m2/d of cytarabine in 2-hour intravenous infusions on days 1 to 5.
It is important to note that most patients in the study (89%) had an intermediate or unfavorable cytogenetic risk status. In addition, the vast majority of patients were older (median age of 60 years).
Combination Shows Antileukemic Activity
The final study analysis indicated that the combination of vosaroxin and cytarabine demonstrated antileukemic activity and an acceptable risk-benefit profile in patients with relapsed or refractory AML. In this pooled set of patients, the rate of complete recovery was 25% in the schedule A group and 21% in the schedule B group.
Overall, responses were observed with both cytarabine schedules and in both primary refractory patients and patients in first relapse. Median overall survival was 6.9 months (95% confidence index [CI] = 4.3–10.1 months), with similar survival in patients in first relapse and those with primary refractory disease.
As for safety, the most common treatment-emergent nonhematologic adverse events of any grade were diarrhea (76%), hypokalemia (73%), nausea (67%), and stomatitis (66%). Serious adverse events were noted in 46% of patients; they included infections such as bacteremia, pneumonia, and sepsis (30%), febrile neutropenia (8%), and stomatitis (4%).
A DNA damage response consistent with DNA double-strand breaks was observed in K562 cells and primary AML peripheral blood samples treated with vosaroxin. Increases in pDNA-PKcs or pCHK2 were evident after 2 hours of treatment. In contrast, the pharmacodynamic response to cytarabine treatment occurred more slowly, with increases first becoming evident after 24 hours of treatment.
Closing Thoughts
The results of this study indicated that the addition of vosaroxin to cytarabine in both primary refractory patients and patients in first relapse proved to be efficacious and safe. Based on the clinical activity of the combination regimen in this study, as well as previous studies of vosaroxin in patients with relapsed/refractory AML, a multinational, randomized, double-blind, placebo-controlled, a phase III study (the VALOR trial) in patients with first-relapsed or refractory AML has been initiated.
The investigators concluded, “This combination therapy has clinically significant activity in patients previously treated with other topoisomerase II inhibitors and is well tolerated, with low rates of early mortality and organ toxicity.”
Jeffrey E. Lancet, MD, of the Moffitt Cancer Center, Tampa, Florida, is the corresponding author of this article in Haematologica.
For full disclosures from the study authors, see the article at www.haematologica.org.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
