Vosaroxin plus decitabine in older AML and MDS patients – a phase II study

Vosaroxin in combination with decitabine is well-tolerated and effective in elderly patients with newly diagnosed Acute Myeloid Leukemia (AML) or high-risk Myelodysplastic Syndrome (MDS) according to results from a phase II study (NCT01893320) published in Haematologica by Naval Daver and colleagues from The University of Texas MD Anderson Cancer Center, Houston, Texas.¹

In this phase II non-randomized study, Daver et al. aimed to assess whether the addition of vosaroxin (anti-cancer quinolone derivative that inhibits DNA topoisomerase II) to decitabine can improve the Overall Response Rate (ORR) and Overall Survival (OS) of older AML or high-risk MDS patients compared to established outcomes with decitabine alone while maintaining an acceptable safety profile.

Sixty-five (median age = 69 years) newly diagnosed AML (n = 58) and high-risk MDS (n = 7) patients were enrolled. Initially, 22 patients were administered decitabine 20mg/m² on days 1–5 and vosaroxin 90mg/m² on days 1 and 4. However, there was a high incidence of mucositis hence amendment of the protocol. The remaining 42 patients were administered decitabine 20mg/m² on days 1–5 and vosaroxin 70mg/m² on days 1 and 4.

The key results of the study were:

• ORR in all patients; 74%
• Median OS in all patients; 9.8 months
• Median OS of patients treated with 70mg/m² and 90mg/m² vosaroxin; 14.6 vs 5.5 months; P = 0.007
• Median OS significantly improved in responders who achieved Minimal Residual Disease (MRD)-negative status (21/39) compared to MRD-positive responders (18/39); 34.0 vs 8.3 months, P < 0.001
• Most common treatment-related Adverse Effects (AEs) was mucositis, which significantly reduced in patients administered 70mg/m² vosaroxin compared to 90mg/m² (grade 1–2 mucositis, 30% vs 59%, respectively, P = 0.02)
• 8-week mortality rate in patients that received 70mg/m² and 90mg/m² vosaroxin; 9% vs 23%, P = 0.14

In previous studies, decitabine monotherapy administered at 20mg/m² in an extended 10-day regimen was shown to result in an ORR of 64%, an OS of 13.7 months, and an 8-week mortality of 15% in older AML patients.²

Daver et al. concluded by stating that “the combination of vosaroxin with decitabine achieves a higher response rate with an equivalent 8-week mortality to that expected with decitabine”. The authors proposed that a prospective randomized study comparing vosaroxin with decitabine with existing regimens should be carried out in older patients with AML.

Abstract

Vosaroxin is an anti-cancer quinolone derived DNA topoisomerase II inhibitor. We investigated vosaroxin with decitabine in patients ≥ 60 years of age with newly diagnosed acute myeloid leukemia (AML) (n=58) or myelodysplastic syndrome (MDS) (≥ 10% blasts) (n=7) in a phase 2 non-randomized trial. The initial 22 patients received vosaroxin 90 mg/m2 on Days 1 and 4 with decitabine 20 mg/m2 Days 1-5 every 4-6 weeks for up to 7 cycles. Due to high incidence of mucositis the subsequent 43 patients received vosaroxin 70 mg/m2 Days 1 and 4. Sixty-five patients with median age 69 years (range 60-78), secondary AML/MDS (22%), adverse karyotype (35%), TP53 mutation (20%) are evaluable. The overall response rate (ORR) was 74% including complete remission (CR) in 31 (48%), complete remission with incomplete platelet recovery (CRp) in 11 (17%), and complete remission with incomplete count recovery (CRi) in 6 (9%). The median number of cycles to response was 1 (1-4). The median duration of response was 9.9 months (0.5-32.0). The ORR among adverse karyotype (n=23) and TP53 mutated (n=13) patients was 65% and 77%, respectively. Grade 3/4 mucositis was noted in 17% of all patients. We compared outcomes between the 70 mg/m2 and the 90 mg/m2 induction doses of vosaroxin. The 70 mg/m2 induction dose of vosaroxin was associated with similar ORR (74% versus 73%) and CR rate (51% versus 41%, P=0.44), reduced incidence of mucositis (30% versus 59%, P=0.02), reduced 8-week mortality (9% versus 23%; P=0.14), and improved median overall survival (OS) (14.6 months versus 5.5 months, P=0.007). MRD-negative status by multiparametric flow-cytometry at response (+/- 3 months) was achieved in 21 of 39 (54%) evaluable responders and was associated with improved median OS (34.0 months versus 8.3 months, P=0.023). The combination of vosaroxin with decitabine is effective and well tolerated at 70 mg/m2 and warrants randomized prospective evaluation. ClinicalTrials.gov: NCT01893320