The backbone of AML induction therapy has been anthracycline-cytarabine combination for decades, and the addition of other cytotoxics, including thioguanine, fludarabine, or etoposide, have offered no additional survival benefit [
7,
8]. However, certain modifications in traditional 7 + 3, including manipulation of treatment intensity and duration of treatment, translated into improved OS for selected populations of adult patients [
9]. Therefore, new formulations of cytotoxic chemotherapy that have similar mechanisms of action might continue to improve outcomes.
CPX-351
CPX-351 is the liposomal formulation of cytarabine and daunorubicin packaged at a 5:1 molar ratio within liposomes, which in animal models demonstrated higher efficacy compared with the same drugs administered conventionally [
10]. The ratio is shown to be maximally synergistic and minimally antagonistic in vitro [
11]. In a randomized, open-label, phase 2 trial, CPX-351 (100 U/m
2, equivalent to 100 mg/m
2 cytarabine and 44 mg/m
2 daunorubicin) was compared with conventional 7 + 3 (100 mg/m
2 cytarabine and 60 mg/m
2 daunorubicin) as an induction therapy, with enrollment of 126 AML patients at age 60–75 years, who were fit for intensive chemotherapy [
10]. The primary efficacy endpoint was composite complete response (CRc), combining morphologic complete response (CR) and morphologic CR with incomplete count recovery (CRi). Overall, CRc rates were higher (66.7 vs 51.2%,
p = 0.07) in the CPX-351 arm, which met the predefined criteria for success (
p < 0.1). There were no differences in true CR rate (48.8% in both arms), event-free survival (EFS), or OS when all patients were analyzed. However, preplanned subgroup analysis of patients with secondary AML (sAML; therapy-related AML or AML with a history of antecedent hematologic disorder) demonstrated an improved response rate (57.6 vs 31.6%,
p = 0.06), with prolonged EFS (
p = 0.08) and OS (
p = 0.01). In a separate phase 2, randomized, open-label study, 125 AML patients at first relapse, who were between the ages of 18 and 65 years, were assigned to CPX-351 or investigators’ choice of first salvage treatment [
12]. Overall, the CR rate was slightly higher in the CPX-351 arm (37 vs 31.8%), but the study did not achieve the predefined goal of survival improvement at 1 year.
Based on the promising results in patients with sAML, a randomized, multicenter, open-label, phase 3 study of first-line CPX-351 (100 U/m
2) vs daunorubicin (60 mg/m
2) plus cytarabine (100 mg/m
2) in high-risk sAML patients was initiated [
13]. A total of 309 patients between the ages of 60 and 75 years were randomized 1:1 to treatment arms. CPX-351 treatment resulted in better OS (median, 9.56 vs 5.95 months,
p = 0.005), EFS (
p = 0.021), and CRc rates (47.7 vs 33.3%,
p = 0.016). Moreover, 60-day mortality was lower in CPX-351 (13.7 vs 21.2%), and grade 3–5 adverse events (AEs) were similar in frequency and severity in both arms. In a subgroup analysis of this large trial, patients aged 60–69 and 70–75 years were analyzed separately and both groups were found to have greater median OS (9.63 vs 6.87 months in patients aged 60–69 years and 8.87 vs 5.62 months in patients aged 70–75 years) and CRc rate (50 vs 36.3% in patients aged 60–69 years and 43.9 vs 27.8% in patients aged 70–75 years) with the CPX-351 treatment [
14]. In another subgroup analysis, 91 transplanted patients were landmarked at the time of hematopoetic stem cell transplant (HSCT) (i.e., time of origin) and patients treated with CPX-351 were found to have better OS as compared to patients treated with standard 7 + 3 (
p = 0.004) [
15]. These results support the use of CPX-351 as first-line induction treatment for fit older patients with sAML, and this formulation may provide an effective bridge to successful HCT in this subset of patients.
In addition, since the drug has shown efficacy (i.e., CRc) at doses of 50 and 75 U/m
2 in phase 1 and 2 trials, a current phase 2 study compares outcomes of newly diagnosed AML patients at these lower doses, who are otherwise at high risk of induction mortality [
16]. Interim results demonstrated significantly better OS (HR, 0.2;
p = 0.005) and EFS (HR, 0.25;
p = 0.019) with 75 U/m
2, and the study continues accrual with the third arm of 100 U/m
2 (NCT02286726). Moreover, comparison of the outcomes of CPX-351 (100 U/m
2) vs daunorubicin (90 mg/m
2) + cytarabine treatment would be valuable to assess the superiority (or non-inferiority) of this formulation.
Vosaroxin
Vosaroxin is a first-in-class, non-anthracycline quinolone derivative that induces replication-dependent DNA damage by intercalating DNA and inhibiting topoisomerase II, thereby inducing G2 cell cycle arrest and apoptosis [
3]. It is minimally metabolized, without production of free radicals that are implicated in the cardiotoxicity observed with other topoisomerase II inhibitors. Based on the encouraging results in early phase 1 and phase 1b/2 studies [
17,
18], the randomized, placebo-controlled, double-blind phase 3 VALOR trial of cytarabine (1 g/m
2 days 1–5) with or without vosaroxin (90 mg/m
2 days 1–4) was conducted in adult patients with primary refractory AML or AML in first relapse [
19]. A total of 711 patients were randomized 1:1 to treatment arms, and the study did not meet the primary endpoint of median OS difference between groups (7.5 months in vosaroxin arm vs 6.1 months in placebo arm,
p = 0.06). However, the overall CR rate was nearly doubled in the vosaroxin arm compared with the placebo arm (30.1 vs 16.3%,
p < 0.0001), and the responses were durable as shown by the leukemia-free survival data. Additionally, in the predefined analysis censoring at the time of HSCT, OS was better in the vosaroxin plus cytarabine group than in the placebo plus cytarabine group (6.7 vs 5.3 months,
p = 0.02). In further preplanned analyses (based on age and time to relapse), vosaroxin-treated patients ≥60 years had significantly better OS (7.1 vs 5 months,
p = 0.003) and those who relapsed <12 months and received vosaroxin had 1.5 months (6.7 vs 5.2 months,
p = 0.03) of median OS benefit as compared to the placebo arm. There was no difference in 30- and 60-day all-cause mortality between treatment groups, but 15% of patients on the vosaroxin arm had grade 3 or 4 stomatitis. The recently presented updated survival data was consistent with the subgroup analysis of the primary report, and after a median of 39.9 months of follow-up, the survival benefit observed in patients ≥60 years was durable through 48 months [
20].
Vosaroxin has also been investigated in the first-line setting for older patients with previously untreated poor-risk AML. In the single-agent, phase 2 REVEAL-1 trial, vosaroxin monotherapy was evaluated at doses of 72 and 90 mg/m
2 and the 72 mg/m
2 dose demonstrated a CRc rate of 35%, with an acceptable 30- and 60-day mortality of 7 and 17%, respectively [
21]. Therefore, this dose was used in a subsequent open-label, randomized phase 2 study, which was designed with the “pick a winner” strategy, comparing in a 1:1 randomization of low-dose cytarabine (LDAC) vs vosaroxin monotherapy and LDAC vs LDAC + vosaroxin combination in older unfit AML patients [
22]. The study demonstrated no CR or survival benefit for vosaroxin, and the trial was prematurely closed at its first interim analysis.
Vosaroxin at the dose of 90 mg/m2 demonstrated clinical activity in combination with cytarabine for relapsed or refractory (R/R) AML patients ≥60 years. However, the OS benefit was 2.1 months. Its utility is limited to the R/R setting, as the drug did not provide benefit when compared to LDAC in the first-line treatment for unfit older patients. A phase 2 study of vosaroxin and decitabine in older patients with newly diagnosed AML or high-risk myelodysplastic syndrome (MDS) is currently ongoing (NCT01893320).