Extended aprepitant in control of delayed emesis during induction chemotherapy for acute myeloid leukaemia – an multicentric, investigator-initiated, open label randomized controlled trial

Abstract IntroductionThe management of chemotherapy induced nausea and vomiting (CINV) during intensive induction chemotherapy for acute myeloid leukaemia (AML) is often not optimal due to prolonged infusion of chemotherapy over 7 days as well as omission of steroids as an anti-emetic due to concern of infections. Addition of single 3-day course of oral aprepitant with ondansetron has shown to improve vomiting control in acute phase (AP), but not in delayed phase (DP) for children with AML. We investigated whether an extended course of aprepitant improves chemotherapy-induced vomiting (CIV) in DP among adults with AML. MethodologyAn investigator-initiated open-label randomized controlled trial was conducted in 4 tertiary care cancer institutes in India, where chemotherapy-naïve adults (≥18 years) who were due to receive intensive chemotherapy-based induction (3+7 regimen) for AML, were screened for inclusion. Patients were centrally randomized 1:1 into extended aprepitant or standard aprepitant group. All patients received intravenous/oral ondansetron 8mg thrice daily for 10 days with first dose starting half an hour before initiation of chemotherapy on day 1. Patients in both standard and extended aprepitant group received oral aprepitant capsules 125 mg on day1 starting 1 hour before chemotherapy and 80 mg on days 2-3 of chemotherapy. Patients in extended aprepitant group received an additional course of aprepitant 125 mg on day 6 and 80 mg on days 7 and 8. Patients received a planned chemotherapy regimen of daunorubicin 60mg/m2 days 1-3 and continuous infusion of cytarabine 100mg/m2/day for 7 days. Targeted therapies were added along with chemotherapy or chemotherapy were interrupted or discontinued based on prevailing clinical scenario as per discretion of local investigator. Rescue anti-emetics were also allowed for breakthrough vomiting/severe nausea as per discretion of clinician, which were recorded. All subjects were followed till day 30. The primary objective was to evaluate rates of complete response (CR) in CIV during DP of CINV (24-hours to 120 hours post chemotherapy). Secondary objectives included CR in CIV in AP (From initiation of chemotherapy to 24 hours post chemotherapy) and overall phase (OP), CR in CINV in all phases, use of rescue anti-emetics, grade and severity of CINV, and adverse effect profile in the two groups. ResultsTotal 224 patients were randomized, among which, 204 patients (Extended aprepitant: 101; Standard aprepitant: 103) were included for modified intention-to-treat analysis. The proportion of patients who achieved CR in CIV in DP were 82.1% (n=83) in extended arm vs 73.7% (n=76) in standard arm, which was not significantly different (p=0.15). The CR rate in AP was 68.3% (n=69) in extended arm vs 72.8% (n=75) in standard arm (p=0.48), while that in OP was 63.3% (n=64) vs 65.0% (n=67) respectively (p=0.80). The CR in CINV, the incidence and severity of vomiting and nausea, and the use of rescue medications also did not differ significantly between the two arms. Adverse effect profile including febrile neutropenia or its complications, also did not differ between the two groups. On subgroup analysis, among patients who received venetoclax additionally with chemotherapy (n=67), the CR rate in DP in extended aprepitant group [78.8% (26/33)] was significantly higher than in standard group [55.9% (19/34)] (p=0.046). ConclusionExtended course of aprepitant did not improve the control of CINV in DP among adults receiving intensive chemotherapy induction as compared to standard 3-day dose; however, it can be explored further in regimens with more emetogenicity or with additional targeted agents.