Palonosetron (PALO) Given Daily for up to 5 Days Is Significantly Better Than Ondansetron (ONDA) in the Prevention of Delayed CINV in Patients (pts) with Acute Myelogenous Leukemia (AML).

Although it is well known that CINV is frequent in pts with hematologic malignancies, the extent of the problem has been weakly investigated as well as the therapeutic options.

1) To compare if PALO given in alternate doses or in multiple-day dosing is better than ondansetron (ONDA) given daily in the prevention of CINV in pts with AML/HR-MDS receiving chemotherapy (CHEMO) with high-dose cytarabine (HDAC)-containing regimens (Ara C =1.5 or 2gm/m2 for 3-5 days); 2) To evaluate the incidence of CINV in patients with AML; 3) to identify the risk factors for CINV.

Eligible pts were randomized to receive 30 minutes before CHEMO: ONDA: 8 mg IV bolus, then 24mg IV, continuous infusion on d1 up to d5 and for 12 hours after Ara C infusion ends [ONDA 1-5]; or PALO 0.25mg IV bolus over 30 seconds, on d1 up to d5 of Ara C infusion, [PALO 1-5]; or PALO 0.25mg IV bolus over 30 seconds, on day 1,3, and 5 of Ara C infusion [PALO 1,3,5]. All patients received methylprednisolone 40 mg IV before Ara C infusion daily. Complete response (CR) was defined as no emesis and no use of rescue medication (RM) during CHEMO and up to 7 days; Complete control (CC) was define as CR + pts with ≤ 1 episode of emesis within 24 hours and no more than moderate nausea with no need of RM for either case. Failure (F) was defined as the needs to use of RM. Pts were followed for 7 days. A diary to evaluate impact of CINV on daily activities was filled by the pts during the 7 days.

150 pts were register in the study, 143 were evaluable. The 3 group of pts were comparable in regards to baseline characteristics. Response rates are shown in the table below.

The proportion of patients without nausea on day 1 was similar in the three study arms, (p = 0.50) (Graphic 1). There was an evident decline in the proportion of patients without nausea from day 2 through day 5 in the 3 study arms.

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However, on study days 6 and 7, [PALO 1-5] significantly reduced the incidence of nausea (p = 0.0001 and 0.024, respectively). Similarly, less number of pts on [PALO 1-5] required RM on days 6 and 7 (p =0.034 and 0.0350, respectively). Severity of nausea, (none, mild, moderate or severe) and the impact of CINV in daily activities were reported by the pts in a diary. Significantly more pts on [PALO 1-5] reported to have none/mild nausea on days 6 and 7 of the study (p = 0.039 and p = 0.219, respectively) and more pts in the same group reported a minimal impact (not at all or little effect) of CINV in their activities on study day 6 (p= 0.0229). Univariate analysis showed that female pts, younger age, good performance status, HDAC + idarubicin and the use of prophylactic antibiotics were significant factors for developing CIN during IC. Only younger age (OR: 1.05, p =0.02); CHEMO with HDAC+ idarubicin (OR: 3.27, p=0.04) and the use of prophylactic antibiotics (OR: 2.86, p=0.009) maintained significance in the multivariate analysis. Three pts, one in each arm, developed NCI G3 adverse events, two pts had headache (one on [ONDA 1-5] and the other on [PALO 1-5]); another pt who received [PALO 1,3,5] had diarrhea. No cardiac adverse events possible or probable related to study drug were reported.

1) No significantly difference was detected between ONDA and PALO in the prevention of acute CINV in ALM and HR-MDS pts 2) PALO given daily for up to 5 days is significantly better than Ondansetron in the prevention of delayed CINV; 2) Young patients, receiving prophylactic antibiotics and HDAC + idarubicin are at higher risk for CIN during IC; 3) Nausea after day 1 of CHEMO in this multi-day regimen remains sub-optimally controlled with any type of 5HT3 antagonist. New strategies need to be incorporated to improve the prevention of nausea during these days.

Mattiuzzi:Eisai, Inc.: Research Funding, Speakers Bureau. Borthakur:Eisai, Inc.: Research Funding. Kantarjian:Eisai: Research Funding.