Doripenem Versus Meropenem As the First-Line Mono-Therapy in High-Risk Febrile Neutropenic Patients with Acute Leukemia: A Randomized, Controlled Trial
Authors: Oyake Tatsuo , Sugawara Norifumi , Miyajima Shinri , Kiyohara Kazuki , Nishiya Maki , Shimoyama Tadashi , Takemasa-Fujisawa Yuka , Sasaki Ryosei , Izumita Wataru , Tsukushi Yasuhiko , Otsu Akihiro , Mine Takahiro , Sugawara Takeshi , Suzuki Yuzo , Okano Yoshiaki , Hanamura Ichiro , Kowata Shugo , Ito Shigeki 
Published: November 2019

BACKGROUND: Febrile neutropenia (FN) is often observed in patients with hematological malignancies (HEM), especially in those with acute leukemia (AL). Monotherapy with antipseudomonal beta-lactams, such as cefepime, carbapenem, or piperacillin-tazobactam, is recommended as first-line empiric antibacterial therapy in FN patients. The efficacy of meropenem (MEPM) as empiric monotherapy for FN patients with cancer has been assessed in randomized comparative trial against cefepime, imipenem/cilastain, ceftazidime with or without amikacin, and piperacillin-tazobactom. Because of those studies, MEPM is considered a standard antibiotic for the empiric treatment of FN patients with HEM.In contrast, doripenem (DRPM) is a relatively new carbapenem, and the clinical study about efficacy and safety of DRPM in FN patients with HEM is limited. Therefore, we conducted a randomized, cooperative group, open-label trial comparing DRPM (1.0 g every 8 hours) with MEPM (1.0 g every 8 hours) as the first-line empirical antibacterial therapy for high-risk FN patients with AL and myelodysplastic syndrome (MDS).
METHODS: One hundred and thirty-three hospitalized patients with acute leukemia or high-risk myelodysplastic syndrome, who developed high-risk FN during or after chemotherapy (AML 77, ALL 43, APL 9, ATL 1, MDS (RAEB-2) 3cases) were randomized to each drug group (DRPM, 65; MEPM, 68). The study drug was started to administer as a mono-therapy and continued at least for 5 days without drug toxicity, and the efficacy and safety were evaluated.
RESULTS: The success rate (Resolution of fever within 3 to 5 days without treatment modification: the primary endpoint) was higher in the DRPM group than in the MEPM group (60.0% vs. 45.6%), although the difference was not significant (P = 0.136). However, resolution of fever within 7 days of treatment was significantly higher in the DRPM group than in the MEPM group (78.4% vs. 60.2%, respectively, P = 0.037). Otherwise, the cumulative number of afebrile cases by day14 was 87.7% and 83.8% in the DRPM and MEPM group, respectively (P = 0.523). The success rate did not depend on neutrophil recovery: success rates for the DRPM group were 58.3% and 60.9%, with and without neutrophil recovery, respectively; success rates for the MEPM group were 33.3% and 40.9%, with and without neutrophil recovery, respectively (P = 0.233, P = 0.346). In all, 40.0% of the DRPM group and 32.3% of the MEPM group received anti-MRSA agent, as empiric or targeted antibacterial therapy of persistent or recurrent fever considering of infections by gram-positive bacteria, including methicillin-resistant species. Antifungal medications were added to 21.5% of the DRPM group and 13.2% of the MEPM group, as empiric or preemptive therapy of persistent or recurrent fevers believed to be caused by fungal infections. Survival rates at 30 days after the start of administration were 98.5% and 100% in the DRPM and MEPM group, respectively (P = 0.304). The rates of adverse events did not significantly differ between the DRPM and MEPM group (38.5% vs. 41.2%, respectively, P = 0.749), and these adverse events were clinically acceptable in the two groups, and most of patients could continue the treatment by both study drugs.
CONCLUSIONS: Our clinical study suggested that DRPM had the non-inferiority of efficacy in comparison with MEPM as the first-line therapy in high-risk FN patients with AL and MDS, and both drugs could be well tolerated clinically.

Disclosures
Oyake: Kyowa-Hakko Kirin: Honoraria; Celgene: Honoraria; Chugai: Honoraria; Astellas: Speakers Bureau. Hanamura:Sanofi: Research Funding; Taiho: Research Funding; MSD: Research Funding; Chugai: Research Funding; Eli Lilly: Research Funding; Fujimoto: Research Funding; Zenyaku: Research Funding; Yamada Yohojo: Research Funding; Chugai: Research Funding; Astellas: Research Funding; Shionogi: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Eisai: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Kyowa-Hakko Kirin: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Ono: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria; Mundi: Honoraria; Nihon Shinyaku: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding. Ito:Bristol-Myers Squibb: Honoraria; Ono: Honoraria; Celgene: Honoraria.