title: Randomized, phase 2 trial of low-dose cytarabine with or without volasertib in AML patients not suitable for induction therapy.
abstract: Treatment outcomes for older patients with acute myeloid leukemia (AML) have remained dismal. This randomized, phase 2 trial in AML patients not considered suitable for intensive induction therapy compared low-dose cytarabine (LDAC) with or without volasertib, a highly potent and selective inhibitor of polo-like kinases. Eighty-seven patients (median age 75 years) received LDAC 20 mg twice daily subcutaneously days 1-10 or LDAC + volasertib 350 mg IV days 1 + 15 every 4 weeks. Response rate (complete remission and complete remission with incomplete blood count recovery) was higher for LDAC + volasertib vs LDAC (31.0% vs 13.3%; odds ratio, 2.91; P = .052). Responses in the LDAC + volasertib arm were observed across all genetic groups, including 5 of 14 patients with adverse cytogenetics. Median event-free survival was significantly prolonged by LDAC + volasertib compared with LDAC (5.6 vs 2.3 months; hazard ratio, 0.57; 95% confidence interval, 0.35-0.92; P = .021); median overall survival was 8.0 vs 5.2 months, respectively (hazard ratio, 0.63; 95% confidence interval, 0.40-1.00; P = .047). LDAC + volasertib led to an increased frequency of adverse events that was most pronounced for neutropenic fever/infections and gastrointestinal events; there was no increase in the death rate at days 60 + 90. This study was registered at www.clinicaltrials.gov as #NCT00804856.
authors.affiliation: Department of Internal Medicine III, Ulm University, Ulm, Germany;
authors.forename: Hartmut
authors.initials: H
authors.lastname: Döhner
authors.affiliation: Department of Internal Medicine I, University of Freiburg, Freiburg, Germany;
authors.forename: Michael
authors.initials: M
authors.lastname: Lübbert
authors.affiliation: Hubertus Wald University Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;
authors.forename: Walter
authors.initials: W
authors.lastname: Fiedler
authors.affiliation: Centre Hospitalier René Dubos, Cergy Pontoise, France;
authors.forename: Loic
authors.initials: L
authors.lastname: Fouillard
authors.affiliation: Oslo University Hospital, Oslo, Norway;
authors.forename: Alf
authors.initials: A
authors.lastname: Haaland
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON, Canada;
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Brandwein
authors.affiliation: Centre de Lutte Contre Le Cancer Henri Becquerel, Rouen, France;
authors.forename: Stephane
authors.initials: S
authors.lastname: Lepretre
authors.affiliation: Centre Hospitalo-Universitaire de Caen, Caen, France;
authors.forename: Oumedaly
authors.initials: O
authors.lastname: Reman
authors.affiliation: Centre Hospitalo-Universitaire de Limoges, Limoges, France;
authors.forename: Pascal
authors.initials: P
authors.lastname: Turlure
authors.affiliation: Department of Internal Medicine II, Goethe University, Frankfurt, Germany;
authors.forename: Oliver G
authors.initials: OG
authors.lastname: Ottmann
authors.affiliation: Department of Medicine A, University of Münster, Münster, Germany;
authors.forename: Carsten
authors.initials: C
authors.lastname: Müller-Tidow
authors.affiliation: University of Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany;
authors.forename: Alwin
authors.initials: A
authors.lastname: Krämer
authors.affiliation: University Hospital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Paris, France;
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Raffoux
authors.affiliation: Department of Internal Medicine III, Ulm University, Ulm, Germany;
authors.forename: Konstanze
authors.initials: K
authors.lastname: Döhner
authors.affiliation: Department of Internal Medicine III, Ulm University, Ulm, Germany;
authors.forename: Richard F
authors.initials: RF
authors.lastname: Schlenk
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany; and.
authors.forename: Florian
authors.initials: F
authors.lastname: Voss
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany; and.
authors.forename: Tillmann
authors.initials: T
authors.lastname: Taube
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany; and.
authors.forename: Holger
authors.initials: H
authors.lastname: Fritsch
authors.affiliation: University Hospital Gasthuisberg Leuven, Leuven, Belgium.
authors.forename: Johan
authors.initials: J
authors.lastname: Maertens
mesh_terms: D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics; D000075202:Contraindications; D003561:Cytarabine / Q000008:administration & dosage* / Q000009:adverse effects; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D060828:Induction Chemotherapy; D053208:Kaplan-Meier Estimate; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D011621:Pteridines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome
chemical_list: C541363:BI 6727; D047428:Protein Kinase Inhibitors; D011621:Pteridines; D003561:Cytarabine