Leading the way in experimental and clinical research in hematology

Randomized, phase 2 trial comparing low-dose cytarabine with or without volasertib in AML patients not suitable for intensive induction therapy

  1. Hartmut Döhner1,*,
  2. Michael Lübbert2,
  3. Walter Fiedler3,
  4. Loic Fouillard4,
  5. Alf Haaland5,
  6. Joseph M. Brandwein6,
  7. Stephane Lepretre7,
  8. Oumedaly Reman8,
  9. Pascal Turlure9,
  10. Oliver G. Ottmann10,
  11. Carsten Müller-Tidow11,
  12. Alwin Krämer12,
  13. Emmanuel Raffoux13,
  14. Konstanze Döhner1,
  15. Richard F. Schlenk1,
  16. Florian Voss14,
  17. Tillmann Taube14,
  18. Holger Fritsch14, and
  19. Johan Maertens15
  1. 1 Department of Internal Medicine III, Ulm University, Ulm, Germany;
  2. 2 Department of Internal Medicine I, University of Freiburg, Freiburg, Germany;
  3. 3 Hubertus Wald University Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;
  4. 4 Centre Hospitalier Rene Dubos, Cergy Pontoise, France;
  5. 5 Oslo University Hospital, Oslo, Norway;
  6. 6 Princess Margaret Cancer Centre, Toronto, ON, Canada;
  7. 7 Centre de Lutte Contre Le Cancer Henri Becquerel, Rouen, France;
  8. 8 Centre Hospitalo-Universitaire de Caen, Caen, France;
  9. 9 Centre Hospitalo-Universitaire de Limoges, Limoges, France;
  10. 10 Department of Internal Medicine II, Goethe University, Frankfurt, Germany;
  11. 11 Department of Medicine A, University of Muenster, Muenster, Germany;
  12. 12 University of Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany;
  13. 13 University Hospital Saint-Louis, Assistance publique-Hopitaux de Paris, Paris, France;
  14. 14 Boehringer Ingelheim Pharma GmbH & Co. KG, Germany;
  15. 15 University Hospital Gasthuisberg Leuven, Leuven, Belgium
  1. * Corresponding author; email: hartmut.doehner{at}uniklinik-ulm.de

Key points

  • Volasertib plus low-dose cytarabine increased the response rate and improved survival in AML patients ineligible for intensive treatment.

  • Volasertib plus low-dose cytarabine resulted in responses across all AML genetic subgroups and had a clinically manageable safety profile.

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 b.i.d. subcutaneously days 1-10 or LDAC + volasertib 350 mg intravenously days 1 + 15, every 4 weeks. Response rate (complete remission [CR] and CR with incomplete blood count recovery [CRi]) was higher for LDAC + volasertib versus 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 [HR], 0.57; 95% confidence interval [CI], 0.35-0.92; P=.021); median overall survival was 8.0 versus 5.2 months, respectively (HR, 0.63; 95% CI, 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 ClinicalTrials.gov, identifier: NCT00804856.

  • Submitted March 7, 2014.
  • Accepted June 18, 2014.