title: Salvage therapy with high-dose cytarabine and mitoxantrone in combination with all-trans retinoic acid and gemtuzumab ozogamicin in acute myeloid leukemia refractory to first induction therapy.
abstract: Outcome of patients with primary refractory acute myeloid leukemia remains unsatisfactory. We conducted a prospective phase II clinical trial with gemtuzumab ozogamicin (3 mg/m(2) intravenously on day 1), all-trans retinoic acid (45 mg/m(2) orally on days 4-6 and 15 mg/m(2) orally on days 7-28), high-dose cytarabine (3 g/m(2)/12 h intravenously on days 1-3) and mitoxantrone (12 mg/m(2) intravenously on days 2-3) in 93 patients aged 18-60 years refractory to one cycle of induction therapy. Primary end point of the study was response to therapy; secondary end points included evaluation of toxicities, in particular, rate of sinusoidal obstruction syndrome after allogeneic hematopoietic cell transplantation. Complete remission or complete remission with incomplete blood count recovery was achieved in 47 (51%) and partial remission in 10 (11%) patients resulting in an overall response rate of 61.5%; 33 (35.5%) patients had refractory disease and 3 patients (3%) died. Allogeneic hematopoietic cell transplantation was performed in 71 (76%) patients; 6 of the 71 (8.5%) patients developed moderate or severe sinusoidal obstruction syndrome after transplantation. Four-year overall survival rate was 32% (95% confidence interval 24%-43%). Patients responding to salvage therapy and undergoing allogeneic hematopoietic cell transplantation (n=51) had a 4-year survival rate of 49% (95% confidence intervaI 37%-64%). Patients with fms-like tyrosine kinase internal tandem duplication positive acute myeloid leukemia had a poor outcome despite transplantation. In conclusion, the described regimen is an effective and tolerable salvage therapy for patients who are primary refractory to one cycle of conventional intensive induction therapy. (clinicaltrials.gov identifier: 00143975).
authors.affiliation: Department of Internal Medicine III, University Hospital Ulm, Germany.
authors.forename: Marie-Luise
authors.initials: ML
authors.lastname: Hütter-Krönke
authors.affiliation: Division of Biostatistics, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Benner
authors.affiliation: Department of Internal Medicine III, University Hospital Ulm, Germany.
authors.forename: Konstanze
authors.initials: K
authors.lastname: Döhner
authors.affiliation: Department of Oncology and Hematology, Klinikum Braunschweig, Germany Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Krauter
authors.affiliation: Department of Internal Medicine III, University Hospital Ulm, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Weber
authors.affiliation: Department of Internal Medicine III, University Hospital Ulm, Germany.
authors.forename: Margit
authors.initials: M
authors.lastname: Moessner
authors.affiliation: Department of Oncology and Hematology, Klinikum Oldenburg, Germany.
authors.forename: Claus-Henning
authors.initials: CH
authors.lastname: Köhne
authors.affiliation: Department of Internal Medicine II, University Hospital Schleswig-Holstein Campus Kiel, Germany.
authors.forename: Heinz A
authors.initials: HA
authors.lastname: Horst
authors.affiliation: Department of Internal Medicine III, CIO, University Hospital of Bonn, Germany.
authors.forename: Ingo G H
authors.initials: IG
authors.lastname: Schmidt-Wolf
authors.affiliation: Department of Hematology/Oncology, University-hospital Giessen, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Rummel
authors.affiliation: Department of Internal Medicine III, Technical University of Munich, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Götze
authors.affiliation: Department of Hematology/Oncology, Hanuschkrankenhaus, Wien, Austria.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Koller
authors.affiliation: Department of Medical Oncology and Hematology, Krankenhaus der Barmherzigen Schwestern, Linz, Austria.
authors.forename: Andreas L
authors.initials: AL
authors.lastname: Petzer
authors.affiliation: Department of Hematology/Oncology, Asklepios Klinik Altona, Hamburg, Germany.
authors.forename: Hans
authors.initials: H
authors.lastname: Salwender
authors.affiliation: Department of Internal Medicine II, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Walter
authors.initials: W
authors.lastname: Fiedler
authors.affiliation: Department of Hematology/Oncology, Krankenhaus der Barmherzigen Brüder, Trier, Germany.
authors.forename: Heinz
authors.initials: H
authors.lastname: Kirchen
authors.affiliation: Department of Hematology and Oncology, Georg-August-University Hospital of Göttingen, Germany.
authors.forename: Detlef
authors.initials: D
authors.lastname: Haase
authors.affiliation: Department of Hematology/Oncology, Caritas-Krankenhaus, Lebach, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Kremers
authors.affiliation: Department of Medicine III, Johannes Gutenberg-University Mainz, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Theobald
authors.affiliation: Department of Hematology/Oncology, Caritas-Krankenhaus, Saarbrücken, Germany.
authors.forename: Axel C
authors.initials: AC
authors.lastname: Matzdorff
authors.affiliation: Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Germany.
authors.forename: Arnold
authors.initials: A
authors.lastname: Ganser
authors.affiliation: Department of Internal Medicine III, University Hospital Ulm, Germany.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Döhner
authors.affiliation: Department of Internal Medicine III, University Hospital Ulm, Germany richard.schlenk@uniklinik-ulm.de.
authors.forename: Richard F
authors.initials: RF
authors.lastname: Schlenk
mesh_terms: D000328:Adult; D000617:Aminoglycosides / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D015897:Comorbidity; D060830:Consolidation Chemotherapy; D003561:Cytarabine / Q000008:administration & dosage; D005260:Female; D000079982:Gemtuzumab; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods; D006801:Humans; D053208:Kaplan-Meier Estimate; D015470:Leukemia, Myeloid, Acute / Q000150:complications / Q000175:diagnosis / Q000401:mortality / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D008942:Mitoxantrone / Q000008:administration & dosage; D012074:Remission Induction; D016879:Salvage Therapy; D016896:Treatment Outcome; D014212:Tretinoin / Q000008:administration & dosage; D055815:Young Adult
chemical_list: D000617:Aminoglycosides; D061067:Antibodies, Monoclonal, Humanized; D003561:Cytarabine; D014212:Tretinoin; D000079982:Gemtuzumab; D008942:Mitoxantrone