Mito-FLAG with Ara-C as bolus versus continuous infusion in recurrent or refractory AML--long-term results of a prospective randomized intergroup study of the East German Study Group Hematology/Oncology (OSHO) and the Study Alliance Leukemia (SAL).
BACKGROUND
For patients with primary refractory or relapsed acute myeloid leukemia (AML), no treatment of choice has until now been defined to date. Cytarabine (Ara-C) is a key drug in the treatment of AML patients, there is still uncertainly regarding its optimal dose and infusion schedule. The aim of this study is to examine the impact of the Ara-C infusion schedule used as part of an intensive salvage regimen, in patients with relapsed or refractory AML.


METHODS
A total of 252 adult patients (median age 59 years) with relapsed or refractory AML were randomly allocated to receive either Mito-FLAG with Ara-C as bolus (B) (1000 mg/m(2) over 1 h, every 12 h, days 1-5), or continuous infusion (CI) (150 mg/m(2) over 24 h, days 1-5) in combination with mitoxantrone, fludarabine, and granulocyte colony-stimulating factor (G-CSF). Autologous or allogeneic hematopoietic stem-cell transplantation was offered as consolidation therapy. Primary end point was the rate of complete remissions (CRs) after the first cycle of Mito-FLAG.


RESULTS
The CR rates after Mito-FLAG (B) and Mito-FLAG (CI) were 54% and 43%, respectively (P = 0.1). There was no statistical difference between rates of grade 3/4 neutropenia, thrombocytopenia, mucositis, renal, and liver toxicity. More infections occurred, however, after Mito-FLAG (B) compared with Mito-FLAG (CI) (80% versus 69%, P = 0.01). The early death rate by day 42 was 13% in both arms. Median disease-free survival was comparable in the two arms (7.8 versus 7.1 months, P = 0.53) as was overall survival (7.1 versus 6.6 months, P = 0.53).


CONCLUSIONS
A 5-day course of Ara-C 2 × 1000 mg/m(2) administered as bolus versus Ara-C 150 mg/m(2) administered by CI (in combination with mitoxantrone, fludarabine, and G-CSF), resulted in a nonsignificant trend in response rates in favor of Mito-FLAG (B) at the selected dose levels, but no differences in the survival outcome in relapsed or refractory AML.


BACKGROUND
LN_NN_2004_39/EudraCT number 2014-000083-18.
Internal Medicine III, Department of Hematology, Oncology, Stem Cell Transplantation, Klinikum Chemnitz gGmbH, Chemnitz.
A
A
Thiel
Department of Internal Medicine I, University Hospital Carl Gustav Carus, University of Dresden, Dresden DKMS, German Bone Marrow Donor Center, Clinical Trials Unit, Dresden.
J
J
Schetelig
Department of Hematology, Clinical Oncology and Hemostasiology, University of Leipzig, Leipzig.
W
W
Pönisch
Medical Clinic 5, Hematology and Oncology, Klinikum Nuernberg, Nuernberg.
K
K
Schäfer-Eckart
Hematology and Oncology, Robert Bosch Krankenhaus, Stuttgart.
W
W
Aulitzky
Department of Oncology, Klinikum Carl Thiem, Cottbus.
N
N
Peter
Medical Clinic, Hematology/Oncology, Helios Clinic Erfurt GmbH, Erfurt.
A
A
Schulze
Department of Hematology, Oncology and Palliative Care, Klinikum Ernst von Bergmann, Potsdam.
G
G
Maschmeyer
WiSP Research, Langenfeld, Germany.
S
S
Neugebauer
Internal Medicine III, Department of Hematology, Oncology, Stem Cell Transplantation, Klinikum Chemnitz gGmbH, Chemnitz.
R
R
Herbst
Internal Medicine III, Department of Hematology, Oncology, Stem Cell Transplantation, Klinikum Chemnitz gGmbH, Chemnitz.
A
A
Hänel
Internal Medicine III, Department of Hematology, Oncology, Stem Cell Transplantation, Klinikum Chemnitz gGmbH, Chemnitz.
A
A
Morgner
Department of Internal Medicine I, University Hospital Carl Gustav Carus, University of Dresden, Dresden.
F
F
Kroschinsky
Department of Internal Medicine I, University Hospital Carl Gustav Carus, University of Dresden, Dresden.
M
M
Bornhäuser
Department of Hematology, Clinical Oncology and Hemostasiology, University of Leipzig, Leipzig.
T
T
Lange
Medical Clinic 5, Hematology and Oncology, Klinikum Nuernberg, Nuernberg.
M
M
Wilhelm
Department of Hematology, Clinical Oncology and Hemostasiology, University of Leipzig, Leipzig.
D
D
Niederwieser
Department of Internal Medicine I, University Hospital Carl Gustav Carus, University of Dresden, Dresden.
G
G
Ehninger
Internal Medicine III, Department of Hematology, Oncology, Stem Cell Transplantation, Klinikum Chemnitz gGmbH, Chemnitz.
F
F
Fiedler
Internal Medicine III, Department of Hematology, Oncology, Stem Cell Transplantation, Klinikum Chemnitz gGmbH, Chemnitz m.haenel@skc.de.
M
M
Hänel
D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D003561:Cytarabine / Q000008:administration & dosage; D004333:Drug Administration Routes; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D005500:Follow-Up Studies; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008942:Mitoxantrone / Q000008:administration & dosage; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D009367:Neoplasm Staging; D011379:Prognosis; D011446:Prospective Studies; D016879:Salvage Therapy; D015996:Survival Rate; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives; D055815:Young Adult
D003561:Cytarabine; D016179:Granulocyte Colony-Stimulating Factor; D008942:Mitoxantrone; D014740:Vidarabine; C024352:fludarabine
acute myeloid leukemia; cytarabine; refractory; relapse; salvage chemotherapy