High prognostic impact of flow cytometric minimal residual disease detection in acute myeloid leukemia: data from the HOVON/SAKK AML 42A study.
OBJECTIVE
Half the patients with acute myeloid leukemia (AML) who achieve complete remission (CR), ultimately relapse. Residual treatment-surviving leukemia is considered responsible for the outgrowth of AML. In many retrospective studies, detection of minimal residual disease (MRD) has been shown to enable identification of these poor-outcome patients by showing its independent prognostic impact. Most studies focus on molecular markers or analyze data in retrospect. This study establishes the value of immunophenotypically assessed MRD in the context of a multicenter clinical trial in adult AML with sample collection and analysis performed in a few specialized centers.


METHODS
In adults (younger than age 60 years) with AML enrolled onto the Dutch-Belgian Hemato-Oncology Cooperative Group/Swiss Group for Clinical Cancer Research Acute Myeloid Leukemia 42A study, MRD was evaluated in bone marrow samples in CR (164 after induction cycle 1, 183 after cycle 2, 124 after consolidation therapy).


RESULTS
After all courses of therapy, low MRD values distinguished patients with relatively favorable outcome from those with high relapse rate and adverse relapse-free and overall survival. In the whole patient group and in the subgroup with intermediate-risk cytogenetics, MRD was an independent prognostic factor. Multivariate analysis after cycle 2, when decisions about consolidation treatment have to be made, confirmed that high MRD values (> 0.1% of WBC) were associated with a higher risk of relapse after adjustment for consolidation treatment time-dependent covariate risk score and early or later CR.


CONCLUSIONS
In future treatment studies, risk stratification should be based not only on risk estimation assessed at diagnosis but also on MRD as a therapy-dependent prognostic factor.
Monique Terwijn, Angèle Kelder, Peter C. Huijgens, Angelika M. Dräger, Yvonne J.M. Oussoren, Willemijn J. Scholten, Alexander N. Snel, Gert J. Ossenkoppele, and Gerrit J. Schuurhuis, VU University Medical Centre; Bart J. Biemond, Academic Medical Centre, Amsterdam; Wim L.J. van Putten, Vincent H.J. van der Velden, Georgine E. de Greef, Peter J.M. Valk, Mojca Jongen-Lavrecic, and Bob Löwenberg, Erasmus University Medical Centre; Rik A. Brooimans, Jan W. Gratama, Erasmus University Medical Centre/Daniel den Hoed Cancer Centre, Rotterdam; Frank W.M.B. Preijers, Radboud University Nijmegen Medical Center, Nijmegen; Michel van Gelder, University Medical Centre, Maastricht; Pierre Wijermans, Haga Hospital, The Hague; Marie-Cecile Legdeur and Jennita Slomp, Medisch Spectrum Twente, Enschede; Jurgen Kuball, University Medical Center Utrecht; Okke de Weerdt, St. Antonius Hospital, Nieuwegein; Leo F. Verdonck, Isala Clinics, Zwolle, the Netherlands; Thomas Pabst, Bern University Hospital, Bern; Urs Schanz, University Hospital, Zürich; Jakob R. Passweg, Basel University Hospital, Basel; Mario Bargetzi, Kantonspital, Aarau; Yves Chalandon, University Hospital of Geneva, Geneva; Urs Hess, Kantonsspital, St. Gallen, Switzerland; Johan Maertens, University Hospital Gasthuisberg; Nancy Boeckx, University Hospitals Leuven and Katholieke Universiteit Leuven, Leuven; Carlos Graux, Cliniques Universitaires-Université Catholique de Louvain, Mont-Godinne, Yvoir; and Marie-Christiane Vekemans, St. Luc Hospital, Brussels, Belgium.
Monique
M
Terwijn
Wim L J
WL
van Putten
Angèle
A
Kelder
Vincent H J
VH
van der Velden
Rik A
RA
Brooimans
Thomas
T
Pabst
Johan
J
Maertens
Nancy
N
Boeckx
Georgine E
GE
de Greef
Peter J M
PJ
Valk
Frank W M B
FW
Preijers
Peter C
PC
Huijgens
Angelika M
AM
Dräger
Urs
U
Schanz
Mojca
M
Jongen-Lavrecic
Bart J
BJ
Biemond
Jakob R
JR
Passweg
Michel
M
van Gelder
Pierre
P
Wijermans
Carlos
C
Graux
Mario
M
Bargetzi
Marie-Cecile
MC
Legdeur
Jurgen
J
Kuball
Okke
O
de Weerdt
Yves
Y
Chalandon
Urs
U
Hess
Leo F
LF
Verdonck
Jan W
JW
Gratama
Yvonne J M
YJ
Oussoren
Willemijn J
WJ
Scholten
Jennita
J
Slomp
Alexander N
AN
Snel
Marie-Christiane
MC
Vekemans
Bob
B
Löwenberg
Gert J
GJ
Ossenkoppele
Gerrit J
GJ
Schuurhuis
D000293:Adolescent; D000328:Adult; D060830:Consolidation Chemotherapy / Q000379:methods; D005260:Female; D005434:Flow Cytometry / Q000379:methods*; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage; D006801:Humans; D060828:Induction Chemotherapy / Q000379:methods; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis* / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis; D018365:Neoplasm, Residual / Q000175:diagnosis*; D011379:Prognosis; D016016:Proportional Hazards Models; D012074:Remission Induction; D055815:Young Adult
D016179:Granulocyte Colony-Stimulating Factor