Correlation of minimal residual disease cell frequency with molecular genotype in patients with acute myeloid leukemia.
BACKGROUND
About 70-80 percent of patients with acute myeloid leukemia enter complete remission, but at least half of these patients who achieve remission go on to relapse. Improved treatment is likely to come from increasing the time to relapse, especially for younger patients. With the vastly increasing number of targeted therapies there is a strong need for short-term end-points to efficiently test such therapies for further pursuance. Minimal residual disease assessment may offer such an end-point since it is a strong independent prognostic factor. As proof of principle we examined this concept for FLT3-ITD status at diagnosis.


METHODS
We determined FLT3-ITD status in bone marrow samples from 196 patients with newly diagnosed acute myeloid leukemia. The frequencies of residual leukemic cells of these 196 patients were assessed in 267 follow-up bone marrow samples using immunophenotypic assessment of minimal residual disease.


RESULTS
The median frequency of residual leukemic cells after the first cycle of chemotherapy was 8.5-fold higher in patients with FLT3-ITD than in those with wild type FLT3. Such a difference translates into differences in survival, even if other potentially outcome-modulating mutations, such as NPM1, KIT, NRAS, KRAS, FLT3-exon 20 and PTPN11 are included in the analysis.


CONCLUSIONS
This study shows that it could be possible to study the efficacy of FLT3 inhibitors using the level of minimal residual disease as a short-term end-point.
Hess
Corine J
CJ
Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands.
Feller
Nicole
N
Denkers
Fedor
F
Kelder
Angèle
A
Merle
Pauline A
PA
Heinrich
Michael C
MC
Harlow
Amy
A
Berkhof
Johannes
J
Ossenkoppele
Gert J
GJ
Waisfisz
Quinten
Q
Schuurhuis
Gerrit J
GJ
D005091:Exons / Q000235:genetics; D005838:Genotype; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology*; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D018365:Neoplasm, Residual / Q000188:drug therapy / Q000453:epidemiology / Q000235:genetics / Q000473:pathology; D000090243:Nucleophosmin; D011994:Recombinant Proteins / Q000235:genetics; D015996:Survival Rate; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics
C000716967:NPM1 protein, human; D011994:Recombinant Proteins; D000090243:Nucleophosmin; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3