Predictive value of pretransplantation molecular minimal residual disease assessment by WT1 gene expression in FLT3-positive acute myeloid leukemia.
The FMS-like tyrosine kinase 3 (FLT3) mutation in acute myeloid leukemia (AML) is a negative prognostic factor and, in these cases, allogeneic stem cell transplantation (allo-SCT) can represent an important therapeutic option, especially if performed in complete remission (CR). However, it is increasingly clear that not all cytological CRs (cCRs) are the same and that minimal residual disease (MRD) before allo-SCT could have an impact on AML outcome. Unfortunately, FLT3, due its instability of expression, is still not considered a good molecular MRD marker. We analyzed the outcome of allo-SCT in a population of FLT3-positive AML patients according to molecular MRD at the pretransplantation workup, assessed by the quantitative expression evaluation of the panleukemic marker Wilms' tumor (WT1) gene. Sixty-two consecutive AML FLT3-positive patients received allo-SCT between 2005 and 2016 in our center. The median age at transplantation was 55 years. The quantitative analysis of the WT1 gene expression (bone marrow samples) was available in 54 out of 62 (87%) cases, both at diagnosis (100% overexpressing WT1 with a mean of 9747 ± 8064 copies) and before allo-SCT (33 WT1-negative and 21 WT1-positive cases at the pretransplantation workup). Of these cases, 33/54 (61%) were both in cCR and molecular remission (WT1-negative) at the time of transplantation, 13/54 (24%) were in cCR but not in molecular remission (WT1-positive), and 8/54 (15%) showed a cytological evidence of disease (relapsed or refractory). Both post-allo-SCT overall survival (OS) and disease-free survival (DFS) were significantly better in patients who were WT1-negative (WT1 <250 copies) at the time of transplantation compared with those who were WT1-positive (WT1 >250 copies), with a median OS and DFS not reached in the WT1-negative group and 10.2 and 5.5 months, respectively, in the WT1-positive group (OS log-rank p = 0.0005; hazard ratio [HR] = 3.7, 95% confidence interval [95% CI] = 1.5-9; DFS log-rank p = 0.0001; HR = 4.38, 95% CI = 1.9-10). Patients with cCR who were WT1-positive had the same negative outcome as those with a cytological evidence of disease. The relapse rate after allo-SCT was 9% (3/33) in pre-allo-SCT WT1-negative cases and 54% (7/13) in WT1-positive cases (p = 0.002). At multivariate analysis, WT1 negativity before allo-SCT and grade <2 acute graft versus host disease were the only independent prognostic factors for improved OS and DFS. These data show that pre-allo-SCT molecular MRD evaluation through WT1 expression is a powerful predictor of posttransplantation outcomes (OS, DFS, relapse rate). Patients with both cCR and a WT1-negative marker before allo-SCT have a very good outcome with very low relapse rate; conversely, patients with positive molecular MRD and refractory/relapsed patients have a negative outcome. The WT1 MRD stratification in FLT3-positive AML is a valuable tool with which to identify patients who are at high risk of relapse and that could be considered from post-allo-SCT prophylaxis with FLT3 inhibitors or other strategies (donor lymphocyte infusion, tapering of immunosuppression, azacitidine).
Division of Hematology and Stem Cell Transplantation, Azienda Sanitaria Universitaria Integrata di Udine, University of Udine, Udine UD, Italy. Electronic address: anna.candoni@asuiud.sanita.fvg.it.
Anna
A
Candoni
Division of Hematology and Stem Cell Transplantation, Azienda Sanitaria Universitaria Integrata di Udine, University of Udine, Udine UD, Italy.
Federico
F
De Marchi
Division of Hematology and Stem Cell Transplantation, Azienda Sanitaria Universitaria Integrata di Udine, University of Udine, Udine UD, Italy.
Francesca
F
Zanini
Division of Hematology and Stem Cell Transplantation, Azienda Sanitaria Universitaria Integrata di Udine, University of Udine, Udine UD, Italy.
Maria Elena
ME
Zannier
Division of Hematology and Stem Cell Transplantation, Azienda Sanitaria Universitaria Integrata di Udine, University of Udine, Udine UD, Italy.
Erica
E
Simeone
Division of Hematology and Stem Cell Transplantation, Azienda Sanitaria Universitaria Integrata di Udine, University of Udine, Udine UD, Italy.
Eleonora
E
Toffoletti
Division of Hematology and Stem Cell Transplantation, Azienda Sanitaria Universitaria Integrata di Udine, University of Udine, Udine UD, Italy.
Alexsia
A
Chiarvesio
Division of Hematology and Stem Cell Transplantation, Azienda Sanitaria Universitaria Integrata di Udine, University of Udine, Udine UD, Italy.
Michela
M
Cerno
Division of Hematology and Stem Cell Transplantation, Azienda Sanitaria Universitaria Integrata di Udine, University of Udine, Udine UD, Italy.
Carla
C
Filì
Division of Hematology and Stem Cell Transplantation, Azienda Sanitaria Universitaria Integrata di Udine, University of Udine, Udine UD, Italy.
Francesca
F
Patriarca
Division of Hematology and Stem Cell Transplantation, Azienda Sanitaria Universitaria Integrata di Udine, University of Udine, Udine UD, Italy.
Renato
R
Fanin
D000328:Adult; D064591:Allografts; D014408:Biomarkers, Tumor / Q000096:biosynthesis*; D018572:Disease-Free Survival; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism / Q000401:mortality / Q000473:pathology / Q000628:therapy; D008297:Male; D008875:Middle Aged; D018365:Neoplasm, Residual; D011237:Predictive Value of Tests; D057234:Preoperative Period; D012074:Remission Induction; D033581:Stem Cell Transplantation; D015996:Survival Rate; D025721:WT1 Proteins / Q000096:biosynthesis*; D051941:fms-Like Tyrosine Kinase 3 / Q000096:biosynthesis*
D014408:Biomarkers, Tumor; D025721:WT1 Proteins; C583751:WT1 protein, human; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3