Impact of FLT3 internal tandem duplication and NPM1 mutations in acute myeloid leukemia treated with allogeneic hematopoietic cell transplantation

Rutvij A Khanolkar; Rehan M Faridi; Megan Kinzel; Kareem Jamani; Mary L Savoie; Mona Shafey; Faisal M Khan; Jan Storek

doi:10.1016/j.jcyt.2021.10.006

Impact of FLT3 internal tandem duplication and NPM1 mutations in acute myeloid leukemia treated with allogeneic hematopoietic cell transplantation

Cytotherapy. 2022 Apr;24(4):413-420. doi: 10.1016/j.jcyt.2021.10.006. Epub 2021 Dec 2.

Authors

Rutvij A Khanolkar¹, Rehan M Faridi², Megan Kinzel³, Kareem Jamani⁴, Mary L Savoie⁴, Mona Shafey⁴, Faisal M Khan², Jan Storek⁴

Affiliations

¹ Cumming School of Medicine, University of Calgary, Calgary, Canada. Electronic address: rutvij.khanolkar@ucalgary.ca.
² Cumming School of Medicine, University of Calgary, Calgary, Canada; Alberta Precision Laboratories, Calgary, Canada.
³ Cumming School of Medicine, University of Calgary, Calgary, Canada.
⁴ Cumming School of Medicine, University of Calgary, Calgary, Canada; Alberta Health Services, Calgary, Canada.

PMID: 34863627
DOI: 10.1016/j.jcyt.2021.10.006

Abstract

Background aims: The internal tandem duplication of FLT3 (FLT3^ITD) and NPM1 mutations (NPM1^mut) are well-established prognostic factors in cytogenetically intermediate-risk acute myeloid leukemia (AML) when treated with chemotherapy alone. However, their prognostic value in the setting of allogeneic hematopoietic cell transplantation (HCT) is controversial.

Methods: FLT3 and NPM1 mutational status was determined at diagnosis using single-gene polymerase chain reaction or next-generation sequencing in 247 adult patients with cytogenetically intermediate-risk AML who underwent myeloablative HCT. Multivariate Fine-Gray and Cox regression was used to analyze the cumulative incidence of relapse (CIR), relapse-free survival (RFS) and overall survival (OS).

Results: FLT3^ITD and NPM1^mut were present in 74 of 247 (30%) and 79 of 247 (32%) patients, respectively. There was no significant difference between patients without a FLT3^ITD or NPM1^mut (FLT3^NONITD/NPM1^WT) and patients with a FLT3^ITD mutation alone (FLT3^ITD/NPM1^WT) with regard to CIR (P = 0.60), RFS (P = 0.91) or OS (P = 0.66). Similarly, there was no significant difference between FLT3^NONITD/NPM1^WT and FLT3^NONITD/NPM1^mut patients with regard to CIR (P = 0.70), RFS (P = 0.75) or OS (P = 0.95). The presence of a concurrent mutation in NPM1 did not appear to modify the impact of having a FLT3^ITD mutation.

Conclusions: In contrast to chemotherapy-only treatment, FLT3 and NPM1 mutational status does not appear to predict outcomes in patients with cytogenetically intermediate-risk AML following HCT. These results suggest that HCT may ameliorate the poor prognostic effect of FLT3^ITD mutation and that HCT should be considered over chemotherapy-only treatment in FLT3^ITD-mutated AML.

Keywords: FLT3; NPM1; acute myeloid leukemia (AML); allogeneic hematopoietic cell transplantation (HCT); disease risk; relapse.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Hematopoietic Stem Cell Transplantation* / methods
Humans
Leukemia, Myeloid, Acute* / genetics
Leukemia, Myeloid, Acute* / therapy
Mutation
Nuclear Proteins / genetics
Nucleophosmin*
Recurrence
fms-Like Tyrosine Kinase 3 / genetics
fms-Like Tyrosine Kinase 3 / therapeutic use

Substances

Nuclear Proteins
Nucleophosmin
FLT3 protein, human
fms-Like Tyrosine Kinase 3