Contributions
Abstract: EP1104
Type: E-Poster Presentation
Session title: Myeloproliferative neoplasms - Clinical
Background
Oncogenic activating STAT5B N642H driver mutation, observed recurrently in aggressive T-cell malignancies, was recently reported as a clonal biomarker in association with myeloid neoplasms (MNs) with eosinophilia. This mutation provides potential therapeutic opportunities using small molecule inhibitors (under development) and tyrosine kinase inhibitors.
Aims
In this study, we sought to characterize the frequency, clinicopathologic and genomic features, and outcomes of all MNs with STAT5B N642H mutation at a single-institution.
Methods
All patients (pts) with a myeloid malignancy with STAT5B N624H mutation detected by using next-generation sequencing and an 81-gene myeloid panel were included (2017-2019). Pts with concurrent T-cell neoplasms or aberrant T/NK cells detected by flow cytometry immunophenotypic analysis were excluded. Bone marrow (BM) morphologic features were reviewed. Clinicopathological data were collected by chart review.
Results
Of 4551 pts who underwent baseline NGS profiling, we identified 14 (0.3%) pts with MNs associated with STAT5B N642H mutations. These pts included 8 men and 6 women with a median age of 76 years (26-87). Using the WHO classification criteria, the diagnoses included myelodysplastic/myeloproliferative neoplasm (MDS/MPN, n=5), MDS (n=4), acute myeloid leukemia (AML, n=3), CALR mutated MPN (n=1) and chronic eosinophilic leukemia (CEL, n=1). Peripheral blood (PB) or BM eosinophilia was noted in 8 (57%) pts: 5 (36%) with PB hypereosinophilia (defined >1500/µL), 3 (21%) with PB eosinophilia (500-1500/µL). Five pts (36%) showed increased eosinophils in BM. Patients with increased eosinophils were negative for rearrangements involving BCR/ABL1, PDGFRA, PDGFRB, and FGFR1 assessed by FISH. BM fibrosis (grade ≥ MF-2) was seen in 2 pts. Seven (50%) pts had normal diploid karyotypes; recurrent abnormalities included +8 and monosomy 7. The median variant allele frequency (VAF) of STAT5B mutation was 21% (range, 2-61). In 9 (64%) pts the mutation was dominant (defined as VAF >20%) and in 5 pts the mutation was sub-clonal. The median number of mutations per pt was 4 (range, 1-7). Frequent concurrent gene mutations included U2AF1 (n=7, 50%), ASXL1 (n=6, 42.9%) and TET2 (n=5, 35.7%). Eleven of 14 (79%) pts had a concurrent mutation in a splicing factor gene. Using the molecular grouping scheme by Cross et al. (PMID: 30573779), 13 (93%) pts were in group 3 (with additional mutations, not SF3B1), 1 in group 2 (with SF3B1 mutations). No cases belonged to group 1 (sole abnormality).
To compare molecular characteristics, we identified 9 pts with STAT5B N642H positive T-cell neoplasms (6 T-prolymphocytic leukemia, 2 T-lymphoblastic leukemia, 1 cytotoxic mature T-cell lymphoma) over the same time-period. Compared to MNs, T-cell malignancies showed a higher median STAT5B VAF [41% (3-72); p=0.25] and fewer concurrent mutations [median 3 (range, 1-4) mutations per pt.; p=0.001]. None showed splicing mutations.
Over a median of 20 months (range, 0-42), 7 (50%) pts died. Follow-up data were available for 11 pts. Six pts transformed to AML; all died except 1 pt with sub-clonal STAT5B mutation with concurrent NPM1 and FLT3 mutations. Four patients showed clearance of STAT5B mutation post therapy.
Conclusion
STAT5 N642H mutations are recurrent in MNs. Although eosinophilia is frequent, this is the first study of an unbiased pt cohort showing that a substantial proportion [6 (43%)] of pts lack eosinophilia. Further investigation of these cases is warranted due to the potential targetable nature of STAT5 N642H using small molecular inhibitors.
Keyword(s): Eosinophilia, Myeloid malignancies, Pathology, STAT5
Abstract: EP1104
Type: E-Poster Presentation
Session title: Myeloproliferative neoplasms - Clinical
Background
Oncogenic activating STAT5B N642H driver mutation, observed recurrently in aggressive T-cell malignancies, was recently reported as a clonal biomarker in association with myeloid neoplasms (MNs) with eosinophilia. This mutation provides potential therapeutic opportunities using small molecule inhibitors (under development) and tyrosine kinase inhibitors.
Aims
In this study, we sought to characterize the frequency, clinicopathologic and genomic features, and outcomes of all MNs with STAT5B N642H mutation at a single-institution.
Methods
All patients (pts) with a myeloid malignancy with STAT5B N624H mutation detected by using next-generation sequencing and an 81-gene myeloid panel were included (2017-2019). Pts with concurrent T-cell neoplasms or aberrant T/NK cells detected by flow cytometry immunophenotypic analysis were excluded. Bone marrow (BM) morphologic features were reviewed. Clinicopathological data were collected by chart review.
Results
Of 4551 pts who underwent baseline NGS profiling, we identified 14 (0.3%) pts with MNs associated with STAT5B N642H mutations. These pts included 8 men and 6 women with a median age of 76 years (26-87). Using the WHO classification criteria, the diagnoses included myelodysplastic/myeloproliferative neoplasm (MDS/MPN, n=5), MDS (n=4), acute myeloid leukemia (AML, n=3), CALR mutated MPN (n=1) and chronic eosinophilic leukemia (CEL, n=1). Peripheral blood (PB) or BM eosinophilia was noted in 8 (57%) pts: 5 (36%) with PB hypereosinophilia (defined >1500/µL), 3 (21%) with PB eosinophilia (500-1500/µL). Five pts (36%) showed increased eosinophils in BM. Patients with increased eosinophils were negative for rearrangements involving BCR/ABL1, PDGFRA, PDGFRB, and FGFR1 assessed by FISH. BM fibrosis (grade ≥ MF-2) was seen in 2 pts. Seven (50%) pts had normal diploid karyotypes; recurrent abnormalities included +8 and monosomy 7. The median variant allele frequency (VAF) of STAT5B mutation was 21% (range, 2-61). In 9 (64%) pts the mutation was dominant (defined as VAF >20%) and in 5 pts the mutation was sub-clonal. The median number of mutations per pt was 4 (range, 1-7). Frequent concurrent gene mutations included U2AF1 (n=7, 50%), ASXL1 (n=6, 42.9%) and TET2 (n=5, 35.7%). Eleven of 14 (79%) pts had a concurrent mutation in a splicing factor gene. Using the molecular grouping scheme by Cross et al. (PMID: 30573779), 13 (93%) pts were in group 3 (with additional mutations, not SF3B1), 1 in group 2 (with SF3B1 mutations). No cases belonged to group 1 (sole abnormality).
To compare molecular characteristics, we identified 9 pts with STAT5B N642H positive T-cell neoplasms (6 T-prolymphocytic leukemia, 2 T-lymphoblastic leukemia, 1 cytotoxic mature T-cell lymphoma) over the same time-period. Compared to MNs, T-cell malignancies showed a higher median STAT5B VAF [41% (3-72); p=0.25] and fewer concurrent mutations [median 3 (range, 1-4) mutations per pt.; p=0.001]. None showed splicing mutations.
Over a median of 20 months (range, 0-42), 7 (50%) pts died. Follow-up data were available for 11 pts. Six pts transformed to AML; all died except 1 pt with sub-clonal STAT5B mutation with concurrent NPM1 and FLT3 mutations. Four patients showed clearance of STAT5B mutation post therapy.
Conclusion
STAT5 N642H mutations are recurrent in MNs. Although eosinophilia is frequent, this is the first study of an unbiased pt cohort showing that a substantial proportion [6 (43%)] of pts lack eosinophilia. Further investigation of these cases is warranted due to the potential targetable nature of STAT5 N642H using small molecular inhibitors.
Keyword(s): Eosinophilia, Myeloid malignancies, Pathology, STAT5