Abstract
Abstract 2510
KIT receptor tyrosine kinase mutations are recurrent genetic alteration found in acute myeloid leukemia (AML) with higher prevalence in those with core binding factor (CBF) AML. Different prognostic significance of these mutations has been found in pediatric and adult AML studies. However, prevalence and prognostic impact of KIT mutations in elderly patients with AML has not been established. In this study, we evaluated the prevalence of KIT mutation and its correlation with cytogenetic, molecular subtypes and clinical outcome in elderly AML patients.
Diagnostic specimens from for 207 patients with AML registered on SWOG trials S-9031 and S-9333 were available for KIT mutation analysis. Both of these clinical protocols enrolled AML patients > 55 years. The samples were analyzed for the presence of KIT mutations via direct sequencing of exons 8 and 17.
In the cohort of 207 patients tested, the median age, WBC, and blast count at diagnosis were 68 years (range, 56–88 years), 29,6 × 109/L (range, 7–289 × 109/L) and 67% (0–99%), respectively. Favorable, intermediate and unfavorable cytogenetics were present in 8%, 57% and 26% of the patients, respectively. Nine percent of the patients had cytogenetics abnormalities of unknown significance. Normal cytogenetics was present in 48% of the patients. Fifty-three patients (26%) harbored mutations for FLT3-ITD, 37 (19%) for DNMT3A, 52 (31%) for NPM1 and 50 (24%) for IDH1/2. Only 3 patients were positive for CEBPA mutation. Of the 207 patient specimens tested, KIT exon 17 mutations were detected in 4 patients (2%). Exon 8 mutations were not identified. The characteristics of the 4 patients with KIT mutations are described in the table. Of the 4 patients who harbored the KIT mutation, 2 had intermediate, 1 had unfavorable risk cytogenetics and 1 patient did not have available cytogenetic data. None of the patients with CBF had KIT mutations. In terms of other molecular markers, all 4 patients were wild-type for NPM1, CEBPA, DNMT3A, IDH1/2 and FLT3-ITD. The very small number of KIT mutations in this group of patient precluded correlation between KIT mutations and clinical outcome.
The prognostic impact of KIT mutations has been shown to vary according to cytogenetics subgroups. Most studies report a negative prognostic impact of these mutations in patients with CBF AML. The prognostic implications of KIT mutations also seem to vary among different age groups, with pediatric studies indicating they have no prognostic significance and adult studies indicating a negative prognostic impact. To date, there is no large study reporting on the incidence and prognostic impact of KIT mutations in elderly patients with AML. The very low incidence of KIT mutations in our study highlights the age-specific characteristics of AML and may correlate with lower prevalence of CBF translocations in older AML. Further studies investigating the relationship among different somatic mutations in elderly AML patients may help to clarify the pathogenetic mechanism of certain AML subtypes in this patient population.
Patient characteristics of the 4 patients with KIT mutations
| Patient . | 1 . | 2 . | 3 . | 4 . |
|---|---|---|---|---|
| KIT mutations | Exon 17 (D816V) | Exon 17 (D816V) | Exon 17 (D816Y) | Exon 17 (D816V) |
| Sex | F | F | M | M |
| Age at diagnosis (years) | 56 | 78 | 65 | 72 |
| WBC x109/L | 68.3 | 215.6 | 29.9 | 12.8 |
| BM blast (%) | 72 | 40 | 51 | 30 |
| Cytogenetics | 46,XX,t(6;11) (q27;q23)t(6;14) (q11;q11)[20]/ 46,XX,t(6;14) (q11;q11)[1] | 46,XX[20] | No data | 46,XY[19]/47,XY,+2[1] |
| NPM1 | WT | WT | WT | WT |
| FLT3-ITD | WT | WT | WT | WT |
| CEBPA | WT | WT | WT | WT |
| DNMT3A | WT | WT | WT | WT |
| IDH1/2 | WT | WT | WT | WT |
| Response to induction chemotherapy | CR | RD | CR | RD |
| Relapse-free survival (days) | 270 | – | 386 | – |
| Overall survival (days) | 646 | 264 | 978 | 575 |
| Patient . | 1 . | 2 . | 3 . | 4 . |
|---|---|---|---|---|
| KIT mutations | Exon 17 (D816V) | Exon 17 (D816V) | Exon 17 (D816Y) | Exon 17 (D816V) |
| Sex | F | F | M | M |
| Age at diagnosis (years) | 56 | 78 | 65 | 72 |
| WBC x109/L | 68.3 | 215.6 | 29.9 | 12.8 |
| BM blast (%) | 72 | 40 | 51 | 30 |
| Cytogenetics | 46,XX,t(6;11) (q27;q23)t(6;14) (q11;q11)[20]/ 46,XX,t(6;14) (q11;q11)[1] | 46,XX[20] | No data | 46,XY[19]/47,XY,+2[1] |
| NPM1 | WT | WT | WT | WT |
| FLT3-ITD | WT | WT | WT | WT |
| CEBPA | WT | WT | WT | WT |
| DNMT3A | WT | WT | WT | WT |
| IDH1/2 | WT | WT | WT | WT |
| Response to induction chemotherapy | CR | RD | CR | RD |
| Relapse-free survival (days) | 270 | – | 386 | – |
| Overall survival (days) | 646 | 264 | 978 | 575 |
Abbreviations: WBC, white blood count; BM, bone marrow; CR, complete remission; RD, refractory disease; WT, wild-type; F, female; M, male.
No relevant conflicts of interest to declare.
Author notes
Asterisk with author names denotes non-ASH members.
