Abstract
Abstract 2520
Age, cytogenetics, FLT3 and NPM1 mutations are the most significant prognostic factors (PFs) for adult AML treated with standard regimens, but the predictive significance of FLT3 and NPM1 with contemporary treatments is unknown. We examined the clinical significance of NPM1 and FLT3 mutations in adult de novo AML pts enrolled on SWOG study S0106.
S0106 was a randomized phase III clinical trial for pts of age 18–60 with de novo non-M3 AML, evaluating the effects of adding Gemtuzumab Ozogamicin (GO) to standard induction therapy (Cytosine Arabinoside and Daunomycin, AD), and of post-consolidation GO vs. no additional therapy (ASH, 2009, Abstract 790). Samples from 198 of the 600 eligible pts were evaluated. Analyses for nucleotide insertions in exon 12 of the NPM1 gene and internal tandem duplications (ITD) within exons 14–15 of FLT3 were performed using fragment analyses in diagnostic bone marrow (BM, N=190) and peripheral blood (PB, N=8) samples. Mutant/wild-type (WT) allelic ratios (AR) were computed for all mutations. Effects of mutations and other PFs on complete response (CR), resistant disease (RD), overall survival (OS) and relapse-free survival (RFS) were analyzed by logistic and Cox regression. P-values are 2-sided.
Patient characteristics and outcomes are shown in Table 1. In univariate analyses, NPM1-Mut pts had significantly higher CR (81% vs. 58%, P=.0018) and lower RD (13% vs. 28%, P=.028) rates, better OS (64% vs. 47%, P=.045) and RFS (54% vs. 41%, P=.50). FLT3-ITD was not associated with CR or RD, but was associated with poorer OS (hazard ratio [HR] 2.28, P=.0011) and RFS (HR 2.74, P=.0009). FLT3-ITD length (range 18–366, median 46), FLT3 AR (range 0.18–8.2, median 0.98), and NPM1 AR (range 0.2–1.0, median 0.8) were not associated with CR, RD, or OS, but RFS tended to be lower with higher ITD length (P=.076).
Pt Characteristics and Outcomes by FLT3 and NPM1 Status
| Good Risk | Intermed. Risk | Poor Risk | ||||
|---|---|---|---|---|---|---|
| FLT3 WT/NPM1 Mut (N=36) | FLT3 WT/NPM1 WT (N=126) | FLT3 ITD/NPM1 WT (N=19) | FLT3 ITD/NPM1 Mut (N=17) | |||
| Pts (%) | P 1 | |||||
| Cyto. | Fav. | 0 (0%) | 30 (29%) | 0 (0%) | 0 (0%) | <0.0001 |
| Risk | Inter. | 28 (97%) | 34 (33%) | 10 (63%) | 15 (94%) | |
| Group | Unfav. | 1 (3%) | 38 (37%) | 6 (38%) | 1 (6%) | |
| Indeterm. | 1 (−) | 7 (−) | 1 (−) | 1 (−) | ||
| Not Avail. | 6 (−) | 17 (−) | 2 (−) | 0 (−) | ||
| Cyto. | Yes | 25 (89%) | 28 (27%) | 6 (35%) | 15 (88%) | <0.0001 |
| Normal | No | 3 (11%) | 75 (73%) | 11 (65%) | 2 (12%) | |
| Unk. | 8 (−) | 23 (−) | 2 (−) | 0 (−) | ||
| Median (Min-Max) | P 1 | |||||
| BM blasts (%) | 60 (8–95) | 63 (7–100) | 66 (30–94) | 85 (3–100) | 0.087 | |
| WBC (109/L) | 19.3 (1.1–109) | 6.3 (0.5–244) | 26.0 (0.7–126) | 43.5 (7.9–187) | <0.0001 | |
| PB blasts (%) | 20 (0–77) | 23 (0–98) | 59 (2–94) | 73 (26–94) | <0.0001 | |
| % (95% CI) | P 2 | |||||
| CR | 83 (67–94) | 59 (50–67) | 53 (29–76) | 76 (50–93) | 0.086 | |
| RD | 11 (3–26) | 25 (18–34) | 42 (20–67) | 18 (4–43) | 0.31 | |
| OS at 3 yrs | 82 (68–95) | 49 (39–59) | 31 (9–54) | 24 (1–47) | 0.0044 | |
| RFS at 3 yrs | 69 (52–86) | 43 (32–55) | 24 (0–51) | 17 (0–39) | 0.0003 | |
| Good Risk | Intermed. Risk | Poor Risk | ||||
|---|---|---|---|---|---|---|
| FLT3 WT/NPM1 Mut (N=36) | FLT3 WT/NPM1 WT (N=126) | FLT3 ITD/NPM1 WT (N=19) | FLT3 ITD/NPM1 Mut (N=17) | |||
| Pts (%) | P 1 | |||||
| Cyto. | Fav. | 0 (0%) | 30 (29%) | 0 (0%) | 0 (0%) | <0.0001 |
| Risk | Inter. | 28 (97%) | 34 (33%) | 10 (63%) | 15 (94%) | |
| Group | Unfav. | 1 (3%) | 38 (37%) | 6 (38%) | 1 (6%) | |
| Indeterm. | 1 (−) | 7 (−) | 1 (−) | 1 (−) | ||
| Not Avail. | 6 (−) | 17 (−) | 2 (−) | 0 (−) | ||
| Cyto. | Yes | 25 (89%) | 28 (27%) | 6 (35%) | 15 (88%) | <0.0001 |
| Normal | No | 3 (11%) | 75 (73%) | 11 (65%) | 2 (12%) | |
| Unk. | 8 (−) | 23 (−) | 2 (−) | 0 (−) | ||
| Median (Min-Max) | P 1 | |||||
| BM blasts (%) | 60 (8–95) | 63 (7–100) | 66 (30–94) | 85 (3–100) | 0.087 | |
| WBC (109/L) | 19.3 (1.1–109) | 6.3 (0.5–244) | 26.0 (0.7–126) | 43.5 (7.9–187) | <0.0001 | |
| PB blasts (%) | 20 (0–77) | 23 (0–98) | 59 (2–94) | 73 (26–94) | <0.0001 | |
| % (95% CI) | P 2 | |||||
| CR | 83 (67–94) | 59 (50–67) | 53 (29–76) | 76 (50–93) | 0.086 | |
| RD | 11 (3–26) | 25 (18–34) | 42 (20–67) | 18 (4–43) | 0.31 | |
| OS at 3 yrs | 82 (68–95) | 49 (39–59) | 31 (9–54) | 24 (1–47) | 0.0044 | |
| RFS at 3 yrs | 69 (52–86) | 43 (32–55) | 24 (0–51) | 17 (0–39) | 0.0003 | |
Pearson chi square or Wilcoxon test of variation among 4 mutation groups
Variation among 3 risk groups by multivariate logistic or Cox regression.
In multivariate analyses with other PFs, neither NPM1 nor FLT3 was associated with CR or RD rates, however the combined effects of FLT3 and NPM1 identified 3 mutation risk groups for OS (P=.0044, Fig 1A) and RFS (P=.0003, Fig 1B), since NPM1 did not significantly affect outcomes within the FLT3-ITD pts. These risk groups are FLT3-WT/NPM1-Mut (Good Risk: 3-yr OS 82%, RFS 69%), FLT3-WT/NPM1-WT (Intermediate Risk: OS 49%, RFS 43%), and FLT3-ITD (Poor Risk: OS 29%, RFS 14%). The impact of adding GO to induction therapy was examined within each risk group. In each risk group, CR rates were higher in the AD+GO arm, though not significantly so. Likewise, the RD rates were lower in the AD+GO arm, but this difference was significant only in the largest group: Intermediate Risk, FLT3-WT/NPM1-WT, 17% vs. 34% (P=.026). Treatment arm did not significantly affect OS and RFS in any mutation risk group.
Kaplan-Meier estimates of OS in 198 pts (A) and RFS in 94 pts with CR (B). Tick marks indicate censored data.
Kaplan-Meier estimates of OS in 198 pts (A) and RFS in 94 pts with CR (B). Tick marks indicate censored data.
This study confirmed prognostic effects of FLT3 and NPM1 mutations in de novo AML pts treated with AD or AD+GO. Analyses of the joint impact of NPM1 and FLT3 mutations do not rule out the possibility that they act independently. With the small numbers of pts in the “good” and “poor” risk groups, there was no clear evidence that mutation status predicts clinical benefit from adding GO to therapy. We are evaluating additional samples and will update these results as data matures.
No relevant conflicts of interest to declare.
