Program: Oral and Poster Abstracts
Session: 636. Myelodysplastic Syndromes – Basic and Translational Studies: Poster II
While neither clinical parameters nor mutations had a significant impact on response rate, both karyotype and mutational profile were strongly associated with survival from the start of treatment, see Table 1 and Figure 1-2. IPSS high-risk cytogenetics was negatively associated with survival (median 20 vs 10 months; p<0.001), whereas mutations in histone modulators (ASXL1, EZH2, MLL) were associated with prolonged survival (22 vs 12 months, p=0.001). This positive association was present in both cohorts and remained highly significant in the multivariate cox model. Importantly, patients with mutations in histone modulators lacking high-risk cytogenetics showed a survival of 29 months (response rate 73%) compared to 10 months (response rate 49%) in patients with the opposite pattern, see Figure 3. While TP53 was negatively associated with survival in the univariate analysis, neither RUNX1-mutations nor the number of mutations, previously reported as negative prognostic markers, appeared to influence survival in this cohort. In contrast, disease duration and cellularity showed a weak negative correlation with survival. We propose a model combining histone modulator mutational screening with cytogenetics in the clinical decision-making process for higher-risk MDS eligible for treatment with Azacitidine.
Tables
Estimated median survival (months) |
Univariate p-value |
Cox regression p-value |
Hazard ratio (95% CI) |
|
Response rate: CR / mCR vs PR/HI vs SD/PD |
20 vs 20 vs 10 |
<0.001 |
|
|
IPSS cytogenetic risk group: Favorable vs Int vs Adverse |
20 vs 20 vs 10 |
<0.001 |
<0.001* |
3.00 (1.9-4.7) |
Disease duration ≥ 4 months: Yes vs No |
14 vs 17 |
0.44 |
0.05** |
1.01 (1.00-1.02) |
Marrow blasts ≥ 11%: Yes vs No |
14 vs 14 |
0.7 |
|
|
Cellularity ≥ 70%: Yes vs No |
14 vs 20 |
0.2 |
0.02 |
1.013 (1.002-1.023)** |
ANC ≥ 1.3: Yes vs No |
14 vs 17 |
0.32 |
|
|
Platelets ≥ 60: Yes vs No |
17 vs 12 |
0.07 |
|
|
Transfusion dependent: Yes vs No |
13 vs 17 |
0.43 |
|
|
Therapy related: Yes vs No |
17 vs 14 |
0.44 |
|
|
Number of mutations: 0 vs 1 vs ≥ 2 |
17 vs 12 vs 17 |
0.64 |
|
|
Epigenetic mutation: Yes vs No |
19 vs 12 |
0.03 |
|
|
DNA methylation mutation: Yes vs No |
14 vs 14 |
0.64 |
|
|
Histone modulator mutation: Yes vs No |
22 vs 12 |
0.001 |
0.007 |
0.499 (0.3-0.83) |
Splicing factor mutation: Yes vs No |
13 vs 17 |
0.31 |
|
|
ASXL1 mutation: Yes vs No |
29 vs 12 |
0.03 |
|
|
TET2 mutation: Yes vs No |
13 vs 16 |
0.45 |
|
|
EZH2 mutation: Yes vs No |
20 vs 14 |
0.37 |
|
|
SF3B1 mutation: Yes vs No |
13 vs 16 |
0.35 |
|
|
RUNX1 mutation: Yes vs No |
17 vs 14 |
0.76 |
|
|
SRSF2 mutation: Yes vs No |
20 vs 14 |
0.5 |
|
|
TP53 mutation: Yes vs No |
9 vs 17 |
<0.001 |
|
|
Table 1: Variables associated with survival. Univariate analyses used the log-rank test. The cox model included all listed variables except response rate in a multivariate analyses. *Comparing adverse cytogenetics vs the other groups. ** Disease duration, marrow blasts, cellularity, ANC and TPK were analyzed as a continuous variable in the cox model
Figure 1: Kaplan-Meier estimated survival stratified for response and pre-treatment parameters
Figure 2: Forest plot indicating hazard ratio including confidence interval for all pre-treatment variables. The hazard ratios were retrieved using cox univariate regression models for each variable analyzed separately.
Figure 3 : Kaplan-Meier estimated survival stratified for the two dominant predictors in the cox regression model: Adverse cytogenetics and histone modulator mutations
Disclosures: McLornan: Novartis: Research Funding , Speakers Bureau . Jädersten: Celgene: Other: speakers fee . Kulasekararaj: Alexion: Consultancy . Mufti: Celgene: Consultancy , Other: Speakers fee . Hellström-Lindberg: Celgene Corporation: Research Funding .
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