Newly Acquired Molecular Mutations and SNP-A Lesions Alters the Natural History of Trisomy 8 Myeloid Neoplasms

Abstract 312

Prognosis in myelodysplastic syndromes (MDS) is heavily influenced by cytogenetics. Trisomy 8 (+8) is reported in 15–20% of MDS patients (pts) and is one of the most commonly identified karyotypes in this disease. Sole +8 is an intermediate-risk karyotype in MDS by the International Prognostic Scoring System (IPSS). However, pts with +8 myeloid malignancies exhibit wide clinical heterogeneity. In chronic myelomonocytic leukemia (CMML), +8 is considered high-risk, while in MDS functional data suggests an “immunopathologic” cause that is responsive to immunosuppressive agents and confers a good prognosis. Single nucleotide polymorphism array (SNP-A) and molecular technologies (next generation sequencing) have led to further refinement of prognosis in MDS, and subsequent discovery of molecular mutations with distinct effects on outcomes. We hypothesized that the differential outcomes noted in +8 MDS are primarily influenced by both clinicomorphologic features and the acquisition of new cytogenetic (isolated, +1, ≥2) and molecular defects. To further characterize the clinical and molecular behavior of +8 myeloid neoplasms, we analyzed 68 pts seen at the Cleveland Clinic with a +8 clone. Hematologic, bone marrow (BM), cytogenetic (metaphase cytogenetic [MC]/SNP-A) and survival data were collected. Survival comparisons were made by Kaplan-Meier analyses. Cox-proportional hazard ratio was used to determine factors predictive of outcomes. Response was evaluated per International Working Group 2006 criteria. Most (69%) pts were male; median age 69 years (38–89), and median follow-up 15 months. 69% (47/68) had MDS, 10% (7/68) MDS/MPN, 3% (2/68) MPN and 18% (12/68) AML. 41% of pts had an isolated +8 abnormality (+8 (i)), 16% had one additional abnormality (+8plus1), and 43% had ≥2 additional abnormalities defined as +8complex. By IPSS, Int-1=34%, Int-2=25%, high=42%. SNP-A data were available in 51% of the cases and detected new lesions in 60% of them (gains[46%], losses[43%], UPD[23%]). Clinically, pts with +8complex had higher median peripheral blood blasts (PB) compared to +8plus1 and +8(i) (3.5 vs 0 vs 0%,p=.04). By treatment, pts received high intensity (BMT±high dose chemo=35%), low intensity (hypomethylating agents [HMA]± lenalidomide=37%) or supportive therapies=28%). Overall response rate was 47%, with 14% CR. By cytogenetic grouping, +8complex had lower response rates compared to +8 with additional karyotype (30 vs 60 vs 52%; p=.06). Median overall survival (OS) was 15 months, and median event free survival (EFS) was 8 months, with worse OS noted in +8 complex compared to +8 plus1 and +8(i) (OS=11 vs 22 vs 29 months, p=.02; EFS=5 vs 10 vs 12 months; p=.04). To investigate the biologic rationale of these observations, we performing direct sequencing for poor prognostic genes in myeloid malignancies, such as ASXL1, IDH1/2, EZH2, K/NRAS, CBL and TP53 and for predictors of good outcomes/response like SF3B1/TET2. Molecular mutations were identified in 9/24 (38%) pts, with mutational frequencies within +8(i) (12 pts) of TET2 (42%), ASXL1 (42%), K-/NRAS (17%), SF3B1 (17%), and TP53 (0%). None of these mutations were detected in the +8plus1 or +8complex cohorts except for TP53 in one +8complex pt. No IDH1/2/EZH2/CBL mutations were found in the entire +8 cohort. Interestingly, mutations in TET2 conferred a better OS (88 vs 12 mos; p=.01). In +8 myeloid malignancies, ASXL1 mutations did not impact OS. We are currently performing whole exome sequencing and other immunogenetic studies in +8 pts to help identify factors that contribute to these group outcomes. To further define factors predictive of worse outcomes in +8 pts, univariate and multivariate analyses were performed and a predictive model of OS was designed. Using a simple scoring system, one point each was assigned to LDH ≥240, platelets <75, complex +8, PB blasts >5%, and 2 points to an ANC <4.5. Three prognostic groups were identified (favorable [score:0 or 1], median OS=33 months; intermediate [score:2], median OS=16 months; and unfavorable [score:>2], median OS=4.6 months; p<.0001). After incorporating SNP-A into the model, new SNP-A lesions were found to have a significant prognostic impact (p<.04). In summary, the clinical outcomes of +8 karyotype are influenced by additional karyotypic abnormalities detected by SNP-A/MC and by good/poor prognostic/predictive molecular mutations.