Outcomes of Myelodysplastic Syndromes (MDS) Patients with Chromosome 17 Abnormalities: A Report on Behalf of the MDS Clinical Research Consortium (MDSCRC)

Introduction

Chromosome (ch) 17 cytogenetic abnormalities (CA) are reported associated with poor outcomes in MDS patients. The Revised International Prognostic Scoring System (R-IPSS) classifies ch 17 CA in the intermediate cytogenetic risk group; however, the majority of patients harbor the ch 17 CA in the context of a complex karyotype, which is considered high risk in the R-IPSS. The TP53 gene is located on the short arm of ch 17, and somatic TP53 mutations or deletions are associated with poor outcomes in MDS, including poor survival after allogeneic stem cell transplant. Recently, a high response rate was described in patients with TP53 mutations and acute myeloid leukemia treated with decitabine (Welch J et al NEJM 2016). Response rates to hypomethylating agents (HMA) are not well characterized among MDS patients with ch 17 CA. We report the outcome and prognosis of ch 17 CA in a large, multi-institutional cohort of MDS patients.

Methods

We identified patients with ch 17 abn within the MDSCRC database and compared them to those without ch 17 abn. CA were identified by G-banging metaphase karyotype analysis. Baseline characteristics were collected at time of diagnosis or prior to any therapy. Response rates to HMA were assessed using International Working Group criteria (IWG 2006), where overall response (OR) was defined as complete remission (CR), marrow CR, partial remission or hematological improvement (HI). Chi -square and t-test were used for comparing baseline characteristics, Kaplan-Meier estimates were used for calculating overall survival (OS) from time of diagnosis and cox regression was used for multivariable analysis.

Results:

We identified 352 MDS patients with ch 17 CA and compared them to 2053 patients with all other CA. Table-1 summarizes baseline characteristics between the two groups. As expected, most MDS patients with ch 17 CA were classified as higher risk R-IPSS. Among those who had molecular testing, 95 patients with ch 17 CA (81%) had TP53 somatic mutations compared to 143 patients (19%) with other CA. (p <.001). The rate of AML transformation was 36% among ch 17 CA group compared to 19% among those without ch 17 CA (p<.001)

The ch 17 CA abnormality was most frequently observed as part of a complex karyotype; 303 patients (86%) had complex karyotype (>3 CA). The ch 17 CA observed included monosomy 17 in 147 patients (42%), add(17p) in 84 patients (24%), trisomy 17 in 29 patients (8%), i(17) in 10 patients (3%), while 91 patients (26%) had other ch 17 CA including chromosomal translocations. Among patients with monosomy 17, 143/147 patients (97%) had complex karyotype.

188 MDS patients with ch 17 CA were treated with HMAs and were compared to 597 patients with other CA treated with HMAs. The OR was 45% and 41%, respectively (p =.42). CR rates were higher among MDS patients with ch 17 CA: 26% compared to 18% for those with other CA (p=.025). The median OS for patients with ch 17 CA was 12 mo (95% CI 11-14) compared to 25 mo (95% CI 23-29) in patients with other CA.

Among 227 MDS patients with detailed ch 17 CA data, the median OS was 12 mo for patients with complex karyotype (n=204) compared to 26 mo for those with ch 17 CA non-complex karyotype (n=23), p=.001. There was no difference in median OS between patients with monosomy 17 and add17p.

In Cox regression analyses adjusting for R-IPSS, Ch 17 CA presence was associated with inferior overall survival, HR 1.5 (95% CI 1.3-1.8), p <.005. The main driver of poor outcome was the presence of TP53 mutations.In a cox regression analysis accounting for R-IPSS, ch 17 CA and TP 53 mutation, The HR of death was 1.7 (p=.003) for TP 53 mutation, and for Ch 17 CA HR 1.1 (p=.7)

Conclusions

In MDS patients, ch 17 CA are often observed in the setting of complex karyotype and are associated with poor outcomes. The majority of patients with ch 17 CA harbor TP53 mutations, which drive poor outcome. CR rates to HMAs were higher among patients with ch 17 CA, but median OS was inferior compared to those with other CAs, similar to TP53 mutated AML patients.

View largeDownload slide

View largeDownload slide

Close modal