In:
Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 7-7
Abstract:
Introduction: Cytogenetic changes occur in 50% of patients (pts) with Myelodysplastic Syndromes (MDS). Complex aberrations (cA, = 3 or more) are associated with a very poor outcome. In about 50% of the cases with cA aberrations of the TP53 locus are detectable. Those pts show an even worse outcome with a significantly shortened median overall survival (OS) compared to pts with wildtype TP53 (wtTP53). One of the most common cytogenetic aberrations in MDS is an interstitial deletion of the long arm of chromosome 5 (5q). As an isolated aberration, it is associated with a rather favorable prognosis. As part of a cA, 5q deletions however are assumed to even worsen the prognosis further. We wanted to find out in which prevalence 5q deletions and TP53 changes appear together and how those two factors in combination or not influence the OS of pts with MDS and cA. Methods: 218 pts with MDS or sAML and cA were identified and extensively characterized. 126 of them were diagnosed with MDS, 89 with sAML and 3 with CMML. Cytogenetic analysis by chromosome banding (CBA) and fluorescence in situ hybridization (FISH) of the TP53 locus on 17p as well as sequencing of TP53 either by Sanger or by Next Generation Sequencing was available for all pts. Multicolour FISH (mFISH) was available for 146 pts, SNP array analysis for 42 pts. The median number of cytogenetic aberrations was 8 (range 3-50). At the time of first diagnosis with cA the median age was 72 (range: 29-95). Median OS of the entire cohort was 10.7 months (95% CI: 8.0-16.4). Results: In 146 of 218 pts we found alterations of TP53: a single hit mutation in 32 pts, a single deletion in 22 pts, a combined mutation and deletion in 67 pts and more than 1 mutation in 25 pts. The OS of those 146 pts was 6.6 months compared to 22 months of the pts with wtTP53 (p-value & lt;0.0001). In 161 of 218 pts we found deletions of 5q (del(5q)). The median OS of those pts was significantly shorter than those of pts without del(5q) (8.4 vs. 20 months, p-value 0.001). 130 of 218 pts both had a del(5q) and an alteration of TP53, 31 pts only had a del(5q) and wtTP53 and 16 pts showed different types of TP53 alterations without del(5q). The median OS of pts with TP53 multi hit status as defined by Bernard (Bernard et al., Nature Medicine 2020) was 6.6 months, 5.3 months in pts with single hit TP53 mutations and a del(5q) and 21.6 months in pts, with wtTP53 and del(5q) (p-value = 0.0025, figure 1). Conclusion: Mutations and/or deletions of TP53 show a strong association with del(5q). Both were frequent in our cohort of 218 pts with MDS and cA. There also was a large intersection of 130 pts with both del(5q) and TP53 alteration. The combination of both changes seems to further worsen the already poor prognosis of pts with MDS and cA. Our observation that those two factors appear together frequently supports the hypothesis that the presence of del(5q) may promote the acquisition of cA. This is in accordance with Hsu´s hypothesis that in small clones with a mono-allelic TP53 mutation a del(5q) may favor the loss of heterozygosity of TP53 which could in a next step lead to a higher complexity of cytogenetic aberrations (Hsu et al, 2019). It is remarkable that the presence of del(5q) in combination with a single hit status of TP53 confers the same bad prognosis compared to multi hit TP53 status (figure 1).We will continue analyzing pts with MDS and cA to examine the influence of different TP53 and 5q alterations on the prognosis, the disease progression and median OS of those pts with cA. Figure 1 Disclosures Platzbecker: Novartis: Consultancy, Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Geron: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; BMS: Consultancy, Honoraria.
Type of Medium:
Online Resource
ISSN:
0006-4971
,
1528-0020
DOI:
10.1182/blood-2020-142508
Language:
English
Publisher:
American Society of Hematology
Publication Date:
2020
detail.hit.zdb_id:
1468538-3
detail.hit.zdb_id:
80069-7
