The Type of Genetic Abnormalities Causing Loss of 5q Varies Between MDS and AML and Is Associated with Worse Prognosis in MDS
Authors: Haferlach Claudia , Grossmann Vera , Kohlmann Alexander , Schnittger Susanne , Kern Wolfgang , Haferlach Torsten 
Published: October 2019

Abstract
Abstract 697

Background:
Deletions of the long arm of chromosome 5 are frequent abnormalities in MDS and AML. Their size varies considerably. Two commonly deleted regions (CDR) have been described on 5q: a distal CDR deleted in the 5q- syndrome and a proximal region lost in higher-risk MDS and AML. However, the majority of MDS and AML patients with del(5q) show large deletions encompassing both CDRs. Recently, Jerez et al. (JCO 2012) reported on commonly retained regions (CRRs) using SNP arrays and observed that deletions involving the centromeric and telomeric extremes of 5q are associated with a more aggressive clinical course. From a cytogenetic view loss of 5q either occurs due to interstitial deletions, unbalanced translocations or monosomy 5. While in interstitial deletions the telomeric region of 5q is retained, this region is lost in cases with unbalanced 5q translocations and monosomy 5.

Aim:
Analyze whether the type of 5q loss (interstitial deletion vs unbalanced translocation/ monosomy) is associated with other biological markers and prognosis in AML and MDS.

Patients and Methods:
In total, 1,200 patients (pts) with loss of 5q were studied including 627 AML pts (de novo: 454, s-AML: 101, t-AML: 72) and 573 MDS pts (de novo: 511, t-MDS: 62) with a median age of 71.7 yrs (range: 30–90) and 73.2 yrs (range: 34–93). Interphase FISH had been performed in all pts with a probe for EGR1 (5q31) and all showed a heterozygous EGR1 deletion. Further, all cases had been studied by chromosome banding analysis and in addition by 24-color FISH whenever necessary to resolve complex karyotypes. Data on TP53 mutation status was available in 263 pts (AML: 152, MDS: 111).

Results:

Type of 5q loss:
AML and MDS cases were separated into 2 groups according to type of 5q loss: 1) interstitial 5q deletion (idel5q): AML: 341/627 (54.4%), MDS: 385/573 (67.2%), and 2) 5q loss due to an unbalanced translocation (ut5q): AML: 286/627 (45.6%), MDS: 188/573 (32.8%). Cases with complete loss of chromosome 5 (AML: 12, MDS: 1) were assigned to the second group. 530/627 (84.5%) AML pts and 303/573 (52.9%) MDS pts with 5q loss showed a complex karyotype (defined as 4 or more abnormalities). Further, in 345 AML (55.0%) and 233 MDS (40.7%) cases clonal evolution was evident as subclones with additional aberrations were detected.

Impact of 5q loss in MDS:
In MDS clonal evolution and complex karyotypes were more frequent in pts with ut5q as compared to idel5q (109/188 (58.0%) vs 124/385 (32.2%), p<0.0001; 179/188 (95.2%) vs 124/385 (32.2%), p<0.0001). In MDS TP53mut was more frequent in ut5q than in idel5q (8/10 (80%) vs 25/101 (24.8%), p=0.001), in pts with clonal evolution (9/14 (64.3%) vs 24/97 (24.7%), p=0.005) and in pts with complex karyotype (13/15 (86.7%) vs 20/96 (20.8%) p<0.0001). Further, median OS was shorter in pts with ut5q as compared to pts with idel5q (15.3 months (mo) vs not reached, p<0.0001).

Impact of 5q loss in AML:
Similar to MDS, in AML complex karyotypes were more frequent in pts with ut5q as compared to pts with idel5q (274/286 (95.8%) vs 256/341 (75.1%) p<0.0001). However, in contrast to MDS no association between ut5q and clonal evolution was observed in AML. Moreover, also in contrast to MDS no association between TP53mut and type of 5q loss was observed in AML (TP53mut 59/67 (88.1%) in ut5q pts and 66/85 (77.6%) in idel5q pts). In AML, median OS was comparable in pts with ut5q and pts with idel5q (5.9 mo vs 5.8 mo). However, complex karyotype and the presence of TP53mut were associated with shorter OS in AML (5.5 mo vs 14.0 mo, p=0.32 and 4.8 mo vs 25.1 mo, p<0.0001). In multivariable Cox regression analysis of AML pts including the parameters significant in univariable analyses (complex karyotype, TP53mut, age and WBC count) only TP53mut (HR: 3.28, p=0.011) and WBC count (HR: 1.15 per 10 G/L, p=0.044) were independently associated with shorter OS.

Conclusions:
1. Loss of 5q due to unbalanced translocations encompassing the telomeric 5q region is more frequent in AML (45.6%) than in MDS (32.8%) and in both entities associated with a complex karyotype. MDS patients with unbalanced 5q translocations show a shorter survival as compared to patients with interstitial 5q deletions. This data suggests that in MDS unbalanced 5q translocations reflect chromosomal instability which most probably is associated with progression to AML and adverse prognosis. 2. In AML with loss of 5q the presence of TP53 mutations is the strongest adverse prognostic factor.

Disclosures:
Haferlach: MLL Munich Leukemia Laboratory: Equity Ownership. Grossmann:MLL Munich Leukemia Laboratory: Employment. Kohlmann:MLL Munich Leukemia Laboratory: Employment. Schnittger:MLL Munich Leukemia Laboratory: Equity Ownership. Kern:MLL Munich Leukemia Laboratory: Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Equity Ownership.