TP53 Status As Well As Cytogenetic Complexity Significantly Impact on Prognosis in Myelodysplastic Syndromes with Complex (≥3 anomalies) Aberrant Karyotypes

Introduction: Complex aberrant karyotypes (CK, ≥3 cytogenetic aberrations, CA) are associated with an unfavorable prognosis and an increased AML transformation rate in MDS. However, even MDS with CK (CK-MDS) are heterogeneous in terms of genetic profile and prognosis. Recently, we demonstrated that a high number of CA as well as mutations in TP53 (TP53^mut) are associated with increased risk in CK-MDS (Haase et al, 2019). However, as there is a strong association between CK-MDS and TP53^mut, it is still a matter of debate whether the karyotype and TP53^mut are prognostically independent genetic markers. Furthermore, loss of heterozygosity (LOH) of 17p13 (TP53^LOH), due to loss of genetic material or to copy number neutral LOH (CN-LOH), is also associated with a poor prognosis. We here aimed to characterize TP53^mut andTP53^LOH in CK-MDS and to elucidate the impact of cytogenetics, TP53^mut and TP53^LOH on the outcome of CK-MDS.

Methods: We included 178 pts with MDS (N=138), CMML (N=5) and secondary AML after MDS (AML with myelodysplasia-related changes, N=35), all with CK. The median precentage of bone marrow (bm) blasts was 11% (range: 0-90%). The median age was 72 yrs (range: 30-95 yrs). The male:female ratio was 1.23:1. The number of CA was determined by banding analysis in all cases. The karyotype was confirmed by multicolor FISH in 134 cases. TP53^LOH was verified by FISH analysis of the TP53 locus in 17p13 (146 analyses) and/or molecular karyotyping (MK, 41 analyses). In 144 cases further FISH probes in addition to TP53 were used. TP53^mut was identified by NGS (54 cases) or Sanger sequencing (124 cases). Follow-up data for survival analyses were available for 127 pts with MDS and oligoblastic AML with less than 30% bm blasts.

Results: The median number of CA was 7 (range: 3-46), 98/178 pts (55%) showed a TP53^mut (median VAF: 34%, range: 8-93%) and 64/178 (36%) a TP53^LOH (median FISH clone size: 65%, range: 6-99%), including 9 pts with a CN-LOH in 17p13. The CN-LOH was either identified by MK (5/41 pts (12%) where MK was available showed a CN-LOH, 4/5 with TP53^mut) or by NGS (4/54 pts (7%) where NGS was available showed a VAF >70% and normal TP53-FISH). In total, a TP53^mut and/or a TP53^LOH was identified in 116/178 pts (65%).

Overall survival (OS) did not significantly differ between CK-MDS with TP53^mut only, TP53^LOH only, and TP53^mut+TP53^LOH (Fig.1). Therefore, we merged TP53^mut and TP53^LOH to TP53^altered in all further analyses. Regarding the cytogenetic characterization of pts with TP53^altered, the number of CA was significantly higher in pts with TP53^altered than in pts with normal TP53 (median 9 CA (range: 3-46) vs 5 CA (range: 3-24), P<0.001). Also notable was that the founder clone of pts with TP53^altered included significantly more cases with del(5q) (determined by FISH, 69/92 cases, 75%) compared to pts with normal TP53 (22/52 cases, 42%, P<0.001).

The number of CA as well as the TP53 status contributed significantly to OS (Fig.2). The presence of anemia (Hb <10 g/dl) at first diagnosis of the CK had the greatest impact on OS (HR: 3.95) in the multivariate model (Cox regression), followed by an altered TP53 gene (TP53^mut and/or TP53^LOH; HR: 3.53) and the presence of ≥5 CA (HR: 2.33). Based on these three parameters with the greatest impact on OS, we created a simple provisional prognostic system. One scoring point each was assigned to anemia (Hb <10 g/dl), TP53^altered, and ≥5 CA. Regarding OS, the resulting four risk groups separated very well (Fig.4).

Conclusions: The presence of ≥5 CA is associated with reduced OS in CK-MDS. A TP53^mut as well as a TP53^LOH both further segregate outcome. The impact of the clone size of TP53^mut and TP53^LOH on survival is currently being evaluated. Our data imply that the TP53 status (TP53^mut and/or TP53^LOH) and the complexity of the karyotype are independent prognostic markers. Based on the presence of anemia, the TP53 status (TP53^mut and/or TP53^LOH), and the number of CA, the individual risk of CK-MDS can be estimated more accurately. This will allow to better tailor treatment decisions for individual pts with CA.

Funding (FS): 2017 SGR 288-GRC

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