TP53-mutated complex karyotype in patients with de novo or therapy-related MDS and AML

A complex karyotype is defined as the presence of three or more chromosomal abnormalities. It occurs in 10–12% of patients diagnosed with acute myeloid leukemia (AML) and in 10–30% of patients with myelodysplastic syndromes (MDS).¹ According to the Revised International Prognostic Scoring System (IPSS-R), the presence of three abnormalities is associated with poor cytogenic risk, and four or more abnormalities are associated with a very poor cytogenetic risk. TP53 mutations are strongly associated with a complex karyotype, occurring in 70–80% of patients with AML and in 55% of patients with MDS.¹

Weinberg et al.¹ evaluated whether distinct diagnostic categories, such as therapy-related MDS and AML with myelodysplasia-related changes, had clinical relevance when associated with a complex karyotype, or if TP53 mutation status could identify a more biologically homogeneous group. We summarize the results below.

Study design

Patient cases and medical records from six centers in the United States between 2012 and 2020 were reviewed. Those found to have inv(16), t(8;21), PML-RARA rearrangement, or KMT2A rearrangement in the context of a complex karyotype were excluded.

Next-generation sequencing (NGS) was performed at initial diagnosis or after initial diagnosis for patients not treated with disease-modifying therapies. Over 90% of the gene coding regions associated with hematopoietic neoplasms were sequenced; 51 genes were found to be common in all three panels and were tested across the cohort. Only mutations that caused or were likely to cause disease were included in the analysis. The minimum variant allele frequency (VAF) cutoff for TP53 was 2%. TP53 mutations were classified as multihit if any of the following criteria were met:

• Two different TP53 mutations
• A single TP53 mutation with a VAF >60%
• A single TP53 mutation with 17p loss on karyotype

Results

A total of 299 patients were included, of which 144 were diagnosed with AML and 155 were diagnosed with MDS. The median age was 69.7 years, with 118 patients considered to have therapy-related disease. A complex karyotype was found in all patients, and the average time between initial diagnosis and NGS was 0.3 months. The median VAF for patients with TP53 mutations was 44%. Results from the mutation analysis are shown in Table 1.

Table 1. Mutation analysis*

*Adapted from Weinberg, et al.1
Mutation status	Patients, n (%) (N = 299)
Any mutation(s)	287 (96)
TP53 mutation	247 (83)
TP53 multihit	180 (63)
TP53 comutations
DNMT3A	31 (10)
TET2	28 (9)
RUNX1	17 (6)
EZH2	11 (4)
NRAS	10 (4)
IDH1	10 (3)
ASXL1	10 (3)
U2AF1	9 (3)
No detectable mutations	11
Single gene mutation	130
Mutations involving >1 gene	158

Therapy-related versus de novo disease

Therapy-related disease, when compared respectively with de novo disease, was associated with

• lower peripheral (0% vs 2%; p = 0.002) and bone marrow (BM) blast counts (12% vs 22%; p = 0.0003) but a trend toward higher BM cellularity (72.5% vs 70%; p = 0.06);
• a higher proportion of monosomal karyotypes (67% vs 56%; p = 0.07) and TP53 mutations (90% vs 78%; p = 0.008); and
• a trend towards worse overall survival (OS; 10.2 months vs 12.2 months).

In the subset of patients with therapy-related disease

• mutated TP53 was strongly associated with worse outcomes (p = 0.0017);
• ≥5% BM blasts trended towards worse outcome (p = 0.065); and
• monosomal karyotype, AML vs MDS diagnosis, and peripheral blood or BM blasts did not significantly impact OS.

TP53-mutated disease versus TP53 wild-type disease

Patients with a TP53 mutation, when compared respectively with TP53 wild-type cases, were associated with

• lower hemoglobin levels (p = 0.004) and BM blast counts (p = 0.02; Table 2);

• more frequent abnormalities in chromosomes 5, 7, and 17p (p < 0.0001, p = 0.028, and p = 0.0001, respectively); and
• a median of eight chromosomal abnormalities compared with four in wild-type cases (p < 0.0001).

In the subset of patients with mutated TP53, there was

• no significant difference in OS between therapy-related and de novo disease (8.5 months vs 10.7 months, respectively);
• no difference in OS between a diagnosis of AML or MDS; and
• no significant impact of monosomal karyotype on OS (9.6 months compared with 11.8 months in those without).

Interestingly, median OS was similar between patients with single TP53 mutations (9.2 months) and those with TP53 and comutations (10.7 months). However, the difference in OS between patients with no TP53 mutation, TP53 monoallelic, and TP53 multihit was significant (33.9 months, 12.5 months, and 9.4 months, respectively; p < 0.0001). Survival was not influenced by VAF, either as a continuous variable or using cutoffs. Further results of the comparison of TP53-mutated disease versus TP53 wild-type disease and multihit versus monoallelic TP53 mutations are shown in Table 2.

Table 2. Comparison of patients with TP53 mutations versus wild-type TP53 and of patients with multihit versus monoallelic TP53-mutations*

BM, bone marrow; F, female; M, male; PB, peripheral blood; WBC, white blood cells. *Adapted from Weinberg, et al.1
	TP53-mutated disease (n = 247)	TP53 wild-type disease (n = 52)	p value	TP53 biallelic disease (n = 180)	TP53 monoallelic disease (n = 67)	p value
Age, years (range)	70 (21–91)	68 (1–87)	0.06	70 (30–91)	70 (22–87)	0.93
Gender, M:F	124:114	26:26		98:82	35:32	0.0009
Monosomal karyotype, n (%)	168 (69)	13 (25)	<0.0001	130 (72)	38 (59)	0.06
Blood counts (median, range)
Platelets	50 (3–464)	54 (5–347)	0.44	49 (3–464)	52 (13–225)	0.5
WBC	3.0 (0.6–88.2)	3.2 (0.1–281.0)	0.28	3.2(0.6–88)	2.6 (0.6–88)	0.035
Hemoglobin	8.5 (3.8–12.9)	9.0 (4.9–13.7)	0.004	8.4 (3.8–12.9)	9 (4.0–12.5)	0.12
PB blasts	1 (0–90)	4 (0–97)	0.17	1 (0–90)	1 (0–45)	0.024
BM features (median, range)
Cellularity	70 (25–100)	60 (20–100)	0.14	70 (10–100)	65 (10–100)	0.036
Blast %	15 (0–95)	35 (1–95)	0.02	19 (0–95)	12 (0–95)	0.015

Multivariate analysis

Multivariate analysis showed that TP53 mutation status, stem cell transplantation, and treatment with low-intensity/hypomethylating agents, with or without venetoclax, were comparable with supportive care—all had an independent impact on prognosis (Table 3). Neither AML versus MDS diagnosis nor therapy-relatedness had any independent significant impact on prognosis or survival.

Table 3. Multivariable results for OS*

HMA, hypomethylating agents; HR, hazard ratio; OS, overall survival. *Adapted from Weinberg, et al.1 †Compared with supportive care.
Variable	HR (95% lower–upper bounds)	p value
Platelets (× 109/L)	0.999 (0.997–1.000)	0.136
TP53 monoallelic	2.081 (1.286–3.369)	0.003
TP53 multihit	2.952 (1.917–4.545)	<0.0001
Stem cell transplant	0.344 (0.000–0.505)	<0.0001
Therapy†
Low-intensity therapies	0.529 (0.000–0.827)	0.005
HMA/venetoclax	0.496 (0.000–0.845)	0.010
Induction therapy	0.732 (0.437–1.226)	0.236

Conclusion

Weinberg et al. concluded that the results from their study suggest that identifying TP53-mutated complex karyotypes in myeloid neoplasms as a separate, highly aggressive entity will aid in the development of new clinical approaches and avoid the current separation between trials and authorized therapies that are restricted to either AML or MDS diagnoses, or to primary versus secondary/therapy-related disease. Further studies are needed to confirm these findings in patients that possess TP53 loss-of-heterozygosity status and to better understand the intrinsic biology.