Clinical and Molecular Characterization of p53-Mutated Acute Myeloid Leukemia

P53 is a multifunctional tumor suppressor protein encoded by the TP53 gene, located on the short arm of chromosome 17.  Among its functions, it plays a role in maintaining genomic stability by reacting to DNA damage, activating DNA repair programs, and triggering cell cycle arrest.  Over half of human malignancies contain mutations or deletions in TP53 that compromise its function.  Mutations in TP53 have been described in 8-10% of cases of acute myeloid leukemia (AML) and are associated with an adverse prognosis.

We examined a cohort of 293 patients (pts) with newly diagnosed, non-CBF, non-APL AML treated at our institution in whom mutation screening was performed.  Mutation testing was performed using a validated 28-gene, whole-exome  sequencing panel.  Our aim was to characterize the clinico-pathologic characteristics of AML pts with TP53 mutations (mut-P53), their response to different therapies, and their survival compared to those with wild-type TP53 (wt-P53). Pts were treated with several different therapies that could be classified has high-dose cytarabine-based (HDAC), hypomethylating agent (HYPO), or low-intensity therapy other than single-agent HYPO (LOW-INT).

Of the 293 pts studied, 97 (33%) and 196 (67%) were < 60 years and ≥ 60 years, respectively.  Overall, 53 (18%) had TP53 mutations, 17 (18%) pts < 60 years and 36 (18%) pts ≥ 60 years.  95% of the mutations were found in exons 5-8 of TP53, the DNA-binding domain.   Patient characteristics by age and TP53 mutation status are summarized in Table 1.  In pts < 60 years, those with mut-P53 had significantly lower peripheral blasts, bone marrow (BM) blasts, and fibrinogen compared to those with wt-P53.  For pts ≥ 60 years, those with mut-P53 were older, had lower WBC counts, lower platelet counts, and significantly lower BM blast counts than those with wt-P53.  Significantly more pts with mut-P53 had complex karyotype (p<0.001), abnormalities of chromosomes 5 and/or 7 (p<0.001), abnormalities of chromosome 17 (p<0.001), and a diagnosis of therapy-related AML (p=0.004) compared to pts with wt-P53.  81% of pts with mut-P53 had a complex karyotype and 55% of pts with a complex karyotype had mut-P53.  A 28-gene mutation screen that was performed detected concomitant mutations and delineated the molecular landscape of AML pts with mut-P53 (Figure 1A).  Mutations in FLT3 (p=0.023), RAS (p=0.037), and NPM1 (p=0.029) were significantly underrepresented in pts with mut-P53 compared to wt-P53.  Rates of CR were lower in pts with mut-P53 compared to those with wt-P53 in the younger and older cohorts (Table 1).  The OS of pts younger and older than 60 years by p53 status is shown in Figure 1B.  Among pts with mut-P53, the CR rates for HDAC, HYPO, and LOW-INT were 60%, 29%, and 50%, respectively compared with 72%, 35%, and 63% in wt-P53 pts, respectively.  When divided into cohorts by age < and ≥ 60yrs, there was no difference in OS for patients with mutated TP53 treated with HDAC, HYPO, or LOW-INT. 

TP53 mutations in AML are associated with low blast counts, low WBC counts, complex karyotype, therapy-related disease, and inferior outcomes compared to those with wt-P53.  In our cohort there was no difference in outcome among different intensity therapies.  Newer therapies are needed to improve outcome in this difficult cohort of pts.

 

Table 1.
Age <60    (N=97)
Characteristic	mut-p53	wt-p53	p-value
Median Age	49  (20-59)	51  (22-59)	0.8
Median WBC	2.7  (0.9 - 30)	4.9  (0.5 - 103)	0.46
Median Platelet	32  (4 - 153)	39  (1 - 708)	0.35
Median periph blasts	6  (0 - 63)	27  (0 - 97)	0.03
Median LDH	937  (392 - 10298)	717  (231 - 11952)	0.25
Median Fibrinogen	330  (43 - 558)	413  (67 - 1117)	0.06
Median BM Blasts	27  (12 - 91)	54  (1 - 96)	0.008
CR Rate (%)	53	70	0.255
Age >60    (N=196)
Characteristic	mut-p53	wt-p53	p-value
Median Age	74  (62-90)	71  (60-92)	0.02
Median WBC	2.3  (0.7-17.5)	2.9 (0.2-164.5)	0.09
Median Platelet	34  (8-321)	45 (1-1069)	0.07
Median periph blasts	10  (0-86)	8 (0-96)	0.8
Median LDH	535  (286-3616)	616 (284-17486)	0.4
Median Fibrinogen	407  (213-753)	388 (102-923)	0.5
Median BM Blasts	32  (3-97)	47 (4-93)	0.009
CR Rate (%)	36	50	0.196