TP53-mutated myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) remain a challenging spectrum of clonal myeloid disease with poor prognosis. Recent studies have shown that in AML, MDS, and MDS/AML with biallelic TP53 loss, the TP53-mutated clone becomes dominant. These are highly aggressive diseases that are resistant to most chemotherapies. The latest 2022 International Consensus Classification categorizes these diseases under “myeloid disease with mutated TP53.” All treatment approaches have not improved survival rates for this disease. Many newer therapies are on the horizon, including chimeric antigen receptor T/NK-cell therapies, mutated p53 reactivators, Fc fusion protein, and monoclonal antibodies targeting various myeloid antigens. This review summarizes the current approaches for myeloid disease with TP53 mutation and provides an overview of emerging nontransplant approaches.

1.
Estey
E
,
Hasserjian
RP
,
Döhner
H.
Distinguishing AML from MDS: a fixed blast percentage may no longer be optimal
.
Blood
.
2022
;
139
(
3
):
323
-
332
.
2.
Daver
NG
,
Maiti
A
,
Kadia
TM
, et al.
TP53-mutated myelodysplastic syndrome and acute myeloid leukemia: biology, current therapy, and future directions
.
Cancer Discov
.
2022
;
12
(
11
):
2516
-
2529
.
3.
Molica
M
,
Mazzone
C
,
Niscola
P
,
de Fabritiis
P.
TP53 mutations in acute myeloid leukemia: still a daunting challenge?
Front Oncol
.
2020
;
10
:
610820
.
4.
Takahashi
K
,
Wang
F
,
Kantarjian
H
, et al.
Preleukaemic clonal haemopoiesis and risk of therapy-related myeloid neoplasms: a case-control study
.
Lancet Oncol
.
2017
;
18
(
1
):
100
-
111
.
5.
Bernard
E
,
Nannya
Y
,
Hasserjian
RP
, et al.
Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes
.
Nat Med
.
2020
;
26
(
10
):
1549
-
1556
.
6.
Khoury
JD
,
Solary
E
,
Abla
O
, et al.
The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: myeloid and histiocytic/dendritic neoplasms
.
Leukemia
.
2022
;
36
(
7
):
1703
-
1719
.
7.
Grob
T
,
Al Hinai
ASA
,
Sanders
MA
, et al.
Molecular characterization of mutant TP53 acute myeloid leukemia and high-risk myelodysplastic syndrome
.
Blood
.
2022
;
139
(
15
):
2347
-
2354
.
8.
Weinberg
OK
,
Siddon
A
,
Madanat
YF
, et al.
TP53 mutation defines a unique subgroup within complex karyotype de novo and therapy-related MDS/AML
.
Blood Adv
.
2022
;
6
(
9
):
2847
-
2853
.
9.
Arber
DA
,
Orazi
A
,
Hasserjian
RP
, et al.
International Consensus Classification of myeloid neoplasms and acute leukemias: integrating morphologic, clinical, and genomic data
.
Blood
.
2022
;
140
(
11
):
1200
-
1228
.
10.
Lindsley
RC
,
Gibson
CJ
,
Murdock
HM
, et al.
Genetic characteristics and outcomes by mutation status in a phase 3 study of CPX-351 versus 7 + 3 in older adults with newly diagnosed, high-risk/secondary acute myeloid leukemia (AML)
.
Blood
.
2019
;
134
(
suppl 1
):
15
.
11.
Lancet
JE
,
Uy
GL
,
Newell
LF
, et al.
CPX-351 versus 7 + 3 cytarabine and daunorubicin chemotherapy in older adults with newly diagnosed high-risk or secondary acute myeloid leukaemia: 5-year results of a randomised, open-label, multicentre, phase 3 trial
.
Lancet Haematol
.
2021
;
8
(
7
):
e481
-
e491
.
12.
Othman
J
,
Wilhelm-Benartzi
C
,
Dillon
R
, et al.
A randomized comparison of CPX-351 and FLAG-Ida in adverse karyotype AML and high-risk MDS: the UK NCRI AML19 trial
.
Blood Adv
.
2023
;
7
(
16
):
4539
-
4549
.
13.
Bally
C
,
Adès
L
,
Renneville
A
, et al.
Prognostic value of TP53 gene mutations in myelodysplastic syndromes and acute myeloid leukemia treated with azacitidine
.
Leuk Res
.
2014
;
38
(
7
):
751
-
755
.
14.
Welch
JS
,
Petti
AA
,
Miller
CA
, et al.
TP53 and decitabine in acute myeloid leukemia and myelodysplastic syndromes
.
N Engl J Med
.
2016
;
375
(
21
):
2023
-
2036
.
15.
Short
NJ
,
Kantarjian
HM
,
Loghavi
S
, et al.
Treatment with a 5-day versus a 10-day schedule of decitabine in older patients with newly diagnosed acute myeloid leukaemia: a randomised phase 2 trial
.
Lancet Haematol
.
2019
;
6
(
1
):
e29
-
e37
.
16.
Savona
MR
,
McCloskey
JK
,
Griffiths
EA
, et al.
Prolonged survival in bi-allelic TP53-mutated (TP53mut) MDS subjects treated with oral decitabine/ cedazuridine in the Ascertain trial (ASTX727-02)
.
Blood
.
2022
;
140
(
suppl 1
):
2066
-
2069
.
17.
Garcia-Manero
G
,
McCloskey
J
,
Griffiths
EA
, et al.
Oral decitabine-cedazuridine versus intravenous decitabine for myelodysplastic syndromes and chronic myelomonocytic leukaemia (ASCERTAIN): a registrational, randomised, crossover, pharmacokinetics, phase 3 study
.
Lancet Haematol
.
2024
;
11
(
1
):
e15
-
e26
.
18.
DiNardo
CD
,
Jonas
BA
,
Pullarkat
V
, et al.
Azacitidine and venetoclax in previously untreated acute myeloid leukemia
.
N Engl J Med
.
2020
;
383
(
7
):
617
-
629
.
19.
Pratz
KW
,
Jonas
BA
,
Pullarkat
V
, et al.
Long-term follow-up of VIALE-A: venetoclax and azacitidine in chemotherapy-ineligible untreated acute myeloid leukemia
.
Am J Hematol
.
2024
;
99
(
4
):
615
-
624
.
20.
Pollyea
DA
,
Pratz
KW
,
Wei
AH
, et al.
Outcomes in patients with poor-risk cytogenetics with or without TP53 mutations treated with venetoclax and azacitidine
.
Clin Cancer Res
.
2022
;
28
(
24
):
5272
-
5279
.
21.
Kim
K
,
Maiti
A
,
Loghavi
S
, et al.
Outcomes of TP53-mutant acute myeloid leukemia with decitabine and venetoclax
.
Cancer
.
2021
;
127
(
20
):
3772
-
3781
.
22.
Schimmer
RR
,
Kovtonyuk
LV
,
Klemm
N
, et al.
TP53 mutations confer resistance to hypomethylating agents and BCL-2 inhibition in myeloid neoplasms
.
Blood Adv
.
2022
;
6
(
11
):
3201
-
3206
.
23.
Badar
T
,
Nanaa
A
,
Atallah
E
, et al.
Comparing venetoclax in combination with hypomethylating agents to hypomethylating agent-based therapies for treatment naive TP53-mutated acute myeloid leukemia: results from the Consortium on Myeloid Malignancies and Neoplastic Diseases (COMMAND)
.
Blood Cancer J
.
2024
;
14
(
1
):
32
.
24.
Daver
NG
,
Iqbal
S
,
Renard
C
, et al.
Treatment outcomes for newly diagnosed, treatment-naïve TP53-mutated acute myeloid leukemia: a systematic review and meta-analysis
.
J Hematol Oncol
.
2023
;
16
(
1
):
19
.
25.
Zhang
W
,
Huang
Q
,
Xiao
W
, et al.
Advances in anti-tumor treatments targeting the CD47/SIRPα axis
.
Front Immunol
.
2020
;
11
:
18
.
26.
Feng
D
,
Gip
P
,
McKenna
KM
, et al.
Combination treatment with 5F9 and azacitidine enhances phagocytic elimination of acute myeloid leukemia
.
Blood
.
2018
;
132
(
suppl 1
):
2729
.
27.
Daver
NG
,
Vyas
P
,
Kambhampati
S
, et al.
Tolerability and efficacy of the anticluster of differentiation 47 antibody magrolimab combined with azacitidine in patients with previously untreated AML: phase Ib results
.
J Clin Oncol
.
2023
;
41
(
31
):
4893
-
4904
.
28.
Sallman
DA
,
Al Malki
MM
,
Asch
AS
, et al.
Magrolimab in combination with azacitidine in patients with higher-risk myelodysplastic syndromes: final results of a phase Ib study
.
J Clin Oncol
.
2023
;
41
(
15
):
2815
-
2826
.
29.
Garcia-Manero
G
,
Daver
NG
,
Xu
J
, et al.
Magrolimab + azacitidine versus azacitidine + placebo in untreated higher risk (HR) myelodysplastic syndrome (MDS): the phase 3, randomized, ENHANCE study
.
J Clin Oncol
.
2021
;
39
(
15 suppl
):
TPS7055
.
30.
Gilead statement on discontinuation of phase 3 ENHANCE-3 study in AML
. Accessed
20
April
2024
. https://www.gilead.com/news-and-press/company-statements/gilead-statement-on-discontinuation-of-phase-3-enhance-3-study-in-aml.
31.
Gilead discontinues phase 3 ENHANCE-2 trial of magrolimab plus azacitidine in TP53-mutant AML
. OncLive.
27
September
2023
. Accessed
20
April
2024
. https://www.onclive.com/view/gilead-discontinues-phase-3-enhance-2-trial-of-magrolimab-plus-azacitidine-in-tp53-mutant-aml.
32.
Deneberg
S
,
Cherif
H
,
Lazarevic
V
, et al.
An open-label phase I dose- finding study of APR-246 in hematological malignancies
.
Blood Cancer J
.
2016
;
6
(
7
):
e447
-
e447
.
33.
Sallman
DA
,
DeZern
AE
,
Garcia-Manero
G
, et al.
Eprenetapopt (APR-246) and azacitidine in TP53-mutant myelodysplastic syndromes
.
J Clin Oncol
.
2021
;
39
(
14
):
1584
-
1594
.
34.
Cluzeau
T
,
Sebert
M
,
Rahmé
R
, et al.
Eprenetapopt plus azacitidine in TP53-mutated myelodysplastic syndromes and acute myeloid leukemia: a phase II study by the Groupe Francophone des Myélodysplasies (GFM)
.
J Clin Oncol
.
2021
;
39
(
14
):
1575
-
1583
.
35.
Garcia-Manero
G
,
Goldberg
AD
,
Winer
ES
, et al.
Eprenetapopt combined with venetoclax and azacitidine in TP53-mutated acute myeloid leukaemia: a phase 1, dose-finding and expansion study
.
Lancet Haematol
.
2023
;
10
(
4
):
e272
-
e283
.
36.
Minimal efficacy observed with eprenetapopt plus azacitidine in TP53- mutant MDS
. Targeted Oncology.
5
January
2021
. Accessed
20
April
2024
. https://www.targetedonc.com/view/minimal-efficacy-observed-with-eprenetapopt-plus-azacitidine-in-tp53-mutant-mds.
37.
Jen
W-Y
,
Konopleva
M
,
Pemmaraju
N.
Tagraxofusp, a first-in-class CD123- targeted agent: five-year postapproval comprehensive review of the literature
.
Cancer
.
2024
;
130
(
13
):
2260
-
2271
.
38.
Lane
AA
,
Garcia
JS
,
Raulston
EG
, et al.
Phase 1b trial of tagraxofusp in combination with azacitidine with or without venetoclax in acute myeloid leukemia
.
Blood Adv
.
2024
;
8
(
3
):
591
-
602
.
39.
Curigliano
G
,
Gelderblom
H
,
Mach
N
, et al.
Phase I/Ib clinical trial of sabatolimab, an anti-TIM-3 antibody, alone and in combination with spartalizumab, an anti-PD-1 antibody, in advanced solid tumors
.
Clin Cancer Res
.
2021
;
27
(
13
):
3620
-
3629
.
40.
Schwartz
S
,
Patel
N
,
Longmire
T
, et al.
Characterization of sabatolimab, a novel immunotherapy with immuno-myeloid activity directed against TIM-3 receptor
.
Immunother Adv
.
2022
;
2
(
1
):
ltac019
.
41.
Brunner
AM
,
Esteve
J
,
Porkka
K
, et al.
Phase Ib study of sabatolimab (MBG453), a novel immunotherapy targeting TIM-3 antibody, in combination with decitabine or azacitidine in high- or very high-risk myelodysplastic syndromes
.
Am J Hematol
.
2024
;
99
(
2
):
E32
-
E36
.
42.
Zeidan
AM
,
Ando
K
,
Rauzy
O
, et al.
Sabatolimab plus hypomethylating agents in previously untreated patients with higher-risk myelodysplastic syndromes (STIMULUS-MDS1): a randomised, double-blind, placebo- controlled, phase 2 trial
.
Lancet Haematol
.
2024
;
11
(
1
):
e38
-
e50
.
43.
de Silva
S
,
Fromm
G
,
Shuptrine
CW
, et al.
CD40 enhances type I interferon responses downstream of CD47 blockade, bridging innate and adaptive immunity
.
Cancer Immunol Res
.
2020
;
8
(
2
):
230
-
245
.
44.
Daver
N
,
Selwyn Stein
A
,
Bixby
D
, et al.
Safety, pharmacodynamic, and anti-tumor activity of SL-172154 as monotherapy and in combination with azacitidine (AZA) in relapsed/refractory (R/R) acute myeloid leukemia (AML) and higher-risk myelodysplastic syndromes/neoplasms (HR-MDS) patients (pts)
.
Blood
.
2023
;
142
(
suppl 1
):
4278
.
45.
Zhang
X
,
Lv
H
,
Xiao
X
, et al.
A phase I clinical trial of CLL-1 CAR-T cells for the treatment of relapsed/refractory acute myeloid leukemia in adults
.
Blood
.
2023
;
142
(
suppl 1
):
2106
.
46.
Mueller
J
,
Schimmer
RR
,
Koch
C
, et al.
Targeting the mevalonate or Wnt pathways to overcome CAR T-cell resistance in TP53-mutant AML cells
.
EMBO Mol Med
.
2024
;
16
(
3
):
445
-
474
.
47.
Uy
GL
,
Aldoss
I
,
Foster
MC
, et al.
Flotetuzumab as salvage immunotherapy for refractory acute myeloid leukemia
.
Blood
.
2021
;
137
(
6
):
751
-
762
.
48.
Vadakekolathu
J
,
Lai
C
,
Reeder
S
, et al.
TP53 abnormalities correlate with immune infiltration and associate with response to flotetuzumab immunotherapy in AML
.
Blood Adv
.
2020
;
4
(
20
):
5011
-
5024
.
49.
Dumbrava
EE
,
Johnson
ML
,
Tolcher
AW
, et al.
First-in-human study of PC14586, a small molecule structural corrector of Y220C mutant p53, in patients with advanced solid tumors harboring a TP53 Y220C mutation
.
J Clin Oncol
.
2022
;
40
(
16 suppl
):
3003
.
50.
Carter
BZ
,
Mak
PY
,
Ke
B
, et al.
Selective targeting of TP53-Y220C mutant AML by PC14586 results in TP53 wild-type conformation and synergistical apoptosis induction by concomitant inhibition of Xpo-1, MDM2, or Bcl-2
.
Blood
.
2023
;
142
(
suppl 1
):
2261
.
51.
Parrales
A
,
Ranjan
A
,
Iyer
SV
, et al.
DNAJA1 controls the fate of misfolded mutant p53 through the mevalonate pathway
.
Nat Cell Biol
.
2016
;
18
(
11
):
1233
-
1243
.
52.
Hsiue
EH
,
Wright
KM
,
Douglass
J
, et al.
Targeting a neoantigen derived from a common TP53 mutation
.
Science
.
2021
;
371
(
6533
):
eabc8697
.
53.
Lancet
JE
,
Uy
GL
,
Cortes
JE
, et al.
CPX-351 (cytarabine and daunorubicin) liposome for injection versus conventional cytarabine plus daunorubicin in older patients with newly diagnosed secondary acute myeloid leukemia
.
J Clin Oncol
.
2018
;
36
(
26
):
2684
-
2692
.
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