Are We Moving the Needle for Patients with TP53-Mutated Acute Myeloid Leukemia?
Abstract
:Simple Summary
Abstract
1. Introduction
2. Mechanisms and the Landscape of TP53 Alteration
3. Current and Insufficient Standards-of-Care
4. Mutant p53 Protein “Refolding” or “Reactivating” Therapies
5. Leveraging the Immune System
5.1. CD47/SIRPα Axis Inhibition
5.2. Immune Checkpoint Inhibition and Other Immunotherapy
6. MDM2–p53 Interaction Destabilization
7. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Regimen | Response Rates | Outcomes | Reference(s) |
---|---|---|---|
Intensive induction therapy | |||
Cytarabine + anthracycline (“7 + 3”) | CR: 28–48% CR/CRi: 33–66% | Median EFS: 1.6–5.7 months Median OS: 5.1–6.5 months | [21,23,24,32,33,34] |
Liposomal cytarabine + daunorubicin (CPX-351) | CR: 29% CR/CRi: 11–41% | Median EFS: 1.0–8.1 months Median OS: 4.5–8.5 months | [33,34,35] |
Less-intensive induction therapy | |||
Azacitidine monotherapy | CR: 40% CR/CRi: 0–40% | Median OS: 7.2 months | [10,36,37] |
Decitabine monotherapy(5-day schedule) | CR/CRi: 29% | Median OS: 2.1–5.5 months | [38,39,40,41] |
Decitabine monotherapy(10-day schedule) | CR: 31% CR/CRi: 38–47% | Median EFS: 5.7 months Median OS: 4.9–7.3 months | [38,40,42,43] |
Azacitidine + venetoclax | CR/CRi: 47–67% | Median EFS: 5.6 months Median OS: 7.2 months | [7,36,44] |
Decitabine (5-day schedule) + venetoclax | CR/CRi: 47–50% | Median EFS: 5.6 months Median OS: 7.2 months | [7,44] |
Decitabine (10-day schedule) + venetoclax | CR/CRi: 50–69% | Median EFS: 3.4–5.7 months Median OS: 5.2–6.9 months | [25,44,45] |
Mechanism of Action | Agent | Interim Clinical Data | References |
---|---|---|---|
Mutant p53 “reactivation” | Eprenetapropt (APR-246) | Eprenetapropt + AZA:
| [15,72,89] |
CD47/SIRPα inhibition | Magrolimab (Hu5F9-G4) | Magrolimab + AZA:
| [90,87] |
TIM-3 inhibition | Sabatolimab (MBG-453) | Sabatolimab + AZA:
| [91] |
CD123 x CD3 bispecific antibody therapy | Flotetuzumab | Flotetuzumab monotherapy (R/R population):
| [92] |
MDM2 inhibition | Idasanutlin | Idasanutlin + cytarabine:
| [93] |
AMG-232 | AMG-232 +/- trametinib:
| [94] | |
NEDD8 activating enzyme inhibition | Pevonedistat | Pevonedistat + azacitidine:
| [11,95] |
Mechanism of Action | Agent | Regimen | ClinicalTrials.gov Identifier |
---|---|---|---|
Mutant p53 “reactivation” | Eprenetapropt (APR-246) | Eprenetapropt + azacitidine + venetoclax | NCT04214860 |
CD47/SIRPα inhibition | SRF213 | Monotherapy | NCT03512340 |
Evorpacept (ALX148) | Evorpacept + azacitidine + venetoclax | NCT04755244 | |
TTI-622 | TTI-622 + azacitidine + venetoclax | NCT03530683 | |
Lemzoparlimab | Lemzoparlimab + azacitidine + venetoclax | NCT04912063 | |
AK117 | AK117 + azacitidine | NCT04980885 | |
DSP107 | DSP107 + azacitidine + venetoclax | NCT04937166 | |
SL-172154 | SL-172154 + azacitidine + venetoclax | NCT05275439 | |
IBI188 | IBI188 + azacitidine | NCT04485052 | |
TIM-3 inhibition | Sabatolimab | Sabatolimab + azacitidine + venetoclax | NCT04150029 |
MDM2 inhibition | Idasanutlin | Idasanutlin + “7 + 3” | NCT03850535 |
Idasanutlin | Idasanutlin + venetoclax (R/R) | NCT02670044 | |
Milademetan | Milademetan + low-dose cytarabine +/− venetoclax (R/R) | NCT03634228 | |
Siremadlin (HDM201) | Siremadlin + azacitidine + venetoclax | NCT05155709 |
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Shallis, R.M.; Bewersdorf, J.P.; Stahl, M.F.; Halene, S.; Zeidan, A.M. Are We Moving the Needle for Patients with TP53-Mutated Acute Myeloid Leukemia? Cancers 2022, 14, 2434. https://doi.org/10.3390/cancers14102434
Shallis RM, Bewersdorf JP, Stahl MF, Halene S, Zeidan AM. Are We Moving the Needle for Patients with TP53-Mutated Acute Myeloid Leukemia? Cancers. 2022; 14(10):2434. https://doi.org/10.3390/cancers14102434
Chicago/Turabian StyleShallis, Rory M., Jan P. Bewersdorf, Maximilian F. Stahl, Stephanie Halene, and Amer M. Zeidan. 2022. "Are We Moving the Needle for Patients with TP53-Mutated Acute Myeloid Leukemia?" Cancers 14, no. 10: 2434. https://doi.org/10.3390/cancers14102434