The Hematologist

January-February 2020, Volume 17, Issue 1

2019 Brings Biologic Understanding and Hope for Patients With TP53 Mutated Myelodysplastic Syndrome

Theodoros Karantanos, MD, PhD Medical Oncology Fellow, Hematologic Malignancies
The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University Hospital, Baltimore, MD
Amy DeZern, MD, MHS Associate Professor of Oncology and Medicine
Johns Hopkins University School of Medicine, Baltimore, MD

Published on: December 26, 2019

Researchers specializing in myeloid diseases have long sought better biologic understanding in TP53-mutated disease in hopes of future refinement to our therapeutic algorithms. TP53-mutated myelodysplastic syndrome (MDS) accounts for 5 to 10 percent of de novo MDS and 20 to 30 percent of therapy-related MDS and defines a cohort of patients with particularly poor prognosis1 and very short survival even following transplantation.2 Patients with TP53-mutated MDS have inferior survival when treated with traditional treatments such as intensive chemotherapy or hypomethylating agents (HMA).3 Similar to analogous malignant diseases (consider HER2-mutated breast cancer or Philadelphia chromosome–positive acute lymphoblastic leukemia)  where targeting the specific genetic alterations led to impressive improvement of survival, p53-targeted or directed therapy has been a goal. However, for this to be a reasonable approach in a patient, it has been thought necessary to have a better comprehension of if and how gain-of-function oncogenesis was associated with the mutation. Gain of function can be interrupted and implies a druggable target. This past year has truly seen an expansion of our scientific knowledge potential for those with TP53-mutated MDS; we can perhaps leave behind the therapeutic nihilism long-associated with TP53-mutated disease.

In 2019, Dr. Steffen Boettcher and colleagues demonstrated that TP53 missense mutations (the most common type of TP53 mutations in myeloid neoplasms) have a dominant negative effect; thus, they provide selective advantage to acute myeloid leukemia (AML) cells in DNA damage.4 The authors showed that the sensitivity of isogenic AML lines carrying TP53 missense mutations to daunorubicin and nutlin-3a is similar to the TP53–/– cell line.4 Interestingly, missense TP53 mutations led to suppression of p53 transcriptional activity, especially related to apoptosis and cell cycle regulation upon DNA damage.4 A saturation mutagenesis screen developed by introducing TP53-mutant cDNAs into a TP53–wild-type AML line showed that missense mutations in the DNA-binding domain were enriched for dominant negative activity.4 Finally, AML cell lines with one missense mutation and one wild-type TP53 allele outcompeted cells with wild-type TP53 in co-culture assays, while hematopoietic stem cells with TP53 missense mutations transplanted to mice outcompeted those with one null allele following sublethal radiation.4 These results support findings that TP53 missense mutations exhibit a dominant negative effect upon DNA damage, but offer no clear evidence that they have a gain-of-function effect.

This finding was further supported by the results from the clinic of Dr. Detlef Haase and colleagues who presented compelling evidence that the effect of these mutations on survival is probably less deleterious compared to more disruptive mutations such as frameshift or nonsense mutations.5 The authors also showed that even among patients with MDS with complex karyotype, TP53 mutation presence is associated with worse survival.5 Interestingly, TP53-mutated patients had fewer additional somatic mutations but higher frequency of high complexity and monosomal karyotype.5 These clinical results highlight the strong and independent negative impact of TP53 mutations in the outcomes of MDS.

The absence of gain-of-function effect of TP53 mutations supports the finding that drugs designed to inhibit mutated p53 will not be as effective as trastuzumab in the treatment of breast cancer or BCR-ABL inhibitors in ALL, respectively. On the contrary, agents that stabilize p53 and reverse the negative effect of the missense mutations, and the survival benefit that they provide to leukemia cells will be more promising for our patients.

In past years, we have seen examples of inhibitors of negative regulators of p53 demonstrate objective clinical responses, but we must recall that their activity requires functional p53. More promising is a newer agent, APR-246. This is a prodrug converted to methylene quinuclidinone that binds to cysteines of mutant p53, stabilizes it, and then promotes the reconformation of the protein, thereby inducing apoptosis and cell cycle arrest selectively in cancer cells carrying TP53 missense mutations.6 Based on the encouraging results of a phase Ib study,7 the combination of this agent with azacytidine was evaluated in HMA-naïve AML and MDS cases in two multi-institutional studies, and their results were presented at the 2019 ASH Annual Meeting. Dr. Thomas Cluzeau and colleagues reviewed their overall response rate (ORR) of 63 percent, 47 percent complete remission (CR) among 53 patients and 100 percent TP53 negativity among the ones who achieved CR.8 Dr. David A. Sallman of Moffitt Cancer Center led the U.S. MDS Clinical Research Consortium in a clinical trial that showed 87 percent ORR with 53 percent CR among 55 patients, while 39 percent of them achieved next-generation sequencing negativity.9 Importantly, the decrease of TP53 variant allele frequency, which correlates with survival outcomes in this subgroup of MDS,5 suggests that APR-246 can reverse the dominant negative effect of TP53 missense mutations.

These exciting findings suggest that APR-246 has a promising effect in TP53-mutated myeloid diseases in 2019. This excitement will be carried forward via the ongoing phase III trial of APR-246 plus azacytidine versus azacytidine alone in patients with TP53-mutated MDS (NCT03745716) and a phase II trial of this combination following allogeneic stem cell transplantation (NCT03931291) as maintenance therapy. Our hope is that reversal of the dominant negative effect of the TP53 mutations could provide a survival benefit to MDS patients, similar to the great benefit that biologically rational therapeutic design has shown in other malignancies.

References

  1. Bejar R, Stevenson K, Abdel-Wahab O, et al. Clinical effect of point mutations in myelodysplastic syndromes. N Engl J Med. 2011;364:2496-2506.
  2. Lindsley RC, Saber W, Mar BG, et al. Prognostic mutations in myelodysplastic syndrome after stem-cell transplantation. N Engl J Med. 2017;376:536-547.
  3. Bejar R, Lord A, Stevenson K, et al. TET2 mutations predict response to hypomethylating agents in myelodysplastic syndrome patients. Blood. 2014;124:2705-2712.
  4. Boettcher S, Miller PG, Sharma R A dominant-negative effect drives selection of TP53 missense mutations in myeloid malignancies. Science. 2019;365:599-604.
  5. Haase D, Stevenson KE, Neuberg D, et al. TP53 mutation status divides myelodysplastic syndromes with complex karyotypes into distinct prognostic subgroups. Leukemia. 2019;33:1747-1758.
  6. Zhang Q, Bykov VJN, Wiman KG, et al. APR-246 reactivates mutant p53 by targeting cysteines 124 and 277. Cell Death Dis. 2018;9:439.
  7. Sallman DA, DeZern A, Sweet K, et al. Abstract CT068: Phase Ib/II combination study of APR-246 and azacitidine (AZA) in patients with TP53 mutant myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Cancer Research. 2018;78: doi: 10.1158/1538-7445.AM2018-CT068.
  8. Cluzeau T, Sebert M, Rahmé R, et al. APR-246 combined with azacitidine (AZA) in TP53 mutated myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). A Phase 2 study by the Groupe Francophone Des Myélodysplasies (GFM). Blood. 2019;637:677.
  9. Sallman DA, DeZern AE, Garcia-Manero G, et al. Phase 2 results of APR-246 and azacitidine (AZA) in patients with TP53 mutant myelodysplastic syndromes (MDS) and oligoblastic acute myeloid leukemia (AML). Blood. 2019;637:676.

Conflict of Interests

Dr. Karantanos indicated no relevant conflicts of interest. Dr. DeZern indicated no relevant conflicts of interest and is a co-investigator on trials utilizing APR-246 in myeloid malignancies. back to top