Navigating the Challenging Landscape of TP53-Mutated MDS and MPN

Managing patients with TP53-mutated myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPNs) presents a challenge because of inherent chemoresistance, increased relapse rates, and poor survival. When these mutations combine with complex karyotypes, standard therapies such as hypomethylating agents (HMAs) or venetoclax (Venclexta) can fall short.¹

In an interview with Targeted Oncology, David Sallman, MD, of Moffitt Cancer Center offered practical guidance on identifying high-risk patients, optimizing treatment strategies, and knowing when to refer for clinical trials or transplant evaluation.

Sallman, who serves as myeloid section head at Moffitt, emphasized that TP53 mutations, particularly those that are multi hit or biallelic, represent a unifying high-risk feature across MDS, acute myeloid leukemia (AML), and even MPN.

“There’s a big push to think about TP53, especially something that we call multi-hit or biallelic, that we may get into a more singular disease, definitely across MDS and AML and maybe across MPN,” Sallman explained.

Recognizing Transplant-Eligible Patients

For practicing oncologists without access to bioinformatics, Sallman offered clear criteria that should prompt immediate referral for allogeneic stem cell transplant consultation.

“If a patient has a TP53 mutation, it’s essentially an automatic referral, regardless of blast percentage,” he said. He noted that these patients are at high risk for rapid progression and that transplant remains the only potentially curative approach. “Allogenic stem cell transplant is the only curative therapy across all of these diseases,” he said.

Managing Venetoclax-Based Regimens

When considering venetoclax with a hypomethylating agent for patients with TP53 mutations, Sallman recommended oncologists maintain cautious expectations. “The durations of response, particularly with HMA/venetoclax, are very, very short,” Sallman said. “Regarding AML and high-risk MDS, we’re talking median overall survival between 6 to 9 months.” He noted that many patients will respond for less than a year, and some will relapse within months.

For transplant-eligible patients, he still favors the combination when a clinical trial is not an option. “You do get faster blast reduction and an overall higher response rate,” he said. “Some of these [patients] can relapse at month 2 or month 3, and so really, the key is that early transplant.” For patients who are not transplant candidates, he expressed a preference for single-agent HMA, with a slight preference for oral decitabine given its ease of administration.

Regarding venetoclax dosing, Sallman noted that in patients with less than 20% blasts, he typically starts with 14 days based on the dosing established in the VERONA trial (NCT04401748).² For patients with higher blast counts whom he is aiming toward transplant, he uses a 21-day schedule for the first cycle, performing a bone marrow biopsy and holding the dose upon response. He emphasized that after achieving a response, he reduces dosing quickly to 14 days in cycle 2 and often to 7 days thereafter.

Immune Checkpoint Inhibitors: Differentiating Approaches

Sallman distinguished between T-cell checkpoint inhibitors and macrophage checkpoint inhibitors, noting that traditional PD-1, PD-L1, and CTLA-4 inhibitors have not demonstrated meaningful activity in myeloid diseases.

“The next wave had been the macrophage activation targets, CD47 or SIRPα being the main two,” he said. He acknowledged the negative phase 3 trials with magrolimab³ but noted that other agents, such as ligufalimab, are still under evaluation.

Managing MPN with High-Risk Features

Constitutional symptoms such as splenomegaly often require a JAK inhibitor. He noted that options such as pacritinib (Vonjo) may be useful in patients with significant cytopenias, while fedratinib (Inrebic) may have theoretical benefit in accelerated phase disease due to its FLT3 antagonistic activity.

He emphasized that combinations of HMAs with JAK inhibitors or venetoclax have shown limited efficacy. Often the responses are poor and durable remissions are uncommon. He cited an ongoing academic consortium trial evaluating an HMA plus LSD1 inhibitor as an example.⁴

Sallman also offered a caution about overtreatment. In patients with MPN who develop increased blast counts but remain relatively stable with preserved blood counts and few transfusion needs, initiating aggressive therapy may not always be the right choice. He warns that intervening solely because of a numeric blast percentage, without considering the patient’s overall clinical stability, can lead to treatment related toxicities that worsen quality of life without providing meaningful benefit. In such cases, the harm from therapy may outweigh any potential gain. “Treatment decisions should be guided by the patient’s symptoms, transfusion burden, and overall clinical picture rather than by blast count alone,” Sallman said.

Emerging Strategies and Clinical Trial Opportunities

Sallman expressed continued optimism around TP53 reactivation strategies. He noted that eprenetapopt was evaluated in a phase 3 trial that was nearly positive, and efforts to bring it forward continue.⁵ He highlighted a specific opportunity for patients with the Y220C TP53 mutation. “There is a drug called rezatapopt. There was just a New England Journal of Medicine article published this past month in solid cancers,” he said.⁶ He added that a trial led by Courtney DiNardo, MD, at The University of Texas MD Anderson Cancer Center, Moffitt Cancer Center, and Memorial Sloan Kettering Cancer Center is evaluating rezatapopt with or without azacitidine in patients with this rare mutation, which represents approximately 0.5% to 1% of cases.

His overarching message for community oncologists was to recognize the homogeneous high-risk nature of TP53-mutated disease, refer promptly for transplant evaluation, prioritize clinical trial enrollment, and carefully weigh the risks and benefits of standard therapies, particularly in patients who may not be transplant candidates.

REFERENCES

1. 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. doi:10.1158/2159-8290.CD-22-0332

2. Garcia-Manero G, Platzbecker W, Fenaux P, et al. Subgroup analyses from the randomized, phase 3 VERONA study of venetoclax with azacitidine (Ven+Aza) versus placebo with azacitidine (Pbo+Aza) in patients with treatment-naïve, intermediate and higher-risk myelodysplastic syndromes (HR MDS). Blood. 2025;146(suppl 1):235. doi:10.1182/blood-2025-235

3. Gilead Statement on Discontinuation of phase 3 ENHANCE-3 Study in AML. February 7, 2024. Accessed March 25, 2026. https://tinyurl.com/5su7n99m

4. Seclidemstat and azacitidine for the treatment of myeldysplastic syndrome or chronic myelomoncytic leukemia. Updated March 5, 2026. ClinicalTrials.gov. https://clinicaltrials.gov/study/NCT04734990

5. 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. doi: 10.1200/JCO.20.02341

6. Dumbrava EE, Shapiro GI, Parikh AR, et al. Phase 1 study of rezatapopt, a p53 reactivator, in tp53 y220c–mutated tumors. N Engl J Med. 2026;394(9):872-883. doi:10.1056/NEJMoa2508820