Less Is More: Advancing Care in TP53-Mutated Myeloid Malignancies

TP53 mutations are present in approximately 10% to 15% of de novo acute myeloid leukemia (AML) cases and more than 30% of therapy-related myeloid malignancies, with increasing instances in older patients with AML or myelodysplastic syndromes (MDS).^1,2 Across these diverse clinical settings, TP53 alterations consistently confer an aggressive disease phenotype, marked by resistance to standard therapies and poor survival outcomes.

Venetoclax (Venclexta) combined with hypomethylating agents (HMAs) has transformed treatment for older or medically unfit patients who cannot tolerate intensive chemotherapy because of advanced age, reduced physical fitness, or other health conditions. Results from the phase 3 VIALE-A trial (NCT02993523) showed that adding the targeted agent venetoclax to azacitidine (Vidaza) produced major improvements in most patients with AML,³ but not in those with TP53 mutations, whose poor outcomes were similar to those receiving azacitidine alone.⁴ The median overall survival (OS) for these patients remained approximately 5 to 6 months with or without the addition of venetoclax in the VIALE-A trial, and responses were often short-lived. Allogeneic hematopoietic stem cell transplantation is the only potentially curative option, but most patients are older and ineligible; even among those who receive transplantation, long-term survival is below 20%, with worse outcomes in the subgroup who have biallelic TP53 mutations.⁵

The poor outcomes largely reflect the underlying biology of TP53-mutated disease. Leukemic cells are inherently resistant to standard cytotoxic therapies, whereas normal hematopoietic cells remain highly sensitive to treatment. This imbalance leads to prolonged cytopenias, increasing the risk of infections, transfusion dependence, and frequent hospitalizations. For many patients, particularly older adults, these treatment-related complications significantly affect quality of life (QOL) and limit meaningful time spent with their families. Recent studies show that many older patients prioritize therapies that allow them to spend more time at home rather than in the hospital,⁶ yet standard HMA/venetoclax regimens often increase cytopenias and hospitalization without decreasing the time patients spend in the hospital.

To overcome the challenges of managing TP53-mutated AML and MDS, investigators have explored a low-dose, once-weekly metronomic regimen that combines decitabine with venetoclax.⁷ As recently reported in Haematologica, this strategy preserves antileukemic activity and significantly reduces treatment-related toxicity.⁷ Administering decitabine at a low dose in combination with venetoclax on an intermittent, once-weekly schedule instead of continuously effectively suppresses malignant cells and spares normal hematopoietic cells. This schedule enhances efficacy by overcoming resistance mechanisms and minimizes cumulative myelosuppression and overall toxicity. This approach aligns more closely with patient priorities, offering effective disease control and better preserving QOL for patients with TP53-mutated myeloid malignancies.

What has early clinical experience with a metronomic regimen looked like in hematologic malignancies?

The concept of a once-weekly metronomic regimen combining low-dose decitabine with venetoclax first emerged during the COVID-19 pandemic, when patients and health care teams alike sought to minimize hospital exposure. By shifting treatment primarily to the outpatient setting, this approach maintained disease control, reduced hospitalizations for neutropenia, and decreased clinic and infusion visits for transfusions, allowing patients to spend more time at home.

This experience was reported in a retrospective study published in Clinical Cancer Research, which compared the metronomic regimen with standard azacitidine or decitabine plus venetoclax.⁸ The study results suggested that antileukemic activity could be preserved and tolerability could be simultaneously improved: Hospitalizations were less frequent, and a greater proportion of patients achieved transfusion independence. Among the subset of patients with TP53-mutated disease, early signals of efficacy were observed, with a composite complete response rate of 71% and a median OS of 10.7 months, providing initial proof of concept that metronomic therapy could maintain efficacy and reduce treatment burden in this high-risk population.

The regimen was subsequently evaluated prospectively in a phase 2 clinical trial (NCT05184842) designed to determine whether patients could remain on therapy without dose reductions or interruptions.⁹ Results reported in Blood demonstrated that the once-weekly schedule enabled most patients to safely complete induction, maintain encouraging response rates, and experience lower toxicity. In this cohort, evaluable patients with TP53-mutated AML or high-risk MDS (n = 10) had a median OS of 11.3 months (95% CI, 8.5-not reached [NR]), further supporting the potential of a metronomic approach to balance efficacy and tolerability.

What were the design and patient characteristics of the Haematologica study of metronomic decitabine and venetoclax in TP53-mutated AML and MDS?

Building on this experience, investigators at Montefiore Einstein Comprehensive Cancer Center assembled a cohort specifically evaluating outcomes in patients with TP53-mutated myeloid malignancies treated with the metronomic regimen.⁷ The analysis combined patients treated in the prospective phase 2 clinical trial with those from the retrospective cohort that originated during the COVID-19 pandemic. In the regimen, decitabine was given at 0.2 mg/kg subcutaneously once weekly in combination with venetoclax at 400 mg orally administered on the same day each week (days 1, 8, 15, and 22 of a 28-day cycle). Treatment included 3 induction cycles, followed by maintenance until disease progression or therapy discontinuation.

The study included 40 patients treated between April 2020 and January 2025: 14 with AML and 26 with high-risk MDS.⁷ Twenty-two patients received the regimen during the prospective trial, whereas 18 were treated as part of the retrospective COVID-19 cohort. The median age was 76.5 years (range, 52-89), reflecting the older population typically affected by these diseases. Thirty-two percent of patients were from non-White backgrounds, representative of the diverse patient population served by Montefiore Einstein, a safety-net hospital system in the Bronx, New York. More than one-fourth of patients (27%) had an ECOG performance status of 2 or 3.

The cohort also exhibited very high–risk disease biology. Complex cytogenetics, defined as 3 or more cytogenetic abnormalities, were present in 70% of patients. Among evaluable patients, 82% had biallelic TP53 mutations, meaning that both copies of the TP53 gene were altered, which is associated with particularly aggressive disease and resistance to standard therapies. At treatment initiation, 65% of patients were transfusion dependent, underscoring the substantial disease burden in this population.

What were the clinical activity, supportive outcomes, and safety findings from the Haematologica study of metronomic treatment in TP53-mutated disease?

Despite a high-risk population, the once-weekly metronomic regimen of decitabine and venetoclax demonstrated encouraging activity. The overall response rate was 70% in patients with AML and 57% in those with high-risk MDS. Using an intention-to-treat analysis, in which nonevaluable patients were considered nonresponders, complete remission rates were 50% in the AML subgroup and 35% in the MDS subgroup. Minimal residual disease negativity was achieved in approximately half of responders (48%; n = 10 of 21), with a median time to best response of 85 days. Among responders, the median duration of response was NR in patients with AML and 11.3 months in those with MDS (Table).

The regimen also improved supportive outcomes. Among 26 patients who were transfusion-dependent at baseline, 15 (58%) became independent of transfusions; 48% discontinued red blood cell transfusions, and 67% discontinued platelet transfusions. Hematologic improvement, defined as an increase in blood counts, occurred in 60% of patients with MDS. At a median follow-up of 12.9 months, the median OS was 11.3 months (95% CI, 8.8-NR) overall, 11.6 months (95% CI, 1.4-NR) in patients with AML, and 9.9 months (95% CI, 8.5-NR) in those with MDS. Among the 31 patients with biallelic TP53 mutations, the median OS was 10.4 months (95% CI, 8.7-NR).

Clinically, the regimen was well tolerated. In this cohort, the 30- and 100-day mortality rates were 2.5% and 7.5%, respectively, with no therapy-related deaths. Patients spent a median of 100 days alive and out of the hospital during the first 100 days (range, 0-100), highlighting the regimen’s safety, outpatient feasibility, and ability to provide patients with more quality time at home.

What are the future directions for investigating metronomic treatment in TP53-mutated AML and MDS?

Cancer clinical trials have historically relied on the maximum tolerated dose, based on the assumption that higher doses yield superior outcomes. However, this paradigm is increasingly being challenged. The FDA’s Project Optimus reflects a shift toward identifying doses that optimize efficacy and minimize toxicity, rather than defaulting to the highest tolerable dose. Our findings align with this evolving framework and reinforce a central principle: more treatment is not always better, and pharmacodynamically optimized dosing can preserve clinical benefit while simultaneously reducing harm.

In this context, metronomic low-dose decitabine plus venetoclax demonstrates that efficacy can be maintained with substantially improved tolerability in TP53-mutated AML and MDS. This approach is associated with reduced early mortality, fewer hospitalizations, improved QOL, and preservation of hematopoiesis—outcomes that are particularly meaningful in this high-risk population.

Importantly, these benefits extend beyond symptom management and may influence access to curative therapy. To date, allogeneic stem cell transplantation remains the only potentially curative option for TP53-mutated myeloid malignancies, yet it is often inaccessible due to treatment-related toxicity from pretransplant therapy. With standard HMA/venetoclax dosing, early complications frequently lead to clinical deterioration, rendering patients ineligible for transplant. By contrast, a metronomic approach may reduce these early toxicities, helping to preserve functional status and maintain eligibility for transplant, thereby keeping a curative pathway within reach.

Building on this foundation, future progress in the management of TP53-mutated myeloid malignancies will likely depend on rational combination strategies. There is growing recognition that improving outcomes in this population will require adding a third agent to the HMA/venetoclax regimen. However, although conventional triplet regimens are often limited by overlapping toxicities, particularly myelosuppression and infection, the metronomic strategy offers a potential advantage: By reducing baseline toxicity, it creates a therapeutic window for safely incorporating additional agents.

Taken together, these findings support a shift in treatment design, from maximizing dose intensity to optimizing therapeutic balance. Future trials should leverage a metronomic approach to expand combination treatments and preserve tolerability, with the ultimate goal of improving both survival and QOL for patients with TP53-mutated myeloid malignancies.

References

1. Bruzzese A, Vigna E, Martino EA, et al. TP53-mutated acute myeloid leukemia: unanswered questions. Hematol Oncol. 2025;43(4):e70106. doi:10.1002/hon.70106
2. George B, Kantarjian H, Baran N, Krocker JD, Rios A. TP53 in acute myeloid leukemia: molecular aspects and patterns of mutation. Int J Mol Sci. 2021;22(19):10782. doi:10.3390/ijms221910782
3. 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. doi:10.1056/NEJMoa2012971
4. 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. doi:10.1158/1078-0432.Ccr-22-1183
5. Fernández HF, Mishra A. Transplant options and outcomes for TP53 myeloid disease. Hematology Am Soc Hematol Educ Program. 2024;2024(1):335-339. doi:10.1182/hematology.2024000558
6. Richardson DR, Zhou X, Reeder-Hayes K, et al. Home time among older adults with acute myeloid leukemia following chemotherapy. JAMA Oncol. 2024;10(8):1038-1046. doi:10.1001/jamaoncol.2024.1823
7. Goldfinger M, Mantzaris I, Shastri A, et al. Treatment of TP53-mutated myelodysplastic syndrome and acute myeloid leukemia with lowintensity metronomic decitabine and venetoclax. Haematologica. Published online April 2, 2026. doi:10.3324/haematol.2026.300534
8. Levitz D, Saunthararajah Y, Fedorov K, et al. A metabolically optimized, noncytotoxic low-dose weekly decitabine/venetoclax in MDS and AML. Clin Cancer Res. 2023;29(15):2774-2780. doi:10.1158/1078-0432.Ccr-23-0842
9. Goldfinger M, Mantzaris I, Shastri A, et al. A weekly low-dose regimen of decitabine and venetoclax is efficacious and less myelotoxic in a racially diverse cohort. Blood. 2024;144(22):2360-2363. doi:10.1182/blood.2024025834