What is the recommended frontline therapy for an adult with TP53‑mutated myelodysplastic syndrome who is not an immediate transplant candidate?

Frontline Therapy for TP53-Mutated MDS in Non-Transplant Candidates

For adults with TP53-mutated myelodysplastic syndrome who are not immediate transplant candidates, hypomethylating agents (specifically azacitidine) remain the standard frontline therapy, though outcomes are poor and allogeneic stem cell transplantation should be pursued as soon as feasible given this represents the only potentially curative option. 1, 2

Treatment Algorithm

Primary Recommendation: Azacitidine

• Azacitidine 75 mg/m² subcutaneously daily for 7 consecutive days every 28 days is the recommended regimen, with at least 6 cycles required before assessing efficacy 1, 3
• The alternative "5-2-2" regimen (5 days on, 2 days off, 2 days on) is acceptable for logistical ease, though it has not demonstrated survival advantage in higher-risk MDS 3
• TP53 mutations represent the single greatest negative prognostic indicator in MDS, with inferior outcomes demonstrated across all approved treatment approaches 2

Critical Prognostic Context

• Patients with TP53 mutations have particularly poor outcomes even with hypomethylating agents, with median survival typically <6 months after HMA failure 1
• TP53 mutations are found in approximately 20% of MDS patients, with increased frequency in complex karyotype and therapy-related MDS 2
• High-risk TP53 aberrations (>1 mutation, one mutation plus allelic deletion, or single mutation with VAF ≥40%) confer worse prognosis than low-risk TP53 (single mutation VAF <40%) 4

Transplant Evaluation

Immediate Considerations

• All patients with TP53-mutated MDS should be evaluated for allogeneic stem cell transplantation eligibility at diagnosis, as this remains the only potentially curative therapy despite poor outcomes 1, 2
• Patients up to age 70 years (and sometimes fit patients >70 years) should be assessed for transplant candidacy 1
• HLA-identical siblings, matched unrelated donors, haploidentical donors, and cord blood are all acceptable donor sources 1

Bridging to Transplant

• 2-6 cycles of azacitidine are commonly used before hematopoietic stem cell transplantation to reduce bone marrow blasts or for logistical reasons 1, 3
• Patients with TP53 mutations and del(5q) who are resistant to lenalidomide should be considered candidates for HMAs and allogeneic SCT whenever possible 1

Response Assessment and Duration

Monitoring Parameters

• Do not discontinue azacitidine before 6 cycles unless there is clear disease progression or unacceptable toxicity, as most patients only respond after several courses 3
• Response criteria include complete remission (CR), partial remission (PR), and hematological improvement (HI) according to IWG 2006 criteria 1
• Achievement of HI is associated with prolongation of survival compared with supportive care 1, 3

Expected Outcomes

• Overall response rates with azacitidine in higher-risk MDS range from 40-60%, but are lower in TP53-mutated patients 2
• Median overall survival in TP53-mutated MDS is significantly shorter than in TP53 wild-type disease 4

Clinical Trial Consideration

Novel Approaches

• Patients with TP53-mutated MDS should be strongly considered for clinical trial enrollment, as standard therapies have demonstrated consistently poor outcomes 1
• Novel agents that directly target the mutant TP53 protein and immunotherapies demonstrate the greatest potential for this molecular subgroup 2
• Combination therapies with azacitidine (such as venetoclax, IDH inhibitors) are being tested but have not yet demonstrated clear advantage over azacitidine monotherapy in TP53-mutated disease 1

Common Pitfalls to Avoid

• Do not delay transplant evaluation: TP53-mutated MDS has aggressive biology and rapid progression; transplant assessment should occur immediately at diagnosis 1, 2
• Do not stop azacitidine prematurely: Responses may be delayed, requiring full 6-cycle evaluation period 3
• Do not use lenalidomide as primary therapy: Even in del(5q) MDS, TP53 mutations confer resistance to lenalidomide and predict poor outcomes 1
• Do not rely on intensive chemotherapy: AML-like chemotherapy has not shown superior outcomes in TP53-mutated MDS compared to hypomethylating agents 2

Supportive Care Requirements

• Regular RBC transfusions to maintain adequate hemoglobin levels 1
• Iron chelation therapy should be considered for transplant-eligible patients with transfusion-dependent iron overload 1
• Antimicrobial prophylaxis and growth factor support as clinically indicated 1