What is the optimal management for a patient with myelodysplastic syndrome harboring a biallelic TP53 mutation?

Management of MDS with Biallelic TP53 Mutation

Patients with MDS harboring biallelic TP53 mutations should be immediately evaluated for allogeneic stem cell transplantation (allo-SCT), as this represents the only potentially curative option, while azacitidine 75 mg/m² subcutaneously for 7 consecutive days every 28 days serves as bridging therapy or first-line treatment for non-transplant candidates. 1, 2

Diagnostic and Prognostic Considerations

Biallelic TP53 inactivation defines a distinct disease entity with uniquely poor outcomes that differs fundamentally from monoallelic TP53 mutations:

• Biallelic TP53 alterations (multi-hit: two mutations, mutation plus deletion, or mutation plus copy-neutral loss of heterozygosity) are associated with complex karyotype, high-risk presentation, rapid leukemic transformation, and median overall survival of 5-10 months 3, 4, 5
• The WHO 2016 and recent 2025 classifications recognize MDS with biallelic TP53 inactivation as a separate diagnostic entity requiring detection of TP53 locus deletion or CN-LOH when single TP53 mutation has VAF <50% 6
• Monoallelic TP53 mutations do not carry the same dire prognosis and patients have outcomes similar to TP53 wild-type MDS, making allelic state determination critical 4
• TP53 mutations predict resistance to lenalidomide even in del(5q) MDS, with diminished response or early relapse 6, 1

First-Line Treatment Algorithm

For Transplant-Eligible Patients (Age ≤70 years, selected fit patients >70)

Immediate allo-SCT evaluation is mandatory at diagnosis 1, 2:

• Acceptable donor sources include HLA-identical siblings, matched unrelated donors, haploidentical donors, and cord blood units 1
• Bridging therapy with azacitidine (2-6 cycles) is commonly employed before transplant to reduce blast burden or for logistical reasons, though responses are typically short-lived 1, 7, 2
• Do not delay transplant referral—TP53-mutated MDS progresses rapidly and early evaluation maximizes curative potential 1

For Non-Transplant Candidates

Azacitidine remains the standard first-line therapy despite limited efficacy 1, 7, 2:

• Dosing regimen: 75 mg/m² subcutaneously daily for 7 consecutive days every 28 days 1, 7, 2
• Minimum 6 cycles required before assessing efficacy, as delayed responses can occur (though less common in TP53-mutated disease) 1, 7, 2
• Alternative 5-2-2 regimen (5 days on, 2 days off, 2 days on) is acceptable for logistical reasons but has not demonstrated survival advantage 7
• Response rates are lower in TP53-mutated patients compared to wild-type, and TP53 mutations correlate with shorter overall survival but do not completely preclude HMA response 6, 3
• Hematologic improvement (HI) by IWG 2006 criteria is clinically meaningful and associated with survival prolongation compared to supportive care alone 1, 7, 2

Critical Treatment Pitfalls to Avoid

• Never use lenalidomide as primary therapy for TP53-mutated MDS, even with del(5q) present—TP53 alterations predict resistance and poor outcomes 6, 1
• Do not postpone transplant evaluation—the window of opportunity closes rapidly as disease progresses 1
• Do not discontinue azacitidine before 6 cycles unless clear progression or unacceptable toxicity occurs 1, 7
• Do not rely on intensive chemotherapy—patients with TP53 mutations have lower response rates and shorter response duration with ICT 6

Post-HMA Failure Management

After hypomethylating agent failure, median overall survival is less than 6 months 1:

• Clinical trial enrollment is strongly recommended given consistently dismal outcomes with standard therapies 1, 3, 8
• Venetoclax-based combinations are under investigation but have not demonstrated clear survival advantage in TP53-mutated populations despite improved response rates 3, 8, 9
• Novel immunotherapeutic approaches (anti-CD47, anti-CD123 antibodies, cellular therapies) are in development and may hold promise as they bypass dysfunctional apoptosis pathways 8
• APR-246 (eprenetapopt), a p53 reactivator, showed initial promise in phase II trials but failed to demonstrate superior outcomes in phase III studies 8

Supportive Care Essentials

Comprehensive supportive measures are critical throughout the disease course 1, 2:

• Red blood cell transfusions should maintain hemoglobin ≥8 g/dL (9-10 g/dL in patients with cardiac/pulmonary comorbidities) 2
• Iron chelation therapy should be considered for transplant-eligible patients developing transfusion-related iron overload 1
• Antimicrobial prophylaxis and growth factor support should be administered as clinically indicated 1
• Psychosocial support and patient support group contacts should be systematically offered 2

Molecular Monitoring Considerations

• TP53 mutations can be detected in peripheral blood using sensitive sequencing techniques, which accurately reflect bone marrow findings 6
• Subclonal low-abundance TP53 mutations may expand during lenalidomide treatment, requiring sensitive detection methods before therapy initiation 6
• Variant allele frequency (VAF) and allelic state dictate clinical course more than blast count, supporting the concept of TP53-mutated HR-MDS/AML as a single molecular entity 4, 9