这是用户在 2025-6-7 15:28 为 https://www.perplexity.ai/search/assume-yourself-is-an-experien-27cNUZU0S_qFTVIH69MTug 保存的双语快照页面,由 沉浸式翻译 提供双语支持。了解如何保存?
User avatar

Assume yourself is an experienced hematologic doctor specialized in treating AML and good at providing best treatment plans to your patient. Now you have a patient, age 63, male, he had previously administered to a hospital for AML, I have attached the bone marrow genetic testing report in file s99_report and his historical blood test report in the pdf file. The patient had diagnosed with MDS and now has progressed to AML, he has completed the first cycle of chemotherapy using 阿扎胞苷 + 维奈克拉 + 西达本胺 starting 5/11/25, blood test were taken every two days and all recorded in Blood Test Report. How can you help me investigate this case and provide some feasible treatment plan? More importantly, is 异体干细胞移植 a good treatment approach given the patient has a few genes mutated with poor prognostic results like TP53

Comprehensive Analysis and Treatment Strategy for High-Risk AML Patient with Multiple Molecular Aberrations
多重分子畸变高危 AML 患者的综合分析及治疗策略

This 63-year-old male patient presents a complex case of myelodysplastic syndrome (MDS) that has progressed to acute myeloid leukemia (AML) with multiple high-risk molecular aberrations. The genomic profile reveals several concerning mutations that significantly impact prognosis and treatment selection, necessitating a carefully tailored therapeutic approach that balances efficacy with the patient's clinical condition.
这名 63 岁的男性患者,病情复杂,患有骨髓增生异常综合征(MDS),并已进展为急性髓系白血病(AML),且伴有多处高危分子畸变。其基因组图谱揭示了若干令人担忧的突变,这些突变会显著影响预后和治疗选择,因此需要根据患者的临床状况,精心制定治疗方案,以平衡疗效。

Molecular Profile Analysis and Risk Stratification
分子谱分析和风险分层

The genomic sequencing results reveal a particularly challenging molecular landscape that places this patient in the highest risk category for AML. The TP53 p.(Val272Met) mutation with a variant allele frequency (VAF) of 79.95% represents the most concerning finding, as TP53 mutations are associated with extremely poor outcomes in AML34. This high VAF suggests a dominant clone and indicates a multi-hit TP53 alteration, which confers the worst prognosis within the TP53-mutated subset4. Studies consistently demonstrate that TP53-mutated AML patients have median overall survival of only 5-9 months with standard therapies45.
基因组测序结果揭示了极具挑战性的分子图谱,使该患者处于 AML 最高风险类别。TP53 p.(Val272Met)突变的变异等位基因频率 (VAF) 为 79.95%, 这是最令人担忧的发现,因为 TP53 突变与 AML 极差的预后相关 3 4 如此高的 VAF 提示存在显性克隆,并提示存在多发性 TP53 变异,这在 TP53 突变亚群中是预后最差的 4 研究一致表明,TP53 突变型 AML 患者在接受标准疗法后,中位总生存期仅为 5-9 个月 4 5

The SF3B1 p.(Lys700Glu) mutation (VAF 48.96%) represents another adverse prognostic factor, as SF3B1 mutations are associated with poor outcomes in myeloid malignancies and indicate disrupted RNA splicing machinery2. Additionally, the patient harbors dual NRAS mutations - p.(Gly12Cys) and p.(Gln61Pro) with VAFs of 11.22% and 38.52% respectively - which activate oncogenic MAPK signaling pathways and may contribute to treatment resistance2. The FLT3 p.(Ile867Ser) mutation, while present at a lower VAF (1.98%), still represents a therapeutically targetable alteration that could influence treatment selection2.
SF3B1 p.(Lys700Glu) 突变 (VAF 48.96%) 代表另一个不良预后因素,因为 SF3B1 突变与髓系恶性肿瘤的不良预后相关,并表明 RNA 剪接机制中断 2 此外,患者还携带双重 NRAS 突变 - p.(Gly12Cys) 和 p.(Gln61Pro),VAF 分别为 11.22% 和 38.52% - 这会激活致癌 MAPK 信号通路,并可能导致治疗耐药性 2 . FLT3 p.(Ile867Ser) 突变虽然 VAF 较低 (1.98%),但仍代表着一种可作为治疗靶点的改变,可能会影响治疗选择 2

The tumor mutational burden (TMB) of 26.4 mutations/megabase classifies as TMB-high, potentially making the patient eligible for immunotherapy approaches, though the clinical significance in AML remains investigational2. The blast percentage of 48% confirms the transformation from MDS to AML, and the history of prior MDS further compounds the adverse risk profile.
肿瘤突变负担 (TMB) 为 26.4 个突变/兆碱基 ,属于 TMB 高,可能使患者适合接受免疫治疗方法,但其在 AML 中的临床意义仍在研究中 2 . 48% 的原始细胞百分比证实了从 MDS 到 AML 的转变,并且先前的 MDS 病史进一步加剧了不利的风险状况。

Current Treatment Response Assessment

The blood test results from the first treatment cycle (azacitidine + venetoclax + chidamide starting 5/11/25) demonstrate the expected pattern of cytotoxic therapy response. The white blood cell count showed dramatic reduction from 377.18 × 10⁹/L on 5/6/25 to 8.23 × 10⁹/L by 5/19/25, indicating effective cytoreduction1. However, several concerning trends emerge from the laboratory data that warrant close monitoring.

The persistent severe anemia with hemoglobin levels remaining critically low (44-55 g/L throughout the treatment period) reflects both disease burden and treatment-related myelosuppression1. The severe thrombocytopenia (platelet counts 11-41 × 10⁹/L) poses significant bleeding risks and may limit treatment intensity1. The progressive decline in albumin levels from 27.8 g/L to 26.3 g/L suggests either poor nutritional status or ongoing inflammation1. Notably, the initial hyperuricemia (908 μmol/L) resolved with treatment, indicating effective tumor lysis management1.

The elevated lactate dehydrogenase levels (853-2669 U/L) throughout the treatment period suggest ongoing cellular turnover and potential residual disease burden1. The fluctuating electrolyte abnormalities, particularly hypokalemia and hypocalcemia, require continued monitoring and replacement therapy1.

Treatment Resistance Mechanisms and Therapeutic Implications

The combination of azacitidine and venetoclax represents current standard-of-care for older AML patients ineligible for intensive chemotherapy. However, TP53 mutations confer significant resistance to venetoclax-based combinations345. Multiple studies demonstrate that TP53-mutated AML patients achieve lower response rates (41-66% versus 89% in TP53 wild-type) and shorter overall survival (5.2 versus 23.4 months) when treated with venetoclax and hypomethylating agents35. The resistance mechanism involves perturbation of mitochondrial homeostasis and increased oxidative phosphorylation in TP53-mutated cells4.

Recent clinical data suggests that adding venetoclax to hypomethylating agents may not significantly improve outcomes compared to hypomethylating agents alone in TP53-mutated AML416. A large retrospective study found no improvement in overall survival when comparing HMA + venetoclax versus HMA alone in TP53-mutated patients, despite higher initial response rates16. This finding challenges the current approach and suggests the need for alternative therapeutic strategies.

Allogeneic Stem Cell Transplantation Considerations

The question of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in TP53-mutated AML represents one of the most challenging decisions in modern hematology. Current evidence suggests mixed but generally poor outcomes for TP53-mutated patients undergoing transplantation678. A systematic review and meta-analysis revealed 2-year overall survival rates of only 15.3-17.2% and relapse rates of 79-86% in TP53-mutated AML patients post-transplant7.

However, several factors may influence transplant outcomes and patient selection. TP53 variant allele frequency emerges as a critical prognostic factor817. Patients with TP53 VAF < 50% demonstrate significantly better outcomes with 2-year progression-free survival of 60% compared to only 3% for those with VAF ≥ 50%8. Unfortunately, this patient's TP53 VAF of 79.95% places him in the highest-risk category for post-transplant relapse.

Cytogenetic abnormalities also influence transplant outcomes8. Patients with complex cytogenetics, 5q deletions, or 7q deletions have inferior results compared to those without these abnormalities8. The absence of complex cytogenetics information in the current genomic report necessitates conventional cytogenetic analysis to better stratify transplant risk.

Despite generally poor outcomes, transplantation may still represent the only potential curative approach for selected TP53-mutated patients619. Recent single-center data suggests that carefully selected patients can achieve long-term survival rates around 30%6. The decision should consider patient age, performance status, comorbidities, donor availability, and response to initial therapy.

Targeted Therapy Optimization

Given the complex molecular profile, several targeted approaches merit consideration. The FLT3 I867S mutation, though present at low VAF, remains therapeutically targetable2910. Guidelines recommend incorporating FLT3 inhibitors such as midostaurin or gilteritinib into treatment regimens for FLT3-mutated AML910. Gilteritinib demonstrates particular efficacy in relapsed/refractory settings and could be considered for combination therapy182021.

The dual NRAS mutations present opportunities for MEK inhibitor therapy2. Clinical trials investigating binimetinib, trametinib, or cobimetinib in RAS-mutated malignancies show promising activity, though specific efficacy in AML remains limited2. The TMB-high status (26.4 mut/MB) potentially qualifies the patient for pembrolizumab therapy, as FDA-approved for TMB-high solid tumors, though evidence in AML remains investigational2.

Novel approaches targeting TP53-mutated AML represent an urgent clinical need. Experimental therapies include eprenetapopt (APR-246), a TP53 reactivator that showed promise in early trials14. Immunotherapeutic approaches, including magrolimab, flotetuzumab, and cusatuzumab, are advancing in clinical trials specifically for high-risk AML4.

Comprehensive Treatment Recommendations

Immediate Management (Current Cycle)

Continue the current azacitidine + venetoclax + chidamide regimen while monitoring response parameters. Obtain formal cytogenetic analysis to complete risk stratification. Add prophylactic antimicrobials given severe neutropenia and infection risk. Implement aggressive supportive care including blood product support, electrolyte management, and nutritional optimization.

Short-term Strategy (Next 1-2 Cycles)

Consider adding a FLT3 inhibitor (gilteritinib 120mg daily) to the current regimen, as combination therapy may improve efficacy without prohibitive toxicity18. Evaluate for clinical trial eligibility, particularly trials investigating novel agents for TP53-mutated AML or combination approaches with immune checkpoint inhibitors. Reassess disease response after 2 cycles using bone marrow evaluation with flow cytometry and molecular monitoring.

Long-term Planning (3-6 Months)

If adequate response is achieved, pursue allogeneic transplantation evaluation despite the poor prognosis associated with high TP53 VAF. The patient's age (63 years), assuming good performance status and adequate organ function, does not preclude transplantation. Identify potential donors including matched siblings, unrelated donors, or haploidentical family members. Consider reduced-intensity conditioning regimens to minimize treatment-related mortality while preserving graft-versus-leukemia effects.

Alternative Approaches

If standard therapy fails or patient is not a transplant candidate, consider experimental approaches including enrollment in clinical trials of TP53-targeted agents, novel immunotherapies, or combination regimens4. Maintenance therapy with FLT3 inhibitors post-remission may help maintain disease control10. Palliative care consultation should be considered early to optimize quality of life and assist with complex decision-making.

Conclusion

This case represents one of the most challenging scenarios in AML management, with multiple adverse molecular features converging to create an extremely high-risk profile. The TP53 mutation with high VAF, in particular, significantly limits treatment options and prognosis. While allogeneic transplantation offers the only potential for cure, the likelihood of long-term success remains disappointingly low at approximately 15-30%. However, given the alternative of certain progression and death with non-transplant approaches, carefully selected patients may still benefit from this aggressive intervention. The key lies in achieving the best possible disease control with current therapy, optimizing the patient's clinical condition, and proceeding expeditiously to transplantation if a suitable donor is available. Concurrent enrollment in clinical trials investigating novel therapeutic approaches should be actively pursued to provide additional treatment options for this challenging patient population.

Related
Given the patient's TP53 mutation, how effective is venetoclax + azacitidine in his case
Should I consider early allogeneic stem cell transplantation despite poor prognostic genes
How do the genetic mutations in s99_report influence my choice of targeted therapies
What are the risks and benefits of 异体干细胞移植 for this patient with adverse genetic features
How can I interpret his blood test trends to assess treatment response and disease progression
Blood-Test-Report.pdf
s99_report.pdf