Finding Treatment Clues in a Tumor Genetic Report: Prof. Qinlong Zheng & Dr. Yuehui Lin Explain What Matters

Summary: Dr. Yuehui Lin of Beijing GoBroad Boren Hospital and Prof. Qinlong Zheng of the GoBroad Diagnostic Center explain how to read a genetic report for hematologic malignancies from three key perspectives: diagnosis, prognosis, and treatment. The diagnostic section reviews the MICM-based integrated workup for AML under current WHO/ICC classifications and the importance of screening for inherited predisposition genes such as TP53 and DDX41. The prognosis section explains the three-tier molecular-genetic risk stratification used in Chinese AML guidelines and why the exact type and location of a TP53 alteration matter. The treatment section links actionable targets such as FLT3, IDH1/2, BCL-2, and JAK2 with corresponding treatment options, illustrating how AML care is moving from a one-size-fits-all model toward truly individualized treatment.

In the era of precision medicine, genetic testing has become an important map and compass in modern cancer care. It can reveal the molecular drivers of disease and provide useful guidance at key decision points - helping clinicians refine the diagnosis, assess prognosis and risk, identify potential targeted therapies, monitor for relapse, investigate drug resistance, and sometimes uncover inherited cancer-predisposition risks. Yet in everyday practice, patients and families often face very practical questions: Do I need genetic testing? Which test should I have? When should it be done? And once I receive a report filled with unfamiliar terms and numbers, which findings actually matter for my treatment?

In this article, Dr. Yuehui Lin, Director of Ward 9, Department of Hematology I (Hematology/Oncology) at Beijing GoBroad Boren Hospital, and Prof. Qinlong Zheng, Director of the Molecular Diagnostics Laboratory at the GoBroad Diagnostic Center, take a closer look at these questions. Step by step, they explain how to identify the most meaningful clues in a complex tumor genetic report and turn laboratory data into information that can guide real-world treatment decisions.

1. Diagnosis

The diagnosis and treatment of hematologic malignancies have entered an era of integrated precision medicine. At diagnosis, clinicians need to bring together morphology, immunophenotyping, cytogenetics, and molecular genetics to achieve accurate WHO classification and ELN risk stratification. These findings help determine disease risk, the intensity of chemotherapy, whether a targeted therapy may be appropriate, and whether allogeneic hematopoietic stem cell transplantation (allo-HSCT) should be considered early. Before transplantation, inherited predisposition testing may also be considered for the patient and potential donors to identify clinically significant variants involving genes such as TP53, BRCA, and DNA-repair pathways. This information can help inform donor selection, conditioning strategies, and, where relevant, targeted treatment options. The ultimate goal is a full-course management strategy spanning diagnosis, classification, treatment, transplantation, measurable residual disease (MRD), and long-term follow-up - maximizing benefit while minimizing toxicity.

Dr. Yuehui Lin reviewed the diagnosis and classification of acute myeloid leukemia (AML) under the fifth edition of the WHO classification and the ICC. At initial diagnosis, AML requires a comprehensive MICM workup: morphology, flow-cytometric immunophenotyping, conventional cytogenetics with relevant FISH testing, and broad molecular genetic testing. This helps identify fusion genes such as PML::RARA, RUNX1::RUNX1T1, and CBFB::MYH11, as well as somatic and germline alterations involving genes including NPM1, CEBPA, FLT3-ITD, DDX41, ETV6, ANKRD26, and GATA2. When an inherited hematologic malignancy syndrome is suspected, paired testing using peripheral blood or buccal mucosa may be used to confirm germline pathogenic or likely pathogenic variants such as DDX41, TP53, RUNX1, CEBPA, GATA2, and ETV6. Reporting both tumor-associated and inherited predisposition variants can provide important evidence for risk stratification, targeted therapy selection, donor screening, and family assessment.

Figure 1. Diagnosis and Classification of Acute Myeloid Leukemia in the WHO 5th Edition and ICC

Figure 2. WHO 5th Edition and ICC Classification of Myeloid Neoplasms With Germline Predisposition

2. Prognosis

According to the Chinese guidelines for the diagnosis and treatment of acute myeloid leukemia (AML), molecular and genetic prognostic assessment should be performed promptly after diagnosis to classify patients into favorable-, intermediate-, or adverse-risk groups. The article notes that adverse-risk features may include TP53 alterations with a variant allele frequency (VAF) of at least 10%, complex karyotype, high-burden FLT3-ITD, and alterations in genes such as ASXL1, RUNX1, and BCOR. For TP53 in particular, the report must be interpreted carefully to distinguish clearly pathogenic alterations from variants of uncertain significance. The clinical meaning depends not only on whether TP53 appears on the report, but also on the exact variant, its location, functional significance, and allele burden.

Figure 3. AML Prognostic Risk Stratification in Chinese Clinical Guidelines

The article also notes that the 2025 CSCO and CACA guidelines stratify AML into favorable-, intermediate-, and adverse-risk groups according to genetic features, helping clinicians decide whether standard chemotherapy may be sufficient or whether intensified treatment and transplantation should be considered. Examples listed in the article include t(8;21)/RUNX1-RUNX1T1, inv(16)/CBFB-MYH11, and NPM1-mutated/FLT3-ITD-low disease in the favorable-risk category, while TP53-mutated disease, high-burden FLT3-ITD, and complex karyotype are described as adverse-risk features that may prompt earlier use of targeted therapy and consideration of allo-HSCT.

3. Treatment

As AML treatment becomes increasingly precise and more focused on long-term disease control, care has evolved beyond conventional chemotherapy alone toward a multidimensional strategy that can combine chemotherapy, targeted therapy, immunotherapy, and transplantation.

• For patients with FLT3 mutations, FLT3 inhibitors such as gilteritinib or midostaurin may be incorporated into treatment, including in combination with chemotherapy when appropriate;

• For IDH1-mutated disease, ivosidenib may be considered; for IDH2-mutated disease, enasidenib is a targeted option;

• For patients in whom BCL-2-directed treatment is appropriate, venetoclax combined with a hypomethylating agent has become an important regimen;

• For patients with JAK2 V617F, JAK inhibition such as ruxolitinib may be considered in relevant disease settings;

• For rare but potentially targetable fusions such as ETV6-ABL1, ABL1 inhibitors - including dasatinib, olverembatinib, or ponatinib - may be considered depending on the clinical context.

This shift in risk stratification and treatment selection reflects the broader move in AML care from standardized treatment for everyone toward strategies tailored to each patient's molecular profile, creating more opportunities for individualized treatment.

Dr. Yuehui Lin noted that targeted approaches can reduce reliance on conventional intensive chemotherapy and, in selected patients with molecularly defined AML such as FLT3- or IDH-mutated disease, may make lower-toxicity or even chemotherapy-free treatment strategies possible. Comprehensive mutation profiling at diagnosis can help the care team match each patient with a more individualized treatment pathway, with the aim of extending survival while preserving quality of life.

4. Treatment Response Monitoring

A central part of response monitoring is the dynamic assessment of measurable residual disease (MRD). Multiparameter flow cytometry (MFC), with sensitivity down to around 10^-4, is commonly used. For patients with trackable fusion genes, real-time quantitative PCR (RQ-PCR) can provide additional monitoring. For patients with somatic mutations, the article describes using the individualized mutation profile identified on the patient's diagnostic next-generation sequencing (NGS) panel for deep sequencing, with sensitivity approaching 10^-6 in some settings. Serial monitoring may be performed in bone marrow and, when appropriate, peripheral blood.

One important point: the timing of testing, the type of sample, and the clinical purpose of each test need to be considered together. These decisions should be made with guidance from an experienced clinician.

Figure 4. Molecular Testing Across the Full Course of Disease Management

5. Case Examples

Case 1 involved a boy born in 2008 who was diagnosed with B-cell acute lymphoblastic leukemia (B-ALL) and an initial white blood cell count of 1202 × 10^9/L. A local 43-fusion-gene panel and a small mutation panel were negative, and he did not achieve remission after two courses of treatment under the CCLG-ALL-2018 protocol. After transfer to our hospital, he received CD19 CAR-T cell therapy and achieved complete remission, followed immediately by haploidentical hematopoietic stem cell transplantation. The disease later relapsed again and responded poorly to several additional treatments. A review of bone marrow RNA sequencing performed at his first admission identified an ABL1 fusion, prompting adjustment of targeted and immune-based therapy. He subsequently achieved remission and continues to maintain molecular remission. The case illustrates how deeper molecular testing can reveal actionable information that may guide targeted and immunotherapeutic strategies.

Case 2 involved a 73-year-old patient with acute myeloid leukemia (AML). The initial white blood cell count was not markedly elevated, and NGS detected FLT3-ITD, NPM1, and IDH2 mutations. The patient received a lower-intensity combination strategy using a hypomethylating agent plus the FLT3 inhibitor gilteritinib and/or the IDH2 inhibitor enasidenib, without standard intensive chemotherapy. After three treatment cycles, morphologic complete remission was achieved, although the NPM1 mutation remained detectable at 0.12%. The patient continued maintenance with azacitidine (AZA) plus gilteritinib and has remained in molecular remission for 39 months without hematopoietic stem cell transplantation. The patient required 17 hospital admissions and 9 units of red blood cell transfusion before becoming transfusion independent. The case highlights how real-time NGS-based MRD assessment and multiparameter flow cytometry can help guide treatment adjustment in older patients or those who may not tolerate intensive chemotherapy.