Q1: In recent years, new treatment approaches for refractory AML—including targeted therapy, immunotherapy, and cell therapy—have emerged. How would you evaluate the current status of treatment for these patients in China?

Prof. Wang: The most significant breakthrough in AML treatment over the past years lies in our deeper understanding of the disease's pathogenesis. We first needed to clarify why some patients fail to respond well to therapy, which led researchers to systematically investigate the mutational landscape associated with treatment resistance. Based on these molecular insights, the development of mutation-specific targeted agents became possible.

Currently, the range of targeted drugs available in clinical practice is expanding. A milestone example is imatinib, the first targeted therapy for hematologic malignancies worldwide, which revolutionized chronic myeloid leukemia (CML) by precisely targeting the BCR-ABL fusion gene—turning CML into a manageable chronic condition, and even achieving clinical cures.

For AML, the introduction of targeted therapies has improved outcomes for some refractory patients. For those unresponsive to conventional chemotherapy, combining targeted drugs can induce remission. However, these agents have notable limitations—monotherapy rarely prevents relapse. Allogeneic hematopoietic stem cell transplantation (allo-HSCT), the traditional curative approach, also faces significant challenges: patients who undergo transplant without achieving remission have a much higher relapse rate, and even those transplanted successfully remain at risk of relapse.

Targeted therapies have transformed transplant strategies in two key ways:

• Pre-transplant: For chemotherapy-resistant patients, targeted drugs can induce remission, creating an opportunity for transplantation.
• Post-transplant: Maintenance therapy with targeted agents significantly reduces relapse risk. Clinical data show that integrating targeted drugs improves transplant success rates primarily by effectively controlling relapse.

In contrast to lymphoid leukemias, progress in cellular therapies for AML has been relatively slow. Despite numerous clinical trials, challenges such as difficult target selection and high tumor heterogeneity have hindered breakthroughs. Consequently, the combination of targeted therapy and allo-HSCT remains the primary curative strategy for AML today.

Q2: Allogeneic HSCT is still regarded as the most important “potentially curative” approach for refractory AML. In which patients should transplant be considered as early as possible?

Prof. Wang: AML treatment strategies are now very clear—precision risk stratification is key. Previously, we leaned toward transplanting all patients. Today, we recognize that some patients can achieve long-term survival with chemotherapy alone, minimizing treatment burden. Therefore, our main task is to identify these patients through precise risk assessment.

The widely adopted European Leukemia Net (ELN) classification divides patients into favorable, intermediate, and adverse risk groups:

• Favorable risk: Transplant is not recommended; chemotherapy alone can achieve cure rates of 50–60%.
• Adverse risk: Due to poor genetic profiles, nearly all patients relapse after chemotherapy, so allo-HSCT is necessary regardless of remission status; otherwise, prognosis is extremely poor.
• Intermediate risk: This group remains the most controversial. According to ELN guidelines and Chinese clinical practice, allo-HSCT is still advised for these patients, as current chemotherapy and targeted approaches remain suboptimal.

Our ultimate goal is to achieve maximal survival benefit with minimal treatment burden. While transplant remains a high-risk and technically demanding “last resort,” for intermediate-risk patients, its feasibility should still be discussed at diagnosis.

Q3: Post-transplant relapse remains the leading cause of treatment failure in refractory AML. How do you optimize risk stratification and monitoring in clinical practice?

Relapse after allo-HSCT continues to be the primary cause of transplant failure. Advances in supportive care have significantly reduced mortality from GVHD and infections, bringing relapse into sharper focus. To address this challenge, we emphasize three key areas:

1. Pre-transplant optimization: Ideally, patients should achieve MRD (measurable residual disease) negativity before transplant. However, in practice, there are two special groups: patients who cannot achieve hematologic remission and high-risk patients requiring urgent transplantation. At our center, 78% of transplant cases are in non-remission states, posing higher relapse risks.
2. Conditioning regimen design: The key lies in balancing intensity—overly aggressive regimens increase transplant-related mortality, while insufficient intensity raises relapse risk.
3. Post-transplant strategies:
• Comprehensive MRD monitoring: We use multiparametric approaches, including flow cytometry, chimerism analysis, and genetic testing, to detect relapse before hematologic recurrence (where salvage therapy success is only 20–30%).
• Targeted maintenance therapy: Evidence shows that graft-versus-leukemia (GVL) effect alone is insufficient to prevent relapse. Early intervention with targeted agents significantly lowers relapse rates.
• Immunomodulation: Our center adopts an interferon-based strategy—early tapering of immunosuppressants combined with long-acting interferon—to enhance GVL in a safer and more controllable way than donor lymphocyte infusion, which carries risks of severe GVHD or marrow suppression.

It is worth noting that our team was among the first in China to apply chimerism monitoring in clinical practice, a technique now widely adopted. By integrating these strategies, we have improved relapse control and overall survival outcomes for transplant patients.