Editor’s Note: Acute myeloid leukemia (AML) is a highly heterogeneous group with varying sensitivities to chemotherapy. The “7+3” regimen has been the standard induction chemotherapy for AML for 50 years. In the era of precision medicine, optimizing induction therapy for AML is a crucial issue. At the recent 65th American Society of Hematology (ASH) Annual Meeting, Professor Junmin Li’s team from the Hematology Department of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, presented the initial results of the RJ-AML2016 study. This multicenter, randomized, Phase III trial investigated the efficacy of adding Homoharringtonine (HHT) to optimize the idarubicin and cytarabine induction regimen based on Day 5 Peripheral Blast Clearance Rate (D5-PBCR) in newly diagnosed young AML patients. “Hematology Frontier” had the privilege of interviewing Professor Li on the study’s key findings and the team’s next research plans.
“Hematology Frontier”: Chemotherapy remains the primary treatment for acute myeloid leukemia (AML), and optimizing combination chemotherapy based on early efficacy biomarkers is crucial. First, why did your team choose “Day 5 Peripheral Blast Clearance Rate (D5-PBCR)” as the early intervention biomarker?
Professor Junmin Li: This is a crucial topic. The “7+3” regimen as the standard induction chemotherapy for AML has been in use for 50 years, and there is a need for further optimization. In an educational session at the conference, we reviewed the cure rate and long-term survival benefits of the “7+3” regimen and discussed the potential of enhancing induction therapy beyond the “7+3” regimen by combining it with other drugs. In yesterday’s session, our team specifically focused on the work we’ve done to optimize the “7+3” regimen for AML. Different AML patients respond differently to the “7+3” regimen, and we wondered if there was an effective way to identify early on those who are insensitive to standard chemotherapy. Therefore, we established the Day 5 Peripheral Blast Clearance Rate (D5-PBCR) as an indicator. Using flow cytometry to detect minimal residual disease (MRD) in peripheral blood, we calculated the clearance rate of leukemia cells on the 5th day of induction, accurately categorizing patients as sensitive or insensitive to standard chemotherapy. We started developing this method ten years ago, initiated sample collection and testing in 2013, and published a related paper in the Journal of Hematology & Oncology in 2015. This method, similar to an in vivo drug sensitivity test, allows us to determine the sensitivity of patients to chemotherapy early in the induction therapy, enabling us to selectively optimize the “7+3” regimen for those who need it. That was the purpose behind establishing the D5-PBCR indicator.
“Hematology Frontier”: At this ASH conference, your team presented the first results of a Phase III study (abstract 829) optimizing AML induction therapy based on Peripheral Blast Clearance Rate. Could you please provide a detailed overview of the study design and results?
Professor Junmin Li: As mentioned earlier, non-elderly AML patients can be stratified based on D5-PBCR during early induction therapy to identify those insensitive to chemotherapy, allowing us to consider additional drug therapy for this group. The question was, which drugs to add? Initially, eight years ago, when designing a small-sample Phase II study, we reduced the initial dose of anthracycline chemotherapy drugs in the standard “7+3” regimen based on international guidelines. We used 10mg/M^2*3d of idarubicin, leaving space for subsequent combination with other drugs. Simultaneously, we systematically examined drugs beyond standard treatment and ultimately chose the traditional Chinese medicine, Homoharringtonine (HHT), to investigate whether its addition could improve the efficacy of the “7+3” regimen for those insensitive to chemotherapy. In the 1970s, HHT was already used in China to treat AML. Ten years ago, scholars in China added HHT to the daunorubicin and cytarabine (DA) regimen, showing promising results. However, that study added HHT to all patients without stratification. Therefore, since 2015, we initiated a Phase II single-arm clinical study, including 151 patients insensitive to chemotherapy (D5-PBCR+), to assess the addition of HHT. The results demonstrated a significant improvement in the overall complete remission rate (CR) to 85% for patients insensitive to the “7+3” regimen during early induction therapy. This study was published in the American Journal of Hematology in 2021, reflecting the design concept of “IA+X” on the basis of idarubicin and cytarabine.
To further validate whether adding HHT to chemotherapy-insensitive patients can increase the complete remission rate and, more importantly, bring long-term survival benefits, we conducted a Phase III, randomized, controlled clinical study spanning seven years. This study included 649 young, newly diagnosed AML patients, and HHT was added in a 1:1 ratio to those insensitive to chemotherapy. We have obtained preliminary results from this study, which were presented at this conference. The study not only confirmed the results of the Phase II clinical study, showing a significant increase in the CR rate for AML induction therapy when HHT is added to chemotherapy-insensitive patients, but also provided more information with a larger sample size. Subgroup analysis revealed that low-risk patients achieved CR after standard treatment, with a near 100% CR rate for patients with CBFβ-MYH11 fusion genes. In other words, the “7+3” regimen is highly effective for low-risk individuals, and most do not need additional HHT. However, for intermediate-risk patients insensitive to chemotherapy, adding HHT significantly increased the CR rate. Notably, there was no significant improvement in the CR rate for high-risk patients, especially those with TP53 and U2AF1 gene mutations, whose remission rate after one induction course was less than 30%.
In conclusion, we found that adding HHT to the “7+3” regimen benefits intermediate-risk AML patients the most, while the benefits for high-risk patients are not significant. Furthermore, the study revealed that adding HHT can improve the overall event-free survival (EFS) for chemotherapy-insensitive patients, although overall survival (OS) did not significantly increase. The analysis suggests that many patients opted for new targeted therapies or underwent allogeneic hematopoietic stem cell transplantation after relapse, which holds great value for high-risk patients.
“Hematology Frontier”: From this study, it is evident that for AML patients with Day 5 Peripheral Blast Clearance Rate (D5-PBCR) positivity, the addition of Homoharringtonine (HHT) to the IA regimen (idarubicin + cytarabine) further improves the complete remission rate and event-free survival (EFS). This therapeutic strategy appears clinically feasible. Could you discuss its clinical significance?
Professor Junmin Li: Currently, AML treatment has entered the era of precision and personalized medicine. We need to build on the 50 years of experience with DA/IA regimens while acknowledging the heterogeneity in AML patient responses. Therefore, it is essential to effectively differentiate and intervene early for those who do not respond to standard chemotherapy. Our study, by adding HHT early in the induction, found that low and intermediate-risk patients benefit, while high-risk patients show less improvement.
So, which drugs can benefit high-risk patients? This is a hot topic that many researchers discussed and investigated at this ASH conference. For high-risk AML patients, a combination of targeted drugs, rather than chemotherapy, may be needed. For instance, patients with FMS-like tyrosine kinase 3 (FLT3) gene mutations might benefit from combining drugs like gilteritinib, quizartinib, or midostaurin, leading to improved long-term survival. For those without specific gene mutations for targeted drugs, combining a BCL-2 inhibitor like venetoclax with standard chemotherapy could be an option to see if it brings EFS and OS benefits to high-risk individuals. Studies both domestically and internationally are exploring these avenues, and our center is also working on this, awaiting further research results.
In conclusion, based on current data and ongoing studies, the future of AML treatment involves adding X to standard chemotherapy. However, not all patients need additional drugs; it’s about identifying those insensitive to standard chemotherapy and, based on their molecular biology, determining which additional drugs might benefit them. From current data, low and intermediate-risk patients may benefit from adding HHT, while high-risk patients may require targeted drugs such as FLT3 inhibitors, isocitrate dehydrogenase (IDH) 1/2 inhibitors, menin inhibitors, etc. Additionally, approved BCL-2 inhibitors or TP53 restoration agents may be used. Ultimately, the goal is to move AML towards a personalized and individualized treatment approach of “IA+X (1–n).”
“Hematology Frontier”: Based on the results obtained from this study, does your team have any next steps or future research plans?
Professor Junmin Li: Currently, in young, newly diagnosed AML patients, the overall CR rate has reached a relatively high level. I believe the focus in the future should be on how to extend patients’ long-term survival. Besides the addition of X drugs to chemotherapy, we need to explore more immunotherapy options. For example, Ruijin Hospital is currently conducting umbilical cord blood treatment for elderly patients, even CAR-T therapy, and hematopoietic stem cell transplantation, which is becoming more widely used.
During treatment, our emphasis should be on controlling the disease rapidly in the first step and then ensuring patients achieve longer survival in the second step. Beyond chemotherapy and targeted therapy, it is crucial to consider how to restore the immune system, allowing patients to achieve genuinely prolonged survival. Apart from hematopoietic stem cell transplantation, there should be other methods. We are currently considering the combination of mRNA vaccines and other approaches for treatment.
Professor Junmin Li
Director, Doctoral Supervisor
Vice President, Wuxi Branch of Ruijin Hospital
Director, Consultation Center for Difficult Cases, Shanghai Jiao Tong University School of Medicine Affiliated Ruijin Hospital
Deputy Director, Shanghai Institute of Hematology
Vice President, Hematology Branch of the Chinese Medical Doctor Association
President, Hematology Branch of the Chinese Geriatrics Medical Association
Vice President, Hematology Branch of the Chinese Medical Promotion Association
Chairman, Shanghai Hematologic Oncology Professional Committee of the Chinese Anti-Cancer Association
Chief Scientist, National Key Project on Tumor mRNA Vaccines, Ministry of Science and Technology
