Study of the Beach Regimen on Relapsed/Refractory Acute Myeloid Leukemia (R/R AML)

An Exploratory Clinical Study of the Beach Regimen on Relapsed/Refractory Acute Myeloid Leukemia for Prospective, Single-arm, Phase II

The purpose of this study is to determine the efficacy and safety of the Beach regimen on relapsed/refractory acute myeloid leukemia

Acute myeloid leukemia (AML), as a highly heterogeneous malignant clonal disease, has seen a continuous increase in incidence in recent years. Moreover, the proportion of relapsed/refractory AML (R/R AML) has also been increasing. Despite great advances in hematopoietic stem cell transplantation (HSCT), there is still up to 35-45% of patients being refractory to treatments or relapsed. The prognosis of R/R AML is dismal, with less than 10% overall survival (OS) at 3 years. There is no standard salvage therapy for patients with R/R AML, it is particularly important to explore safe and effective new treatment methods.

HSCT is the only potentially curative strategy for most patients, but for R/R AML patients, which enrolled in clinical trials should be first priority. Targeted drugs have provided opportunities for some patients with R/R AML to achieve remission again. The 2025 NCCN guidelines, emphasize the importance of comprehensive mutational profiling at diagnosis and at relapse to guide targeted treatment strategies for patients with R/R AML, and the guidelines have added two targeted drugs specifically for certain molecular subtypes, significantly altering the treatment landscape for patients in this category. Zifnomenib is specifically used for the treatment of R/R AML patients with NPM1 mutations. Revumenib is applicable to patients with R/R AML who have KMT2A rearrangement or NPM1 mutation.

BCL-2 inhibitor, the Venetoclax (VEN) is an effective and selective small molecule, which has been widely used for R/R AML, and it showed the synergistic activity with low-dose demethylating drugs in AML. Now, our center was ongoing a single-arm phase 2 trial, the VEN combined with Chidamidec, Azacitidine, Cytarabine, Aclacinomycin, and G-CSF was explored as an induction scheme for elderly patients with newly diagnosed AML (referred to as CACAG-VEN) to investigate its safety and efficacy. The results showed that the overall response rate (ORR) reached 97.5%, and the composite complete response rate (CRc) was 85.0% in the first cycle. Among the patients with ELN adverse risk, the CRc rate was 81.3%. The 12-month overall survival rate (OS) was 73.4% (95% CI: 55.9-84.8%), and there was no early death within 30 days. The main grade 3-4 non-hematological adverse events were febrile neutropenia (37.5%) and pneumonia (7.5%), indicating good tolerance of this regimen. For the adult AML patients (N=30) reported similar results, with an ORR of 96.7%, CRc rate of 93.3%, and a CRc rate of 86.7% among NCCN high-risk patients. The CRc rate could reach 100% after two cycles of treatment.

In recent years, EZH2 inhibitor have been approved for market and have advanced to the clinical trial stage, and have also generated a number of clinical research results in AML. EZH2 inhibitors not only can re-activate tumor suppressor genes by reducing the abnormal compactness of chromatin caused by H3K27me3 and enhancing the accessibility of chromatin, they can also inhibit the activity of EZH2 protein to eliminate the excessive accumulation of H3K27me3 on DNA, thereby relieving the stemness and excessive proliferation of malignant cells and promoting the differentiation and apoptosis of AML cancer cells. Furthermore, EZH2 inhibitors was conjunction with chemotherapy/targeted drugs to overcome drug resistance and promote the differentiation and apoptosis of leukemia stem cells (LSCs). At the 2025 American Hematology Association Conference, the phase I clinical study of the combination of EZH2 inhibitor and CPX-351 (NCT05627232) were announced for R/R AML after previous chemotherapy.

Base the research confirmed the combined effect of the epigenetic drug EZH2 inhibitor and the targeted drug has also been preliminarily verified. Therefore, this study, based on the previous CACAG-VEN protocol, reduced the use of chemotherapy drugs and replaced the aclacinomycin in the protocol with the EZH2 inhibitor Zemestosita. A prospective, single-arm clinical trial is planned to be conducted to explore the effectiveness and safety of the Beach protocol (BCL-2 inhibitor, Zemestosita, Azacitidine, Cytarabine, Chidamide, and G-CSF) for the treatment of R/R AML, to further improve the survival benefits of patients and enable more patients to tolerate this treatment protocol.

Inclusion Criteria:

1. Age 18-75 years
2. Confirmed diagnosis of R/R AML
3. Adequate organ function: TBIL ≤2×ULN; ALT/AST ≤2.5×ULN; Cr ≤ULN or Ccr ≥50 mL/min
4. ECOG performance status ≤2
5. Life expectancy ≥4 months
6. No severe allergic history
7. Not participating in other interventional trials during study
8. Signed informed consent -

Exclusion Criteria:

1. Hypersensitivity to any study drug
2. Dysphagia or uncontrolled gastrointestinal disease impairing oral intake
3. Acute promyelocytic leukemia (APL)
4. Prior treatment with EZH1/2 inhibitors
5. Allogeneic hematopoietic stem cell transplantation within 6 months
6. Participation in another interventional trial within 4 weeks
7. Smoking and excessive drinking have affected the evaluation of the test results;
8. Undergone major organ surgery within the previous 6 weeks and whose recovery was not complete
9. Severe chronic respiratory disease requiring continuous oxygen
10. Clinically significant cardiac, renal, hepatic, neurologic, or endocrine disease; Child-Pugh B/C cirrhosis
11. Active uncontrolled infection including HBV, HCV, HIV, syphilis
12. Pregnant or breastfeeding women; women planning pregnancy during study
13. The patients deemed unsuitable by the researchers to participate in this study. -