Hypomethylating Agent and Venetoclax in Newly Diagnosed and Relapsed CBFβ::MYH11(+) Acute Myeloid Leukemia
Authors: Feng Ziyu , Hu Xiaohui , Li Weiyang , Xu Ting , Xu Yang , Xue Shengli , Qiu Huiying , Tang Xiaowen , Han Yue , Chen Suning , Sun Aining , Wu Depei , Wang Ying 
Published: December 2024

Background:
The combination of a hypomethylating agent (HMA) and venetoclax (Ven) has become the standard of care for patients with newly diagnosed acute myeloid leukemia (AML) who are not candidates for intensive chemotherapy. Due to the regimen's simplicity, effectiveness, and lower toxicity, research is being conducted to explore its broader application. However, data on its efficacy in patients with CBFβ::MYH11(+) AML are scarce, as these patients have typically been excluded from most Ven-related studies. To address this gap, we have conducted an investigation into the efficacy of HMA+Ven in patients with CBFβ::MYH11(+) AML.
Methods:
We retrospectively analyzed 42 patients with CBFβ::MYH11(+) AML who received induction treatment with HMA+Ven at the First Affiliated Hospital of Soochow University between 2019 and 2024. Patients were divided into two cohorts: (1) those with newly diagnosed AML and (2) those with relapsed AML. The primary objective of this study was to evaluate the overall response rate, which included complete remission (CR), CR with incomplete blood count recovery (CRi), and morphologic leukemia-free state. Measurable residual disease (MRD) was monitored using real-time quantitative reverse transcriptase-polymerase chain reaction. The absolute copy numbers of the fusion gene transcripts were normalized to those of the ABL gene (expressed as copies per 10^4 copies of ABL). Complete molecular remission (CMR) was defined as a fusion transcript level of less than 0.01%. The choice of postinduction therapy was at the discretion of the treating physician. The probability of overall survival (OS) was estimated using the Kaplan-Meier method.
Results:
Thirty-eight patients with newly diagnosed CBFβ::MYH11(+) AML were treated. The median age was 48 years (range, 15-79 years), and 23 were males. Thirty-three (86.8%) patients had tyrosine kinase gene mutations (including KIT, N/KRAS, and FLT3). After a single course of induction therapy, 34 patients (89.5%) achieved CR and 4 patients (10.5%) achieved CRi for a composite CR/CRi rate of 100%. The median transcript level of CBFβ::MYH11 at the end of cycle 1 was 54 copies (range, 0-2065). The post-induction therapy was varied according to the treating physician's discretion, and 14 patients received a second course of HMA plus Ven. The median transcript level after cycle 2 was 32 copies (range, 0-171). CMR was achieved in 3 patients within 2 cycles of HMA+Ven (one after the first cycle and two after the second cycle). The median duration of follow-up in the frontline cohort is 13 months (range, 2-52 months), and the 2-year probability of OS was 94.6% (95% CI, 87.6-100%). One patient died of infection in the consolidation with high-dose cytarabine, one patient died of disease recurrence and twelve patients proceeded to allogeneic hematopoietic stem cell transplantation (allo-HSCT) due to persistent MRD or relapse.
Ten patients with relapsed CBFβ::MYH11(+) AML were treated, including 6 patients from the aforementioned cohort. The median age was 51 years (range, 19-79 years), and 8 were males. Eight (80%) patients had tyrosine kinase gene mutations. Four out of the six patients with prior treatment using HMA plus Ven, and one out of the four patients without prior HMA plus Ven treatment, achieved CR/CRi after one cycle of re-induction therapy. Among the responders, 3 patients proceeded to myeloablative allogeneic HSCT directly, while two patients who did not undergo allo-HSCT remained in CR2 for 2 and 3 months at last follow-up, respectively.
As expected, the treatment was well-tolerated, and all side effects were temporary and reversible. No death was observed in the entire cohort during the induction period.
Conclusion:
Combination therapy with HMA+Ven yielded impressive responses as frontline therapy in patients with CBFβ::MYH11(+) AML. However, the efficacy of this combination in the salvage setting showed reduced response rates.