Clinical Study Protocol for the Treatment of Newly Diagnosed and Relapsed/Refractory Acute Myeloid Leukemia With KMT2A Gene Abnormalities Using VHEA（Venetoclax With Homoharringtonine，Etoposide，Cytarabine）

This study is a multicenter, single-arm, open-label clinical trial aimed at evaluating the efficacy and safety of the VHEA（Venetoclax with Homoharringtonine，Etoposide，Cytarabine）regimen in the treatment of newly diagnosed and relapsed/refractory acute myeloid leukemia (AML) with MLL gene abnormalities.

Leukemia is a malignant tumor of the blood system that seriously endangers human health, ranking among the top 10 in the mortality rate of malignant tumors in all age groups in China. Acute myeloid leukemia (AML) is a malignant clonal blood system disease originating from hematopoietic stem and progenitor cells, accounting for about 35% of newly diagnosed leukemia cases each year and 80% of adult leukemia cases. The overall prognosis is poor, with approximately 10-40% of newly diagnosed AML patients unable to achieve CR, and over 50% of AML patients eventually relapse. Especially in AML with KMT2A gene abnormalities, the conventional "3+7" chemotherapy regimen has a low remission rate and a high relapse rate.

Chromosomal translocations include the Mixed Lineage Leukemia gene (MLL), also known as the KMT2A gene, which produces various MLL fusion genes, including AF4, AF6, AF9, AF10, ENL, ELL, and AF1q. Currently, more than 70 MLL fusion genes have been reported. MLL gene abnormalities associated with leukemia account for 5% to 10% of all acute leukemias, and MLL-related leukemia has a poor prognosis. There is currently no standard treatment regimen for MLL-related AML with good efficacy. Current treatment options include conventional chemotherapy, targeted epigenetic and DNA damage response therapies. Conventional chemotherapy includes regimens composed of anthracyclines, cytarabine, and etoposide, followed by consolidation therapy with allogeneic hematopoietic stem cell transplantation, but the efficacy is still unsatisfactory.

Based on preliminary data from our institution, there have been a total of 30 cases of AML with MLL gene abnormalities since 2016, accounting for approximately 12% of all AML cases. Among these, 14 cases received initial induction chemotherapy using the standard "3+7" regimen, with only 4 cases achieving complete remission (28.6%), 3 cases achieving partial remission (21.4%), and 7 cases showing no response (50%). Five cases received induction chemotherapy using a priming regimen, but none achieved remission. Additionally, 11 patients either refused chemotherapy or sought treatment at other hospitals, indicating that conventional chemotherapy regimens do not yield satisfactory results in AML patients with MLL gene abnormalities. Therefore, it is of great clinical significance to explore more effective chemotherapy regimens for MLL gene abnormality-associated acute leukemia.

Venetoclax has demonstrated anti-tumor activity in various hematologic malignancies. In November 2018, the U.S. Food and Drug Administration (FDA) approved the use of Venetoclax in combination with hypomethylating agents (HMAs) or low-dose cytarabine for newly diagnosed AML patients aged 75 years and older who are unfit for intensive chemotherapy. According to the 2021 NCCN guidelines, Venetoclax in combination with HMAs or low-dose cytarabine is an important treatment strategy for both newly diagnosed elderly AML patients and relapsed/refractory AML patients who are not suitable for intensive chemotherapy. Recent exploratory studies have also been conducted on the use of Venetoclax in combination with hypomethylating therapy in newly diagnosed and relapsed/refractory AML with KMT2A gene rearrangement. These studies found that Venetoclax in combination with decitabine or azacitidine achieved an overall response rate (ORR) of 83% and a complete response/complete response with incomplete hematologic recovery (CR/CRi) of 75% in newly diagnosed AML with KMT2A gene rearrangement. However, in relapsed/refractory AML with KMT2A rearrangement, the ORR and CR/CRi were only 17% and 8%, respectively.