Venetoclax Plus Azacitidine Versus Intensive Chemotherapy for Fit Patients With Newly Diagnosed NPM1 Mutated AML

AML is a heterogeneous disease of malignant early myeloid cells with a poor prognosis. Currently the only potentially curative treatment for patients with AML is intensive induction chemotherapy with 7 days of standard-dose cytarabine plus 3 days of an anthracyclin (7+3) followed either by several courses of consolidation chemotherapy with high-dose cytarabine or by allogeneic stem cell transplantation as standard of care (SOC). Complete remission (CR) is achieved in 60-80% of younger patients (aged 16-60 years) and in around 50% of older patients aged ≥ 60 years by this induction chemotherapy. However, this induction chemotherapy is toxic, due to prolonged myelosuppression with resulting infectious complications and organ toxicity with severe nausea, mucositis, colitis and cardiotoxicity. Each cycle of this intensive chemotherapy usually results in prolonged hospitalization of the patients and requires extensive supportive care with blood products and anti-infective agents. In addition, patients treated with intensive induction chemotherapy are at increased risk for several serious long-term side effects including cardiac and neurological sequelae, infertility and secondary cancers. The high toxicity burden in general and cardiovascular toxicity specifically consistently increase total costs in intensive induction and consolidation chemotherapy. From this perspective there is a need for therapies with lower toxicity and better efficacy.

Due to the high risk of early mortality, older patients and those with severe pre-existing conditions are typically treated with non-intensive chemotherapy with either low-dose cytarabine (LDAC) or a hypomethylating agent (HMA) either azacitidine or decitabine.While these treatments offer at best modest efficacy with CR rates of only 10%-30% and median overall survival of 6-12 months, combinations with the B-cell lymphoma-2 inhibitor venetoclax have been shown to produce CR rates between 50-75% in patients not eligible for intensive chemotherapy. The best response of venetoclax-based regimens with response rates up to 93% and two-year overall survival of 75% has been found among others in the large group of AML patients with mutations in the NPM1 gene. Standard intensive treatment in NPM1 mutated AML patients without adverse risk features usually consisting of standard of care chemotherapy plus gemtuzumab ozogamicin (GO) induces CR rates around 85%, and leads to a 5-year overall survival of around 40% - 50%.The rate and durability of response to venetoclax-based combinations in single arm studies with NPM1 mutated AML patients compared favourably with outcomes from intensive chemotherapy. A retrospective analysis in elderly AML patients with NPM1 mutation found remission rates of 73% in the entire cohort and 96 % in patients \> 65 years. The venetoclax-based combination with the HMA azacitidine is generally well tolerated and has a better safety profile than intensive chemotherapy.