*1.3.1.1 Venetoclax*

*Acute Leukemias*

*1.2.1.2 Ivosidenib*

syndrome (6%) [67]. These results led to the FDA approval of enasidenib in r/r IDH2 mutated AML patients on 1 August 2017. With regard to predictors of response, the IDH2 mutation allele burden at study entry had no effect on response rate [66]. In a open-label, multicenter, phase 1 study patients 134 newlydiagnosed mIDH1 or mIDH2 AML were treated with induction therapy in combination with either ivosidenib 500 mg once daily (for mIDH1) or enasidenib (mIDH2) 100 mg daily. Among the 77 enasidenib-treated patients evaluable for efficacy, a response of CR, CRi, or CRp was achieved in 73% patients with de novo AML and in 63% patients with sAML. The most frequent co-occurring baseline mutations for patients with IDH2 mutations were DNMT3A, SRSF2 and ASXL1 [68].

Ivosidenib (AG-120) is a potent and selective IDH1 mutation small-molecule inhibitor. In phase 1, multicenter, open-label, dose-escalation and dose-expansion study 258 patients received ivosidenib orally, daily, in 28-day cycles. In the primary efficacy population (125 patients), the rate of complete remission or complete remission with partial hematologic recovery was 30.4%, the rate of complete remission was 21.6% and the overall response rate was 41.6%. The median durations of these responses were 8.2 months, 9.3 months, and 6.5 months, respectively. No residual detectable IDH1 mutations on digital polymerase-chain-reaction assay were detected in 21% patients who had a complete remission or complete remission with partial hematologic recovery. The most common adverse events (in ≥20% of the patients), irrespective of a relationship to ivosidenib, were diarrhea, leukocytosis, febrile neutropenia, nausea, fatigue, dyspnea, prolongation of the QT interval. Peripheral edema, anemia, pyrexia, cough and and differentiation syndrome [69]. The results of this study led to the FDA approval of ivosidenib in r/r IDH1 mutated AML patients on 2 may 2019. Prescribing information contains a boxed warning about the risk of differentiation syndrome which may be life-threatening or fatal. In a open-label, multicenter, phase 1 study patients 134 newlydiagnosed mIDH1 or mIDH2 AML were treated with induction therapy in combination with either ivosidenib 500 mg once daily (for mIDH1) or enasidenib (mIDH2) 100 mg daily. Among the 41 ivosidenib-treated patients evaluable for efficacy, a response of CR, CRi or CRp was achieved in 93% patients with de novo AML and 46% patients with sAML. Twenty-one patients received ≥1 cycle of consolidation therapy and 11 patients received maintenance after consolidation. Seventeen patients proceeded to HSCT. For patients with IDH1 mutations the most frequent co-occurring baseline mutations were DNMT3A, NPM1 and NRAS. MRD-negative CRs using flow cytometry were observed in 89% of patients with IDH1 positive mutational status [68].

Bcl-2 gene is located on chromosome 18q21.33 and it was discovered in 1985 through cloning the breakpoint of a translocation of t(14;18) found in follicular B lymphomas [70]. Bcl-2 is an integral protein of the mitochondrial membrane but has also been identified on endoplasmic reticulum and the nuclear envelope [71]. BCL2 family members are classified into pro and anti-apoptotic proteins. The anti-apoptotic BCL2 family contains 4 proteins: BCL2, BCLXL, BCL-w, and MCL-1. Through direct activation of the effector proteins or antagonizing the effect of antiapoptotic proteins the pro-apoptotic proteins lead to an activation of caspase proteases [72]. Bcl 2 has proven to be major negative regulator in apoptosis, playing

**248**

**1.3 Pro-apoptotic agents**

*1.3.1 Bcl-2 inhibitors*

Venetoclax (ABT-199/GDC- 0199) is a highly selective oral BCL2 inhibitor and does not show significant BCL-XL antagonism [75]. Venetoclax induces apoptosis in AML cell lines, in-vitro patient samples and in mouse xenograft models [75, 76]. In a phase II, single-arm study in 32 patients with high-risk relapsed/refractory AML or unfit for intensive chemotherapy venetoclax was given at a dose of 800 mg daily. The overall response rate was 19%, an additional 19% of patients demonstrated antileukemic activity not meeting IWG criteria (partial bone marrow response and incomplete hematologic recovery). Twelve (38%) patients had IDH 1/2 mutations, of whom 4 (33%) achieved complete response or complete response with incomplete blood count recovery. The responses median progression free interval was 2.5 months. Common adverse events included nausea, diarrhea, febrile neutropenia and hypokalemia. Due to potential tumour lysis syndrome as seen in chronic lymphocytic leukemia, a daily dosing ramp up of venetoclax was executed until 800 mg per day [77]. More effective results were achieved in studies where venetoclax was combined with either low-dose cytarabine (LDAC) or hypomethylating agents (HMAs). In a phase Ib/II study in previously untreated patients with AML venetoclax was combined with low-dose cytarabine in 82 adults 60 years or older. The median age was 74 years, 49% had secondary AML, 29% had prior HMA treatment, and 32% had poor-risk cytogenetic features. 54% achieved complete remission (CR)/CR with incomplete blood count recovery. The median OS was 10.1 months (95% CI, 5.7 to 14.2), and median duration of response (DOR) was 8.1 months (95% CI, 5.3 to 14.9 months). Early (30-day) mortality was 6% [78]. In another phase 1b study of venetoclax plus decitabine or azacitidine in untreated AML patients ≥65 years ineligible for standard induction therapy 145 patients were enrolled. Median age was 74 years, with poor-risk cytogenetics in 49% of patients. With a median time on study of 8.9 months, 67% of patients (all doses) achieved complete remission (CR) + CR with incomplete count recovery (CRi), with a CR + CRi rate of 73% in the venetoclax 400 mg + HMA cohort. No tumor lysis syndrome was observed. Common adverse events (>30%) included nausea, diarrhea, constipation, febrile neutropenia, fatigue, hypokalemia, decreased appetite, and decreased white blood cell count [79]. Due to these marked results venetoclax received FDA approval for combination with low dose cytarabine and HMAs. DiNardo et al. assessed the safety and efficacy of venetoclax in combination with FLAG-IDA in a heavily pre-treated r/r AML patients. Study included 12 patients, of 11 patients, 8 patients (73%) achieved a best response of CR/CRi (7 CR, 1 CRi) with a 6-month survival rate of 67%. Of the 8 responding patients, three patients proceeded to allogeneic SCT [80].
