*1.3.1 Bcl-2 inhibitors*

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

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proceeded to allogeneic SCT [80].

**1.4 Hedgehog inhibition**

*1.4.1 Smoothened inhibitors*

*Target Therapy in Acute Myeloid Leukemia DOI: http://dx.doi.org/10.5772/intechopen.94422*

*1.3.1.1 Venetoclax*

key roles in neoplastic transformation and leukemogenesis [73]. Overexpression of anti-apoptotic BCL2 proteins such as BCL2, BCL2L1 and MCL1 is widely associated

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

The Hedgehog (Hh) family of proteins control cell growth and survival. The Hedgehog signalling pathway (HhP) is essential for embryonic development and usually silenced in adult tissues. Germline mutations that subtly affect Hh pathway activity are associated with developmental disorders, whereas somatic mutations activating the pathway have been linked to multiple forms of human

with tumour initiation, progression and chemo resistance in AML [74].

key roles in neoplastic transformation and leukemogenesis [73]. Overexpression of anti-apoptotic BCL2 proteins such as BCL2, BCL2L1 and MCL1 is widely associated with tumour initiation, progression and chemo resistance in AML [74].
