**6. New developments**

Since 2017 the FDA has approved 8 new drugs for the treatment of AML [54]. New developments to treat AML, especially in older patients, include 1) drugs targeting specific signalling pathways (like the hedgehog pathway or apoptosis); 2) drugs specifically targeting mutations in AML (e.g. targeting the epigenetic modifiers IDH1/IDH2 and mutated cytokine receptor FLT3) and 3) an alternative formulation of classic chemotherapeutic drugs (CPX-315).

#### **6.1 Venetoclax**

Venetoclax (ABT-199/GDC-0199), an orally available inhibitor of the antiapoptotic molecule Bcl-2, has shown great efficacy in chronic lymphocytic leukaemia [55–57]. After observing single-agent activity in AML cell lines [58], venetoclax has been tested as monotherapy in relapsed and refractory AML patients showing activity with a CR/CRi rate of 19% [59]. Promising results have been reported for combinatorial studies with venetoclax in AML. In the randomised phase 3 trial VIALE-C (LDAC +/− venetoclax) 211 patients were randomised 2:1 to venetoclax (n = 143) or placebo (n = 68) in 28-day cycles, plus LDAC on days 1 to 10 [60]. The primary analysis showed a 25% reduction in risk of death with venetoclax plus LDAC vs. LDAC alone, although not statistically significant (hazard ratio [HR], 0.75; P = .11), and a median OS of 7.2 vs. 4.1 months, respectively. An unplanned analysis with additional 6-month follow-up did demonstrate a significant benefit with a median OS of 8.4 months for venetoclax added to LDAC (HR, 0.70; P = .04).

In addition, the results of a phase 3 study of venetoclax in combination with azacitidine versus azacitidine alone in treatment-naïve older AML patients, who were ineligible for standard induction therapy, have recently been reported (VIALE-A trial; NCT02993523). This study confirms the additive value of venetoclax to azacitidine by a significant increase in CR/CRi rate from 28–66% and an increase in median OS from 9.6 months to 14.7 months [19]. The high remission rate which can be achieved by adding venetoclax to azacitidine treatment is striking. The impressive results of this study will likely make the combination of an hypomethylating agent with venetoclax the new standard for the treatment of older unfit AML patients.

#### **6.2 IDH inhibitors**

*IDH* mutations are present in approximately 20% of AML patients and are more frequent in older patients. Mutations in *IDH* lead to the production of the oncometabolite 2-hydroxyglutarate and result in DNA hypermethylation and arrest

**173**

**6.5 CPX-315**

**6.4 Glasdegib**

(BRIGHT AML1019, NCT03416179).

*Treatment of AML in Older Patients*

*DOI: http://dx.doi.org/10.5772/intechopen.94979*

of myeloid differentiation [54]. Inhibition of these mutant metabolic enzymes by ivosidenib (IDH1) and enasidenib (IDH2) induces myeloid differentiation of leukaemic blasts. In a subgroup analysis of 34 newly diagnosed AML patients unfit for standard chemotherapy harbouring IDH1 mutations, monotherapy with ivosidenib resulted in a remission rate of 42.4% and median OS of 12.6 months [61]. In a phase I/II trial of older untreated AML patients, enasidenib induced a response in 30.8% of patients of whom 18% had a complete remission and a median OS of 11.3 months [62]. In addition to the proven efficacy and tolerability, ivosidenib and enasidenib are orally available, making them attractive for treatment of older AML patients. Both inhibitors are under investigation in combination with other AML treatments,

including intensive chemotherapy ("3 + 7") and hypomethylating agents.

The *FLT3* mutations (mainly *FLT3* internal tandem duplications (*FLT3*-ITD), but also tyrosine kinase mutations (*FLT3*-TKD)) occur in about 20–30% of adult AML patients, although its prevalence decreases in older patients. The RATIFY study proved the favourable impact of adding midostaurin to intensive chemotherapy for AML patients with mutated *FLT3* under 60 years of age [63]. In older patients with *FLT3*-ITD the CR rate and 2-year OS was 77.9% and 45.6% respectively with the addition of midostaurin to conventional chemotherapy [33]. In comparison to historical controls, addition of midostaurin resulted in significant risk reduction for an event (refractory disease, relapse, death) with an HR of 0.42. Based on the results of this study the treatment label of midostaurin was expanded to include older patients with mutated *FLT3*. New FLT3 inhibitors, like gilteritinib, have shown to be potent inhibitors of mutated *FLT3* in relapsed/refractory AML patients, though limited data is available on the safety and efficacy of gilteritinib when combined with intensive chemotherapy or hypomethylating agents.

Glasdegib is small molecule inhibitor of the hedgehog receptor smoothened. The hedgehog pathway is important during embryogenesis but repressed after birth. However, aberrant hedgehog signalling has been identified in AML, particularly in leukaemic stem cells, and has been associated with chemoresistance [64]. Inhibition of hedgehog signalling with glasdegib has shown promising results. A phase II study evaluating the combination of glasdegib and intensive chemotherapy in patients over 55 years of age with newly diagnosed AML reported a CR rate of 40% and median OS of 14.7 months [65]. Glasdegib was also evaluated in combination with LDAC in older patients unfit for intensive chemotherapy. Patients receiving glasdegib + LDAC had increased CR rates, 17.0% vs. 2.3%, and improved median OS 8.8 vs. 4.9 months, compared to patients receiving LDAC alone [66]. Based on these results, the FDA has approved glasdegib in combination with LDAC for AML patients ≥75 years or patients ineligible for intensive chemotherapy. In addition, glasdegib is being evaluated in combination with hypomethylating agents and a phase III trial of glasdegib in combination with intensive chemotherapy is ongoing

CPX-315 is a liposomal formulation that delivers a 5:1 fixed-molar ratio of cytarabine and daunorubicine. With the liposomal encapsulation both drugs can be delivered in a fixed ratio with the highest proportion of synergy to enhance

**6.3 FLT3 inhibitors: midostaurin and gilteritinib**

#### *Treatment of AML in Older Patients DOI: http://dx.doi.org/10.5772/intechopen.94979*

*Acute Leukemias*

LDAC (see 7.1).

**6.1 Venetoclax**

**6. New developments**

tion of classic chemotherapeutic drugs (CPX-315).

significantly better, it is worth noting that in absolute terms, the therapeutic advantage is marginal, with a prolongation of OS of only a few months.

Additionally, the benefit is restricted to the small fraction of patients who achieve a response (median survival 19 months vs. 2 months in responders vs. nonresponders respectively) [15]. Patients with adverse cytogenetics do not seem to benefit from LDAC. Combinations of LDAC with other agents have been tested in clinical trials and although some additions resulted in higher CR rates survival was not improved [48–53]. Thus, the OS in patients receiving LDAC is still highly unsatisfactory (median 5 months) [3]. Recently, the results of the VIALE-C trial have been reported, demonstrating an increased efficacy by adding venetoclax to

Since 2017 the FDA has approved 8 new drugs for the treatment of AML [54]. New developments to treat AML, especially in older patients, include 1) drugs targeting specific signalling pathways (like the hedgehog pathway or apoptosis); 2) drugs specifically targeting mutations in AML (e.g. targeting the epigenetic modifiers IDH1/IDH2 and mutated cytokine receptor FLT3) and 3) an alternative formula-

Venetoclax (ABT-199/GDC-0199), an orally available inhibitor of the antiapoptotic molecule Bcl-2, has shown great efficacy in chronic lymphocytic leukaemia [55–57]. After observing single-agent activity in AML cell lines [58], venetoclax has been tested as monotherapy in relapsed and refractory AML patients showing activity with a CR/CRi rate of 19% [59]. Promising results have been reported for combinatorial studies with venetoclax in AML. In the randomised phase 3 trial VIALE-C (LDAC +/− venetoclax) 211 patients were randomised 2:1 to venetoclax (n = 143) or placebo (n = 68) in 28-day cycles, plus LDAC on days 1 to 10 [60]. The primary analysis showed a 25% reduction in risk of death with venetoclax plus LDAC vs. LDAC alone, although not statistically significant (hazard ratio [HR], 0.75; P = .11), and a median OS of 7.2 vs. 4.1 months, respectively. An unplanned analysis with additional 6-month follow-up did demonstrate a significant benefit with a median OS of 8.4 months for venetoclax added to LDAC (HR, 0.70; P = .04). In addition, the results of a phase 3 study of venetoclax in combination with azacitidine versus azacitidine alone in treatment-naïve older AML patients, who were ineligible for standard induction therapy, have recently been reported (VIALE-A trial; NCT02993523). This study confirms the additive value of venetoclax to azacitidine by a significant increase in CR/CRi rate from 28–66% and an increase in median OS from 9.6 months to 14.7 months [19]. The high remission rate which can be achieved by adding venetoclax to azacitidine treatment is striking. The impressive results of this study will likely make the combination of an hypomethylating agent with venetoclax the new standard for the treatment of older unfit AML

*IDH* mutations are present in approximately 20% of AML patients and are more frequent in older patients. Mutations in *IDH* lead to the production of the oncometabolite 2-hydroxyglutarate and result in DNA hypermethylation and arrest

**172**

patients.

**6.2 IDH inhibitors**

of myeloid differentiation [54]. Inhibition of these mutant metabolic enzymes by ivosidenib (IDH1) and enasidenib (IDH2) induces myeloid differentiation of leukaemic blasts. In a subgroup analysis of 34 newly diagnosed AML patients unfit for standard chemotherapy harbouring IDH1 mutations, monotherapy with ivosidenib resulted in a remission rate of 42.4% and median OS of 12.6 months [61]. In a phase I/II trial of older untreated AML patients, enasidenib induced a response in 30.8% of patients of whom 18% had a complete remission and a median OS of 11.3 months [62]. In addition to the proven efficacy and tolerability, ivosidenib and enasidenib are orally available, making them attractive for treatment of older AML patients. Both inhibitors are under investigation in combination with other AML treatments, including intensive chemotherapy ("3 + 7") and hypomethylating agents.

## **6.3 FLT3 inhibitors: midostaurin and gilteritinib**

The *FLT3* mutations (mainly *FLT3* internal tandem duplications (*FLT3*-ITD), but also tyrosine kinase mutations (*FLT3*-TKD)) occur in about 20–30% of adult AML patients, although its prevalence decreases in older patients. The RATIFY study proved the favourable impact of adding midostaurin to intensive chemotherapy for AML patients with mutated *FLT3* under 60 years of age [63]. In older patients with *FLT3*-ITD the CR rate and 2-year OS was 77.9% and 45.6% respectively with the addition of midostaurin to conventional chemotherapy [33]. In comparison to historical controls, addition of midostaurin resulted in significant risk reduction for an event (refractory disease, relapse, death) with an HR of 0.42. Based on the results of this study the treatment label of midostaurin was expanded to include older patients with mutated *FLT3*. New FLT3 inhibitors, like gilteritinib, have shown to be potent inhibitors of mutated *FLT3* in relapsed/refractory AML patients, though limited data is available on the safety and efficacy of gilteritinib when combined with intensive chemotherapy or hypomethylating agents.
