General AML

Venetoclax and other BH3 mimetics in Acute Myeloid Leukemia – current practice and future perspective

On 21st of May, Michael R. Savona from Vanderbilt University Medical Center, Nashville, US, and Andrew Wei from Monash University, Clayton, AU, published a commentary in Journal of Clinical Oncology.1 The article highlights the clinical impact of venetoclax in potential therapy combinations, discusses possible mechanisms of resistance and ways to overcome them, as well as the future of ventoclax and other BH3 mimetics in acute myeloid leukemia (AML).

Current standard treatment for patients with AML is cytotoxic chemotherapy, which lacks specificity, destroying both cancer and normal cells leading to a range of side effects. Moreover, older patients have poor response to chemotherapy, while having increased risk of treatment-related complications. Therefore, a selective therapy targeting cancer cells and leaving the surrounding normal tissue undamaged is urgently needed.

Venetoclax, a highly specific, second generation B-cell lymphoma 2 Homology 3 (BH3) mimetic targeting pro-survival protein B-cell lymphoma 2 (BCL-2) was developed to address this need. Although single agent clinical phase I data2 showed only a modest response of 19% in relapse/refractory AML (R/R AML), combination with DNA methyltransferase inhibitors3,4 (DNMTi) or low dose cytarabine5 (LDAC), achieved a high rate of clinical response (67% and 54% accordingly) and was well tolerated (Table 1). Based on this evidence, in November 2018, the FDA approved venetoclax combination therapy for the use in older/unfit patients with AML.

Table 1. Clinical characteristics and outcome of venetoclax with DNMTi (Azacitidine/ Decitabine) or LDAC in older patients with AML.4,5*

Parameter

Venetoclax + DNMTi

Venetoclax + LDAC

Characteristics

Venetoclax RP2D

400mg days 1–28

600mg days 1–28

No.

145

82

Median age (range), years

74 (65–86)

74 (63–90)

Secondary AML, No. (%)

36 (25)

40 (49)

Prior DNMTi therapy, No (%)

24 (29)

Poor risk CG, No (%)

71 (49)

26 (32)

Treatment

30-day mortality (%)

3

6

Median time to response (months)

1.2

1.4

Median cycles, No. (range)

5 (1–25)

5 (1–30)

CR/ CRi (%)

Total

67

54

No prior DNMTi

62

OS (months)

Total

17.5

10.1

No prior DNMTi

13.5

*OS, overall survival; CR, complete remission; CRi, complete remission with incomplete hematologic recovery

The authors stress the importance of understanding potential mechanisms underlying resistance to BH3 (BCL-2, BCL-XL and MCL1) mimetics, in order to fully utilise the benefits of venetoclax combination therapy. Some evidence suggests that BCL-2 mutations similar to those seen in chronic lymphatic leukemia6 and an altered metabolic control of apoptosome leading to overexpression of MCL17,8 could be associated with resistance. Therefore, BH3 profiling of patients9 and mutation screening might guide identification of those who are most likely to benefit, and could potentially be useful in monitoring cancer evolution in response to the therapy.

Additionally, the efficacy of venetoclax in a fitter population of patients with AML is currently being investigated. Early data in NPM1 or IDH mutant AML subgroups indicates high efficacy with CR and incomplete hematopoietic count recovery rates around 90% and 70% respectively.4,6 However, long-term studies are needed to confirm these results and to explore the potential benefits of combination with other targeted therapies including FLT3 or IDH inhibitors.

The success of venetoclax has stimulated interest in other BH3 mimetics. Preclinical studies using MCL1 inhibitors (S63845,10 VU661013,11 AMG-176,12 and AZD59912813) showed enhanced sensitivity of malignant cells to simultaneous inhibition of MCL1 and BCL-2, indicating their importance in survival of leukemic cells. However most importantly, this combination approach seems to have the potential to overcome resistance, and has been shown to be effective in chemotherapy R/R AML and tumours resistant to BCL-2 inhibition10,11,. This therapy may also solve problems arising from genomic diversity and clonal plasticity, which currently complicate long-term disease control with conventional cytotoxic therapies.

Several new drugs targeting MCL1 are in clinical development for hematologic cancers, including AML, as a single agent and in combination with venetoclax (NCT02979366, NCT02675452, NCT03218683, and NCT03672695). Moreover, efficacy and safety of venetoclax combinations with compounds indirectly targeting MCL1, such as XPO1, CDK9, MDM2, and MEK are also being studied14-16. Time will show which of these approaches will be able to balance high efficacy with good tolerability.

Currently, elderly patients are the only subgroup of AML population with proven benefit of venetoclax. However in the next few years, we should have a clearer picture whether younger patients with more aggressive disease will respond equally as well to venetoclax combinations. In the future, novel BH3 mimetic combinations could replace the more toxic chemotherapy in the clinic, and potentially overcome chemotherapy resistance in R/R AML.

References
  1. Savona M. & Wei A.H. Incorporating Precision BH3 Warheads into the Offensive Against Acute Myeloid Leukemia. J Clin Oncol. 2019 May 21; JCO1900400. DOI: 10.1200/JCO.19.00400
  2. Konopleva M. et al. Efficacy and Biological Correlates of Response in a Phase II Study of Venetoclax Monotherapy in Patients with Acute Myelogenous Leukemia. Cancer Discov. 2016 August 12; 6(10); 1–12. DOI: 10.1158/2159-8290.CD-16-0313
  3. DiNardo C.D. et al. Safety and preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with previously untreated acute myeloid leukaemia: A non-randomised, open-label, phase 1b study. Lancet Oncol. 2018 Feb; 19(2):216-228. DOI: 10.1016/S1470-2045(18)30010-X
  4. DiNardo C.D. et al. Venetoclax Combined with Decitabine or Azacitidine in Treatment-Naive, Elderly Patients with Acute Myeloid Leukemia. Blood. 2019 Jan 3; 133(1):7-17. DOI: 10.1182/blood-2018-08-868752
  5. Wei A.H. et al. Venetoclax Combined with Low-Dose Cytarabine for Previously Untreated Patients with Acute Myeloid Leukemia: Results from a Phase Ib/II Study. J Clin Oncol. 2019 May 20; 37(15):1277-1284. DOI: 10.1200/JCO.18.01600
  6. Blombery P. et al. Acquisition of the recurrent Gly101Val mutation in BCL2 confers resistance to venetoclax in patients with progressive chronic lymphocytic leukemia. Cancer Discov. 2019 Mar; 9(3):342-353. DOI: 10.1158/2159-8290.CD-18-1119
  7. Pollyea D.A. et al. Venetoclax with azacitidine disrupts energy metabolism and targets leukemia stem cells in patients with acute myeloid leukemia. Nat Med. 2018 Dec; 24(12):1859-1866. DOI: 10.1038/s41591-018-0233-1
  8. Jones C.L. et al. Inhibition of amino acid metabolism selectively targets human leukemia stem cells. Cancer Cell. 2018 Nov 12; 34(5):724-740.e4. DOI: 10.1016/j.ccell.2018.10.005
  9. Montero J. & Letai A. Dynamic BH3 profiling-poking cancer cells with a stick. Mol Cell Oncol. 2016 Mar 10; 3(3):e1040144. DOI: 10.1080/23723556.2015.1040144
  10. Moujalled D.Met al. Combining BH3-mimetics to target both BCL-2 and MCL1 has potent activity in pre-clinical models of acute myeloid leukemia. Leukemia. 2019 Apr; 33(4):905-917. DOI: 10.1038/s41375-018-0261-3
  11. Ramsey H.E. et al. A novel MCL1 inhibitor combined with venetoclax rescues venetoclax-resistant acute myelogenous leukemia. Cancer Discov. 2018 Dec; 8(12):1566-1581. DOI: 10.1158/2159-8290.CD-18-0140
  12. Caenepeel S. et al. AMG 176, a selective MCL1 inhibitor, is effective in hematologic cancer models alone and in combination with established therapies. Cancer Discov. 2018 Dec; 8(12):1582-1597. DOI: 10.1158/2159-8290.CD-18-0387
  13. Tron A.E. et al. Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia. Nat Commun. 2018 Dec 17; 9(1):5341. DOI: 10.1038/s41467-018-07551-w
  14. Fischer M.A. et al. Combination of selective inhibitor of nuclear export (SINE) compounds, selinexor and KPT-8602, with venetoclax (ABT-199) displays enhanced activity in leukemia and large cell lymphoma. Blood 2016; 128(22):3949. Retrieved from http://www.bloodjournal.org/content/128/22/3949
  15. Bogenberger J. et al. Combined venetoclax and alvocidib in acute myeloid leukemia. Oncotarget. 2017 Nov 3; 8(63):107206-107222. DOI: 10.18632/oncotarget.22284
  16. Daver N. et al. Preliminary results from a phase Ib study evaluating BCL-2 inhibitor venetoclax in combination with MEK inhibitor cobimetinib or MDM2 inhibitor idasanutlin in patients with relapsed or refractory (R/R). Blood 2017; 130(Suppl 1):813. Retrieved from  http://www.bloodjournal.org/content/130/Suppl_1/813
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