NPM1,   General AML

ESH 2018 | Targeting cell survival in AML

At the European School of Hematology (ESH) Clinical Updates on Acute Leukemias Meeting on 4–6 May 2018, in Budapest, Hungary, an educational talk was presented by Professor Andrew H. Wei, chair of the AGP Rest of the World Steering Committee, from the The Alfred HospitalMelbourne, Australia, on how to target cell survival in acute myeloid leukemia (AML).1

"Targeting cell survival in AML is the result of 30 years of basic research that led to the development of an oral anti-apoptotic B-cell lymphoma 2 (BCL-2) protein inhibitor, venetoclax, which has shown superior single-agent activity in patients with AML" said Professor Wei. 

Venetoclax first line studies

Professor Wei discussed data from a phase Ib study (NCT02203773), which assessed the safety and preliminary efficacy of venetoclax in combination with decitabine or azacitidine in previously untreated older AML patients who are ineligible for standard induction therapy. Findings of this study, which was published in the Feburary 2018 issue of Lancet Oncology by Courtney DiNardo and colleagues, demonstrated that venetoclax in combination with hypomethylating agents is a novel, well-tolerated regimen with promising activity in elderly AML patients (median age = 74 years; range, 65–86).2  More results from this study are reported to here.

Next, the 1-year outcome and biomarker analysis from phase I/II study (NCT02287233), which evaluated the safety and efficacy of venetoclax in combination with low-dose cytarabine (LDAC) in 61 newly diagnosed elderly AML patients (median age = 74 years; range, 66–87) and presented at the 2017 American Society of Hematology Meeting by the speaker, Andrew Wei, was discussed. The updated safety and efficacy data showed a CR/CRi rate of 62% and a 1-year overall survival (OS) of 46% with a 30-day early death rate of 3%, thus indicating a clinically durable activity for this regimen in elderly patients with newly diagnosed AML who are eligible for intensive chemotherapy. Additionally, it was observed in this phase I/II study that patients with NPM1 mutation (n = 7) had a high response rate (CR/CRi = 100%) and good survival (1-year OS = not reached).3

Why is NPM1 mutated AML sensitive to venetoclax?

Professor Wei continued his talk by explaining the correlation between NPM1 mutation and better outcomes in patients with AML treated with venetoclax and LDAC. Kontro and colleagues published results of their study evaluating the ex vivo sensitivity of leukemic cells from 73 relapsed/refractory AML patients, and broadly assessed whether the responses correlated with specific mutations or gene expression signatures. They found that venetoclax sensitivity associated with specific HOX gene expression pattern which can possibly be used as a biomarker to identify venetoclax-sensitive AML patients for clinical trials.4 Mullighan and colleagues found that mutated NPM1 AML is characterized by HOX signature and led to dysregulated HOX expression via different mechanisms.5 Becker et al. showed that NPM1 mutations constitute a significant, independent predictive factor for favorable treatment response and survival in older patients with AML. Professor Wei asked the question whether elimination of NPM1 mutated clones by venetoclax require combination with chemotherapy or is it possible to use venetoclax in monotherapy alone. The answer is complicated and requires further investigation, possibly in a context of a maintenance study.

Co-targeting BCL-2 and MCL1 as alternative to chemotherapy

The speaker then referred back to the data from the phase I/II study evaluating LDAC in combination with venetoclax. Biomarker analysis of this study demonstrated that patients (n = 20) TP53-aneuploidy had a CRi/CR rate of 50% and a poor 1-year OS rate of 6.5%, thus suggesting an emergence of resistance to this treatment combination.3 Alternative treatment options are thus required.

Targeted therapies are frequently combined with standard cytotoxic drugs to enhance clinical response, thus recent translational studies were investigating the outcomes of the combination of venetoclax with a MCL1 inhibitor. According to previously published studies, co-targeting BCL-2 and MCL1 seems effective and feasible.6,7

In summary, Andrew Wei concluded that BH3 mimetics targeting leukemic survival represents a new therapeutic alternative for AML patients. He further added that precision tools triggering cell death in AML now available and may provide personalized, non-chemotherapy based remission for AML patients in the future.

References
  1. Wei AH. Targeting cell survival in AML. European School of Hematology (ESH) Clinical Updates on Acute Leukemias Meeting. 2018 May 4–6.

  2. DiNardo C. 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. [Epub 2018 Jan 12.]

  3. Wei AH. et al. Phase 1/2 Study of Venetoclax with Low-Dose Cytarabine in Treatment-Naive, Elderly Patients with Acute Myeloid Leukemia Unfit for Intensive Chemotherapy: 1-Year Outcomes. 59th ASH Annual Meeting and Exposition, Atlanta, GA.

  4. Kontro M. et al. HOX gene expression predicts response to BCL-2 inhibition in acute myeloid leukemia. 2017 Feb; 31(2): 301–309. DOI: 10.1038/leu.2016.222. Epub 2016 Aug 8.

  5. Mullighan CG. et al. Pediatric acute myeloid leukemia with NPM1 mutations is characterized by a gene expression profile with dysregulated HOX gene expression distinct from MLL-rearranged leukemias. 2007 Sep; 21(9): 2000–9. Epub 2007 Jun 28.

  6. Kotschy A. et al. The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models. 2016 Oct 27; 538(7626): 477–482. DOI: 10.1038/nature19830. Epub 2016 Oct 19.

  7. Hughes PE. et al. Preclinical evaluation of AMG 176, a novel, potent and selective Mcl-1 inhibitor with robust anti-tumor activity in Mcl-1 dependent cancer models. [Abstract]. Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. AACR. Cancer Res 2017; 77(13 Suppl): Abstract 2027. DOI: 1158/1538-7445.AM2017-2027.

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