Advances in the targeted therapy of hematological neoplasm

Research into the underlying pathogenetic mechanisms of hematological neoplasias has led in recent years to remarkable advances in our understanding of these diseases. Cytogenetic and molecular aberrations are the most pertinent factors to consider when determining response to chemotherapy. They also help to predict long-term outcome and are also potentially promising therapeutic targets. An improved understanding of the pathogenesis of these diseases, particularly through Next-Generation Sequencing (NGS), has contributed to drive the development of novel therapeutic algorithms for the treatment of leukemia and lymphoma. Recent clinical trials have investigated several new agents, in particular tyrosine kinase inhibitors (TKIs), immune checkpoint inhibitors, monoclonal or bispecific T-cell engager antibodies, metabolic and proapoptotic agents, that have now been approved as novel targeted therapies. The best response rates are often achieved when novel molecular targeted therapies are combined with standard chemotherapy. In this current issue of the newsletter, we would like to start by giving an overview of novel AML therapies. 

Approximately one third of AML patients are found to have mutations in the FLT3 kinase coding sequences. Midostaurin (Rydapt®, Novartis Pharmaceuticals, Inc.) is the first TKI to be approved as part of a combination therapy with standard 7+3 chemotherapy in newly diagnosed AML patients with FLT3-mutations, independently of patient age.

Midostaurin was approved for AML with FLT3-mutations based on the positive results of a large international randomized phase III trial (Cancer and Leukemia Group B [CALGB] 10603 / RATIFY). As both a concurrent NPM1 mutation and the FLT3-ITD to wild type allele ratio affects the prognosis of an otherwise cytogenetically normal FLT3-mutated AML, these two characteristics need be established. The MLL has the capacity to monitor the mutation as well as the allelic ratio at the initial diagnosis and during the course of the disease to allow as early an individually tailored therapeutic intervention as possible.

Other TKI studies in phase II/III trials include:

IDH1 and IDH2 mutations are respectively detected in approximately 8% and 12% of AML patients (Papaemmanuil et al. 2016). IDH1 mutations occur almost exclusively at R132, whereas IDH2 substitutions are observed at R140 or R172 (Stein 2015). In terms of function, IDH mutations block the differentiation of hematopoietic cells by increasing levels of the oncometabolite 2-hydroxyglutarate, which indirectly results in DNA hypermethylation by inhibiting histone demethylation (Stein 2015).

A dose-finding study in a cohort of predominantly relapsed/refractory AML patients with the selective and potent IDH2 inhibitor enasidenib (AG-221 / CC-90007; Celgene Corp.) showed promising results when used as a single agent treatment in patients with IDH2 mutations.

Based on these results, enasidenib was approved in the U.S.A. by the FDA (August 1, 2017) for the treatment of relapsed/refractory AML with an IDH2 mutation.

The initial data on a combination therapy with the IDH1 inhibitor ivosidenib and azacytidine in newly diagnosed IDH1-mutated AML in elderly patients, also appears promising, with a reported complete remission rate of 61% (DiNardo 2020). But approval of these active substances in Europe is currently not imminent.

The anti-apoptotic B-cell lymphoma 2 (BCL2) protein, which is frequently expressed in hematological neoplasias, plays an essential role in AML cell survival (Adams & Cory 2007). Overexpression of BCL2 has been correlated with AML chemoresistance (Pan et al. 2014). Venetoclax (Venclexta®, AbbVie Inc.) is a highly selective oral BCL2-inhibitor that has shown activity in BCL2-dependent leukemia and lymphoma cell lines (Andreeff et al. 1999, Pan et al. 2014, Souers et al. 2013, Vogler et al. 2013). The inhibition of BCL2 induces cell death in progenitor and stem cells of AML patients (Konopleva et al. 2006, Lagadinou et al. 2013).

BCL2 inhibition may thus have the potential to eliminate chemotherapy-resistant leukemia stem cells while at the same time sparing normal hematopoietic stem cells (Konopleva et al. 2006, Lagadinou et al. 2013). In clinical trials, combination treatments with HypoMethylating Agents (HAM) and the BCL2-inhibitor venetoclax showed a significantly higher overall CR/CRi rate of 67%, with the highest complete remission rate of 91% in patients with NPM1-mutated disease and the lowest complete remission rate of 47% in patients with a TP53 mutation. The median overall survival was 17.5 months (DiNardo et al. 2019). Similarly, an early clinical trial evaluating the combination treatment of low-dose cytarabine (LDAC) and venetoclax reported a CR/CRi rate of 54% with a median OS of 10.1 months (Wei et al. 2019).

The combination treatment of venetoclax and azacytidine has already been approved by the FDA, and an application for its approval in Europe was submitted to the EMA in the summer of 2020. A very recent publication also reported that this combination improves the treatment response of diseases which include an additional mutation, either in the IDH1 (but not in IDH2), NPM1, or the SRSF2 gene (Chua et al. 2020).

The advanced clinical development of the BCL2-inhibitor venetoclax, the IDH1 inhibitor ivosidenib, the selective FLT3 inhibitors quizartinib and gilteritinib, the hedgehog inhibitor glasdegib, the MDM2 inhibitor idasanutlin, the oral azacitidine, the histone deacetylase inhibitor pracinostat, and the hypomethylating agent guadecitabine, give reason to hope that the therapeutic options and thereby also the improved prospects for curing AML will increase significantly in the near future.