AML Hub

During the European School of Haematology (ESH) 2nd How to Diagnose and Treat: Acute Leukaemia meeting, the AML Hub spoke to Jorge Sierra, Hospital de la Santa Creu i Sant Pau, Barcelona, ES. In this podcast, Jorge Sierra talks about how close we are to offering treatment tailored to mutational profile.

Jorge Sierra describes the clinical benefit of adding drugs that target mutations into treatment regimens and explains the importance of mutational profiling at diagnosis and relapse to determine treatment options. He discusses target therapies that are available to patients, including the following:

• midostaurin (FLT3 inhibitor) for the frontline setting
• ivosidenib (IDH1 inhibitor) for the relapsed/refractory (R/R) setting
• enasidenib (IDH2 inhibitor) for the R/R setting
• gilteritinib (FLT3 inhibitor) for the R/R setting

He concludes by discussing other novel agents that have shown efficacy in the treatment of AML, including venetoclax and gemtuzumab ozogamicin.

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During the 25th Congress of the European Hematology Association (EHA), the AML Hub spoke to a member of our steering committee, Naval Daver, The University of Texas MD Anderson Cancer Center, Houston, US, about novel approaches and emerging therapies for TP53 AML.

Identification of disease-driving genetic aberrations has allowed for major advancements in the AML setting. TP53 mutations are observed in around 15% of patients with AML, with distinct patterns between patient subsets. Despite the development of targeted therapies, such as FLT3 and IDH1/2 inhibitors, treatments targeting TP53 mutations are yet to be established.

TP53-mutant AML is an area of unmet need, demonstrating high interpatient heterogeneity. Here, Naval Daver describes the efforts being made to establish TP53 as a therapeutic target, with the aim to further improve patient outcomes.

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During the American Association of Cancer Research (AACR) Virtual Annual Meeting I, the AML Hub was pleased to speak to Christine Spencer, Parker Institute for Cancer Immunotherapy, San-Francisco, US and Diwakar Davar, University of Pennsylvania Medical Center, Pittsburgh, US. We asked: how can we use the microbiome to improve cancer immunotherapy and alleviate side effects such as graft-versus-host-disease?

In this podcast, Dr Davar starts by providing a background on the importance of the microbiome in adaptive and innate immunity, while Dr Spencer states the importance of the cross-talk between the microbiome and immune system through microbial products, peptides, and metabolites. Dr Davar then explains the concept of immunosurveillance, immunoediting, and checkpoint inhibitors. Dr Spencer describes fecal microbiome transplant studies that showed features of the microbiome can predict response to immunotherapy and effect T-cell expression. Dr Davar then describes some of the studies that are looking at fecal microbiome transplant in combination with checkpoint inhibitors. He goes on to discuss studies investigating the use of live bacterial products to elicit the same effects as fecal microbiome transplant, particularly the mediation of CD8 T cells. Dr Spencer also talks about probiotics, antibiotics, and diet and explains how this can affect the gut microbiome and describes studies looking at these features in terms of response to immunotherapies. She also describes the microbiome research related to graft-versus-host-disease and the impact of higher alpha diversity on post-transplant survival, while Dr Davar explains how the microbiome may also affect toxicity and side-effects of cancer immunotherapies. 

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During the 25th Congress of the European Hematology Association (EHA), the AML Hub hosted a discussion between David Sallman, Moffitt Cancer Center, Tampa, US, and Steering Committee Member Naval Daver, MD Anderson Cancer Center, Houston, US.

The question was, Is CD47-directed antibody therapy safe and effective in patients with AML and myelodysplastic syndromes?

CD47 is a dominant negative immune checkpoint expressed by cancer cells, which facilitates immune evasion by decreasing recognition by macrophages. Increased expression of CD47 on cancer cells has been associated with inferior survival in patients with AML. The first-in-class anti-CD47 antibody magrolimab reinstates macrophage-mediated phagocytosis of tumor cells and has demonstrated anti-tumor activity in preclinical models.

Here, David Sallman and Naval Daver discuss the potential and clinical status of CD47-directed antibody therapy for the treatment of AML and myelodysplastic syndromes.

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During the American Society of Clinical Oncology (ASCO) Annual Meeting, Alexander Maurer from the AML Hub hosted a group discussion with Michael Ozga and Caner Saygin, both from The Ohio State University, Columbus, US and Abhay Singh from Roswell Park Comprehensive Cancer Center, Buffalo, US. This podcast discusses how the type of prior treatment can affect the risk of therapy-related myeloid neoplasms.

The group start by discussing the problems clinicians face when deciding treatment plans for patients with secondary myeloid neoplasms and describe how exposure to prior DNA damaging agents, cytotoxic therapies, and genotoxic therapies, can lead to a complex karyotype in these patients.

The group then discuss the role of clonal hematopoiesis in the evolution of secondary myeloid neoplasms. Dr Saygin describes how this could be a possibility especially for TP53 mutated, therapy-related AML, he also provides another hypothesis that genotoxic agents could cause de novo mutations. The group also discuss other driving mutations for clonal hematopoiesis including MPN1, SRSF2, and ASXL1, before moving on to discuss how specific genotoxic therapies can generate specific mutations. Dr Saygin and Dr Ozga describe their study in which they analyzed the molecular footprint of patients who had received various genotoxic and cytotoxic agents in order to answer this. Dr Singh also discusses his data on how the development of novel agents, such as immunotherapies may actually reduce the risk of secondary myeloid neoplasms compared to previous treatment options.

The discussion ends on the note that these types of studies will eventuality allow clinicians to predict disease risk better and provide more suitable therapies based on the patient's particular molecular profile.

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