A personalised approach to treating patients with haematological malignancies

Programme stream(s): Treatment
Programme session type(s): Recent Advances session

Chair: Mhairi Copland, University of Glasgow, UK
Speaker: Anna Schuh, University of Oxford, UK
Speaker: Paresh Vyas, University of Oxford, UK
Speaker: Susanne Saussele, University of Mannheim, Germany

11:00-12:30

Room: Alsh

This session will explore how therapies are becoming increasingly targeted and individualised in the management of haematological cancers. Firstly, the session will consider how genomics in chronic lymphocytic leukaemia is guiding first line treatment and the use of targeted therapies. Next, the use of next generation sequencing to molecularly categorise patients with acute myeloid leukaemia will be discussed, together with how this is influencing delivery of standard and novel chemotherapeutic agents. Finally, we will review how targeted therapy in chronic myeloid leukaemia with tyrosine kinase inhibitors is leading to successful discontinuation of therapy in a substantial number of patients. Participants will gain an improved understanding of how molecular genomic studies are influencing therapy in haematological malignancies.

A personalised approach to treating patients with haematological malignancies
Speaker: Susanne Saussele
Affiliation: Universitätsmedizin Mannheim

Abstract:

Chronic myeloid leukemia (CML) is a model for cancer disease due to the fact that a unique translocation determines the disease. With the introduction of tyrosine kinase inhibitors (TKI) to treatment, the disease has changed from a fatal one to a chronic disease in the majority of patients. The life expectancy of patients with CML receiving TKI treatment is nearly comparable now to that of the general population. Treatment strategies not only comprise overall survival anymore but achievement of deep molecular remission even successfully stop therapy (treatment-free remission, TFR). It is under discussion for which patients how deep the molecular remission should be. An individualized treatment plan from the time point of diagnosis for each patient seems to be the future of CML therapy. This compromise also the choice of the TKI for first line in order to increase the number of patients in TFR.

Clone Wars in Leukaemia: Are there lessons for all cancers?
Speaker: Paresh Vyas
Affiliation: University of Oxford

Abstract:

Mutations in the gene encoding isocitrate dehydrogenase 2 (IDH2) occur in several types of cancer, including acute myeloid leukemia (AML). In model systems, mutant IDH2 causes hematopoietic differentiation arrest. Enasidenib, a selective small-molecule inhibitor of mutant IDH2, produces a clinical response in 40% of treated relapsed/ refractory AML patients by promoting leukemic cell differentiation. Here, we studied the clonal basis of response and acquired resistance to enasidenib treatment. Using sequential patient samples, we determined the clonal structure of hematopoietic cell populations at different stages of differentiation. Pre-therapy IDH2 mutant clones showed variable differentiation arrest. Enasidenib treatment promoted hematopoietic differentiation from either terminal or ancestral mutant clones; less frequently, treatment promoted differentiation of non-mutant cells. Analysis of paired diagnosis/relapse samples did not identify second site mutations in IDH2 at relapse. Instead, relapse arose by clonal evolution, or selection, of terminal or ancestral clones, highlighting multiple bypass pathways that could potentially be targeted to restore differentiation arrest. Mapping clonal structure in cell populations at different stages of differentiation during therapy illustrates how different clones respond and evolve during relapse.