Targeted leukaemia therapy: a chemotherapy-free future?

In the UK, the National Institute for Health and Care Excellence (NICE), which provides national guidance on best practice in health care, announced on Nov 10, 2020, approval of venetoclax plus obinutuzumab for adults with untreated chronic lymphocytic leukaemia (CLL) with a 17p deletion or TP53 mutation. This regimen provides a first-line chemotherapy-free option for patients with this common form of leukaemia. The NICE approval comes after the European Society for Medical Oncology (ESMO) published their latest clinical practice guideline for CLL, which presents venetoclax plus obinutuzumab as an alternative first-line treatment to standard chemotherapy. Targeted treatments, which require understanding the tumour biology and microenvironment, provide a route to personalised therapy without the need for cytotoxic chemotherapy. Accordingly, the ESMO guidelines for CLL include recommendations for fluorescence in-situ hybridisation and next-generation sequencing to identify chromosomal or genetic abnormalities for targeted therapy. Tyrosine kinase inhibitors (TKIs) targeting the BCR-ABL pathway are an established treatment for patients with Philadelphia (Ph) chromosome abnormality, such as those with chronic myeloid leukaemia (CML) and acute lymphocytic leukaemia (ALL). CML is an example of early success in use of TKIs for first-line targeted therapy, with patients' life expectancy being unaffected by the CML diagnosis due to the efficacy of BCL-ABL TKIs in preventing disease progression. CML is now a chronic disease and the focus has shifted towards treatment-free remission and therapy discontinuation. Similarly, at the ASH 2020 annual meeting, results of the CAPTIVATE trial showed that treatment-free remission after a fixed-dose chemotherapy-free regimen is a possibility for patients with CLL too. In a recent phase 2 study in adults with Ph-positive ALL, the second-generation TKI dasatinib was assessed as first-line treatment with blinatumomab. A complete haematological response was reported in 98% of patients after 85 days of induction treatment with dasatinib, and a molecular response was seen in 29%, rising to 60% after consolidation with blinatumomab. Additionally, a retrospective cohort study published in this month's issue of The Lancet Haematology offers a reference for assessing the benefit of first-line TKIs in paediatric patients with ALL associated with ABL-fusion genes. Children with ABL-class ALL, who were enrolled to trials when TKIs were not given as first-line treatment (2000–18), had poor outcomes with chemotherapy only. These data provide a baseline for chemotherapy-only outcomes that ongoing and future trials can use to assess the benefit of TKIs in this setting. We now have reason to hope that patients identified with Ph-like ALL might one day be managed with TKIs, without the need for chemotherapy. Acute myeloid leukaemia (AML) has been slow to catch up with the other forms of leukaemia in terms of targeted treatments. The Beat AML trial has assessed how to personalise the decision-making process; treatment was delayed by 7 days to do a cytogenetic analysis and check hypermethylation status. Adult patients were enrolled to substudies specific to their mutational status and received treatment accordingly, including enasidenib for IDH2-positive AML and entospletinib plus decitabine for TP53-positive disease. Importantly, the 7-day treatment delay did not affect patients' survival. Assessing the genetic heterogeneity of disease could bear fruit in terms of determining how patients are treated. Another breakthrough in achieving a chemotherapy-free future for patients with haematological disorders is chimeric antigen receptor (CAR) T-cell therapy. To bolster this field of cellular targeted treatment, the European Hematology Association (EHA) and European Society of Blood and Marrow Transplantation (EBMT) announced on Nov 18, 2020, they had joined forces to promote the GoCART coalition. This initiative was founded by the EHA and EBMT to bring together relevant stakeholders with an interest in cellular therapy and put Europe at the heart of this new and exciting area of medicine. Similar to the Cellular Immunotherapy Data Resource in the USA, the aims of the GoCART coalition include creating a register of long-term safety and efficacy data, ensuring data collection processes are aligned, and removing barriers to treatment regulation and access. The GoCART coalition is in the early stages of development but has outlined an ambitious vision for decades to come. At the beginning of a new decade, haematology is at the forefront of personalised treatment, with advances in cytogenetic analysis and ground-breaking developments in drug discovery and cell-based treatments. This progress heralds a great future for targeted therapy, putting the patient first. Outcomes of paediatric patients with B-cell acute lymphocytic leukaemia with ABL-class fusion in the pre-tyrosine-kinase inhibitor era: a multicentre, retrospective, cohort studyChildren with ABL-class fusion B-cell acute lymphocytic leukaemia have poor outcomes when treated with regimens that do not contain a tyrosine-kinase inhibitor, despite the use of high-risk chemotherapy regimens and frequent HSCT upon first remission. Our findings provide a reference for evaluating the potential benefit of first-line tyrosine-kinase inhibitor treatment in patients with ABL-class fusion B-cell acute lymphocytic leukaemia. Full-Text PDF Open Access