Skip to 0 minutes and 15 secondsCLL is the most common leukaemia in the Western world and involves B lymphocytes. A number of markers have been identified, which are able to classify patients into good and poor prognosis. These include the mutational status of the immunoglobulin heavy chain, loss of P53 or loss of ATM, all associated with the worse prognosis. At present, it is only P53 status, which is used in clinical practice. The targeted immunotherapy treatment approach, harnesses the body's own immune system to kill the leukaemia cells. Each type of leukaemia has its own profile of markers on the cell surface. Antibodies, which target the specific markers on each type of leukaemia cells, can be developed. In CLL, antibodies have been developed to the surface marker CD20.
Skip to 1 minute and 3 secondsThe patient is given an infusion of the monoclonal antibody, which then circulates in the bloodstream and binds to the leukaemia cells. This will trigger the body to mount an adaptive immune response. The patient's own immune system will then try to kill the leukaemia cell. The use of the anti CD20 monoclonal antibody, Rituximab, in combination with chemotherapy, has dramatically improved the survival rate for CLL patients. CML is a clonal myeloproliferative disease, driven by the Philadelphia chromosome. The Philadelphia chromosome arises from a reciprocal translocation between the long arms of chromosomes 9 and 22 resulting in the BCR and ABL genes ending up next to each other on the chromosome.
Skip to 1 minute and 47 secondsThis leads to the production of a new fusion protein, called BCR-ABL, which is a constitutively active tyrosine kinase enzyme. The tyrosine kinase activity of BCR-ABL activates several growth and survival pathways within the cell, causing the transformed cells to divide and multiply. Tyrosine kinase inhibitors, TKIs, are small molecules, which selectively inhibit the kinase activity of BCR-ABL. The first TKI, developed for clinical use in the early 1990s, was Imatinib Mesylate. This revolutionised the outlook for patients with CML. However, Imatinib resistance and intolerance often occurs, particularly in later stages of CML. And importantly, despite impressive rates of response, Imatinib does not cure CML in the vast majority of patients. Therefore, BCR-ABL remains an important target for the development of additional, selective TKIs.
Skip to 2 minutes and 41 secondsA number of second and third generation compounds are in development with some already in clinical use for Imatinib resistant patients. AML is a heterogeneous clonal disorder, which means it has a wide range of morphologic, immunological, cytogenetic, and molecular characteristics. Untreated, AML typically results in bone marrow failure leading to fatal infection, bleeding, or organ infiltration within one year of diagnosis, but often within weeks to months. The correct categorisation of AML, shown in this table, is important because it aids appropriate further management. Treatment and prognosis vary significantly depending on subtype, mutational status, and age with younger patients being able to tolerate the intensive chemotherapy better. Treatment generally consists of a combination of an anthrocycline and/or fludarabine, plus cytarabine.
Skip to 3 minutes and 36 secondsThese drugs inhibit DNA synthesis and damage DNA. Despite being associated with considerable morbidity and mortality, a cure for the majority of adults remains elusive. There have been advances, however. For example, acute promyelocytic leukaemia, a type of AML which was once rapidly fatal, is now classed as one of the favourable risk leukemias. APML was found to be commonly associated with the 15/17 translocation, placing the PML gene next to the RARA gene, creating a novel PML-RARA fusion gene, preventing normal myeloid differentiation. These cells are uniquely sensitive to All trans retinoic acid, otherwise known as ATRA. ATRA overcomes this block in differentiation, enabling the immature leukaemic blast cells to form mature cells resulting in improved overall outcome when combined with conventional chemotherapy.
Skip to 4 minutes and 28 secondsUnfortunately, the AML chromosome classification technique, only works with a subgroup of patients. Most of the time we can't tell how an AML patient will respond to therapy. This is where new techniques, such as whole genome sequencing, come into play. The Genome Institute sequenced 200 de Novo AML samples with the goal of defining all the mutations that occur in adult AML cells. They discovered many mutations in AML cells, including very high frequency mutations in the genes shown in this graph, such as FLT3 and NPM1. These genes may therefore be good candidate genes for new or improved targeted therapeutics.
Skip to 5 minutes and 7 secondsWhilst haematological malignancies remain a significant cause of cancer deaths throughout the world, our knowledge and understanding of these diseases is rapidly advancing, enabling the development of targeted therapies and small molecule inhibitors. This will enable us to tailor the treatment regime to the individual genetic profile, rather than the disease, providing a more personalised approach in the future. These advances in identifying the genetic background to leukaemia are exciting for all those involved in trying to improve patient outcome.
Personalised medicine in practice: leukaemia
Dr Victoria Campbell outlines how personalised treatments have become a reality in the treatment of leukaemia.
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