March 2015 treatment update written for CLLSA by Dr Christopher Fox, Nottingham University Hospitals NHS Trust,
Over a relatively short time period a remarkable number of effective new therapies have been developed for patients with CLL. In some instances, these treatments have gained a marketing authorisation licence in Europe and, currently, some are funded within the NHS for patients who meet specific criteria. However, patients and clinicians should be mindful that this is a rapidly developing field that is likely to further evolve over the next year or two. Moreover, there are a number of further treatments, with different mechanisms of action, at various stages of development with promising efficacy and safety.
It’s important to appreciate that award of an EMEA licence simply means that the safety and efficacy data for a given therapeutic agent have been approved by the European authorities for clinical use in specific disease stages/patient groups. An EMEA licence does not, unfortunately, translate into an agreed funding stream by the NHS (or other healthcare systems). Typically, an interval of time elapses between EMEA licence and funding approval by NICE. The NHS England funded CDF initiated in 2010 has, for some therapies, ‘bridged’ the period between licence and NICE approval. However, this is not consistently applied and, particularly given the rapidly changing therapeutic landscape, patients should discuss current licensing and funding issues with their CLL clinician. In particular, patients should be encouraged to ask their CLL clinical team about the possibility of enrolling into a clinical trial where many new agents are currently being evaluated and/or where existing agents are being combined together in an attempt to further improve efficacy.
The newly licensed agents can be broadly divided into two groups
Firstly, monoclonal antibodies that, like Rituximab specifically target B lymphocytes. There are a number of mechanisms by which Rituximab induces B cell death: ‘direct’ cell killing following engagement with the CD20 antigen; complement (an immune system protein)-mediated cell death; and cellular cytoxicity (harnessing the patient’s own immune system cells such as T and NK cells to cause B cell death). Akin to Rituximab, Ofatumumab is a so-called Type I anti-CD20 antibody, targeting a different part of the CD20 molecule, but causing cell death in a similar way, including complement-mediated killing. Obinutuzumab is termed a type II anti-CD20 MAb, that binds to the same B cell target but appears to cause more ‘direct’ cell killing (i.e. less dependent on immune system proteins known as complement). In terms of clinical data, Ofatumumab (Arzerra) has previously been used as a monotherapy for relapsed/refractory CLL whereas Obinutuzumab (Gazyvaro) has not previously had an approved place in CLL management. Both antibodies appear to be more effective than Rituximab, particularly when combined with chemotherapy. Arzerra is approved by the EMEA in combination with chlorambucil or bendamustine for patients with CLL who have not received prior therapy and who are not eligible for fludarabine-based therapy. Gazyvaro is approved in combination with chlorambucil for the previously untreated CLL patients with comorbidities making them unsuitable for full-dose fludarabine based therapy. These marketing authorisation approvals are based on large randomised clinical trials where the comparator arm(s) was/were Chlorambucil monotherapy (Arzerra) or Chlorambucil and Chlorambucil/Rituximab (Gazyvaro). In both the Arzerra and Gazyvaro studies, patients treated with these newer antibodies together with Chlorambucil experienced a significant improvement in progression-free survival (duration of response).
The second class of drugs that has changed the treatment paradigm for CLL patients are B cell receptor pathway inhibitors. In simple terms, these orally administered targeted kinase inhibitors interfere with cell signalling within the B cell and impair its growth and survival. Published data from clinical trials demonstrates impressive efficacy in patients with relapsed/refractory CLL, including those with high-risk disease. For such patients (eg those with p53 deletion), these BCR pathway inhibitors have revolutionised the treatment of a disease that was associated with a short survival time with conventional treatments. The two agents that are most advanced in development and that now have a marketing authorisation in Europe are Ibrutinib (Imbruvica) which is a BTK inhibitor, and Idelalisib (Zydelig), a PI3kinase inhibitor. Imbruvica is approved for the treatment of patients with CLL who have received at least one prior therapy, or in first line in the presence of 17p deletion or TP53 mutation in patients unsuitable for chemo-immunotherapy. For Zydelig, the approved indication is in combination with rituximab for patients CLL who have received at least one prior therapy, or as first line treatment in the presence of 17p deletion or TP53 mutation in patients unsuitable for chemo-immunotherapy. Both ibrutinib and idelalisib have an encouraging safety profile, typically with fewer side-effects than conventional immunochemotherapy treatments but the risk/benefit of any treatment for an individual should be carefully discussed with the CLL clinical team.
Treatment of CLL
By Professor Andy Pettitt, Consultant Haematologist, Royal Liverpool University Hospital
Updated by Dr Anna Schuh, Consultant Haematologist, Oxford University Hospitals
CLL is really a type of so-called indolent, or slowly growing, B-cell non-Hodgkin’s lymphoma (NHL). It is called a leukaemia because it almost always involves the blood. Problems arise when the malignant cells accumulate to the point at which they stop the immune system or bone marrow from working properly when lymph nodes become so enlarged that they start to press on important structures or when patients get constitutional symptoms such as night sweats, weight loss or loss of appetite. Like other types of indolent B-cell NHL, CLL is not curable except with a bone marrow or stem-cell transplant from another individual. This is a risky proposition that can be difficult to justify in a disease with a natural history that can often be measured in decades. So, for most patients, treatment is aimed at alleviating symptoms and preventing life-threatening complications.
There are four basic questions in relation to treating CLL: when to start, what to give, when to stop and what to do next. The answers to these questions are likely to vary depending on whether one is dealing with a gentle or more aggressive type of CLL, and also on patient age and fitness. For example, in an elderly person with relatively benign form of CLL and other medical problems, a ‘softy, softly’ approach would be appropriate. At the other end of the spectrum, a fit young patient with a malignant form of CLL might benefit from more aggressive treatment.
Consideration needs to be given not only to initial treatment but also what to do when the disease relapses. In general, the more the disease comes back, the less well it responds to further therapy. If relapse occurs after a reasonably long time interval, say more than two years or so, it is reasonable to give the same treatment again if it was well tolerated the first time round. This particularly applies to more gentle treatments such as chlorambucil (see below). If, on the other hand, the disease comes back early after initial therapy or does not respond, different and probably stronger second-line treatment is indicated.
For current updates watch our webcasts produced following recent talks at CLLSA meetings by leading UK clinical consultants
June 2014- Dr George Follows - CLL Overview
June 2014- Dr George Follows - The New Treatment Landscape
December 2014 Dr Claire Dearden - CLL Therapy Update - part 1
December 2014 Dr Claire Dearden - CLL Therapy & Trials Update - part 2