The SMC recommends aclabrutinib to become a treatment option for certain groups of CLL patients in Scotland.

The SMC looked at three groups of CLL patients separately. These were:

• Previously treated CLL patients (has been approved for those who are not eligible for chemoimmunotherapy).
• Untreated patients with 17p deletion or TP53 mutations. These are genetic mutations that affect how well current treatments, such as FCR, work.
• Untreated patients who are unsuitable for current treatments, such as FCR, for other reasons. For example, some patients are too unwell to have strong chemotherapy-based treatments or have other health conditions that mean chemotherapy would make them very unwell, and so need to have alternative options for treatment.

Two of these groups being assessed above were assessed through what is known as an abbreviated submission process. This is a process that is designed to be quicker, where a full assessment of the medicine is not necessarily needed. It is usually used in circumstances like when a treatment is changing from an injection to an oral tablet, or similar small changes that are unlikely to affect the decision to approve the treatment.

However, during the COVID-19 pandemic, the SMC allowed abbreviated submissions to happen for treatments where there is already another treatment available in the same class. A class is a group of drugs that have the same mechanism of action, meaning they work the same way. In the case of acalabrutinib, the SMC had already approved ibrutinib for use in two of the three groups; the previously treated CLL population and those who are untreated with 17p or TP53 mutations. This means SMC approved acalabrutinib for these two groups much quicker.

However, Leukaemia Care were unable to be involved in the appraisal of acalabrutinib for the two groups that went through abbreviated submissions. The abbreviated submission process does not involve any submission or input from patient groups. Additionally, because this faster process relies heavily on information from appraisals done on ibrutinib in the past, any restrictions on access to ibrutinib were also put in place on acalabrutinib. For the previously treated group of CLL patients, this meant that acalabrutinib is also restricted to those who cannot have chemotherapy, because this was what was done for ibrutinib too. At the time of writing, we do not believe this will have a significant impact on patients, as most patients wanting access to acalabrutinib will have had chemoimmunotherapy before or are not eligible for it anyway. However, Leukaemia Care will continue to monitor the impact of this restriction.

Leukaemia Care were able to get involved in arguing for access to acalabrutinib for the group of patients who are not yet treated but are unfit for chemoimmunotherapy. We provided a written submission, including data from surveys and quotes from people who had taken acalabrutinib. We also attended the SMC committee meeting where the decision is made, alongside a representative from the charity CLL Support. Leukaemia Care argued that more options for patients are always important, so patients can discuss with their doctor the therapy that is right for them. The alternative treatments of venetoclax and ibrutinib, whilst highly effective treatments, come with side effects that also mean they are not suitable for all. For example, ibrutinib can cause serious heart issues and is rarely suitable for those with existing heart issues. Therefore, acalabrutinib is needed and we are pleased to see it approved.

Whilst FCR is a treatment that is highly effective, it comes with side effects, some of which are long term, and many patients would like to avoid these. Therefore, Leukaemia Care, along with other patient groups, argued that there is still an unmet need in the population of patients who would otherwise be treated with FCR. Another recently approved treatment, venetoclax in combination with obinutuzumab, was also not approved for this group in Scotland, meaning the FCR suitable population cannot access any of the novel treatments that have come along in the last few years until they have relapsed.

Leukaemia Care will continue to work closely with AstraZeneca, NICE and SMC to work towards greater access to therapies for patients.

As part of our submission to SMC, Leukaemia Care presented the results of a survey of patients who had taken acalabrutinib. 40 people who had been treated with acalabrutinib took part and overall reported a good experience with the treatment. For example, 68% of patients said that acalabrutinib managed all their symptoms, with 45% reporting a reduction in fatigue and 82% a reduction in their lymph nodes.

Side effects of treatment are also important; 36% of patients had no side effects, 25% said they did have side effects but these had no impact on their life, and 23% said the side effects had only a small impact on their life.

Acalabrutinib is a Bruton’s tyrosine kinase (BTK) inhibitor (often shortened to BTKi). BTK is a protein that is active in B-cells, the type of immune cell that becomes cancerous in CLL. Normally the protein relays signals from outside the cell to a series of other proteins, ultimately causing the B-cells to divide. However, in CLL, the BTK protein is mutated and always switched on, rather than needing to be switched on by an outside signal. This means the B-cells divide when they are immature, creating too many underdeveloped cells that do not work properly (these are the CLL cells). A BTK inhibitor stops the BTK protein from working, therefore stopping too many cells from being made and allowing the remaining cells to correctly develop.

Importantly, acalabrutinib inhibits the BTK protein in a different way to the other BTKi drugs used – ibrutinib and idealisib. This means that it can work for those who have previously had these other BTK inhibitors, opening up more treatment options for patients who have tried all other treatments.

The main clinical trial evidence came from the ELEVATE clinical trial, which compared acalabrutinib (sometimes given with obinutuzumab) with a combination of chlorambucil and obinutuzumab. This trial showed a significant improvement in progression-free survival (i.e., an increase in the length of time people survive without their CLL getting worse) in patients who took acalabrutinib, compared with those who had the chlorambucil instead. Chlorambucil is still used in some patients who cannot have FCR, so this trial showed that acalabrutinib would be an effective option for these patients.

Many patients who were being considered as potential groups to be offered acalabrutinib would usually be offered ibrutinib as their alternative treatment. Whilst there are currently no trials directly comparing people on acalabrutinib with people taking ibrutinib, a comparison between acalabrutinib and a different BTK inhibitor, idealisib, was available from the ASCEND trial. Additionally, NICE were able to look at the effectiveness of ibrutinib in patients in another trial, RESONATE. Trials that directly compare treatment options are the best type of evidence to use for decision making but are not always available.

As well as acalabrutinib being shown to be as effective or more effective than alternatives, evidence also suggested that acalabrutinib is likely to be cost saving compared to using ibrutinib, which is a positive for the NHS. However, this does not mean other treatments will not be available to patients; all approved options remain available, and clinicians and patients are able to choose the treatment that works best for them.