The Scottish Medicine Consortium (SMC) has announced that it is recommending the use of venetoclax with rituximab on the NHS for chronic lymphocytic leukaemia (CLL) patients who have had at least one prior therapy. Venetoclax with rituximab was approved for use in England and Wales in January 2019, so this decision creates equal access for CLL patients in the UK.
In response to the decision, our Patient Advocacy Director, Zack Pemberton-Whiteley, said: “We’re delighted the SMC has decided to make the venetoclax plus rituximab combination treatment available in Scotland on the NHS to people living with relapsed or refractory CLL. This decision has the potential to change outcomes in an area where we have seen few clinical advances until recently. Hearing your disease has relapsed or become refractory can be overwhelming for patients and their families, so the SMC’s decision to make available an effective chemotherapy-free option with a fixed treatment duration is very much welcomed by the patient community.”
How does venetoclax work?
Venetoclax (brand name Venclyxto) is produced by AbbVie. Venetoclax works by targeting a molecule called BCL-2, preventing it from working. BCL-2 normally prevents cancer cells from dying; venetoclax removes the Bcl-2, causing the cancer cells to die.
What was the evidence that venetoclax with rituximab worked?
The SMC was presented with data from the MURANO clinical trial. This trial compared venetoclax plus rituximab with bendamustine plus rituximab. Bendamustine was the standard treatment given at the time the trial was made. The trial showed an 83% reduction in the risk of disease progression when taking venetoclax with rituximab, which was significantly more than seen when taking bendamustine with the rituximab. After 36 months, 60% of the venetoclax patients had no detectable disease.
The manufacturer, Abbvie, also presented evidence that their drug was cost effective. In the UK, the NHS has set a limit on the amount of money that can be spent on a drug per Quality Adjusted Life Year. A QALY is a way of measuring the extra survival time that a treatment can give a patient, whilst also account for the quality of life during those extra years. The limit that was applied to this treatment was a maximum of £30000 per QALY. The company presented economic models that suggested that the drug would not cost more than the limit, and the SMC deemed venetoclax and rituximab to be cost effective.
Why are new treatment options important for CLL patients?
One of Leukaemia Care’s role in the drug appraisal process is to inform the SMC team about how CLL affects people’s lives day to day. We also provide evidence for patient preferences, such as types of treatments people prefer or where they would prefer treatment to be delivered. This evidence comes from our survey, Living with Leukaemia, as well as focus groups and conversations with individual patients. We provide this information by submitting a written statement, and by attending a meeting known as Patient and Clinician Engagement (PACE) meetings, where we engage in a discussions about the needs of patients and how the new treatments meet those needs.
CLL is a chronic condition, meaning that current treatments do not cure it. This uncertainty may contribute to the negative emotional impact that patients report in our survey. 37% of CLL patients report feeling depressed or anxious more often since diagnosis, increasing to 41% of those who have relapsed from a previous treatment. We argued that the extra stress associated with relapse could in part be addressed by ensuring there is a line of effective treatments, so patients feel reassured that they can be treated again.
Venetoclax with rituximab is being looked at for patients who have relapsed from their first line of treatment, usually chemotherapy. In this instance, the second option can be a drug called ibrutinib. This targets a molecule called the Bruton’s tyrosine kinase, which is found on the B cells, which are the types of cells that have turned cancerous in CLL. In theory, this means ibrutinib should affect healthy cells less than chemotherapy does, with fewer side effects. Fewer side effects are one of the things that patients report as an important feature of new treatments, favoured by 56% of CLL patients. 68% also mark improved quality of life as important for new treatments; quality of life is often linked to reduced side effects too.
So why do need venetoclax if ibrutinib is more targeted than chemotherapy? More generally, 84% of CLL patients said they would like a choice of treatment options. It is important that patients feel like are involved in the decisions about their own healthcare. Also, ibrutinib does still have side effects, so there is always room to improve that aspect of treatment for patients. Additionally, ibrutinib must be taken continuously. Whilst this may not be an issue for some, for those experiencing side effects, they will not stop unless you stop the treatment.
Venetoclax and rituximab, on the other hand, is taken for a set period of two years, followed a period of active monitoring without treatment. We asked patients whether they would view a treatment free period as a positive thing; 64% of CLL patients reported that they would. We also explored why they would see this as a positive in a follow up focus group, and patients agreed that it’s a positive; this is not just because they are free of side effects, but it might also allow them to visit hospital less often and generally get back to a normal life.
Finally, venetoclax is delivered as an oral chemotherapy, which is a popular method of delivery according to our survey. This means that, after the first few days, venetoclax and rituximab can be delivered in an outpatient clinic. 67% of CLL patients would prefer outpatient treatment, with the focus group telling us that this provides the best balance between hospital/nurse support and maintaining normal home life.
Venetoclax is not without its disadvantages too, so it was also important for Leukaemia Care to address those on behalf of patients. Despite being more targeted than chemotherapy, venetoclax still has side effects. One of the potential side effects is tumour lysis syndrome; this happens when the venetoclax is given at a high dose. Venetoclax works so well at high doses that it kills the cells too rapidly. The patient’s immune system overreacts to the presence of too many dying cells, making the patient very ill. This was a concern of the SMC, but there is plenty of evidence that this has been well managed by dose escalation, hence the need for an small initial inpatient period at the start. We also helped the committee to understand that patients are aware that there are risks to cancer therapies and any concerns can be managed by discussion with their clinicians. Discussions about the disadvantages, as well as advantages, are important to the appraisal process, ensuring only truly beneficial treatments are approved.
If venetoclax has already been approved and is seen positively by patients, why has it been assessed again?
Venetoclax has been approved previously for use on its own; it can be used for patients who have tried chemotherapy and a BCR inhibitor (e.g. ibrutinib) or those with genetic mutations (a 17p deletion or TP53 mutation) that mean they cannot have chemotherapy and have relapsed from or can’t have a BCR inhibitor. It was assessed by the SMC again because it was proposed by the manufacturer that it would work better in combination with rituximab. Rituximab is a drug that binds to a molecule on the surface of B cells, called CD20. Binding to CD-20 also initiates the cell death process. Therefore, in theory, it should help venetoclax to kills the cells, as the cell will be encouraged to die by two different mechanisms, increasing the chances that it will actually be killed.
When drugs are combined with one another, it is important that they are reassessed for safety. It is possible that drugs can interfere with each other or cause extra side effects when combined. Therefore, Abbvie had to conduct extra clinical trials and the SMC had to assess both drugs as a combination. Additionally, it is the job of the SMC to make sure any treatment, including combinations like this, is cost-effective for the NHS. Using two drugs is more expensive than using just one, so the SMC examined whether any extra benefits of using a second drug was worth the extra cost.
You can find out more about this decision here: https://www.scottishmedicines.org.uk/medicines-advice/venetoclax-venclyxto-full-smc2166/ or contact our advocacy team by emailing firstname.lastname@example.org or calling our helpline 08088 010 444.