Acalabrutinib and venetoclax with or without obinutuzumab for untreated chronic lymphocytic leukaemia

Chronic lymphocytic leukaemia (CLL) is a malignant disorder of the white blood cells. It is the most common type of leukaemia in England. The patient experts explained that the physical and psychological effects of CLL have a debilitating effect on their daily lives. The risk of having CLL increases with age. The condition usually progresses slowly, and symptoms develop over time. More rapid progression and a poor prognosis is commonly caused by a deletion of chromosome 17p (17p deletion) or a mutation in the gene that produces the tumour protein p53 (TP53 mutation). But 90% to 95% of people with CLL do not have the 17p deletion or TP53 mutation and so are considered to have non-high-risk CLL. The committee concluded that CLL substantially affects physical and psychological quality of life.

Usual treatment for untreated CLL includes:

• fixed-duration options, which are recommended for untreated CLL in adults (irrespective of 17p deletion or TP53 mutation status):

  • venetoclax plus ibrutinib (see NICE's technology appraisal guidance on ibrutinib with venetoclax for untreated CLL, from here referred to as TA891)

  • venetoclax plus obinutuzumab (see NICE's technology appraisal guidance on venetoclax with obinutuzumab for untreated CLL

• treat-to-progression options, which are recommended for untreated CLL in adults with a 17p deletion or TP53 mutation, or without a 17p deletion or TP53 mutation if fludarabine plus cyclophosphamide and rituximab (FCR) or bendamustine plus rituximab (BR) is unsuitable:

  • acalabrutinib monotherapy (see NICE's technology appraisal guidance on acalabrutinib for treating CLL

  • zanubrutinib monotherapy (see NICE's technology appraisal guidance on zanubrutinib for treating CLL, from here referred to as TA931).
    
    The committee was aware that FCR and BR are no longer used for non-high-risk CLL. This is because targeted treatments, such as venetoclax plus ibrutinib and venetoclax plus obinutuzumab, have largely replaced chemoimmunotherapy in practice. The NHS England Cancer Drugs Fund clinical lead (from here, Cancer Drugs Fund lead) stated that Blueteq data confirms that venetoclax plus ibrutinib, venetoclax plus obinutuzumab, and acalabrutinib or zanubrutinib monotherapy are commonly used in NHS practice for untreated CLL. Patient experts explained that treatment preference is shaped by individual health and social circumstances. This includes their ability to follow treatment schedules and to continue normal work and family activities. The committee was aware that the company submission did not include untreated high-risk CLL (see section 3.3). Clinical experts at the meeting commented that if recommended, acalabrutinib plus venetoclax has the potential to provide a valuable additional fixed-duration option that is taken orally. They explained that fixed duration and treat to progression are 2 different treatment paradigms with different progressions and risks. They added that fixed-duration treatments are more intensive than treat-to-progression treatments but offer patients valuable time off treatment and may reduce the occurrence of treatment-related comorbidity. So, treatment selection needs to consider a range of clinical factors, including age, comorbidity, genetic factors and lifestyle, and be individualised to suit patient preferences and circumstances. But both fixed-duration and treat-to-progression treatments are standard first-line treatment for untreated CLL in the NHS, and all the treatment options are available to people with the condition. Patient experts at the meeting commented that people with untreated CLL tend to prefer having fixed-duration treatment. But they added that the need for regular hospital visits for obinutuzumab, which is given intravenously (with oral venetoclax), does not suit everyone. The EAG said that their clinical experts highlighted that the lower toxicity profile of acalabrutinib plus venetoclax could make it an option for older fitter patients wanting a fixed-term all-oral treatment. Clinical experts in the meeting stated there is evidence that acalabrutinib plus venetoclax may be better tolerated than venetoclax plus ibrutinib or venetoclax plus obinutuzumab. So, acalabrutinib plus venetoclax may be suitable for a broader range of people than existing fixed-duration options. The committee concluded that acalabrutinib plus venetoclax would be welcomed as a new treatment option for people with untreated non-high-risk CLL.

The company's submission only included people with untreated non-high-risk CLL, which is people without a 17p deletion or TP53 mutation. It also only presented evidence for acalabrutinib plus venetoclax without obinutuzumab. The committee understood that this was narrower than the marketing authorisation (see section 2.1) and NICE's final scope on acalabrutinib and venetoclax with or without obinutuzumab for untreated CLL. The company explained that it had focused on people with untreated non-high-risk CLL because this is the population included in the AMPLIFY trial (see section 3.5). The clinical experts explained that triplet therapy including obinutuzumab was likely to be associated with greater toxicity and would potentially be used more for people with high-risk CLL.

The EAG noted that the marketing authorisation for acalabrutinib plus venetoclax applied to both high-risk and non-high-risk subgroups. It thought that considering people with untreated high-risk CLL (people who have a 17p deletion or TP53 mutation) would broaden treatment options for this subgroup. It added that the fixed-duration options currently available in the NHS were recommended for everyone with untreated CLL. But that evidence on the clinical and cost effectiveness of acalabrutinib plus venetoclax in the high-risk subgroup would be needed for this consideration. The Cancer Drugs Fund lead said that there is an unmet need in the high-risk subgroup and there may be benefit to extending the recommendation to this subgroup. The committee concluded that the company's target population of untreated non-high-risk CLL was reasonable. But it would also like to see evidence on the clinical and cost effectiveness of acalabrutinib plus venetoclax in untreated high-risk CLL.

The comparators included in the company's submission were venetoclax plus ibrutinib and venetoclax plus obinutuzumab (see section 3.8 and section 3.12). The company explained that this was because acalabrutinib plus venetoclax is a fixed-duration option and so would be used in the same population as that for which venetoclax plus ibrutinib or venetoclax plus obinutuzumab is suitable. The committee noted comments from clinical experts and the Cancer Drugs Fund lead in the meeting about current standard care in the NHS (see section 3.2). It concluded that both fixed-duration and treat-to-progression treatments are relevant comparators for this appraisal.