Targeted therapies for chronic lymphocytic leukaemia in an evolving treatment landscape

Chronic lymphocytic leukaemia (CLL) is the most prevalent adult leukaemia in Western countries with more than 100,000 incidences and more than 40,000 deaths reported globally in 2019.¹ The cancer is a slow-growing but potentially life-threatening B-cell malignancy, in which increased activation of B-cell receptor signalling pathways leads to overgrowth of lymphocytes in bone marrow and other disease compartments. Targeted therapies introduced over the last 10 years, such as Bruton’s tyrosine kinase inhibitors (BTKis), which block a B-cell receptor pathway, and B-cell lymphoma 2 inhibitors (BCL2i), which are medicines designed to induce apoptosis (programmed cell death) in cancer cells, have led to a dramatic change in the CLL treatment landscape.

CLL treatment evolution: from chemo-based options to targeted therapies

Advances in the understanding of CLL biology have resulted in the development of new therapeutic approaches that have dramatically improved patient outcomes, even prolonging patients’ lives.

BTKis, oral drugs given as continuous monotherapy, have revolutionised the treatment of CLL, with the first generation BTKi ibrutinib receiving European Medicines Agency (EMA) approval in 2014; however, side-effects (such as cardiovascular toxicities²) have limited its suitability.

Second generation BTKi, acalabrutinib, was designed to be more specific against the target to mitigate some of the toxicities associated with ibrutinib and has demonstrated an improved safety profile in head-to-head clinical trial ELEVATE-RR (acalabrutinib vs ibrutinib) but with similar efficacy (non-inferiority trial with hazard ratio (HR)=1.0).

Zanubrutinib, a next-generation BTKi, designed to be more specific, more potent, and provide round the clock inhibition of the target, demonstrated superior efficacy (HR=0.65 for all-comers; HR=0.52 for patients with del(17p)/TP53 mutation) and a favourable safety profile, including cardiac events, compared to ibrutinib (ALPINE study).

Another targeted treatment option is the combination of an oral BCL2i (so far, only venetoclax is approved) with an injectable B-cell targeted immunotherapy, for example, the anti-CD20 antibodies, rituximab or obinutuzumab as tested in the MURANO, CLL14 and CLL13 trials in relapsed/refractory and treatment-naive CLL. Alternatively, a BTKi can be given in fixed duration; these regimens have also shown efficacy benefit over chemo-immunotherapy (GLOW trial).

Continuous and fixed duration targeted therapies – shifting the CLL treatment paradigm in Europe

Continuous targeted therapies approved by the EMA are:

• first generation covalent BTKi: ibrutinib
• second generation covalent BTKi: acalabrutinib
• next generation covalent BTKi: zanubrutinib.

All are orally administered as monotherapy and given continuously until disease progression or unacceptable toxicity.

The approved fixed duration targeted therapies are:

• Venetoclax + rituximab (Ven+R) in relapsed/refractory CLL – this combination requires infusions. Venetoclax is given for 24 months including five-week ramp-up, to reduce risk of tumour lysis syndrome (TLS) followed by six cycles of rituximab.
• Venetoclax + obinutuzumab (Ven+Obi) in treatment-naive CLL – this combination requires infusions. Venetoclax is given for 12 cycles, including five-week ramp-up: six cycles with obinutuzumab, then six cycles alone.
• Venetoclax + ibrutinib (Ven+Ibru) – this combination is oral. Ibrutinib is given as a single agent for three cycles of 28 days, followed by 12 cycles of Ven+Ibru, including five-week venetoclax ramp-up.

Pivotal clinical trials for each treatment include:

INV: investigator-assessed; IRC: assessed by independent review committee; MRD: minimal residual disease; ORR: overall response rate; PFS: progression-free survival. ^†Arms showing significant primary endpoint efficacy benefit shown in bold.

Development challenges to achieve regulatory approval

Comparative trials of novel agents require large samples and for long-term follow up to adequately show the benefit of one arm over another to gain approval. It can be challenging to enrol patients given that, in areas of rapid advances in treatment like CLL, there are so many ongoing trials of new therapeutic approaches.

Furthermore, standard-of-care comparator arms can quickly become outdated as the landscape evolves, making it difficult for clinicians to base treatment decisions on data upon study read out.

Moreover, regulatory bodies may require demonstration of superiority in later endpoints such as PFS or overall survival (OS) even when intermediate/surrogate endpoints, such as complete response (CR) or undetectable minimal residual disease (uMRD), show improvements.

Factors favouring continuous versus fixed duration treatment for CLL

To date, there are no data from randomised studies comparing continuous treatment to fixed duration targeted treatment but such trials may be planned. While cross-trial comparisons are discouraged, comparing outcomes of subsets of patients in different trials has led to treatment preferences for certain patient populations (eg, BTKis may be preferred in high-risk patients with del(17p)/TP53^mut).

Several studies have compared targeted therapy combinations of BTKi and BCL2i versus Ven-Obi, including uMRD guided trials; MAJIC of Ven-Obi vs Ven-Acala; and CELESTIAL-TN CLL comparing fixed duration Ven-Obi vs fixed duration zanubrutinib + novel BCL2i sonrotoclax, which has shown promising safety and efficacy in Phase I/II studies.

Some of the key considerations favouring one approach over the other are shown in the table below.

New agents and regimens are continually being approved, shifting the treatment landscape. For example, chemoimmunotherapy now has a smaller role in treating the disease except in cases when all targeted therapy options are exhausted.

Future developments

While great strides have been made in the treatment of CLL, there are new approaches on the horizon that may further improve outcomes for patients.

One option is to improve fixed duration combinations by using novel BTKis in combination with venetoclax, or triple combinations of a BTKi + Ven-Obi, as in the BOVen study of zanubrutinib + Ven-Obi¹⁰, which showed durable rates of PFS and undetectable minimal residual disease after long-term follow-up.

These new combinations may mitigate some of the toxicity issues with current fixed duration treatments. The SEQUOIA trial⁵ included a cohort of patients (Cohort 3) with high-risk CLL or small lymphocytic lymphoma (SLL) (del(17p)/TP53^mut) who received a combination of zanubrutinib + venetoclax: preliminary data demonstrated promising efficacy with deep responses and good tolerability in this hard-to-treat population. SEQUOIA Cohort 3 also included a cohort of low-risk patients with data pending. There is also an ongoing Phase III study, the AMPLIFY trial, which is evaluating fixed duration acalabrutinib and venetoclax, with and without obinutuzumab, versus chemoimmunotherapy (FCR/BR) in patients with treatment-naive CLL without high-risk features.

Noncovalent BTKi pirtobrutinib, which is in Phase III studies as monotherapy and in combination as fixed duration, has demonstrated promising and durable efficacy in patients with CLL/SLL post-covalent BTKi (BRUIN Phase I/II trial) and has accelerated approval in US.

A second fixed duration avenue to explore is next-generation BCL2is, such as sonrotoclax – a more selective and potent BCL2i with unique PK properties – which is being studied in combination with zanubrutinib vs Ven-Obi as fixed duration in the CELESTIAL-TN CLL Phase III study.

Additional promising treatments for CLL

Other mechanisms of action such CAR-T therapies have shown efficacy in heavily pre-treated CLL; Liso-cel, for example, is approved for CLL in the US. Bispecific antibodies are being studied in CLL and epcoritamab has generated promising monotherapy data in heavily pre-treated CLL patients.

There are further novel drug classes and mechanisms in development, including BTK degraders. The BTK degrader BGB-16673 demonstrated encouraging preliminary results from the first-in-human study (CaDAnCE-101), with a tolerable safety profile and clinical responses in heavily pretreated patients with B-cell malignancies, including those with BTKi-resistant disease and those CLL patients who have been treated with covalent BTKis, non-covalent BTKis and BCL2is.  

Conclusions

With targeted therapies, the CLL treatment landscape has rapidly evolved to improve patient outcomes. Looking ahead, the future holds even more promise: there are novel treatments, combinations and strategies on the horizon that should lead to further improvements in survival and quality of life for patients, while addressing current and future areas of unmet need.

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