Chronic Lymphocytic Leukaemia Refractory

When chronic lymphocytic leukaemia stops responding to treatment or returns after therapy, patients face a challenging situation. However, significant advances in targeted treatments over the past two decades have transformed the outlook, offering new hope and multiple options for controlling this relapsing disease.

Table of contents

• What is Relapsed and Refractory CLL?
• Understanding Treatment Goals
• Current Treatment Options
• BTK Inhibitors
• Venetoclax-Based Therapy
• Emerging and Novel Therapies
• Monitoring and Managing Your Health

What is Relapsed and Refractory CLL?

Chronic lymphocytic leukaemia (CLL) is a type of cancer that affects the blood and bone marrow, causing the body to make too many white blood cells called lymphocytes. These abnormal cells cannot fight infection properly and crowd out healthy blood cells^[1].

When CLL comes back or stops responding to treatment, doctors use specific terms to describe the situation. Relapsed CLL means the disease has returned after a patient previously achieved complete or partial remission, with evidence of disease progression occurring after a period of six months or more^[1]. Refractory CLL refers to disease that does not respond adequately to treatment^[1].

CLL predominantly affects older adults and is characterized by a pattern of relapsing and remitting, meaning many patients will receive multiple treatments over time^[1][3]. When the disease relapses, healthcare teams carefully monitor disease burden, how quickly it is progressing, and check for specific genetic changes that may affect treatment decisions^[3].

Understanding Treatment Goals

The main goal when treating relapsed or refractory CLL is to control the disease and delay its progression while maintaining a good quality of life^[1]. Currently, treatment aims to control the disease rather than cure it, as a complete cure remains largely out of reach^[1].

Several important factors influence treatment decisions for relapsed disease. These include the patient’s overall physical condition, the presence of other health problems, how long it has been since the last treatment, and which treatments were used previously^[1][3]. The time between relapse and starting the next treatment provides an important opportunity to optimize the patient’s health, including ensuring proper vaccinations, checking for other cancers, and treating non-CLL health conditions that may affect well-being^[3].

Current Treatment Options

Treatment options for relapsed or refractory CLL have expanded significantly over the past two decades. Patients with this condition now have more choices than ever before^[1].

The preferred standard treatments for relapsed CLL today are targeted therapies, which work by attacking specific molecules on cancer cells. These include continuous BTK inhibitors and fixed-duration treatment combining venetoclax with an anti-CD20 antibody^[1][3]. These targeted therapies have proven superior to older chemoimmunotherapy treatments and have become the preferred standard of care^[1].

While both classes of targeted therapy are effective for relapsed or refractory CLL, they differ in their potential side effects and how they are administered. Importantly, these treatments may be used in either sequence, though there is limited data from randomized studies showing the best order to use them^[3].

BTK Inhibitors

BTK inhibitors are a type of targeted therapy that blocks a protein called Bruton’s tyrosine kinase (BTK), which helps CLL cells survive and grow. There are two types of BTK inhibitors: covalent and non-covalent, based on how they attach to the BTK protein.

The first BTK inhibitor approved was ibrutinib, which showed much better results than older treatments. In a key study comparing ibrutinib to an antibody treatment, patients taking ibrutinib had a median progression-free survival of 44.1 months compared to only 8.1 months with the older treatment^[9]. Patients who received ibrutinib earlier in their disease course tended to have longer remissions^[9].

Second-generation BTK inhibitors, including acalabrutinib and zanubrutinib, have shown improved safety profiles compared to ibrutinib^[1]. These medications are taken continuously, meaning patients stay on them for as long as they continue to work.

However, resistance to these covalent BTK inhibitors can develop over time, often because of mutations in the BTK protein or other related enzymes^[1]. When this happens, newer non-covalent BTK inhibitors such as pirtobrutinib and nemtabrutinib are showing promising results^[1]. Pirtobrutinib, for example, demonstrated prolonged progression-free survival with a median time to next treatment of approximately two years, even in heavily pretreated patients^[10].

Venetoclax-Based Therapy

Venetoclax is a different type of targeted therapy that works by blocking a protein called BCL-2, which helps cancer cells avoid death. Unlike BTK inhibitors, venetoclax is given for a fixed duration rather than continuously, typically in combination with an anti-CD20 monoclonal antibody^[1][3].

This fixed-duration approach means patients receive treatment for a set period and then stop, rather than taking medication indefinitely. This can be an advantage for some patients, as it limits long-term exposure to treatment and potential side effects.

Measurable residual disease (MRD) testing has become increasingly important with venetoclax-based therapy. This highly sensitive test can detect very small amounts of cancer cells remaining after treatment. Evidence suggests that patients who achieve MRD negativity (meaning no detectable cancer cells) have better outcomes^[1]. However, it remains to be determined whether MRD testing will become a standard way to measure treatment success.

Emerging and Novel Therapies

Several innovative treatment approaches are showing significant promise for patients with relapsed and refractory CLL who have limited options.

Chimeric antigen receptor (CAR) T-cell therapy is an advanced treatment that involves modifying a patient’s own immune cells to recognize and attack cancer cells. This therapy has shown significant activity for relapsed and refractory CLL and is now approved by regulatory authorities^[1][3]. However, its use is currently limited because many patients are not eligible due to age and other health conditions^[10].

Bispecific antibodies are another novel approach that connects immune cells to cancer cells, helping the immune system destroy the cancer. Early studies show that bispecific antibodies like epcoritamab have achieved complete remissions in approximately 40% of heavily pretreated patients^[10].

BTK degraders represent a new class of drugs that work differently from BTK inhibitors. Rather than just blocking the BTK protein, these drugs cause it to be broken down and destroyed. Early-phase results show these molecules have clinical activity even after patients have received non-covalent BTK inhibitors^[3][10].

Other potential treatments being studied include allogeneic stem cell transplantation, which may be considered in specific situations in the era of novel therapies^[3].

Monitoring and Managing Your Health

When CLL relapses, identification should prompt close monitoring and early discussion about next treatment options when specific signs indicate treatment is needed^[3]. Healthcare teams use various tests to monitor disease and check for progression.

Several factors beyond the cancer itself affect treatment decisions and overall well-being. Performance status and the presence of other health conditions are important considerations when deciding the best treatment options^[1]. Data shows that health-related quality of life decreases with worsening performance status and is lower in patients experiencing fatigue^[1].

The period between recognizing relapse and starting new treatment represents an opportunity to optimize overall health. This includes establishing adequate vaccination protection, screening for second cancers, and treating health problems not related to CLL that may impact well-being and the ability to tolerate CLL therapy^[3].

Because treatments can cause serious side effects, choosing appropriate therapy should account for overall physical condition and define both the goal and role of treatment. Given that CLL is a chronic disease, and considering that the average age at death for patients with leukaemia is 79 years, decisions about if and when to treat must be carefully considered^[2].

The optimal sequence of various treatment options remains to be determined, and research continues to explore the best ways to use these therapies^[1]. As the therapeutic options continue to expand with emerging treatments, there is optimism for shifting novel agents into earlier lines of treatment, with the ultimate goal of achieving long-term remission or cure^[10].