New Horizons in Chronic Lymphocytic Leukemia Treatment: 2023

• Chronic Lymphocytic Leukemia (CLL) is a serious condition, and the current standard treatment involves a combination of Ibrutinib and Obinutuzumab (IO).

• A new treatment approach, the combination of Ibrutinib, Venetoclax, and Obinutuzumab (IVO), shows promising results in clinical trials, potentially paving the way for a new standard in CLL treatment.

• The COVID-19 pandemic has had significant impacts on patients with CLL, emphasizing the importance of comprehensive disease management and prevention measures.

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• Expert insights, such as those provided by Brian Hill MD, provide valuable context and understanding of the rapidly evolving field of CLL treatment.

• The potential to achieve undetectable minimal residual disease (uMRD) could mean a future where CLL patients can discontinue therapy after a year, minimizing long-term side effects.

Chronic Lymphocytic Leukemia (CLL) is a type of blood cancer that starts from cells that become certain white blood cells (called lymphocytes) in the bone marrow; over time, these abnormal cells accumulate and begin to affect the function of the immune system.

CLL predominantly affects older adults and progresses slowly, often remaining undiagnosed until routine blood work reveals an elevated white blood cell count.

According to the American Cancer Society, it’s the most common type of leukemia in adults, making it vital for both patients and healthcare providers to stay informed about the best treatment options.

This brings us to the central focus of our article: a comprehensive examination of a recent study published by the Alliance for Clinical Trials in Oncology: the study pits the combination of Ibrutinib and anti-CD20 antibody Obinutuzumab, also known as IO, against the same regimen supplemented with Venetoclax, or IVO, in a bid to evaluate their respective efficacy in treating older, previously untreated CLL patients.

Over the course of this article, we will answer some important questions like:

• What is the best treatment for CLL?

• Is it the standard regimen IO?

• Does the additional drug in IVO bring about a marked improvement?

A Closer Look at Chronic Lymphocytic Leukemia

Before we delve into the recent study results, let’s better understand Chronic Lymphocytic Leukemia. CLL is not merely a disease; it’s a journey that patients navigate with the help of medical professionals, loved ones, and their resilience.

But what does Chronic Lymphocytic Leukemia entail?

• It’s a type of cancer that starts in the white blood cells (lymphocytes) in the bone marrow.

• It then invades the blood and can spread to other parts of the body including the lymph nodes, liver, and spleen.

• According to the Leukemia & Lymphoma Society, CLL is one of four main types of leukemia and typically affects adults over the age of 55.

What is The Life Expectancy of a Person with CLL?

When it comes to life expectancy, it’s important to note that every patient’s journey with Chronic Lymphocytic Leukemia (CLL) is unique.

Different factors like age, overall health, and disease stage can greatly affect prognosis.

However, advancements in the field have greatly improved survival rates over the years. The Cancer Research Center (UK) reports that the 5-year survival rate for people with CLL is approximately 85%. It’s also essential to remember that many people live with CLL for many years, with a considerable number living for decades.

So, does this mean that CLL is a serious cancer?

Any cancer diagnosis is serious, but there are several nuances to CLL that are worth noting:

1. CLL typically progresses very slowly, and some people do not require treatment for years after their diagnosis.

2. When CLL becomes more aggressive or when symptoms start to impact the quality of life, treatment becomes necessary.

Key Terms

As we go further into our discussion, it’s essential to understand a few key terms:

• Chronic Lymphocytic Leukemia: As we’ve already covered, this is a type of blood and bone marrow cancer that affects white blood cells.

• IVO vs IO: These are two treatment regimens for CLL. IO refers to the combination of Ibrutinib and anti-CD20 antibody Obinutuzumab. IVO refers to the same combination, but with the addition of a third drug, Venetoclax.

• COVID-19: The global pandemic caused by the novel SARS-CoV-2 virus. We’ll be discussing its impact on CLL treatment later in this article.

• Bruton’s Tyrosine Kinase Inhibitor: This is a type of medication that blocks the enzyme BTK, which is essential in the development of B cells. Ibrutinib, one of the medications in the IO and IVO regimens, is a BTK inhibitor.

• Ibrutinib: A Bruton’s Tyrosine Kinase Inhibitor that is used in the treatment of various types of leukemia, including CLL.

As we progress through this article, we’ll explore the roles these terms play in CLL treatment and how they come together to form the broader picture of our understanding of CLL.

Current Treatment Options for Chronic Lymphocytic Leukemia

In the ever-evolving landscape of medical science, treatment options for Chronic Lymphocytic Leukemia have witnessed significant progress.

The first line of treatment is commonly Chemotherapy, once the standard of care for CLL, has gradually been phased out in favor of targeted therapies and immunotherapies, which have shown promising results in managing the disease.

Another one of these targeted therapies is a Bruton’s Tyrosine Kinase Inhibitor (BTKi).

But, what role does it play in CLL treatment?

• BTK inhibitors, such as ibrutinib, have revolutionized the treatment of CLL.

• BTK is an enzyme that plays a pivotal role in the maturation of B-cells, the type of white blood cell that goes awry in CLL.

• By inhibiting BTK, these drugs disrupt the signals that help cancerous cells survive and proliferate.

The effectiveness of BTK inhibitors in managing CLL led to the emergence of a standard frontline regimen: Ibrutinib and anti-CD20 antibody Obinutuzumab, known as IO.

The IO Regimen: A Frontline Treatment for CLL

The combination of ibrutinib plus obinutuzumab is a potent weapon against Chronic Lymphocytic Leukemia. This is how they both work:

• Ibrutinib, the BTK inhibitor, blocks the survival signals of the cancer cells.

• Obinutuzumab, an anti-CD20 antibody, enlists the body’s immune system to target and kill these cells.

The result is a comprehensive attack on CLL from two angles:

1. Disrupting the survival and proliferation of the cancerous cells

2. Flagging them for destruction by the immune system.

This dual-action approach forms the backbone of the standard IO regimen used to treat CLL.

But how do we gauge the success of these treatments? This brings us to two critical markers:

• Complete response (CR)

• Undetectable minimal residual disease (uMRD)

A complete response means that all signs of the cancer have disappeared following treatment.

However, even in CR, microscopic levels of cancer may remain in the body, which can lead to a relapse over time.

This is where uMRD comes into the picture.

Achieving undetectable minimal residual disease means that the levels of cancer in the body are so low that they can’t be detected with standard testing methods.

The IVO Regimen

While the IO regimen is the current standard, researchers are continuously exploring more effective treatments. One such promising strategy that has emerged is a combination of IO with another potent drug: Venetoclax.

This new treatment approach is known as the IVO regimen, which works in the next way:

• The BTK inhibitor ibrutinib and the anti-CD20 antibody obinutuzumab are combined with Venetoclax, a BCL-2 inhibitor.

• The BCL-2 protein is pivotal for the survival of CLL cells.

• By inhibiting BCL-2, Venetoclax disrupts the balance within the cancer cell, initiating a process called apoptosis, or programmed cell death.

Adding Venetoclax to the IO regimen aims to increase the depth of response in the therapy.

While ibrutinib and obinutuzumab disrupt CLL cells’ growth and flag them for destruction by the immune system, Venetoclax pushes the cells towards apoptosis.

This triple-pronged approach aims to deliver a more powerful blow to the cancer.

Why is the IVO Regimen Considered Promising for CLL?

The rationale for considering IVO as a potentially effective treatment for chronic lymphocytic leukemia (CLL) lies in the unique mechanism of Venetoclax.

As CLL cells are heavily dependent on BCL-2 for survival, the introduction of a BCL-2 inhibitor adds another layer of attack.

This might lead to deeper and more durable responses compared to IO alone.

Importantly, the IVO regimen opens the door for a response-guided approach. In this treatment strategy, clinicians assess patients’ response to therapy, particularly looking for undetectable minimal residual disease (uMRD). If a patient achieves uMRD, it might be possible to discontinue ibrutinib, reducing the duration of therapy, potential side effects, and costs.

The promising potential of the IVO regimen is not purely theoretical.

Early-phase trials have suggested that combining IO with Venetoclax could lead to deeper remissions. In these smaller trials, IVO was shown to induce undetectable minimal residual disease (uMRD) and complete responses (CRs), which may allow successful discontinuation of ibrutinib.

Comparing IVO vs IO in the Treatment of CLL

Recent medical advancements have led to the implementation of more in-depth studies to assess the efficacy of different treatment regimens.

One such study that deserves our attention is the phase III trial conducted by the Alliance for Clinical Trials in Oncology titled “A041702”.

This research is a multicenter study that randomized patients into two groups:

1. Those receiving the standard IO treatment

2. Those receiving the experimental IVO regimen

The study aimed to assess if IVO, followed by response-guided discontinuation of ibrutinib, improved progression-free survival (PFS) versus the IO regimen where ibrutinib is given indefinitely.

To put it simply, progression-free survival (PFS) is the length of time during and after treatment that a patient lives with the disease but it does not get worse. PFS is a commonly used endpoint in clinical trials studying cancers like CLL. In this case, longer PFS implies that the treatment regimen is more effective at controlling the disease.

Eligibility and Inclusion Criteria

Patients eligible for this study were 70 years or older (later amended to 65 years or older) who had not previously undergone any treatment for CLL.

Additional inclusion criteria included creatinine clearance (CrCl) of 40 mL/min or more, bilirubin levels less than or equal to 1.5 times the upper limit of normal (ULN), and the absence of any other life-threatening diseases.

Participants were stratified based on Rai stage and deletion 17p13.1 by FISH, an important genetic marker in CLL.

A total of 465 patients were registered and randomized equally to receive either IO or IVO treatments.

Detailed Treatment Regimens

In the IO arm:

The standard treatment included ibrutinib and obinutuzumab. Ibrutinib was given until the disease progressed or until the patient experienced unacceptable toxicity.

The IVO arm was a bit more complex:

Here, venetoclax was added to the IO regimen at cycle 3, day 1 (C3D1), and continued until cycle 14, day 28 (C14D28). After 14 cycles, the response to treatment was evaluated, including CT scans and bone marrow biopsies. Patients who achieved uMRD complete response (CR) discontinued ibrutinib; all others continued ibrutinib until disease progression or unacceptable toxicity.

This study design, although rigorous, allowed researchers to compare the efficacy and safety of the standard IO regimen to the new IVO regimen.

Study Results: A Close Look at PFS in IO and IVO

Interpreting the results of such comprehensive studies can often seem complicated, but fear not, we’re here to simplify it for you.

The A041702 trial ran from January 4, 2019, until July 15, 2022, during which 465 patients were registered:

• 232 received the standard IO regimen

• 233 received the IVO regimen

The patients had a median age of 74 years, and the majority (67%) were men.

A significant proportion of patients had high-risk disease features. Around 55% of patients presented with Rai stage 3-4, and 13% of patients had deletion 17p13.1, a high-risk genetic abnormality in CLL.

After a median follow-up of 14 months, the PFS of the IO group was 87.5% compared to 85% in the IVO group.

Here, the PFS represents the proportion of patients who have not had their disease progress or have not died, out of all the patients in the group.

The study reported the hazard ratio (HR) to compare the risk of progression or death in the two treatment arms. The hazard ratio (HR) is a measure of how often events (in this case, disease progression or death) happen in one group compared to how often they happen in another group, over time.

Interestingly, the predefined futility boundary was crossed, with a HR of 1.20 in favor of IO. This means that the risk of disease progression or death was 20% higher in the IVO group than in the IO group. This result challenged the initial hypothesis that IVO could be superior to IO for CLL treatment in older patients.

Impact of COVID-19 on the Study

In a surprising twist, the COVID-19 pandemic significantly impacted the study’s outcome.

COVID-19 was the leading cause of death in both arms of the study, with 11 deaths in the IO group and 19 deaths in the IVO group.

Interestingly, if we censor patients with COVID-19 related deaths, the hazard ratio swings in favor of IVO, with a HR of 0.82. This suggests that in the absence of COVID-19, patients on the IVO regimen could have had an 18% lower risk of disease progression or death compared to those on the IO regimen.

These results emphasize the complex interplay between CLL treatment and external factors like COVID-19, which undoubtedly impact patients’ lives and outcomes.

Patients with CLL are particularly vulnerable to COVID-19 due to their compromised immune systems, and this was evident in the A041702 trial. The interplay between CLL and COVID-19 is multifaceted and warrants careful consideration.

A recent study published in The Lancet suggested that patients with hematological malignancies, like CLL, were particularly susceptible to severe COVID-19 outcomes. This is likely due to their weakened immune systems, caused by both the cancer itself and the treatment regimens.

In the A041702 study, the COVID-19 pandemic had a profound impact on the outcomes of CLL patients.

While this might initially suggest a higher risk associated with the IVO regimen, it’s important to remember that the overall rate of COVID-19 in a given patient population can be influenced by numerous external factors such as local infection rates, individual behaviors, and preventive measures.

Interestingly, when the researchers adjusted the hazard ratio calculation to censor patients who died from COVID-19, the hazard ratio swung in favor of the IVO regimen, underscoring the substantial impact of the pandemic on the study outcomes.

Expert Insight: Interview with Brian Hill, MD, PHD

For an in-depth understanding of the recent developments in CLL treatment, we had the opportunity to gain insights from a leading expert in the field, Dr. Brian Hill, he is the Director of the Lymphoid Malignancies Program at the Cleveland Clinic, with a specialization in CLL. His extensive experience and profound knowledge have made significant contributions to the field of oncology, particularly in lymphoid cancers.

During his enlightening discussion at the American Society of Clinical Oncology (ASCO) 2023, Dr. Hill shared some valuable insights about the IVO vs. IO study and the future of CLL treatment. For a more comprehensive understanding of his insights, you can view Dr. Hill’s full interview here:

Conclusion

Chronic Lymphocytic Leukemia, while a serious and life-altering disease, is rapidly evolving in terms of available treatments and prognostic outcomes. The promising research regarding the combination therapy of Ibrutinib, Venetoclax, and Obinutuzumab (IVO) has sparked hope for both clinicians and patients alike, indicating that a better, more efficient treatment strategy might be just around the corner.

However, it is essential to remember that while the recent trial’s results were encouraging, further research is required to confirm these findings and translate them into clinical practice.

As we navigate the ongoing COVID-19 pandemic, it’s important to understand its impact on patients with CLL, and the study’s results in this area offer key insights. The journey to finding the most effective treatment for CLL continues, and with advanced research and scientific discovery, there’s significant hope for improved outcomes.

By staying informed and hopeful, we can look forward to the future advancements in the treatment of CLL.