Innovation of CLL Treatments: Modern Targeted Therapies

Over the years, the treatment for CLL has undergone significant advancements, shifting from non-specific chemotherapy to targeted therapies. 

Before Targeted Therapies - The Era of Chemotherapy

Initially, chemotherapy was the go-to option for treating CLL. The most common regimen was a combination of Fludarabine, Cyclophosphamide, and Rituximab (FCR). Chemotherapy killed cancer cells but also destroyed many healthy cells in the process, which resulted in uncomfortable and, sometimes, life-threatening side effects. 

With chemotherapy, approximately 70% of patients achieved remission, but patients with high-risk chemo-associated genetic mutations did not respond well to treatment and needed better treatment options. 

What are the Targeted Therapies for CLL?

The late 2000s and 2010s marked a turning point in CLL treatment with the advent of targeted therapies. These medicines are specifically designed to attack cancerous B-cells (CLL cells). They can also reduce healthy B-cells; however, they leave other healthy cells alone, which chemo did not do. 

• Imbruvica (Ibrutinib)
  • Approved by the FDA in 2014 
  • Ibrutinib is a BTK inhibitor that acts by blocking a protein that helps CLL cells multiply and survive
  • It's an oral medication, making it easier to administer than intravenous treatments
  • About 72% of CLL patients don't progress
  • The patient can take it indefinitely until their body's CLL cells no longer respond to the medicine or until side effects are intolerable
  • Although effective, it has heart-related and blood-thinning side effects
• Venclexta (Venetoclax)
  • Approved in 2016
  • It's a BCL2 inhibitor 
  • Works by blocking a protein that makes CLL cells resistant to self-destruction, thus helping destroy the cancerous cells
  • It's an oral medication, but it also has an intravenous presentation
  • Can help CLL patients who have blood thinning and heart health issues
  • Approximately 80% of patients go into remission (partial or complete reduction of cancer cells) 
  • It requires a slow dose increase and close monitoring at the beginning because of the risk for tumor lysis syndrome
• Calquence (Acalabrutinib)
  • Approved in 2019
  • Acalabrutinib is a second-generation BTK inhibitor that targets specific proteins to restrict CLL cell growth
  •  It is an oral medication
  • 41% of CLL patients could tolerate taking acalabrutinib longer than ibrutinib
  • It has significantly fewer heart-related side effects than ibrutinib 
• Brukinsa (Zanubrutinib)
  • Approved in 2023
  • Zanubrutinib is another second-generation BTK inhibitor like acalabrutinib
  • In studies, zanubrutinib limited disease progression in 80% of patients without del(17p) and in 88% of patients with high-risk del(17p). 
• Jaypirca (Pirtobrutinib) 
  • Approved in 2023
  • More than 70% of CLL patients responded well after failing with therapies of BTK inhibitors and venetoclax
• Phosphoinositide 3′-kinase (PI3K) inhibitors 
  • Zydelig (idelalisib) and Copiktra (duvelisib)
  • It is for relapsed or refractory CLL patients who have had more than two therapies and have not yet controlled their CLL
  • Requires close monitoring for adverse events that may include infections and autoimmune disease

Can Targeted Therapies be Combined with Other Medications? 

Yes! One of the most promising advances in CLL treatment is combining different targeted therapies. The rationale is to attack the CLL cells from different angles, making it hard for leukemia cells to survive or become resistant to treatment.

• Venetoclax + Obinutuzumab
  • Approved by the FDA in 2019 for CLL patients to take for a fixed duration period of 1 year
  • It is used for previously untreated CLL patients and aims to enhance the effectiveness of each drug. Venetoclax and anti-body treatment rituximab were later approved for previously treated CLL patients to take in a fixed-duration period of 2 years
  • About 85% of CLL patients achieved remission with this combination, marking it as one of the most effective treatments for CLL with a manageable side-effect profile
  • Also helped CLL patients with high-risk genetic feature del(17p)/TP53 mutation achieve a longer remission than taking venetoclax alone

• Idelalisib + Rituximab   
  • Approved by the FDA since 2016 for relapsed or refractory CLL
  • Can be prescribed for patients who progress with BTK inhibitors and venetoclax
  • Not for previously untreated CLL 
  • The response rate is over 70% 

What are the Current Treatments for CLL?  

To this date, the only potential cure for CLL is an allogeneic hematopoietic cell transplant, which remains an option after using targeted agents. Fortunately, CLL patients can achieve remission and live cancer-free for over 10 years. Some others with high-risk genetics may struggle due to relapse or have a refractory disease meaning that CLL cells are not responding to treatment. The BTK inhibitors, such as ibrutinib, acalabrutunib, and zanubrutinib, can be used indefinitely as only therapy because they continuously inhibit an enzyme that is essential to stop cancer cells from spreading, and they can be used as initial therapy for recently diagnosed CLL patients who require treatment. 

Combinations have proven to be really useful for refractory CLL patients and can provide alternatives when a patient is intolerant to conventional therapy.

What's the Future of CLL Care? 

CLL specialists are pleased with the advances of non-chemo-targeted therapies, which have improved both the length and quality of CLL patients’ lives. These specialists and their research teams understand that more work is needed to help bridge treatment care gaps for relapsed/refractory CLL patients (patients whose disease comes back after treatment or whose cancer cells no longer respond to targeted therapies). 

Future treatments for CLL are currently in clinical trials. These new and improved medicines test their effectiveness against the current CLL medicines. Clinical trials include CAR T-cell therapy for CLL and combinations of non-chemo-targeted therapies to improve treatment effectiveness compared to what is currently approved for CLL treatment. 

You Can Participate in the Future of CLL Care!

HealthTree’s community has seen that patients and their caregivers who are involved in learning about their cancer have better treatment outcomes. We invite you to use HealthTree’s programs to educate yourself about the facets of this disease. Doing so will prepare you to be an active participant in advancing toward a cure for CLL through research. 

If you are interested in participating in or finding a clinical trial, locating a CLL specialist, or staying informed about updates on CLL with a biweekly newsletter, you can create a free HealthTree Cure Hub account!

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