Blood Cancer Uncensored is honoured to have been selected as a partner site to the CLL Pharmacist, and is delighted to welcome their founder Tom Henry as one of our authors. 

Join him as he explains two trials of the combination of two widely used modern selective treatments for CLL. This is an abridged version of an article you can also read in full.

Ibrutinib and venetoclax are two “targeted” chronic lymphocytic leukemia (CLL) treatments and are relatively new additions to the toolkit physicians use to control CLL. These studies show that when used together they have even better efficacy without unexpected side effects. 

Let’s begin with some background:

In February 2014, Imbruvica® (ibrutinib) received approval for patients who had received at least one prior CLL treatment. (Relapsed or Refractory). The FDA approved ibrutinib for first-line therapy in March 2016. This treatment is also approved in Europe but some countries including the UK will only fund it for second line treatment except in the presence of 17p deletion or TP53 mutations.

Ibrutinib is the first agent found to inhibit Bruton’s Tyrosine Kinase (BTK). BTK is a protein that is over-expressed on the surface of malignant B-cells. The over-expression of BTK is associated with rapid growth and survival as the cells don’t die at the rate of healthy cells.

Venetoclax (Venclexta®) received FDA approval for patients with deletion 17p, and who had at least one prior line of therapy as of April 2016. The most recent FDA approval for venetoclax, came in May 2019 when the combination of venetoclax and obinutuzumab (Gayzva®) first-line treatment of gained FDA support. This combination treatment is also approved in Europe and is fully funded as a first line option for all CLL patients via the UK’s NICE and several other similar funding bodies.

Venetoclax is the first, and currently only, agent that is a selective inhibitor of B-cell chronic lymphoma 2 (BCL-2). BCL-2 is an anti-apoptotic protein in that it blocks the normal cycle of cell death known as apoptosis. BCL-2 is overexpressed, in CLL, resulting in tumor cell survival. Venetoclax works by restoring the normal pathway of apoptosis, or cell death.

My Personal Experience – Ibrutinib and Venetoclax

My first introduction to combining ibrutinib and venetoclax came when I attended a presentation by Dr. Nitin Jain, M.D., from M.D. Anderson Comprehensive Cancer Center at ASH 2018, in San Diego.

Later, I became aware of similar research lead by Professor Constantine Tam, M.D., Director of Haematology and Lead of the Chronic Lymphocytic Leukemia (CLL) and Low-Grade Lymphoma Program at Peter MacCallum Cancer Centre in Melbourne, Australia. Dr. Tam’s research project is called CAPTIVATE. In this post, we will discuss updated data from these two trials presented at ASH-2019, in Orlando.

I discussed the post ASH-2019 data from these two trials, with my CLL specialist, Dr. Javier Pinilla, M.D., Ph.D. at Moffitt Cancer Center in Tampa. The FDA does not presently approve this combination. Dr. Pinilla agreed to combine ibrutinib and venetoclax if my insurance approved. As a retired Air Force officer, I have TriCare insurance, and they allowed the addition of venetoclax to ibrutinib, which I had been on for 46-months, when I began venetoclax in February, of 2020.

Basics – Ibrutinib and Venetoclax Combo a Potential Time Limited Treatment

These two trials hope to show that the combination of Imbruvica® and Venclexta® allow a higher percentage of patients to reach undetectable MRD (uMRD) status than with either drug as the sole therapy. Further, hope abounds that this approach may lead to a time-limited treatment. Where patients can return to “Watch and Wait” status after a defined period. 

Methods:

The M.D. Anderson (MDA) trial enrolled 80 patients who were previously untreated. All patients had a least one high-risk factor, including; deletion 17p, mutated TP53 gene, deletion 11q, unmutated IGHV, or the age of 65 or higher.

Patients started with ibrutinib monotherapy for three months to reduce the tumor burden and the risk of tumor lysis syndrome. In month four, in addition to ibrutinib, they began the ramp-up of venetoclax. After the ramp-up, patients take 400mg a day for twenty months for a total of 24-months treatment.

Patients who attained undetectable minimal residual disease (uMRD) with a sensitivity of 1 in 10,000 cells after 24 months of treatment will stop both medications. Patients who remained MRD positive continue ibrutinib indefinitely. After three months of single-agent therapy with IBR, no patients reached uMRD. Figure 1, shows the cumulative percentage of patients who attained uMRD over time.

The CAPTIVATE trial included 164 patients. Like the MDA study, all patients had no prior treatment for CLL. This twelve-month treatment study started with the same three-month monotherapy with ibrutinib. The addition of Venetoclax used the standard four-week ramp up. Unlike the MDA trial, the combination continues for a total of only fifteen (15) months. Of the original 164 patients, 151 completed the full 15 cycles. This group included a significant number of high-risk patients (16% had deletion 17p, 20% had either 17p deletion or TP53 mutation, 16% had 11q deletion without 17p, 19% were complex karyotypes (multiple mutations) and 59% had un-mutated IGHV. The results presented were from the Phase II portion of the study.

At some point during the Captivate trial 75% of participants reached uMRD in the blood and 72% reached uMRD in the bone marrow. The term uMRD is used when a lab is not able to find a single cancer cell when looking at a sample of 10,000 lymphocytes or 10^-4. You may have heard of very new and even more sensitive tests that can detect 1 malignant cell in a sample of 1,000,000 lymphocytes or 10^-6.

Conclusions

Personally, I am excited to be on this combination. I believe that it provides a great opportunity for me to remain happy and healthy.

The percentage of patients with ibrutinib alone who reach a complete response (CR) or uMRD in multiple studies is consistently less than 10%. Likewise, venetoclax monotherapy lead to approximately 16% CR, according to National Institute of Health (NIH) data. 

These two trials both show promise of much higher rates of complete remission than with either drug as a single agent. The feasibility of changing practice to include this combination as a potential time-limited treatment is still being studied and larger Phase III trials will likely follow.

If patients reach uMRD, there is potential that they could then enjoy a “drug holiday” where they would continue to be monitored for signs of progression and possibly require treatment again in the future.Researchers believe that the efficacy of both ibrutinib and venetoclax would remain as options for future treatment. 

The attainment of uMRD has been shown to increase both progression free survival (PFS) and overall survival (OS) in CLL based primarily on extensive experience with chemoimmunotherapy (e.g. FCR)

This is one of many combination therapy trials currently underway. More successful trials translate into more clinical tools for our CLL Specialists to use to individualize our CLL care to meet our individual disease characteristics and any existing comorbidities.