What is the Most Appropriate First-Line Treatment in CLL?

There has been a tremendous amount of research and approvals advancing the initial treatment of chronic lymphocytic leukemia (CLL) in recent years.

For quite some time, chemotherapy was the mainstay of treatment, usually seen as a combination of a purine analog (ie, fludarabine) and an alkylating agent (ie, chlorambucil, cyclophosphamide, or bendamustine). Next came the first of the targeted class of agents, the CD20 antibodies, starting with rituximab, followed by humanized forms in ofatumumab and obinutuzumab. The next class providing a major advancement in the treatment of CLL was the Bruton tyrosine kinase (BTK) inhibitors, the most notable of which being ibrutinib. While ibrutinib inhibits tyrosine kinase targets associated with CLL, it also inhibits tyrosine kinase pathways in other targets, leading to its adverse effect profile. Most recently, the second generation BTK inhibitor acalabrutinib was approved to inhibit tyrosine kinase more selectively, thus improving on the safety and efficacy of ibrutinib. Finally, the newest class of agents to be approved are the BCL2 inhibitors (ie, venetoclax), which acts to upregulate the apoptosis process.

To date, no comprehensive head-to-head trials have been conducted in a “real-world-setting,” as well as no comprehensive cost-effective assessments completed to examine the various first-line treatments for CLL. In short, there is no standard agreed upon treatment.

However, we do have consistent opinions. There is a general agreement that the choice of initial therapy for CLL patients should be based on patient and tumor characteristics, patient preference, and goals of therapy. The presence—or lack thereof—of an IgVH mutation, del (17p) or TP53 mutation, and physical fitness appear to be the drivers upon which the initial treatment decisions are usually made. While all of the possible treatment options have shown similar efficacies in slowing the progression of the disease, it is the cost of the regimens that forces us to differentiate the options and define their place in therapy.

In a recent interview appearing in MedPage Today, Nitin Jain, MD, The University of Texas MD Anderson Cancer Center, noted that "the big question in the field" will be which option clinicians choose in the frontline setting for a new patient needing treatment – chemoimmunotherapy, an ibrutinib-based regimen, or venetoclax plus obinutuzumab. Some opinions, though not the consensus, tend to lean towards the use of a chemotherapy combination—fludarabine plus cyclophosphamide and rituximab—for patients with IgVH mutated CLL without del (17p) or TP53 mutation. Dr Jain agrees with this treatment approach in this subpopulation, stating "For young fit patients… I think chemoimmunotherapy should still remain the standard of care."

In the same article, Jennifer Brown, MD, Dana Farber Cancer Institute, agreed as well: "In the mutated subgroup, we have three different studies that suggest that FCR is potentially curative – 55% of patients with mutated IgVH are still in remission 12 years later – and it is 6 months of therapy." 

For higher-risk patients, with 17p and 11q deletion or TP53 mutation, with or without the IgVH mutation, Drs Jain and Brown agreed that novel agents are the preferred course of therapy. As we start to evaluate combinations of these novel agent, we are digging into the details and determining if the incremental clinical benefits outweigh the increase in cost. We are examining whether humanized CD20 inhibitors are more effective or better tolerated while offsetting cost? What is the net clinical benefit for the more selective and potent BTK inhibitor acalabrutinib? And finally, is a combination utilizing venetoclax cost-effective because when used in combination, the duration of the treatment regimen is limited?

When venetoclax is administered as a single agent, the treatment is continuous until there is disease progression. The adverse effects associated with ibrutinib are well documented and known, and the incremental improvement presented by acalabrutinib  have not been clearly demonstrated in the “real-world setting.” Therefore, the question raised is should venetoclax be considered ahead of a BTK inhibitor? Dr Jain argued that, “For patients, the argument really comes down to a question of 1-year therapy with venetoclax plus obinutuzumab vs lifelong therapy with ibrutinib. At the end of the day, I think both are very effective options and the clinician should provide both options to the patients."

But the bottom-line is that we really do not have enough experience nor data to determine if there is any difference when sequencing a BCL2 inhibitor prior to a BTK inhibitor, or visa versa. Thus, the main driver at this point may be the presence of comorbidities.

In short, the tremendous research and advancement in CLL has resulted in a variety of additional therapeutic options. But have we gained any improvement in clinical outcomes, quality of care, and quality of life? I am not sure that the data exists to answer these questions at this time. A true real-world-evidence study is needed, but until this occurs, we will have to rely on our current traditional evaluation frameworks and allow oncologists to gain experience with the different treatment options. The market will have to play itself out.