Sonya Collins

Ten years ago, diagnosis of chronic lymphocytic leukemia (CLL) meant treatment with chemotherapy and, for most patients, a shorter life expectancy than before diagnosis. Today, those are no longer foregone conclusions. The past decade has seen the FDA approve a handful of new targeted therapies for CLL that are prompting a move toward chemotherapy-free treatment of the disease. Patients are living longer, often with higher quality of life, and many remain on treatment until they die of other causes.

“Probably the most remarkable advance in CLL in the last 10 years has been the improvement in overall survival that we’ve seen in patients with the availability of these new drugs that are better tolerated and more effective than chemotherapy options,” said William Wierda, MD, PhD, who is section chief, chronic lymphocytic leukemia, at The University of Texas MD Anderson Cancer Center in Houston. “We’re seeing the life expectancy in patients over 65 to 70 years not being shortened by their diagnosis of CLL. Even if they need treatment, they’re living a similar life span to what they would if they didn’t have a diagnosis of CLL.”

Treatment advancements have been further enhanced by researchers’ discovery and improved understanding of the prognostic role of several somatic gene alterations. Novel agents have also prompted researchers to rethink the role of minimal residual disease (MRD) tracking in CLL.

Before several novel targeted agents for CLL became available in the past decade, chemotherapy with fludarabine, cyclophosphamide, and CD20 antibody rituximab (FCR) was the gold standard.1 The therapy comes with the typical toxicities of chemotherapy, and median progression-free sur- vival (PFS) is about 4 to 5 years.

“All we had previously were chemotherapy-based approaches,” said Matthew Davids, MD, MMSc, director of clinical research in the Division of Lymphoma at Dana-Farber Cancer Institute in Boston, Massachusetts. “Particularly for high-risk patients, their median survival was only about 2 to 3 years from the time of diagnosis.”

When ibrutinib (Imbruvica) came to market, the survival improvement over standard chemotherapy was dramatic. “Basically overnight, when ibrutinib hit the scene, these patients who were dying were resurrected,” Davids said.

Ibrutinib, which got the nod from the FDA in 2014,

 was the drug that began to drive CLL treatment away from the then-standard chemoimmunotherapy approach nearly a decade ago. A Bruton tyrosine kinase (BTK) inhibitor, the oral medication targets and binds to BTK to suppress its activity. This blocks B-cell receptor signaling, which prohibits further growth of B-cell malignancies.

Patients take ibrutinib, and more recently second-generation and third-generation BTK inhibitors, continuously until their disease progresses. In published long-term studies of ibrutinib, patients had not yet reached median PFS.

 The latest data suggest that it may be about 8 years.

But some patients stop ibrutinib before they progress, because of intolerable toxicities. Along with its higher rates of PFS over chemoimmunotherapy, ibrutinib also brings a substantial risk for atrial fibrillation and hypertension.

Since 2014, however, improvements on ibrutinib have come to the clinic in the form of acalabrutinib (Calquence), which earned FDA approval in 2019, and zanubrutinib (Brukinsa), which is now used off-label in CLL. It is expected to get the green light from the FDA later this year. In head-to-head studies, these second-generation and third-generation BTK inhibitors are just as effective as ibrutinib but with lower cardiovascular risks.

“Plenty of patients tolerate these drugs extremely well and stay on them until they die of other causes,” said Catherine Coombs, MD, MS, an assistant professor of medicine at the University of North Carolina School of Medicine in Chapel Hill. She researches and treats CLL. “With the newer generation of drugs, hopefully these toxicity discontinuations become less frequent.”

Venetoclax (Venclexta) offers a different approach to treatment. The only FDA- approved drug in the BCL2 inhibitor class, it first earned approval in 2016 as a therapy for patients with CLL who have relapsed or refractory disease and high-risk 17p deletion [del(17p)]. The oral medication now has FDA approval in the relapsed setting as monotherapy and in combination with the CD20 antibody rituximab (Rituxan) and as first-line therapy in combination with the CD20 antibody obinutuzumab (Gazyva) for all CLL patients regardless of del(17p) status.

 Venetoclax inhibits B-cell leukemia/lymphoma-2; the dysregulation of this protein in CLL helps promote the ongoing survival of cancer cells.

A major difference between treatment with venetoclax and BTK inhibitors is duration. Patients who receive venetoclax as a first-line treatment stay on the medication for 1 year. In the relapsed setting, patients typically take the medication for 2 years.

“This approach gets patients into a deep remission with the expectation that they’ll have a long time off treatment,” Wierda said. “Then, if the disease comes back, you can [treat them again].”

Initially, venetoclax was found to carry a risk of tumor lysis syndrome. Starting at a low dose of 20 mg with gradual dose escalation to 400 mg/d over the first 5 weeks has helped reduce that risk significantly. “You have to monitor patients closely during that time, but after you get them on their target dose, it’s extremely well tolerated,” Wierda said.

Two PI3 kinase inhibitors, duvelisib (Copiktra) and idelalisib (Zydelig), garnered FDA approval in the last 10 years as well. Although they are effective drugs, they are less often used due to their adverse effect profile, which can include diarrhea, colitis, liver inflammation, and infections. “These drugs can be highly effective for some patients, but they are more difficult to administer safely compared with the other approved novel agents in CLL,” Davids said.

A third agent in this class, umbralisib (Ukoniq), is being investigated by the FDA regarding a potentially increased risk of death in patients with lymphomas following data presented in the UNITY-CLL trial (NCT02612311). As a result, the FDA sent out a notice to patients and health care providers stating the agency’s intention to reevaluate the agent in its FDA-approved indications.

The past decade has provided better tools for making more precise prognoses. “Understanding the significance of certain somatic mutations has probably made the biggest impact in that area recently,” Davids said. Several mutations in CLL cells, which have gotten more robust evidence behind them in recent years, can help clinicians predict patient outcomes.

, found in about 10% of patients with CLL, and del(17p), found in about 7% of patients, are each associated with poor prognosis and poor response to chemotherapy. As treatment continues to shift away from an exclusively chemotherapy-based approach, research has explored the role of these gene changes in other treatment settings. Although 

 mutations may lead to less durable response with time-limited novel-agent–based regimens, research shows high rates of PFS among patients with CLL who have 

 mutations and who are on continuous therapy with BTK inhibitors.

 or 17p deletion, I would be more inclined to treat that patient with a BTK inhibitor–based therapy than a venetoclax-based therapy because I feel those patients need more of a maintenance strategy than a finite duration and time-off treatment strategy,” Wierda said.

The past decade has also shed more light on the implications of 

 mutations in CLL. Among the most common gene changes in CLL, NOTCH1 mutations occur in almost a quarter of patients.

 Due in large part to their association with increased risk for Richter transformation, the mutations do suggest a more aggressive disease biology.

 status itself does not currently have implications for treatment decisions, patients may need more close monitoring for complications.

“Richter transformation is a rare event in CLL, but when we see it evolving, it requires a completely different type of treatment,” Davids said. “We watch those patients a little more closely if they have 

 mutation, and we have a lower threshold to work them up for Richter syndrome.”


Immunoglobulin heavy chain variable region (IGHV) status, which can be mutated (lower risk) or unmutated (higher risk), is another important prognostic marker in CLL.

 Mutated IGHV may be one setting in which oncologists continue to offer chemotherapy with FCR as an option.

 Data show that patients with mutated IGHV have the best chance for long-term remission after chemotherapy. Just over 50% of patients are still in remission 10 to 15 years after treatment. “It raises the question of whether or not FCR may potentially cure that small subset of patients,” Coombs said. “Specifically, those who are young and fit enough to get FCR.” Unmutated IGHV, on the other hand, is a predictor of poor outcomes, but research shows that novel-agent–based approaches may be equally effective in patients regardless of IGHV mutational status.

The advent of targeted therapy for CLL and the shift away from chemotherapy prompts a need to reconsider the role of MRD tracking. Although MRD tracking is useful in assessing response to chemotherapy, it is less relevant in maintenance therapy with a BTK inhibitor. Maintenance therapy may keep the disease at bay for many years without eliminating all the cancer cells. “On this therapy, patients may only have a partial response, so they could still have evidence of residual lymph node disease, for example, yet those patients still do very well,” Davids said.

The highly sensitive test may, however, have utility in monitoring venetoclax therapy. Given that the aim of time-restricted venetoclax therapy is to achieve deep remission and allow patients treatment-free periods, MRD tracking could help guide decisions regarding duration of treatment and intervals between treatments. Oncologists are already using MRD testing to evaluate patients after venetoclax therapy, Coombs said.

“Personally, I use MRD with patients,” she said. “I think it’s indisputable that negative MRD following venetoclax is favorable prognostically. However, the knowledge gap that persists is whether that should lead to a change in management. I think this is going to be a very hot topic over the next decade.”

As it stands, venetoclax is approved for use during a fixed time period. MRD-guided continuation or discontinuation of therapy is not standard of care. Research currently under way could one day make MRD testing standard of care in these treatment decisions. Potentially, patients who test negative could discontinue treatment early and patients who test positive could stay on treatment longer.

MRD status at the end of finite-duration treatment predicts for PFS,” Wierda said. “It isn’t useful yet in terms of how to treat patients, so that’s what we’re working on in our clinical trials: MRD-directed therapy.”

Increasingly sensitive tests of MRD are in development and coming to market. Davids cites one of the newest: clonoSeq by Adaptive, which “can provide up to 100-fold more sensitive detection of MRD than the standard flow cytometry tests.”

“We’re finding that to be useful to understand depth of response to help counsel patients about their likely durability of benefit,” he said.

Advancements in CLL treatment over the past 10 years have driven the field further away from chemotherapy-based approaches to care. In the United States, where targeted drugs are readily accessible, instances of chemotherapy use are becoming increasingly infrequent in CLL.

Targeted therapies have brought about an increased life expectancy for many individuals with a CLL diagnosis. “In the past, the ‘chronic’ in CLL meant you could live 10 years,” Davids said. “Today, the goal for many patients is to live out a normal life span and not die from CLL.”

But there remain the unmet needs of patients who do not respond to treatment or become resistant. Research continues to explore and improve on these chemotherapy-free approaches. Current research examines, for example, combining BTK inhibitors, such as ibrutinib, with venetoclax. The phase 3 MAJIC trial (NCT05057494), on which Davids is one of the investigators, is evaluating MRD-guided administration of venetoclax plus acalabrutinib or obinutuzumab.

“The promise of these new combinations,” Coombs said, “is that it would be an all-oral regimen that could induce deep MRD-negative responses similar to the venetoclax regimen allowing for a time-limited approach, but obviate the need for an intravenous therapy,” Coombs said.

Researchers also have their eyes on next-generation BTK inhibitors, in particular a drug called pirtobrutinib. “These are reversible inhibitors that potentially will work in patients who’ve developed resistance to irreversible inhibitors,” Wierda said.

For patients who develop resistance to tareted therapy, researchers have set their sights on CAR T-cell therapy for CLL—an approach that has made a major impact in many other blood cancers. “For our relapsed patients,” Coombs said, “this may be something that could offer excellent disease control.”

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The past decade has seen the FDA approve a handful of new targeted therapies for chronic lymphocytic leukemia that are prompting a move toward chemotherapy-free treatment of the disease.

Sonya Collins | Authors

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