Emory’s Jonathan Cohen, MD, Traces Evolution in CLL Therapy

Chronic lymphocytic leukemia (CLL) might be the most common type of leukemia in this part of the world, but that doesn’t mean there’s one way to treat these patients, according to Jonathan B. Cohen, MD, associate professor, Department of Hematology and Medical Oncology, and co-director, Lymphoma Program, Winship Cancer Institute, Emory University.

Cohen

Cohen discussed targeted therapies in CLL at the July 25 session of the Institute for Value-Based Medicine®, presented by The American Journal of Managed Care in partnership with Winship Cancer Institute. He noted that although many CLL patients are in their 60s or 70s, “I do have some patients in their 30s. And for those patients, when you’re talking about a chronic disease, it’s a little bit of different perspective than someone who might be 75 or 80.”

CLL has its nuances, starting with the fact that one form of the disease, small lymphocytic lymphoma, behaves more like lymphoma, which Cohen said can be confusing for patients. The diseases are treated the same way, and most patients are asymptomatic at diagnosis—they tend to be referred to an oncologist after routine tests show an abnormal white cell count. Sometimes treatment is not necessary right away.

“Those are some of my most challenging clinic visits, because it's often somebody who's feeling well, where you're really just trying to decide, does this person need treatment?” Cohen said.

Some of the original biomarkers in CLL are less useful today, Cohen said, although 2 discovered a generation ago remain part of a patient’s workup: TP53 sequencing can reveal the presence of 17p deletion, which is an indicator of poor overall survival (OS), and IGHV mutation status is associated with better survival odds.

Patients may live with CLL for months, years, or decades; this is a consideration when deciding a treatment approach in CLL, Cohen said. As treatment has advanced from the chemotherapy options that were common a decade ago, a patient’s willingness and financial ability to take daily therapy indefinitely can drive decisions.

Ten to 15 years ago, when Cohen treated patients newly diagnosed with CLL, the typical choices were a pair of chemotherapy-based combinations: bendamustine plus rituximab (BR) or fludarabine, cyclophosphamide and rituximab (FCR). Today, that’s all changed with the arrival of Bruton tyrosine kinase (BTK) inhibitors, which now have multiple options approved, as well as BCL-2 inhibitors, of which venetoclax is approved and more are under development.

The chemotherapy combinations had tradeoffs. Although a randomized trial showed the FCR combination offered better progression-free survival, the 6-month regimen caused significant bone marrow suppression, and patients typically had to miss work through the entire treatment course. They were at high risk for infection, and “often patients can go months, if not years without normal bone marrow function.”

“It was a big ordeal,” he said.

Arrival of Newer Therapies

Then came the BTK inhibitors—first ibrutinib, followed by zanubrutinib and acalabrutinib, and now pirtobrutinib, which thus far has FDA approval only in mantle cell lymphoma. Approval of ibrutinib in 2014 “significantly changed the way we thought about treating patients with CLL,” Cohen said.

Initially, BTK inhibitors were approved as second-line therapy. Ibrutinib was approved for frontline use in 2016, and second-generation BTK inhibitors zanubrutinib and acalabrutinib have since been approved for frontline use.

Cohen went through the pros and cons of BTK regimens vs a BCL-2 inhibitor. “The BTK inhibitors are given orally. They're convenient; they're dispensed from the specialty pharmacy, so they come to the patient's house,” he said. Patients have no intensive monitoring at the start of therapy.

Venetoclax, the BCL-2 inhibitor, is also an oral therapy, but Cohen noted, “It is different in the frontline. It’s only administered for one year, so it’s a time limited therapy; it doesn't have some of the cardiac or bleeding toxicities that are associated with the BTK inhibitors. And so, for patients that have a history of cardiac disease, often we may think about venetoclax.”

Adherence is also a consideration. For younger patients, the 1-year duration of venetoclax has appeal compared with BTK inhibitors, which are taken indefinitely. “Putting somebody on a therapy that you're asking them to take for the next 15 years—that can be challenging, as you can imagine, to adhere to that.”

Although he did not characterize it as a cost-effectiveness analysis, Cohen said for patients looking at paying for a year of upfront therapy compared with therapy indefinitely, the venetoclax option “is a little cheaper for patients, and especially those patients with a larger copay. Often, they can make it work for a year,” he said.

Cohen went through studies that showed the survival advantage of BTK inhibitors over the chemotherapy combinations, including studies in which Emory participated that support the use of ibrutinib in untreated CLL.^1,2

In second-generation therapy, the ELEVATE-TN trial compared acalabrutinib vs acalabrutinib plus the CD20 antibody obinutuzumab, vs obinutuzumab/chlorambucil.³ Cohen explained that this was part of a series of trials designed for patients who were older and had many comorbidities—typical of a real-world population—and who were not candidates for traditional therapy. (Of note, venetoclax is often used with obinutuzumab). He presented the data that showed the acalabrutinib arms produced much longer remissions than the chlorambucil arm.

He also shared a 2022 study comparing zanubrutinib vs the BR combination, which showed a 58% PFS advantage for zanubrutinib.⁴

“Again, this certainly indicates with all 3 of these that we are able to improve the remission duration; we're able to keep people in remission longer, which obviously is a laudable goal,” Cohen said. “It does come at the expense of continuous therapy…Fortunately, these tend to be very well-tolerated therapies.”

When using BTK inhibitors, patients are not observed at an infusion center, so it’s important that staff members are counseled about the types of adverse events (AEs) patients may experience if they call the clinic.

“Atrial fibrillation is the most common type we see. It's about 10% to 15% of patients,” he said. Patients must be warned to stop treatment temporarily if having minor surgery or a tooth removed, for example. Cardiac deaths are very rare, but they do occur. The grade 1-2 AEs, such as infections, fatigue, joint aches, or diarrhea may not seem severe, but if these are happening every day, “It can certainly impact your life.”

Despite all this, Cohen said, most patients do not experience toxicity. “They feel fine. I would say the majority of patients that come to see me in clinic are annoyed that we have to see them every 3 months.”

In reviewing data on venetoclax, he presented data that show the majority of patients have not had disease progression 4 years after stopping therapy.⁵ It does have different toxicities, including tumor lysis syndrome. Even so, the time-limited duration means “this is certainly a very appealing approach for some patients.”

Questions, Combinations, and Sequencing

A big question today, Cohen said, is whether there’s still a role for chemotherapy in CLL. “I would say there may still be a role in a very few instances, perhaps for a young patient who doesn’t want to be on a longer-term course of therapy and who has low risk disease. But I would say it’s been at least 3 years since I’ve started somebody on chemotherapy for CLL. And I would say there’s almost no role for chemotherapy in the relapsed setting.”

Combining novel agents is an area of study. Cohen noted that while combining agents maximizes remission duration in multiple myeloma, “that is something that we haven’t necessarily seen in CLL.”

Adding more therapies without adding benefit would increase the cost impact, so right now, this is not the standard of care in CLL, he said. Sequencing—deciding which drug to give first, knowing that a relapse may come years from now—is a consideration.

“We expect that most patients will ultimately relapse, despite the really fantastic results. We don't know yet whether one does better than the other, or if the order matters,” Cohen said. “So really, right now, it's primarily a matter of talking to patients about what's important to them and taking into account comorbidities. And then we think about what's next.”

Immunotherapies, he said, “are the next frontier for CLL.” And other studies are asking the question of when therapy can stop, which may not be the same for every patient. In venetoclax, for example, “I wouldn't be surprised in the next 5 to 10 years, if we get to a place where we can identify some people that maybe stop after 6 months, some people go for a year, some people go 2 years, some people don't stop.”

Even if these practices aren’t in place today, he said. “Those are all things that are attainable.

References

1. Shanafelt TD, Wang XV, Kay NE, et al.Ibrutinib–rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med. 2019;381:432-443. doi: 10.1056/NEJMoa1817073
2. Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib alone or in combination with rituximab produces superior progression free survival (PFS) compared with bendamustine plus rituximab in untreated older patients with chronic lymphocytic leukemia (CLL): results of Alliance North American Intergroup Study A041202. Presented at: 60th American Society of Hematology Annual Meeting; December 1-4, 2018; San Diego, CA. Abstract 6. ash.confex.com/ash/2018/webprogram/Paper116653.html.
3. Sharman JP, Egyed M, Jurczak W, et al. Efficacy and safety in a 4-year follow-up of the ELEVATE-TN study comparing acalabrutinib with or without obinutuzumab versus obinutuzumab plus chlorambucil in treatment-naïve chronic lymphocytic leukemia. Leukemia. 2022;36(4):1171-1175.doi: 10.1038/s41375-021-01485-x
4. Tam CS, Brown JR, Kahl BS, et al. Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): a randomised, controlled, phase 3 trial. Lancet Oncol. 2022;23(8):1031-1043. doi: 10.1016/S1470-2045(22)00293-5
5. Eichhorst B, Niemann CU, Kater AP; GAIA-CLL13 Investigators. First-line venetoclax combinations in chronic lymphocytic leukemia. N Engl J Med. 2023;388(19):1739-1754. doi:10.1056/NEJMoa2213093