Dr Choi Discusses How To Best Sequence Regimens for Patients With CLL

Michael Choi, MD, UC San Diego Health, Moores Cancer Center, La Jolla, California, discusses how to best sequence regiments in the management of patients with recurrent chronic lymphocytic leukemia (CLL) during the virtual 2021 Lymphoma, Leukemia & Myeloma (LL&M) Congress.

Dr Choi said that although the LL&M conference is covering several “outstanding discussions” regarding all the main treatment options for patients with CLL, he’s hopeful that the information he is sharing can be viewed as a consolidation and help patients select the best treatment for their case.

In terms of tailoring therapy for individual patients, Dr Choi said there is currently not much comparative data out there—exception being a phase 3 trial of ibrutinib and acalabrutinib.

“Largely, we have an opportunity to work with our patients to figure out which treatment may fit best with their profiles and their priorities,” Dr Choi said.

Dr Choi said there are 3 ways he tailors therapy for individual CLL patients.

The first step considers factors that are specific to the individual patient—like their fitness and cardiovascular comorbidities—as well as the treatment goals and whether patients prioritize or wish to prioritize treatments that have a fixed duration or not.

Dr Choi said the second step is to consider a patients prior treatment history—including if they have received a BTK inhibitor, a BLC2 inhibitor, or both—and how they tolerated it.

“I think it’s also important how long their remissions were (and) how well they responded to those treatments,” Dr Choi said. “A patient who had a long remission after a previous fixed-duration therapy—like venetoclax and obinutuzumab—may be a candidate to repeat that. But a patient who had a very brief remission will probably be more appropriate to move to a different treatment approach.”

The last step is to consider the molecular factors on the patient’s case, including traditional prognostic factors that are associated with responses to new therapies—like Del 17p—as well as specific resistance mutations.

“Right now, many of these may not be ‘actionable’, but as we continue to develop new therapies—like the noncovalent BTK inhibitors—knowing the reasons that patients have progressed on their previous therapy may be of relevance,” Dr Choi said.

Dr Choi then focused on patients who progressed on or after a BTK inhibitor.

He said although he can usually count on BTK inhibitors—like ibrutinib and acalabrutinib—to maintain remissions for CLL patients for long periods of time, some will unfortunately develop resistance. The risk factors that are associated with this include baseline karyotypic complexity and Del 17p. Most cases will have mutations in either BTK or PLCG2, or both. By high-sensitivity assays, about 80% of patients with resistance to a BTK inhibitor will have 1 of these mutations. In many cases, these mutations will precede clinically overt progressions by a median of 9 months.

An initial report on how patients did after developing resistance to BTKi’s was dismal, Dr Choi said. In that report, Nitin Jain, MD, MD Anderson. Cancer Center, et al found the overall survival (OS) for patients to be just 3.1 months. Fortunately, new therapies have improved the outlook for patients, Dr Choi said. Particularly, the development of venetoclax and other kinase inhibitors.

“I found it would be worthwhile, especially as our treatment options continue to expand, to discuss this middle context of patients that may be stopping 1 kinase inhibitor due to intolerance,” Dr Choi said.

Thus, Dr Choi mentioned a study by Anthony Mato, MD, MSCE, Director, CLL Program, Memorial Sloan Kettering Cancer Center, et al on real-world data on the management of BTKi resistance in patients with CLL. In 2017, patients that had progressed or had discontinued the kinase inhibitor generally did not have long remissions with chemoimmunotherapy (CIT) or single-agent antibodies. Patients that were switched to a different kinase inhibitor—this meant switching from ibrutinib to idelalisib or idelalisib to ibrutinib—did OK, Dr Choi said, but only if they were switching in the context of tolerance rather than progression. Patients that progressed on 1 kinase inhibitor generally did not have great or durable responses. Patients that were treated with venetoclax did respond and had some durability of remission.

There are several alternative treatment options for patients who have an intolerance to ibrutinib, Dr Choi said, such as acalabrutinib, spebrutinib, zanabrutinib and tirabrutinib. All of these inhibit BTK, he said, but have varying degrees of inhibition of other kinases, such as TEC, ITK, EGFR, and more.

“It is thought that these differences in inhibition of other kinases may associate with the different side effect profiles,” Dr Choi said.

Dr Choi said this has borne out in John C. Byrd, MD, The Ohio State University Comprehensive Cancer Center, et al’s recently published and “highly awaited” open label, randomized, non-inferiority trial that randomized acalabrutinib versus ibrutinib in patients with relapsed or refractory (R/R) CLL. This trial enrolled 533 patients with high-risk factors, including Del 17p or Del 11q. The Kaplan Meyer curves demonstrated noninferiority, and the progression free survival (PFS) and overall survival (OS) estimates were largely overlapping.

There were some differences seen in the adverse events profiles that were consistent with early or non-comparative trials, Dr Choi said. Particularly, Dr Choi said, the risk of cardiovascular adverse events appeared to be distinct, where hypertension and atrial fibrillation were higher on ibrutinib compared to acalabrutinib. The most common adverse events occurring in ≥10% (any grade) or ≥5% (grade ≥3) were largely similar, including upper respiratory infection, nausea, thrombocytopenia, pyrexia, anemia, pneumonia, neutropenia, dizziness, and more. Notable differences were seen in diarrhea, headache, cough, arthralgia, hypertension, contusion, and atrial fibrillation.

Zooming in on hypertension, Dr Choi said the rate of any grade or grade ≥3 hypertension event was higher with ibrutinib. In both groups, the majority of patients who developed any grade or grade ≥3 hypertension were more likely to have a history of hypertension prior to starting treatment.

Doing the same with arrhythmias, Dr Choi said the rate of any grade atrial fibrillation was higher with ibrutinib compared to acalabrutinib (16% vs 9.4%). Of note, the grade ≥3 rate was lower with ibrutinib compared to acalabrutinib (3.8% vs 4.9%).

“It does appear based on this randomized trial, that patients with cardiovascular risk factors, pre-existing hypertension, or pre-existing atrial fibrillation, may be better candidates for acalabrutinib, and that they may be less likely to have complications on treatment or worsening of those conditions,” Dr Choi said.

Based on these results, Dr Choi said he hasn’t been categorically switching patients from ibrutinib to acalabrutinib since they are otherwise tolerating the treatment, but this does provide useful information for patients that are deciding between the agents.

Regarding the situation of patients who are having side effects on ibrutinib, Dr Choi referred to a trial conducted by Kerry A. Rogers, MD, Ohio State University, et al where patients who were intolerant to ibrutinib switched to acalabrutinib due to factors including atrial fibrillation, diarrhea, rash, bleeding, and arthralgia.  Dr Choi said these patients experienced less severity of those adverse events or didn’t experience them at all after switching.

Dr Choi said: “Certainly, patients who are having a large impact on their quality of life have high motivation to switch off ibrutinib. We now have both directly comparative data as well as this retrospective trial that gives some reassurance that they can switch to acalabrutinib or other kinase inhibitors,” such as PI3 kinase inhibitors including idelalisib, duvelisib, umbralisib, and zandelisib.

Shifting not only to patients with ibrutinib intolerances, but patients who are progressing on a BTK inhibitor, Dr Choi said most data support the use of venetoclax in this setting. An earlier single agent trial, conducted by Jeff Jones, MD, MPH, The Ohio State University, et al, showed that with single agent ibrutinib, patients with CLL had a 65% overall response rate (ORR) and a 24-month PFS.

“These both leave room for improvement. In my practice, I tend to include a CD20 antibody with venetoclax in hopes to get maximal effects and maximal durability in this setting,” Dr Choi said.

Regarding emerging strategies, the main agents in this context are non-covalent BTK inhibitors, Dr Choi said. These include pirtobrutinib (LOXO-305), MK-1026 (ARQ-531), and luxeptinib (CG-806). Pirtobrutinib, Dr Choi said, is furthest along in testing and is starting a randomized phase 3 trial.

“Certainly, a lot of optimism that even patients who progress on a BTK inhibitor will have treatment options ready to go and able to regain remission and maintain remissions,” Dr Choi said.

Dr Choi then summarized his approach to patients who need treatment after a BTKi. For patients who have intolerance to the first BTKi, Dr Choi said he switches patients to other inhibitors or venetoclax. For patients who are developing resistance, he said his approach is to consider Richter transformation lymphoma, particularly the pace of progression, LDH, PET FDG avidity, and marrow/node biopsy to support that. He also investigates resistance mechanisms including repeating cytogenetics and next-generation sequencing (NGS).

“Outside of trials I use venetoclax, but with the knowledge that their response to this may not always be durable,” Dr Choi said.

Shifting the discussion to patients who have progressed on or after venetoclax, patients who relapse after venetoclax often do not have resistance to it. In an earlier trial (Seymour et al 2017), about a dozen patients had stopped venetoclax due to complete remission and remained off it. However, some of these patients progressed, resumed venetoclax, and were able to regain remission. Many patients remained in remission, Dr Choi said, so more data is still to come.

“Certainly patients who have been off venetoclax or stopped it may be retreated with venetoclax upon progression,” Dr Choi said.

However, patients who progress on venetoclax are in a whole different category. Dr Choi said many of these cases may be due to mutations in the BCL2 gene itself.  

Dr Choi then posed the question, “How do we manage these patients with BTKi?”

He then noted 2 main datasets: a collection of cases in the US and Australia. In both, patients tended to respond to a BTKi particularly if they had not received a BTKi in earlier lines of treatment. Dr Choi said there are concerns since responses were not always durable. For patients who subsequently progressed on the BTKi, Dr Choi said the prognosis right now is “not great.”

“I suppose this makes sense based on the limited availability of other standard of care treatments in that setting,” Dr Choi said.

Dr Choi said treatment options for patients after a BTKi and venetoclax include CAR-T as an appropriate salvage option.

“Finally, in keeping transplant on our radar, I think it’s in this setting where patients have progressed after BTKi and after venetoclax, or even progressed after 1 and are back in remission on the other… I do think it would be appropriate to at least consider allogeneic stem cell transplant in this setting for the appropriate patient,” Dr Choi concluded.