Patients with chronic lymphocytic leukemia (CLL) who fail on ibrutinib (Imbruvica) still have a number of options, but data are limited depending on the scenario, and considerations need to be made based both on whether failure stems from intolerance or disease progression and whether the patient was being treated in the first-line or relapsed setting.
A recent study of 320 CLL patients treated with the Bruton tyrosine kinase (BTK) inhibitor ibrutinib found that and 32% because of of intolerance.
"So, how do I manage patients after ibrutinib stopped for adverse events?" said Jennifer Brown, MD, PhD, of the Dana-Farber Cancer Institute in Boston, at an education session at the American Society of Hematology (ASH) meeting. "If the patients have been on the drug for some time they may have achieved quite a deep remission, and they may no longer meet criteria for needing therapy, so I will usually just observe them, let them recover from the side effects, and see what happens."
Sometimes years can go by while a patient doesn't require therapy, but if ibrutinib had to be stopped early and treatment is still required, it becomes a bit like an initial treatment decision, she said, with considerations made for age, comorbidities, and prognostics.
"For those who stop ibrutinib for adverse events and do not progress rapidly there are broad options but very limited data," she said.
Chemoimmunotherapy could potentially be an option for low-risk patients naive to it, but no data exists to guide physicians in this setting.
Anthony Mato, MD, of Memorial Sloan Kettering Cancer Center in New York City, told 鶹ý that this remains a big question with chemoimmunotherapy for patients who would have been favorable to receive it but instead start, and fail, on a chemotherapy-free path.
"Whether or not there's still a role to bring that back, assuming they maintain those favorable characteristics in later lines of therapy, that's unanswered -- but that's a very important question to not abandon those regimens altogether," he said.
The only data on chemoimmunotherapy after a novel agent comes from a real-world analysis of over 600 patients treated with ibrutinib. The discontinuation rate in the study was 42% (median of 17 months), and the median progression-free survival (PFS) in this cohort was 36 months. PFS was higher in patients who stopped for intolerance rather than progression, and in general outcomes were better for those who then went on to venetoclax (Venclexta) compared with those who received a PI3K inhibitor or chemoimmunotherapy.
"But this was in a population of patients who'd seen prior chemoimmunotherapy, had high-risk genetics, and a median of two prior regimens," Brown pointed out. "So this is really unknown in a chemoimmunotherapy-naive population."
Reasonable options for patients who progress on ibrutinib include the BCL2 inhibitor venetoclax with a CD-20 antibody such as rituximab (Rituxan) or obinutuzumab (Gazyva). And another option might be a more specific BTK inhibitor such as acalabrutinib (Calquence), which is approved in second-line for mantle cell lymphoma.
"It would be an off-label use here, based on a 33-patient study in ibrutinib-intolerant patients where about 70% of the patients did not have recurrence of their prior toxicity and many were able to remain on acalabrutinib," said Brown, but added that if the CLL progresses soon after stopping ibrutinib and patients have been heavily pretreated or have high-risk genetics, venetoclax with a CD-20 antibody would be favored.
"I think that most people would opt to use venetoclax if the patient failed ibrutinib," Susan O'Brien, MD, of the University of California Irvine, told 鶹ý.
She highlighted data on single-agent venetoclax or failures, where among 91 patients whose last line of therapy was ibrutinib (median of 20 months), 65% had an overall response with 9% achieving a complete response. Median progression-free survival in these patients was 2 years.
"Keep in mind that these are not people who just had single-agent biologic, in either cohort these were extensively pretreated patients," said O'Brien, noting that the ibrutinib cohort was a highly refractory group of patients, with a median of four prior regimens and half having a 17p deletion.
"These patients are sort of disappearing," she said. "We're not going to see people who have had three and four prior regimens before they get to targeted therapy, so one can only imagine moving forward that the data will even look better."
Brown noted that these venetoclax results are not as favorable as in ibrutinib-naive patients and pointed to a steady PFS decline even in patients with undetectable minimal residual disease (MRD), suggesting that even these more favorable patients may not have long-term benefit.
Brown said that when switching to venetoclax she generally continues ibrutinib until the day before.
"If you stop the BTK inhibitor you can sometimes get an explosive flare of disease, which can be dangerous," she said. "For aggressive relapses I will consider overlapping ibrutinib with venetoclax for a few weeks."
In these cases a rapid dose escalation could be an option, but this must be done in the hospital with the high-risk protocol according to published guidelines. "I would not recommend it for anyone without extensive experience with venetoclax, but it can be helpful in this setting," said Brown.
If the patient responds she said she will look for a complete remission or undetectable MRD at the 9- to 12-month time point, as these are likely to predict durability of remission.
Brown said that the time to really worry with BCL2 inhibition is when disease progresses while patients are actively taking the drug.
"This is likely distinct from patients who have a planned discontinuation of venetoclax, remain in remission for some time, and subsequently relapse, those patients may respond again to venetoclax," she explained, though noted that data is limited for that scenario.
In general, patients on venetoclax are more likely to have poor outcomes if they achieve a partial rather than complete response, have a complex karyotype, or are refractory to fludarabine. And new data at ASH reported that the acquired Gly101Val mutation confers resistance to the agent.
"This is really a new unmet need that we have -- progression on novel agent therapy," said Brown. "And certainly progression after two novel agents -- both of them -- is very much an unmet need for which we don't have a known established effective therapy."
Clinical Trials
Even as they start their first therapy, Brown said she'll explain to patients with very high-risk disease -- those with biallelic TP53 or complex karyotype, for example -- that their remission may be shorter, and said that these patients are excellent candidates for combination or CAR T-cell therapies in clinical trials to try to reduce that likelihood of earlier relapse. About 80% of patients who relapse on novel agents carry BTK or PLCG2 mutations.
Combinations could put less pressure on mechanisms of resistance and offer the potential of fixed-duration treatment, which could reduce issues with adherence, reduce costs, and potentially mitigate cumulative adverse events. Unknown is whether a ibrutinib-venetoclax combination would be effective after failing on single-agent venetoclax or ibrutinib.
Brown said that even when high-risk patients achieve a very deep remission, she still worries, as if they were to progress on a second drug there's no known ability to get them back in remission.
"I encourage my patients even if they achieve a deep remission to proceed with a potential cellular therapy, but I find many patients prefer not to and want to maintain their good remission on the drug where they're feeling very well," said Brown. "But this does open up the possibility that we won't know what to do at the time of progression."
Outside of trials for CAR T-cell therapies, other agents under investigation in CLL include more BTK-specific inhibitors such as acalabrutinib, zanubrutinib, and tirabrutinib; non-covalent BTK inhibitors that targets C481S mutations such as vecabrutinib or ARQ-531; delta-specific PI3K inhibitors or the pan-specific PI3K inhibitor copanlisib (Aliqopa); as well as SYK, MCL-1, and CDK9 inhibitors.