Following new data from this year’s American Society of Hematology (ASH) annual meeting, ibrutinib (Imbruvica) is primed to become standard first-line therapy in more and more chronic lymphocytic leukemia (CLL) patients, both younger and older, but clinicians will still encounter those who have relapsed after upfront chemoimmunotherapy and have yet to be treated with novel agents.
For these patients, a number of approved options are at the disposal of treating physicans, from the Bruton tyrosine kinase (BTK) inhibitor ibrutinib to the BCL2-targeting agent venetoclax (Venclexta) plus rituximab, to the PI3K inhibitors idelalisib (Zydelig) and duvelisib (Copiktra).
During an education session at the ASH meeting, Jennifer Brown, MD, PhD, of the Dana-Farber Cancer Institute in Boston, walked through the various considerations in this setting.
“Patients who relapse after prior chemoimmunotherapy we know have substantially less response to subsequent chemoimmunotherapy,” said Brown. “In general, most patients should receive a targeted agent in this setting, most if not all.”
She noted that one possible exception might be for a very low-risk patient who experienced a long remission after their prior therapy and strongly wanted to repeat that therapy, but added that targeted agents have proven more effective both head to head with and in addition to chemoimmunotherapy.
Ibrutinib or Venetoclax
Favoring ibrutinib over venetoclax are longer-term follow-up results in this setting, data supporting post-ibrutinib venetoclax but little for the reverse scenario, and the intense monitoring for tumor lysis syndrome required with venetoclax.
Median progression-free survival (PFS) with ibrutinib in the relapsed/refractory setting at 7 years was 51 months — though just 26 and 31 months in del(17p) and complex karyotype patients, respectively. The overall survival rate in the full cohort of relapsed or refractory patients was 52% at this time point, with 89% of patients responding overall and 10% achieving a complete response (CR).
Brown noted that while older patients have been included in clinical trials, ibrutinib is not well studied in those with comorbidities, and recent studies suggest worst outcomes in this group. Risk of trial fibrillation and hypertension are most of concern in older patients with cardiac disease, she said, but other side effects include bleeding risk due to platelet dysfunction, rash, active uncontrolled autoimmunity, and fungal infections that require pause of ibrutinib therapy.
Hepatitis B and C should be treated prior to initiation, strong CYP3A4 inhibitors should be avoided due to drug interactions, and even moderate CYP3A4 inhibitors require dose reductions.
Favoring venetoclax are the possibility for fixed-duration therapy and reduced long-term side effects, as patients in the phase III MURANO trial that led to FDA approval for all relapsed or refractory CLL patients were treated for 2 years. Patients may prefer this option for that reason.
In MURANO, patients on venetoclax had a PFS rate of 85% and 71% at 2 and 3 years, respectively, with benefit seen regardless of del(17p) status.
And 26.8% of venetoclax-treated patients attained a CR or CR with incomplete hematologic recovery compared with 8.2% of those in the control arm of bendamustine-rituximab. Higher rates of minimal residual disease (MRD) were also seen in the venetoclax arm, as measured by both peripheral blood (62.4% vs 13.3%) and bone marrow aspirate (27.3% vs 1.5%).
“I think for right now most people would use ibrutinib because they have extensive experience with it, and it’s a very effective drug,” said Susan O’Brien, MD, of the University of California Irvine, in an interview with MedPage Today. “So even though the CR rate is low and we’re generally not talking about MRD negativity at all (because we’re not talking about morphologic CRs in the relapsed setting with ibrutinib), the bottom line is those responses are very durable.”
But, she added, “the trade-off is the patient has to stay on the drug.”
Venetoclax carries its own risks, tumor lysis syndrome chief among them.
“It’s very important to follow the label, in its description of categorizing risk of tumor lysis, including with CT scans, and then following the monitoring required for patients’ level of risk,” said Brown. “In that setting, the comorbidity that concerns me the most with this drug is renal failure, which can make it difficult to clear the byproduct of tumor lysis or manage tumor lysis.”
O’Brien highlighted that those in private practice don’t regard venetoclax as very user friendly due to the necessary monitoring for tumor lysis syndrome.
Patients at high risk for the syndrome need to be hospitalized when commencing treatment and are thus turned over to a hospitalist, she explained. But for those that don’t fall into that category, the treating physician will need to perform monitoring lab work 4 to 6 hours after a patient starts on the initial 20-mg venetoclax dose.
“Let’s say you bring your patient and you start them at 9 or 10 in the morning, and now you’re checking labs at 4 or 5, and the potassium is elevated — well now you’re closing your office, so what do you do?” she said. “Not only do you have to do that for the 20-mg dose, but you have to do it the following week for the 50-mg dose.”
Other concerning side effects include neutropenia unrelated to CLL, and similar drug interactions with CYP3A4 inhibitors. While venetoclax appears safer than BTK inhibitors with regard to active uncontrolled autoimmunity and fungal infections, data are limited in this regard.
The PI3K-delta inhibitor idelalisib was approved by the FDA in 2014, and the PI3K-delta/gamma inhibitor duvelisib received approval from the FDA earlier this year. CRs with either agent in their respective trials were rare (0% and 0.6%).
O’Brien said that idelalisib “has fallen out of favor to a large extent” due to issues in its frontline trials, which were stopped early by the FDA and led to a black box warning on the drug‘s labeling for adverse events.
While results from the registration trial of idelalisib in the relapsed setting showed improvement in PFS over placebo, 2-year follow-up data revealed that 40.7% of patients discontinued the drug due to adverse events, including transaminitis, severe infections such as pneumonia, and autoimmune toxicities such as colitis. The incidence was higher in younger patients and those that had received fewer lines of prior therapy.
So, which patients might be appropriate for these drugs?
“I would say that older, heavily pretreated patients are at low-risk for autoimmune toxicity — and if they have significant comorbidities that impact BTK inhibitor or venetoclax tolerability — they may be a candidate,” said Brown, noting that the drug is not contraindicated in cardiac or renal disease, and the registration trial did enroll patients with a high level of comorbidities who tolerated it well if they didn’t develop infections or autoimmune toxicity.
She said that idelalisib should be avoided in patients with hepatic disease, inflammatory bowel disease, and those with active infection or autoimmunity. Infection prophylaxis is needed with the treatment, and as the drug is a strong inhibitor of CYP3A4, additional CYP3A4 inhibition should likewise be avoided.
For duvelisib, Brown said the considerations for idelalisib apply as well. “Currently the toxicity profile seems roughly similar to idelalisib, although there’s less transaminitis and the suggestion that patients may be better able to be maintained on the drug,” she said.
O’Brien said that for community physicians, there could be potential interest in trying a PI3K inhibitor prior to venetoclax.
“They don’t have to do all the tumor lysis monitoring,” she explained. “They can start the patient on the drug, and bring them back 2 or 3 weeks later.”
But in the academic setting, she suspected most would assume that switching to duvelisib would be no different than switching to idelalisib and likely sequence in venetoclax first.
“In summary, for relapsed CLL our choice of therapy continues to depend on risk profile, 17p or IgVH, prior therapy, and comorbidity profile,” concluded Brown. “As a first novel agent, ibrutinib has primarily been used, but we now also have venetoclax-rituximab,” adding that PI3K inhibitors are reserved for later.