Jennifer Brown, MD, PhD
The treatment landscape for patients with chronic lymphocytic leukemia (CLL) continues to evolve, as long-term data become available from pivotal studies that led to the FDA approvals for the BTK inhibitor ibrutinib (Imbruvica) and the PI3K inhibitor idelalisib (Zydelig), according to a presentation by Jennifer Brown, MD, PhD, at the 2016 ASCO Annual Meeting.
For BTK inhibition, follow-up data have identified distinct groups of patients who benefit the most from ibrutinib. These data have shown that patients with del17p CLL respond but still remain at high risk of progression; furthermore, those who progress on ibrutinib have limited options and poor outcomes.
While the efficacy data for PI3K inhibitors is promising, these agents have been fraught with toxicity concerns, specifically in the frontline setting when used in combination. Newer agents are in development and clinical studies continue to assess the optimal use of these therapies.
Ibrutinib Standard of Care
The longest follow-up data for ibrutinib is available from the pivotal PCYC-1102-CA study, which led to an accelerated approval for ibrutinib in CLL. In this study, treatment-naive patients (n = 31) had an objective response rate (ORR) with ibrutinib of 84%, which included a complete remission (CR) rate of 23%. For those with relapsed/refractory disease, the ORR reached 90%, with a CR rate of 7%.
The 30-month progression-free survival (PFS) rate with ibrutinib in those without del17p/11q was 87%. In the del11q group, the 30-month PFS rate was 74.2%. In those with del17p CLL, the 30-month PFS rate was 45.9% and the median PFS was 28.1 months. Median PFS was not yet reached in the other 2 groups.
"The progression-free survival in those with low-risk disease is 87% at 2 and a half years, so really quite excellent in a patient population with a median of 4 prior therapies," said Brown, from the Dana-Farber Cancer Institute. "For the 11q patients, this declines to 74%—still quite excellent—but for the 17p patients there's a continuous drop-off, and they have reached a median PFS of a little more than 2 years. These patients are still at high risk for relapse."
At this point, those who progress on ibrutinib typically have poor outcomes. In available data, median overall survival (OS) in those with progressive CLL is 17 months and patients who experience Richter's transformation (n = 18) have a median OS of 3.5 months.
"If you do have a patient actively progressing on ibrutinib, you don't want to stop ibrutinib until you have another plan clearly in place, because sometimes these patients will develop quite explosive disease flare that one can lose control of quite quickly," said Brown. "I generally maintain the ibrutinib until the next therapy is selected and ready to go."
In addition to progression, 10% to 30% of patients will discontinue ibrutinib due to adverse events (AEs). Stopping treatment due to AEs is more common seen in older patients, such as those between the ages of 70 and 80. The most common causes for discontinuation are diarrhea, fatigue, arthralgia, and muscle spasm, which are mostly low-grade events that can be managed. Other reasons include atrial fibrillation and bleeding-related events.
"In terms of managing the bleeding, there is expanding anecdotal experience with anticoagulation with ibrutinib but it is still fairly limited, so we try to avoid it. There is similarly limited data with antiplatelet agents," said Brown. "For now, we hold ibrutinib 3 to 7 days prior to or post surgery, or for anything with stitches."
In the more recent RESONATE-2 trial, the 18-month PFS rate with ibrutinib in the frontline setting was 90% versus 52% with chlorambucil. The 24-month OS rate was 98% with ibrutinib versus 85% with chlorambucil. There were 3 deaths in the ibrutinib arm versus 17 deaths with chlorambucil.
In terms of AEs in the ibrutinib arm, 14% of patients experienced hypertension and 6% had atrial fibrillation. Furthermore, a major hemorrhage was experienced by 4% of patients and 2 had sudden deaths.
"This study has short follow-up still, and chlorambucil is a poor comparator—not a standard of care anymore," said Brown. "The patients were low risk and had quite low comorbidity for their age. Toxicity was not negligible, and therapy is planned indefinitely, so over time we expect to see problems with compliance that can lead to an increased risk for resistance."
Other studies are looking at ibrutinib in comparison with standard of care options in the frontline setting, Brown noted. A phase III study is looking at ibrutinib plus rituximab compared with fludarabine, cyclophosphamide, and rituximab.