B-cell Pathway Inhibitors Show Clear Benefit in CLL

B-cell pathway inhibitors have shown impressive survival benefits for patients with chronic lymphocytic leukemia, but require careful monitoring and possible suspension to control adverse events.

Susan M. O’Brien, MD

B-cell pathway inhibitors have shown impressive survival benefits for patients with chronic lymphocytic leukemia (CLL), but require careful monitoring and possible suspension to control adverse events (AEs), Susan M. O’Brien, MD, said in an opening presentation at the 33rd Annual Chemotherapy Foundation Symposium.

Chief among the therapies mentioned by O’Brien, a researcher at UC Irvine Health, were the BTK inhibitor ibrutinib (Imbruvica) and the PI3 kinase inhibitor idelalisib (Zydelig). Both agents are FDA-approved for the treatment of patients with CLL, ibrutinib as a monotherapy and idelalisib in combination with rituximab.

In the case of ibrutinib, “The first thing you notice when you give the drug to patients is a very rapid and dramatic reduction of the lymph nodes,” she noted. The typically huge lymphocytosis response caused by ibrutinib ordinarily is not cause for alarm, she said. “There is no need to worry about it or do anything about it.”

In the phase II PCYC 1102 and extension PCYC 1103 studies, patients with CLL and small lymphocytic lymphoma (SLL) were treated with ibrutinib at 420mg/day. In patients with deletion 17p, the frontline progression-free survival (PFS) was 32.4 months. The best PFS previously in this category was 11 months, O’Brien said.

Equally impressive results for ibrutinib emerged from the phase III RESONATE study. In this analysis, ibrutinib lowered the risk of progression by 75% in patients with CLL who harbored a 17p deletion and by 78% in the full population of the study when compared with ofatumumab. At 12 months, the overall survival (OS) rate was 90% for patients treated with ibrutinib compared with 81% in the ofatumumab group (HR, 0.43; 95% CI, 0.24-0.79; P = .005).

In the ibrutinib-only arm, atrial fibrillation of any grade occurred in 10 patients versus 1 for the ofatumumab arm. O’Brien noted that the median age of patients was 73, and most had predisposing risk factors. All-grade bleeding-related AEs were 44% with ibrutinib and 12% for ofatumumab.

The second recently approved agent, idelalisib, has shown striking results in reduction of peripheral lymphadenopathy, O’Brian said, adding that a trial of idelalisib and rituximab in refractory CLL clearly showed the power of the combination among an aged and fragile population of older adults. “These were people where you needed to treat them but you’d be very hard pressed to give them chemo,” she said.

In the pivotal phase III study, 220 patients with a median age of 71 years were randomized in a 1:1 ratio to receive rituximab plus idelalisib (n = 110) or rituximab and placebo (n = 110). Patients in the study had received 3 prior therapies, including prior treatment with rituximab.

In the idelalisib plus rituximab arm, median PFS was not reached after 14 months, whereas in the placebo plus rituximab group the median PFS was 5.5 months (HR, 0.15; 95% CI, 0.08-0.28; P < 0.0001). However, the trial was controversial, O’Brien said, since rituximab is not very effective as monotherapy and the patient population was aged and delicate; yet the combination of idelalisib proved effective, she said.

Major AEs in the idelalisib versus placebo arms, respectively, included pyrexia (32% vs 17%), fatigue (26% vs 29%), nausea (26% vs 23%), chills (24% vs 17%), and diarrhea (21% vs 15%).

Idelalisib and rituximab together yielded “highly effective, durable remissions,” she said, though problems were seen with transaminitis, early pneumonitis, and late colitis.

“If you have a patient on a drug for a year and they start to develop diarrhea, don’t leave the patient on the drug and try to work it out,” she said, referring to both treatments. “Put a hold on the drug, and then work it out. Because if it’s colitis and you leave them on it, it’s going to get much worse.”

In closing, O’Brien also noted the clinical value of the BCL-2 inhibitor venetoclax, which showed complete responses in heavily pretreated patients. “You never see complete responses,” O’Brien said. A significant number of patients were also minimal residual disease negative.

“These drugs are changing the landscape,” O’Brien added. “All of them are highly effective.”


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