Updates for Second Generation BTK Inhibitors in R/R Mantle Cell Lymphoma

Selection of any BTK inhibitors for mantle cell lymphoma should consider factors such as cardiovascular or bleeding risks, predisposition for gastrointestinal adverse effects, and potential medication nonadherence.

Second generation Bruton’s tyrosine kinase (BTK) inhibitors showed promise for patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL) in short-term follow up, as well as fewer off-target adverse effects (AEs), according to Andrea LeVoir, PharmD, BCOP, a clinical pharmacy specialist in lymphoma for Memorial Sloan Kettering Cancer Center. LeVoir presented data supporting these results on Thursday at the virtual Hematology/Oncology Pharmacy Association Annual Conference 2021.

Approximately 3% of newly diagnosed non-Hodgkin lymphomas with both indolent and aggressive presentations are MCL, LeVoir said. The session compared primary literature for BTK inhibitors in the treatment of R/R MCL with a focus on second generation agents.

According to LeVoir, second-line treatment was previously based on the duration of response to front-line therapy; however current practice guidelines for second-line treatment of R/R MCL recommend initiation of BTK or lenalidomide-based therapy for all patients.

“BTK is commonly overexpressed in MCL, which leads to enhanced survival and reduced apoptosis,” LeVoir said.

She first discussed ibrutinib (Imbruvica; Pharmacyclics and Janssen), an oral BTK inhibitor indicated for the treatment of adult patients with MCL, who have received at least 1 prior therapy.

Data pooled from the PCYC-1104-CA (NCT01236391), phase 2 SPARK, and phase 3 RAY studies support the use of ibrutinib (Imbruvica; Pharmacyclics and Janssen). Prolonged progression-free survival (PFS; median 12.8 months) and overall survival (OS; 25 months) in patients with R/R MCL were consistently high with ibrutinib. The pooled studies also showed overall response rate (ORR) at 66% (CR 20%, PR 46%).

“Patients who were treated earlier in therapy may have had better outcomes,” LeVoir added.

LeVoir said no unexpected late toxicities occurred in patients over the 7-year period included in the pooled analysis; however hematologic toxicities occurred in roughly 15%-20% of patients, including neutropenia, thrombocytopenia, and anemia.

“Diarrhea was still a prominent nonhematologic toxicity, with roughly 40% of patients experiencing any grade. Six percent of patients experienced atrial fibrillation of grade 3 or higher, and 5% of patients experienced major bleeding of grade 3 or greater,” LeVoir said.

According to LeVoir, another analysis evaluated the outcomes of ibrutinib compared to prior regiment. Investigators found that patients who used ibrutinib with 1 prior line of therapy who achieved CR had the best outcomes. Patients using ibrutinib with 1 prior line of therapy showed median PFS of 25 months and median OS of 62 months.

Although patients have durable responses to ibrutinib and no unexpected toxicities were shown in these studies, LeVoir said, secondary and primary resistance to ibrutinib can occur, with mechanisms of resistance not yet fully understood.

There are currently 2 FDA-approved, second-generation BTK inhibitors on the market: acalabrutinib (Calquence; AstraZeneca) and zanubrutinib (Brukinsa; BeiGene).

“Both exhibit irreversible BTK inhibition, like ibrutinib, but they are able to bind to both the C481 and C481S residues,” LeVoir said. “These agents were designed to be more potent and to have less off-site targets that could lead to some of the less tolerable ibrutinib side effects.”

According to LeVoir, the second-generation BTK inhibitors have minimal binding to TEC and epidermal growth factor receptors, which theoretically limit bleeding, and gastrointestinal and dermatological toxicity, respectively.

In 2020, the ACE-LY-004 (NCT02213926) trial demonstrated ORR of 81% (CR 48%; PR 33%), and PFS of 37.2% at 36 months. The trial’s OS at 36 months was 60.5%, but final OS results were not yet available. The trial also showed that acalabrutinib produces prolonged durations of responses with a more tolerable AE profile than ibrutinib.

“Diarrhea was still a prominent nonhematologic toxicity, with roughly 31% of patients experiencing any grade of diarrhea and 13% experiencing grade 3 or greater,” LeVoir said.

Although there were no instances reported for atrial fibrillation, 8% experienced cardiac AEs, including 2% of patients experiencing grade 3 or greater. Additionally, 31% of patients experienced bleeding, including 1 instance of grade 3 or greater.

The BGB-3111-206 (NCT03206970) study showed results with zanubrutinib that were similar to the ORR and PFS for acalabrutinib. Data updated in 2019 demonstrated 83.7% ORR (CR 77.9%; PR 5.8%), and PFS of 72.1% at 15 months, with OS not reported.

Data for adverse events reported with zanubrutinib include bleeding (25.6% with 0 grade 3 or greater), diarrhea (15.1% with 0 grade 3 or greater), and hypertension (15.1%, including 3.5% grade 3 or greater).

According to LeVoir, selection of any BTK inhibitors should consider factors such as cardiovascular or bleeding risks, and predisposition for gastrointestinal AEs, as well as potential medication nonadherence with a twice-daily dosing schedule.


From ACE-LY-004 to Zuma-2: focused updates in relapsed/refractory mantle cell lymphoma. Presented at: Hematology/Oncology Pharmacy Association Annual Conference 2021; virtual. April 15, 2021.