Adding to the Regimen: NCCN Updates in Leukemia and Lymphoma

The National Comprehensive Cancer Network (NCCN) recommended Brukinsa (zanubrutinib), a Bruton tyrosine kinase (BTK) inhibitor, for the treatment of chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).

Recent NCCN guidelines that were updated on Dec. 3, 2020, now recommend the drug as both

a first- and second-line treatment in CLL/SLL, including:

- First-line therapy of Brukinsa as a single agent is recommended for the treatment of CLL/SLL with del(17p) and TP53 gene mutations in patients with a contraindication to other BTK inhibitors who have indications for treatment.

- For second-line treatment and subsequent therapy, the NCCN recommends the indication as a single agent for the treatment of CLL/SLL with or without del(17p) and TP53 mutations in patients with intolerance or contraindication to other BTK inhibitors who have indications for retreatment.

The first-line treatment recommendation was based on results from the phase 3 SEQUOIA study, designed to evaluate Brukinsa monotherapy in treatment-naive patients with CLL or SLL and del(17p). After a follow-up of 21.9 months, patients treated with Brukinsa showed an overall response rate of 94.5%, with a complete response/ complete response with incomplete bone marrow recovery rate of 6.4%. Moreover, the 18-month progression-free survival, or the time from treatment to disease progression or worsening, and overall survival rates were 90.6% and 95.4%, respectively.

The BTK inhibitor’s tolerability in this study were consistent with what was previously reported. The most common side effects included contusion (20.2%), upper respiratory tract infection (19.3%), diarrhea (17.4%), nausea (14.7%), back pain (13.8%), constipation (13.8%), rash (13.8%), cough (12.8%), neutropenia (11.9%), arthralgia (11.0%) and pneumonia (10.1%).

“BTK inhibitors have demonstrated positive outcomes in CLL or SLL patients with del(17p), who usually respond poorly to standard chemoimmunotherapy, even in the front-line setting,” Dr. Jennifer R. Brown, director of the Dana-Farber Cancer Institute CLL Center and professor of medicine at Harvard Medical School, said in a press release issued by BeiGene, the agent’s manufacturer.

The second-line treatment recommendation was based on results of a phase 2 trial, designed to evaluate Brukinsa in patients with/without del(17p) and/or TP53 mutations, who have an intolerance or contraindication to other BTK inhibitors. After a median follow-up of 15.1 months, Brukinsa induced an overall response rate of 84.6%. In addition, the 12-month overall response rate was 96% for those treated with Brukinsa. The most common grade 3 or higher side effects seen were neutropenia (44%), thrombocytopenia (15.4%) and lung infection/ pneumonia (13.2%).

Brukinsa is a small molecule BTK inhibitor that has been investigated as a single agent and in combination with other agents to treat patients with a wide range of B-cell malignancies. It is currently approved by the Food and Drug Administration for the treatment of adult patients with mantle cell lymphoma (MCL).

The NCCN’s recommendation could have two implications for patients with CLL/SLL. First, insurance companies may pay for Brukinsa, in particular, because it is already approved to treat patients with MCL, a closely related blood cancer. However, of note, its use in CLL would be considered off label, as the agent is not approved in this disease state as of yet. On the other hand, the NCCN’s recommendation may aid in the FDA’s approval of the first- and second-line indications.