In 2023, pirtobrutinib (Jaypirca), a non-covalent BTK inhibitor, received accelerated approval from the FDA as an alternative later-line treatment for patients with Chronic Lymphocytic Leukemia. In December 2025, the FDA granted traditional approval to pirtobrutinib for adults with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) who have previously been treated with a covalent BTK inhibitor
About Chronic Lymphocytic Leukemia
Chronic Lymphocytic Leukemia (CLL) is the most prevalent form of adult leukemia, with an estimated 60,000 cases in the United States alone. Current treatments, including covalent BTK (Bruton’s tyrosine kinase) inhibitor and BCL-2 inhibitor therapies, have considerable success in managing this disease. However, challenges persist for patients experiencing ongoing cancer progression despite these interventions, so developing alternative therapies is crucial.
What is Pirtobrutinib and How Does it Work?
Pirtobrutinib is a non-covalent BTK inhibitor treatment, FDA approved for patients with CLL who have already received at least two lines of therapy.
Because Pirtobrutinib is a non-covalent BTK inhibitor, it binds reversibly to its target, as opposed to covalent BTK inhibitors which irreversibly modify their targets. Because of this reversible quality, non-covalent BTK inhibitors can overcome resistance associated with covalent BTK inhibitors.
CLL is characterized by the production of atypical B and T cells, specialized immune cells called lymphocytes that help the body fight infection. In most patients, cancerous mature B cells live longer and can accumulate in various parts of the body. BTK is an enzyme involved in the growth and survival of cancerous B cells, so by blocking specific enzymatic activity, a BTK inhibitor can help slow the progression of CLL.
New results from a phase 1/2 clinical trial indicated that pirtobrutinib effectively controlled the progression of CLL in many patients where previous treatments were ineffective. An ongoing phase 3 trial will further evaluate the effectiveness of pirtobrutinib versus covalent BTK inhibitors to potentially introduce the treatment earlier to patients with CLL/SLL.
Results
Initial results from the phase 1/2 BRUIN trial indicated that pirtobrutinib was well tolerated and highly effective for patients regardless of previous treatments.
- Over 80% of patients previously treated with a covalent BTK inhibitor experienced substantial improvement (objective response rate of 81.3%) after being treated with pirtobrutinib.
- Patients previously treated with a BCL-2 inhibitor experienced a median 15.9-month progression free survival after being treated with pirtobrutinib.
- Patients never treated with a BCL-2 inhibitor experienced a median 23.0-month progression free survival, and over 80% experienced substantial improvement (objective response rate of 83.1%) after being treated with pirtobrutinib.
- Patients previously treated with covalent BTK inhibition and BCL-2 inhibition had a 2-year survival rate of approximately 60% after receiving pirtobrutinib.
Adverse Effects
While pirtobrutinib was tolerated well by most patients, potential adverse effects included fatigue, diarrhea, cough, and a small risk of bruising and bleeding, in addition to low rates of hypertension, atrial fibrillation, and neutropenia.
Implications
Pirtobrutinib is one of the first alternative options for patients with treatment resistant CLL/SLL. If pirtobrutinib displays superior effectiveness over current covalent BTK inhibitors, it may earn a spot in frontline therapy.
Which therapy is more effective: Covalent BTK Inhibition or BCL-2 Inhibition?
While no data directly compares the two therapies, both covalent BTK inhibitors and BCL-2 inhibitors are effective at controlling CLL progression. Often, the decision to choose one over the other is patient-driven. BTK inhibition treatment is indefinite, while BCL-2 inhibition therapy is time limited but requires a six-month course of infusions. In the case of genetic abnormalities that confer increased risk (17p deletion), BTK inhibition is the preferred treatment.
References
- Furqan, Fateeha. “The Role of Noncovalent BTK Inhibitors in the Era of Covalent BTK Inhibitors.” Hematology Oncology, Clinical Advances in Hematology and Oncology, Apr. 2024.
- Jaypirca (pirtobrutinib) now approved by US FDA for the treatment of adult patients with chronic lymphocytic leukemia or small lymphocytic lymphoma who have received at least two lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor. News release. Eli Lilly and Company. December 1, 2023. Accessed May 13, 2024.
