The Real-World Safety and Tolerability of Pirtobrutinib Among Patients with B Cell Lymphomas; A Single Center Experience
Authors: Ammad Ud Din Mohammad , Tobon Katherine , Chavez Julio C. , Nodzon Lisa , Saeed Hayder , Gaballa Sameh , Dong Ning , Isenalumhe Leidy Lismeris , Bello Celeste M. , Grajales-Cruz Ariel , Shain Kenneth H. , Sokol Lubomir , Shah Bijal D , Pinilla-Ibarz Javier 
Published: December 2024

Background: Pirtobrutinib is an oral highly selective noncovalent Bruton tyrosine kinase inhibitor (BTKi) that has shown promising efficacy in heavily treated patients with relapsed/refractory (R/R) B cell lymphomas. We conducted a single-center retrospective study evaluating the safety and tolerability of pirtobrutinib in the real-world setting.

Methods: The data for this study was gathered using the prescription records from the outpatient pharmacy at the H Lee Moffitt Cancer Center and Research Institute. All patients who were prescribed pirtobrutinib from June 1st, 2022 to June 1st, 2024 as part of standard-of-care regimens, off-label, or compassionate use were included in this study. All patients received at least one month of treatment with pirtobrutinib. The electronic medical records (EMR) of these patients were then accessed to review their treatment history and tolerance to pirtobrutinib. Data regarding adverse events (AEs) were collected from the medical documentation in the EMR. Descriptive analysis was performed using Statistical Package for the Social Sciences (SPSS) version 28.0.

Results: A total of 29 patients received pirtobrutinib. Among these 12 (41.1%) were treated for R/R chronic lymphocytic leukemia (CLL), 11 (37.9%) for R/R mantle cell lymphoma (MCL), 4 (13.8%) for Richter's transformation, and 1 (3.4%) patient each for R/R Waldenström macroglobulinemia and R/R marginal zone lymphoma, respectively. The median age was 72 (interquartile range [IQR] 66.5-76] years. Most patients were male (n=23, 79.3%). This was a heavily treated population with a median 4 (IQR 3-5) prior lines of therapy. All patients had disease progression on a BTKi. Nine (75%) of the CLL patients had disease progression on both a BTKi and venetoclax. Six of these CLL patients had a documented BTK C481 mutation on next-generation sequencing. All patients with MCL had received at least 1 line of chemotherapy and overall, 24 (82.8%) of patients had received prior chemotherapy. A total of 6 (20.7%) patients had received prior chimeric antigen receptor (CAR) T-cell therapy, while 4 (13.8%) had undergone a hematopoietic stem cell transplant before initiating treatment with pirtobrutinib. The median follow-up time was 6 (IQR 3-10.5) months. The median duration of treatment was 4 (2-8.5) months. Ten (34.5%) patients had disease progression on pirtobrutinib. Nine (31.0%) patients received pirtobrutinib as part of the bridging therapy to CAR T- cell therapy. At the time of data cut-off, 12 (41.3%) patients were continuing treatment on pirtobrutinib. The dose of pirtobrutinib was 200 mg daily for 27 patients, while 3 patients were treated with a reduced dose of 100 mg daily due to a personal history of atrial fibrillation and/ or potential drug interactions.

In terms of safety, 27 (93.1%) had at least 1 AE of any grade documented in the EMR after initiation of therapy. Most of these were grade I/II AEs (79.3%). The most common AE was fatigue (27.6%), followed by infections (17.2%) and thrombocytopenia (17.2%). Other common grade I/II AEs included hypertension (10.3%), bruising (10.3%), nausea/ vomiting (10.3%), diarrhea (10.3%), anemia (6.9%), and rash (6.9%). Six patients experienced ≥grade 3 AEs. Among them, 4 patients required temporary discontinuation of pirtobrutinib. Two of these were due to severe infection, resulting in sepsis and hospitalization, 1 for neutropenia requiring granulocyte-colony stimulating factor support, and 1 for atrial fibrillation where the drug was later resumed at a reduced dose of 100 mg. No other dose reduction due to AEs were noted. An additional 2 patients permanently discontinued pirtobrutinib due to grade IV hepatic injury and recurrent pleural effusions with negative cytology, respectively. No sudden cardiac deaths were observed. In total, 8 (27.6%) patients died during the study period, of which 6 were directly related to disease progression.

Conclusion: The AE profile seen in our real-world data is comparable to that reported in the original clinical trial population suggesting pirtobrutinib is safe and well-tolerated in this high-risk population. Longer-term follow-up with larger multicenter data would be required to determine the true incidence of some rare side effects such as severe hepatic injury and pleural effusions that were recorded in our patient cohort.