Page 102 - Haematologica Vol. 110 - January 2025

ARTICLE - Pirtobrutinib in patients with prior intolerance to BTKi
N.N. Shah et al.
atrial fibrillation on prior BTKi were also allowed to enter the study. Treatment with pirtobrutinib continued until disease progression, unacceptable toxicity, or withdrawal.
All patients who received at least one dose of pirtobrutinib comprised the overall safety population. Patients who had received prior BTKi and discontinued due to intolerance, defined as having discontinued treatment due to persistent / recurrent AE as assessed by the physician in the absence of progressive disease, comprised the prior BTKi-intolerant subgroup.
The institutional review boards or independent ethics com- mittees overseeing each site approved the BRUIN study pro- tocol, and the study was carried out in compliance with the Declaration of Helsinki, Good Clinical Practice guidelines, and local laws. All patients provided written informed consent.
Assessment of adverse events
The following reasons for discontinuing a prior BTKi due to intolerance were collected: bleeding, atrial fibrillation, neu- tropenia, cardiac events, diarrhea, arrhythmia, infection, and other events including rash, arthralgias / myalgias, fatigue, and pain. More than one AE could be reported in an individ- ual patient. Data concerning the severity of the AE leading to discontinuation of a prior BTKi was not collected.
Safety with pirtobrutinib treatment was determined by fre- quency and severity of AE, graded according to the Common Terminology Criteria for Adverse Events version 5.0. Treatment emergent AE (TEAE) were defined as all AE reported from the date of the first dose through the date of the last dose plus 37 days or start of subsequent anticancer therapy, whichever was earlier. Treatment-related AE (TRAE) were defined as all TEAE with an investigator-determined attribution related to pirtobrutinib.
Statistical analysis
A data cutoff of 29 July 2022 was used for all analyses. The AE categories that led to discontinuation of a prior BTKi were summarized using frequencies and percentages. Atrial fibril- lation was reported individually and also under the category of cardiac disorders. Diarrhea was reported individually and also under the category of gastrointestinal disorders. Pirto- brutinib TEAE recurring in the same patient as those leading to prior BTKi discontinuation were summarized. Pirtobrutinib TEAE and TRAE were also summarized by type and severity, according to maximum grade, using frequencies and per- centages. In addition, efficacy data for patients in the prior BTKi intolerant subgroup who had CLL/SLL or MCL were determined. Overall response rate (ORR) as assessed by the investigator, and using either the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) guidelines15 or the Lugano criteria16 for CLL/SLL and MCL, respectively, was estimated with corresponding 95% two-sided exact Confi- dence Intervals (CI). The Kaplan-Meier method was used to analyze progression-free survival (PFS) and overall survival (OS). Analyses were performed using SAS version 9.4.
Table 1. Patients’ characteristics.
Characteristics
Prior BTKi- intolerant N=127
Disease types, N (%) CLL/SLL
MCL
WM
RT FL/MZL
78 (61.4) 21 (16.5) 16 (12.6) 8 (6.3)
4 (3.1)
Age in years, median (range) <50
50-64 65-74 75-84 ≥85
70 (42-87) 2 (1.6) 36 (28.3) 53 (41.7) 33 (26.0) 3 (2.4)
Male, N (%)
81 (63.8)
ECOG PS, N (%) 012
70 (55.1) 48 (37.8) 9 (7.1)
Prior lines of systemic therapy, median (range)
3 (1-11)
Prior systemic therapy, N (%) BTKi
Anti-CD20 antibody Chemotherapy BCL2 inhibitor
PI3K inhibitor Immunomodulator Stem cell transplant
Autologous
Allogeneic
CAR T-cell therapy Other systemic therapy
127 (100) 108 (85.0) 97 (76.4) 34 (26.8) 24 (18.9) 13 (10.2) 9 (7.1)
7 (5.5)
2 (1.6)
9 (7.1) 35 (27.6)
Prior lines of BTKi, N (%) 12≥3
81 (63.8) 34 (26.8) 12 (9.4)
Prior BTKi therapy with toxicity as reason for discontinuation, N (%)*
Ibrutinib Acalabrutinib Nemtabrutinib Zanubrutinib DTRMWXHS-12
120 (94.5) 9 (7.1)
4 (3.1)
3 (2.4)
1 (0.8)
Time in months since end of last prior BTKi discontinued for toxicity to first pirtobrutinib dose, median (range)
18.8 (0.1-90.5)
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*Sum >100% due to some patients having multiple prior Bruton tyrosine kinase inhibitors (BTKi). CLL: chronic lymphocytic lympho- ma; SLL: small lymphocytic lymphoma; MCL: mantle cell lymphoma; WM: Waldenström macroglobulinemia; RT: Richter transformation; FL: follicular lymphoma; MZL: marginal zone lymphoma; ECOG PS: Eastern Cooperative Oncology Group Performance Status; BTKi: Bruton tyrosine kinase inhibitors; BCL2: B-cell lymphoma 2; PI3K: phosphatidylinositol 3-kinase; CAR: chimeric antigen receptor; N: number.