Feasibility of Discontinuation of Bruton's Tyrosine Kinase Inhibitors in Patients with Chronic Lymphocytic Leukemia: A Patient Survey

Introduction

While Bruton's tyrosine kinase inhibitors (BTKi) have significantly prolonged survival for patients (pts) with chronic lymphocytic leukemia (CLL), continuous administration can increase the burden of physical, emotional, and financial toxicity. Little is known about the feasibility of time-limited administration of BTKi for CLL pts or clinical outcomes of discontinuation (DC) of BTKi for reasons other than CLL progression. We aimed to analyze and report the outcomes of this group via a pt survey.

Methods

Utilizing the email distribution list from the CLL Society (pt advocacy group), we solicited volunteers with CLL who self-reported DC of a BTKi for reasons other than CLL progression to fill out a de-identified web-based survey. Pts reported the length of time on BTKi, the clinical circumstances surrounding BTKi DC, and the clinical outcomes following BTKi DC. Perceived quality of life (QOL) was assessed on a 5-point scale with 1=Poor QOL and 5=Very Good QOL. Differences in perceived QOL were evaluated using Wilcoxon signed Rank Tests. Statistical significance was set at p<0.05.

Results

Of the 170 pts included in the analysis, 57% received their first BTKi in the frontline setting. First BTKi received included ibrutinib (79%), acalabrutinib (17%), and zanubrutinib (4%). BTKi was DC in <6 months (mos), 6-12 mos, 1-2 years (yrs), 2-4 yrs, and >4 yrs in 19%, 18%, 21%, 28%, and 14% of pts, respectively. While the most common reason for DC BTKi was toxicity (62%), 14% and 8% reported DC because their CLL was in remission or a personal choice, respectively. The most common adverse events (AE) that led to BTKi DC were atrial fibrillation (20%) arthralgias (17%), and bleeding/bruising (11%). Of those who DC due to AE, 67% reported that the AE resolved quickly, and an additional 24% reported that the AE at least partially improved after DC. When asked how they would feel about stopping the BTKi, the majority of pts were relieved that they may eliminate AE (45%), could focus less on their CLL (11%), and would no longer have to pay for the medicine (7%), while 29% experienced anxiety. A statistically significant increase in perceived QOL was observed from prior versus post BTKi DC. Prior to BTKi DC, 31% indicated a poor/somewhat poor QOL, with only 5% reporting the same after DC. Those who reported moderately/very good QOL increased from 52% pre-DC to 78% post-DC.

Following BTKi DC, 45% (76/170) reported that their CLL had not come back. Of these, 42%, 32%, and 27%, have been off BTKi treatment for <1 yr, 1-2 yrs, and >2 yrs, respectively. Of pts who reported that they experienced evidence of CLL progression by detection of increasing white blood cell counts or size of lymph nodes (n=80), 46% reported that these events did not happen for ≥1 yr after BTKi DC. Those that were on a BTKi for ≥2 yrs before DC had more time without CLL relapse. Of pts that received BTKi for ≥2 yrs and reported CLL relapse (n=25), 44% were off therapy for ≥2 yrs before disease relapse and only 8% relapsed within 3 mos. Of pts that received BTKi for <2 yrs and reported CLL relapse (n=55), 11% were off therapy for ≥2 yrs before disease relapse and 31% relapsed within 3 mos.

While 36% reported starting a new treatment for CLL within 6 mos of BTKi DC, a larger number of pts (50%) did not begin another CLL treatment for ≥1 yr after DC. Those that were on a BTKi for ≥2 yrs before DC had more time before starting a new CLL treatment. Of pts that received BTKi for ≥2 yrs and then received subsequent CLL treatment (n=20), 60% were off therapy for ≥2 yrs without receiving subsequent CLL treatment, while only 15% received subsequent CLL treatment within 3 mos. Of pts that received BTKi for <2 yrs and then received subsequent CLL treatment (n=58), 14% were off therapy for ≥2 yrs without receiving subsequent CLL treatment, while 22% received subsequent CLL treatment within 3 mos.

Conclusion

In a survey of CLL pts who DC BTKi for reasons other than CLL progression, their perceived QOL significantly improved after BTKi DC and 45% reported no CLL progression with the majority >1 yr out from DC. Those that were on a BTKi for ≥2 yrs before DC appear to have longer periods of time without the CLL returning and/or needing to start a new CLL treatment. While limited by the constraints of a survey, these data suggest that a prospective study of utilization of time-limited BTKi therapy for CLL is warranted to better understand the clinical feasibility and impact of this treatment course.

Stephens:AstraZeneca, Beigene, Novartis: Research Funding; Abbvie, AstraZeneca, Beigene, BMS, Celegene, Eli Lilly, Genentech, Janssen, Pharmacyclics: Consultancy. Stewart:Eli Lilly, Johnson & Johnson, Kenvue, Novartis, Pacific Biosciences of California, Dr. Reddy's Laboratories Limited.: Current equity holder in publicly-traded company. Coombs:Bluebird Bio, Geron, Pfizer: Current equity holder in publicly-traded company; AbbVie, AstraZeneca, Beigene, Genentech, Lilly: Speakers Bureau; AbbVie, AstraZeneca, CarnaBio, LOXO/Lilly: Research Funding; AbbVie, Allogene, AstraZeneca, Beigene, Genentech, Janssen, LOXO/Lilly, MEI Pharma, Mingsight, Octapharma, TG Therapeutics, have served on speaker's bureaus for AbbVie, AstraZeneca, Beigene, Genentech, Lilly: Consultancy, Honoraria. Danilov:Cyclacel: Research Funding; Bristol Meyers Squibb: Consultancy, Research Funding; Genentech: Consultancy; BeiGene: Consultancy; Incyte: Consultancy; MorphoSys: Consultancy; Nurix: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; ADCT: Consultancy; MEI Pharma: Research Funding; Takeda: Research Funding; Janssen: Consultancy; AbbVie: Consultancy; AstraZeneca: Consultancy, Research Funding; GenMab: Consultancy, Research Funding. Hill:BMS: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Consultancy, Honoraria, Research Funding. Shadman:Bristol Myers Squibb: Consultancy; Morphosys/Incyte: Consultancy, Research Funding; Kite Pharma: Consultancy; Eli Lilly: Consultancy; Fate therapeutics: Consultancy; Nurix: Consultancy; Merck: Consultancy; Mustang Bio: Research Funding; Vincerx: Research Funding; Koi Biotherapeutics: Current holder of stock options in a privately-held company; Bristol Myers Squibb (spouse): Current Employment; BeiGene: Consultancy, Research Funding; Janssen: Consultancy; Genmab: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding. Gerrie:AstraZeneca, Beigene, Janssen, Lilly: Research Funding; AstraZeneca, Beigene, Janssen, Lily, Celgene: Honoraria. Jensen:Abbvie: Consultancy, Research Funding. Hoffmann:Bristol Myers Squibb: Other: Travel; Genentech: Consultancy, Research Funding; ADC, Janssen, Pharmacyclics, BeiGene, Novartis, Astra-Zeneca, Abbvie, Kite, TG: Consultancy, Honoraria. Winter:BeiGene: Consultancy; AstraZeneca: Consultancy; BTG Pharmaceuticals: Consultancy; ADC Therapeutics: Consultancy. Ermann:AstraZeneca: Speakers Bureau; Beigene, ADC therapeutics: Consultancy. Barr:Genentech: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Bristol Myers Squibb: Consultancy; AbbVie: Consultancy; AstraZeneca: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Seagen: Consultancy; Merck: Consultancy; MEI Pharma: Consultancy; Gilead: Consultancy; Pharmacyclics LLC, an AbbVie company: Consultancy; MorphoSys: Consultancy. O'Brien:Nurix Therapeautics, Inc.: Research Funding; Mustang Bio: Research Funding; Merck: Consultancy; Loxo Oncology, Inc: Consultancy; Kite: Research Funding; Johnson and Johnson: Consultancy; Janssen Oncology: Consultancy; GlaxoSmithKline: Consultancy; Gilead: Research Funding; Eli Lilly and Company: Consultancy; Caribou Biosciences, Inc.: Research Funding; Bristol Myers Squibb: Consultancy; Beigene, Ltd: Consultancy; Autolus: Consultancy; AstraZeneca: Consultancy, Research Funding; Alliance: Research Funding; Abbvie: Consultancy; Pfizer: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Regeneron Pharmaceuticals, Inc.: Research Funding; TG Therapeutics: Consultancy, Research Funding; Vaniam Group LLC: Consultancy. Koffman:Abbvie, AstraZeneca, BMEA, BMS, Invyvid, JNJ, Merck, Nurix, Pfizer, Vincerix: Current equity holder in publicly-traded company; Abbvie, Beigene, BMEA, BMS, JNJ, Lilly: Consultancy; AstraZeneca, BMS, GenMab, Invivyd,: Honoraria. Byrd:Abbvie, AstraZeneca, and Syndax: Consultancy; Vincerx Pharma, Eilean Therapeutics, and Kurome Therapeutics: Current equity holder in private company.

Utilization of BTK inhibitors as a time-limited therapy (currently recommended as continuous therapy).