Long-Term Outcome of Treatment-Naïve and Relapsed/Refractory Patients with CLL and TP53 Aberrations Treated with Ibrutinib, with or without Rituximab
Authors: Sivina Mariela , Kim Ekaterina , Wierda William G. , Ferrajoli Alessandra , Jain Nitin , Thompson Philip A. , Estrov Zeev E. , Kantarjian Hagop , Keating Michael J. , Burger Jan A. 
Published: November 2021

Abstract
Introduction: Ibrutinib has remarkably improved outcomes for patients with chronic lymphocytic leukemia (CLL), including those with TP53 aberrations (17p deletion and/or mutated TP53). However, patients harboring TP53 aberrations treated with ibrutinib have inferior outcomes compared to CLL patients without TP53 alterations. For example, in the RESONATE trial (Ibr arm), the median progression free survival (PFS) of patients with relapsed/refractory (R/R) CLL and carrying TP53 alterations was 40.7 months, but the median PFS was not reached in patients without TP53 alterations (Byrd, Blood 2019). Nevertheless, treatment-naive patients with TP53 aberrations treated with ibrutinib had a 6-year PFS of 61%, indicating a long-term PFS benefit in the frontline setting (Ahn, NEJM 2020). Here, we report the long-term outcomes for patients with CLL and TP53 aberrations in first-line and relapsed settings, as part of a randomized phase 2 study that compared ibrutinib (Ibr) monotherapy versus ibrutinib plus rituximab (Ibr + R) (NCT02007044).
Patients: This analysis includes a cohort of 78 pts with CLL and TP53 aberrations. 41 pts received Ibr alone and 37 pts received Ibr + R. 27 were treatment-naïve and 51 had R/R CLL, with a median of 2 prior therapies (range, 1 - 10). Responses were evaluated according to 2008 iwCLL criteria, with the exception that lymphocytosis was not the sole criterion for disease progression. PFS was defined as the time from start of treatment to progression, death or last follow-up. Survival curves and median time to response were calculated using the method of Kaplan and Meier, and univariate comparisons were made with the log-rank test. The cut-off date for analysis was July 12, 2021.
Results: The median age was 65 years (range, 45 - 80 years), 65% were male, 64% had unmutated IGHV , and 35% advanced stage disease (Rai stage III-IV). After a median follow-up of 69 months (range, 5 - 89 months), 21 patients (27%) remain on study. The estimated median PFS for the entire cohort was 72 months and median not reached for OS. The estimated 6-year PFS and OS were 47% and 72%, respectively (Figure A-B). There were no significant differences in PFS and OS for pts receiving Ibr alone versus combined Ibr + R (p=0.7833). The 6-year PFS for treatment-naïve (n=27) was 59.3% and 41.2% for R/R pts (n=51); OS was 79.5% and 67.4%, respectively (Figure C).
77 pts were evaluable for response assessment (40 pts from Ibr and 37 pts from Ibr +R arm). A complete remission (CR) was achieved in 25 pts (32.5%), partial remissions (PR) were achieved in 50 pts (64.9%), and 2 patients had stable disease (SD), accounting for an overall response rate (ORR) of 97.4%. Among the 40 pts receiving Ibr alone, 11 pts (27.5%) achieved CR (all with minimal residual disease [MRD], 10 -4 sensitivity), 27 pts (67.5%) achieved PR, and 2 pts had stable disease (SD) accounting for an ORR of 95.0%. Among the 37 pts treated with Ibr + R, 14 patients (37.8%) achieved a CR (three with undetectable MRD), which was maintained for the time the pts were on study, and 23 patients (62.2%) patients achieved a PR, accounting for an ORR of 100%. The median time to achieve CR in pts treated with Ibr alone was 22 months (range, 11 - 47 months), and for pts treated with Ibr + R it was 12 months (range, 4 - 52 months). PFS was significantly different when pts were segregated based on depth of best responses (CR vs PR), demonstrating that achievement of CR in these high-risk pts was associated with longer PFS (Figure D).
Among the 57 pts (73%) that came off study (30 pts from Ibr and 27 pts from Ibr + R arm), side effects and/or toxicities (n=14, 18%) and disease progression (n=14, 18%) were the most common reasons for treatment discontinuation. Three cases with progressive CLL were reported with histologically confirmed Richter's transformation. Other reasons for treatment discontinuation included a change to an alternative therapy as per physician's choice in 10 pts (13%), and death which occurred in 6 pts (8%).
Conclusions: In this long-term follow-up, patients with CLL and TP53 aberrations treated with ibrutinib had an estimated 6-year PFS and OS of 47% and 72%, respectively. First-line treatment with ibrutinib induced more durable remissions with a 6-year PFS of 59% compared to R/R pts with a PFS of 41%. Quality of remission was important, longer PFS was associated with achieving CR in this high-risk population.

Figure 1 Figure 1.

Disclosures
Wierda: Genentech: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Loxo Oncology, Inc.: Research Funding; Acerta Pharma Inc.: Research Funding; Karyopharm: Research Funding; Juno Therapeutics: Research Funding; Janssen: Research Funding; Xencor: Research Funding; Gilead Sciences: Research Funding; KITE Pharma: Research Funding; Sunesis: Research Funding; Miragen: Research Funding; Oncternal Therapeutics, Inc.: Research Funding; Cyclacel: Research Funding; GSK/Novartis: Research Funding; Genzyme Corporation: Consultancy; AbbVie: Research Funding; AstraZeneca: Research Funding. Ferrajoli: Janssen: Other: Advisory Board ; BeiGene: Other: Advisory Board, Research Funding; AstraZeneca: Other: Advisory Board, Research Funding. Jain: Genentech: Honoraria, Research Funding; Aprea Therapeutics: Research Funding; Cellectis: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Adaptive Biotechnologies: Honoraria, Research Funding; Janssen: Honoraria; Beigene: Honoraria; Servier: Honoraria, Research Funding; TG Therapeutics: Honoraria; Precision Biosciences: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Incyte: Research Funding; Fate Therapeutics: Research Funding; Pfizer: Research Funding; AbbVie: Honoraria, Research Funding; Pharmacyclics: Research Funding. Thompson: Adaptive Biotechnologies: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding, Expert Testimony; Genentech: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Amgen: Other: Institution: Honoraria, Research Grant/Funding; Pharmacyclics: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Janssen: Consultancy, Honoraria; AbbVie: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Gilead: Other: Institution: Advisory/Consultancy, Honoraria. Kantarjian: Immunogen: Research Funding; Jazz: Research Funding; Taiho Pharmaceutical Canada: Honoraria; Amgen: Honoraria, Research Funding; Ipsen Pharmaceuticals: Honoraria; Astra Zeneca: Honoraria; Astellas Health: Honoraria; Ascentage: Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Aptitude Health: Honoraria; BMS: Research Funding; Daiichi-Sankyo: Research Funding; Pfizer: Honoraria, Research Funding; Precision Biosciences: Honoraria; NOVA Research: Honoraria; KAHR Medical Ltd: Honoraria. Burger: Gilead: Consultancy, Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau; AstraZeneca: Consultancy; Pharmacyclics LLC: Consultancy, Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau; Beigene: Research Funding, Speakers Bureau; TG Therapeutics: Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel/Accommodations/Expenses, Speakers Bureau; Janssen: Consultancy, Other: Travel/Accommodations/Expenses, Speakers Bureau.