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Ibrutinib-based therapies are costly and require continuous administration. We hypothesized combining BTK inhibition with anti-CD20 monoclonal antibodies would yield deep remissions allowing discontinuation. We enrolled 32 therapy-naïve CLL patients to receive ibrutinib plus obinutuzumab, followed by single-agent ibrutinib. Patients could discontinue ibrutinib after 36 months with sustained complete response (CR). We evaluated treatment safety, efficacy, and outcomes after ibrutinib discontinuation. The overall response rate was 100%, 28% achieved a CR, and 12.5% achieved bone marrow undetectable minimal residual disease. At a three-year median follow-up, 91% remain in remission with 100% overall survival. Five patients in sustained CR stopped ibrutinib and have not progressed. Eight non-CR patients discontinued for other reasons, with only two progressing. The treatment was safe, with a lower IRR rate. All patients responded to treatment with longer time-to-progression after discontinuation of ibrutinib. Our data support the evaluation of ibrutinib discontinuation strategies in more extensive clinical trials (https://Clinicaltrials.gov Identifier https://clinicaltrials.gov/ct2/show/NCT02315768).

Background: Chimeric Antigen Receptor (CAR) T-cell therapy has changed the treatment landscape for patients with Non-Hodgkin Lymphoma (NHL). Despite the excellent responses in relapsed or refractory (R/R) aggressive NHL (aNHL), the outcome of patients (pts) that fail CAR T-cell therapy remains poor, and there is not a clear path for management of their disease. Methods: We conducted a retrospective analysis of aNHL pts treated with axicabtagene ciloleucel (axi-cel) at the Mayo Clinic campuses in Arizona and Florida between June 2018 and August 2020. We evaluated the predisposing factors, management, toxicities, and response after CAR T-cell therapy failure. Statistical calculations using parametric tests were performed, and survival curves were estimated using the Kaplan-Meier method and compared statistically using the log-rank test and Pearson's correlation. Results: Thirty-four pts with aNHL received axi-cel. The median age was 53 years [IQR 42-63], and 62% were male. All pts received inpatient axi-cel infusions and the median length of hospital stay was 14 days (IQR: 11-17). Cytokine Release Syndrome (CRS) was observed in 91% of pts (3% grade ≥3), while Immune Effector Cell Associated Neurotoxicity Syndrome (ICANS) was observed in 41% (24% grade ≥3). At day 30 response assessment, 16 pts (47%) had complete responses (CR), 9 (26%) had a partial response (PR), 4 (12%) had stable disease (SD), 4 (12%) showed progression with primary refractory disease (PD) and 1 (3%) died before assessment due to grade 5 ICANS (Table 1). After a median follow-up of 178 days, we observed PD in 12 (35%) pts. The median time-to-progression was 72 days (IQR 58-93) and most of the pts (83%) progressed during the first 3 months. None of the patients with more than 5 months of sustained response developed progression of disease. The likelihood of progression during the first 6 months after axi-cel infusion was 19%, 57%, 50% for pts that initially achieved a CR, PR, SD, respectively. Expression of CD19 was observed in 66% (4/6) of pts with available biopsies after axi-cel suggesting a failure mechanism other than antigen escape. The mortality rate of the R/R aNHL group was 58% with a median survival time of 83 days (IQR: 50-109). There was no association between age, stage, number of previous therapies, time from previous therapy to axi-cel infusion, time from apheresis to infusion, use of tocilizumab, or steroids with progression of disease. Of note, no correlation between CRS or ICANS with progression of disease was found (2-way ANOVA test F (1, 4) = 3.802, p=0.1230). Maintaining a response to axi-cel treatment (CR, PR, or SD) for ≥ 3 months was a strong predictor of durable response with an HR of 0.05 (p= Eleven R/R pts received subsequent therapies with a median time to retreatment of 76 days. Those treatments included: Radiotherapy (n=7), pembrolizumab (n=3), polatuzumab-rituximab with (n=3) and without (n=1) bendamustine, obinutuzumab with (n=1) or without (n=1) lenalidomide, Hyper-CVAD (n=2), R-GemOx (n=1), rituximab with lenalidomide (n=1) and intrathecal methotrexate (n=1). Only 2 (17%) patients have responded to salvage therapy achieving PR (one patient treated with radiotherapy and the other with rituximab-lenalidomide after two other salvage therapies). Conclusion: Our experience demonstrates the majority of aNHL patients respond to axi-cel. If patients maintain their response for more than 3 months, the likelihood of progression is very low - 15%. Similar to what has been previously reported in the literature, our series showed that 35% of patients progressed after axi-cel, and subsequently have a poor prognosis with median survival after a relapse of only 83 days (IQR: 50-109). Therapy options following axi-cel were limited due to severe cytopenias, only 2 of 11 patients have responded to salvage therapy, suggesting that conventional treatments are probably not effective/safe in this high-risk group of patients. Interestingly, the majority of R/R pts with available biopsies showed persistent CD19 expression suggesting that CAR T-cell exhaustion, poor in vivo expansion, and inhibitory signals of the tumor microenvironment may contribute to resistance. Additional strategies for monitoring of axi-cel persistence and its immunophenotypic profile could be helpful for prognosis and management of CAR T-cell pts receiving axi-cel. Disclosures Kharfan-Dabaja: Daiichi Sankyo: Consultancy; Pharmacyclics: Consultancy. Castro:Fate Therapeutics: Research Funding; Kite Pharma: Research Funding; Pharmacyclics: Research Funding.

Single oral targeted therapies have emerged as a standard of care in chronic lymphocytic leukemia (CLL). However, accessibility, side effects, and financial burden associated with long term administration limit their clinical use. Mainly, it is unclear in what clinical situation discontinuation of oral therapy can be recommended. The combination of type II anti-CD20 antibody obinutuzumab-Gazyva® with ibrutinib (GI) has shown a significant progression-free survival benefit in patients (pts) with CLL, including those with high-risk genomic aberrations. We conducted a phase 1b/2, single-arm, open-label trial to evaluate the safety and efficacy of GI as first-line treatment in 32 CLL pts. We report the outcome in pts that discontinued ibrutinib (either after 3 years of sustained complete response (CR) as stipulated in the clinical protocol, or due to other reasons). CLL pts enrolled in this protocol were ≥65 years old, or unfit/unwilling to receive chemotherapy. Pts received GI for six cycles, followed by daily single-agent ibrutinib. The protocol was designed to ensure that pts with a sustained CR after 36 months were allowed to discontinue ibrutinib. The median age was 66 years (IQR 59-73), and 6% of the evaluated pts had 17p deletion. All pts were able to complete the six planned cycles of obinutuzumab. The combination regimen was well-tolerated, and the most common adverse events (>5% CTCAE grade 3-4) were neutropenia, thrombocytopenia, and hyperglycemia. The rate and severity of infusion-related reactions (IRR) were much lower than expected (Grade≥ 3, 3%), and pts without IRR had lower serum levels of cytokines/chemokines CCL3 (P=0.0460), IFN-γ (P=0.0457), and TNF-α (P=0.0032) after infusion. The overall response rate was 100%, with nine pts (28%) achieving a CR, and four pts (12.5%) with undetectable minimal residual disease (uMRD) in the bone marrow, defined as Sixteen pts have completed a long-term follow-up of 36 months. Six pts showed CR, with three of them achieving uMRD in the bone marrow. Ten of these pts were in PR, and only one had disease progression and started treatment for symptomatic stage I disease with obinutuzumab plus venetoclax. In total, thirteen pts (41%) have stopped ibrutinib, with a median time on treatment prior to discontinuation of 35 months. Five (16%) of these pts had CRs and discontinued after 36 months. Eight additional pts (25%) had PRs and discontinued ibrutinib without being eligible: three pts discontinued prior to 36 months due to toxicities, and five pts discontinued after 36 months (3 due to side effects, and 2 due to financially driven decision). One patient eligible to discontinue ibrutinib, decided to remain on treatment despite sustained CR. After a median follow up time following ibrutinib discontinuation of 8 months (IQR 3.5-17), only two out of 13 pts have progressed (10 and 17 months after Ibrutinib discontinuation). None of the pts that stopped ibrutinib after achieving a CR have shown signs of disease progression. Of note, the pharmaceutical sponsor provided ibrutinib for the first 36 months, after which pts or their insurer became financially responsible. This particular scenario could bias the discontinuation pattern compared to a real world experience. It also provided us with a perspective about diverse factors affecting the treatment choices of pts. In summary, the obinutuzumab plus ibrutinib combination therapy was well-tolerated, with a much lower IRR rate. Efficacy compares favorably with historical controls with all pts responding to therapy, no deaths associated with treatment or disease progression, and a longer than expected time-to-progression after discontinuation of ibrutinib. The rate of ibrutinib discontinuation was higher than reported in the literature, most likely influenced by the protocol design and financial decisions driven by the switch from sponsor-provided ibrutinib to insurance or self-paid medication. Our observations regarding safety, efficacy and lack of disease progression after ibrutinib discontinuation are encouraging, and warrant confirmation in long-term prospective studies. Clinicaltrials.gov Identifier NCT02315768. Funding: Pharmacyclics LLC. Disclosures Choi: AbbVie: Consultancy, Speakers Bureau. Amaya-Chanaga:AbbVie: Ended employment in the past 24 months, Other: Research performed while employed as an investigator of this study at UCSD.. Kipps:Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Castro:Kite Pharma: Research Funding; Pharmacyclics: Research Funding; Fate Therapeutics: Research Funding.