Use Of Ibrutinib Research Articles

The Use of Ibrutinib in Extranodal Marginal Zone Lymphoma of the Ocular Adnexa with Multifocal Disease that is Refractory to Rituximab

Tumors of the ocular adnexa been well documented. The most common ocular adnexal lymphoma is extranodalmarginal zone B-cell lymphoma (EMZL), with about a quarter of those occurring in the conjunctiva. We present acase with a patient suspected ocular EMZL, confirmed with biopsy. Positron emission tomography (PET) scan wasperformed to evaluate for distal lesions and the patient was found to have multiple hypermetabolic lesionsthroughout the body. Treatment with rituximab was initiated, and after four weekly treatments, subsequent PETscan showed that the original hypermetabolic lesions remained and new lesions appeared. Rituximab was stoppedand ibrutinib started. After eight months of ibrutinib treatment, PET scan showed that the original hypermetaboliclesions had disappeared. 19 months from initiation of treatment, a new hilar lesion was found. This progressedinto bilateral hilar and mediastinal lymphadenopathy, which was seen on PET scan performed 29 months intotreatment. These findings remained stable 35 months post-initiation of treatment. The use of ibrutinib in thispatient that initially presented with a lesion in the conjunctiva resulted in an initial resolution of the originalsystemic hypermetabolic regions on PET scan. While more studies are needed on ibrutinib in the treatment ofocular EMZL, physicians should be aware of the presentation of this disease and the range of treatment modalities.

Abstract A038: Epigenetic compound library screen of ovarian clear cell carcinoma cell line models identifies decreased cell viability following treatment with the Bruton tyrosine kinase inhibitor ibrutinib

Abstract Ovarian clear cell carcinoma (OCCC) is a difficult to treat histological subtype of ovarian cancer, demonstrating resistance to standard chemotherapy. New approaches are required in order to identify compounds with the potential to target this tumor. OCCC are characterized by mutations in ARID1A and/or ARID1B (AT-rich interactive domain-containing proteins) that encode for members of the mammalian SWI/SNF (SWItch/Sucrose Non-Fermentable) chromatin remodeling complex. We have used an epigenetic library consisting of 160 compounds that targets epigenetic readers, writers, erasers, and transcriptional modulators, to screen seven OCCC cell line models (RMG1, JHOC5, OVTOKO, OVMANA, OVISE, OV207 and TOV21G) and three non-OCCC ovarian cancer cell line models (A2780, COV434 and OVCAR8). Cell lines were seeded in triplicate into 96-well plates and treated with all 160 compounds at both 5 µM and 0.5 µM, as well as with a DMSO vehicle control, for 72 hours. Following treatment, cell viability was determined using a MTS assay and each data point normalized to the DMSO control. Based on the results of viability assays, drugs were sought that preferentially targeted OCCC relative to non-OCCC cell lines. Drugs that increased cell proliferation in two or more of the OCCC lines were removed from the analysis, as were drugs that did not impact upon viability. Drug 152, ibrutinib, inhibited cell viability between 53 to 78% in 6 of the 7 OCCC cell lines at 5 µM, with an average inhibition of 64%. In non-OCCC cell lines, the average cell viability after treatment with 5 µM ibrutinib was 91% (range, 84 – 103%). Ibrutinib is a small molecule inhibitor of Bruton tyrosine kinase (BTK) that has been approved by the FDA for treatment of a number of hematological malignancies including mantle cell lymphoma, small lymphocytic lymphoma and chronic lymphocytic leukemia. BTK functions in B-cell receptor signaling, regulating B cell proliferation and survival. Ibrutinib works by irreversibly blocking the kinase activity of BTK. Interestingly, ibrutinib binding sites are also present in other tyrosine kinases, including EGFR, raising the possibility of off-target effects that can function to decrease tumor cell viability. In addition to hematological malignancies, ibrutinib is being investigated in clinical trials for the potential to impact on solid tumors including non-small cell lung cancer, certain oesophagogastric carcinoma, advanced carcinoid and pancreatic neuroendocrine tumors, squamous cell carcinoma of the head and neck, renal cell carcinoma and glioblastoma, including in some cases in combination with other therapeutic drugs including cisplatin, temozolomide and nivolumab. Following organoid drug testing, off-label use of ibrutinib in a patient with low-grade serous ovarian cancer has recently shown promising results. Research is on-going to determine the effectiveness of ibrutinib in pre-clinical models of OCCC, including analyses of the effectiveness of ibrutinib in ARID1A and ARID1B wild-type and mutant CRISPR-engineered isogenic cell line panels of OCCC. Citation Format: Yue Ma, Kristie Ann Dickson, Natisha Field, Tao Xie, Nham Tran, Deborah Joy Marsh. Epigenetic compound library screen of ovarian clear cell carcinoma cell line models identifies decreased cell viability following treatment with the Bruton tyrosine kinase inhibitor ibrutinib [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A038.

An effective treatment and suspicious adverse reaction to Ibrutinib in a patient diagnosed with splenic B-cell lymphoma/leukaemia with prominent nucleoli: A first case report

Rationale: Splenic B-cell lymphoma/leukemia with prominent nucleoli (SBLPN) is a new classification, which is so rare that it lacks clinical data. Patient concerns: An increased proportion of prolymphocytes (84%) in the bone marrow smear. Whole exon sequence analysis revealed a TP53 mutation. Diagnoses: Combining the clinical features with laboratory test results led to a diagnosis of SBLPN which was made according to the 5th edition of the WHO classification of hematolymphoid tumors, although the patient was diagnosed with B-PLL when guided by the 4th edition of the WHO classification. Interventions: The use of Ibrutinib as an effective treatment. Outcomes: The patient was in complete remission after 5 months of Ibrutinib and then died of sudden aortic dissection. Lessons: Ibrutinib was an effective regimen for SBLPN. Aortic dissection might be considered as a suspicious adverse reaction to Ibrutinib.

Recent Patterns of Care with BTK Inhibitors and Distribution of Social Determinants of Health Among Patients with CLL/SLL in the US Community Setting

BACKGROUND: The treatment landscape for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) has shifted with the introduction of second-generation Bruton tyrosine kinase (BTK) inhibitors. Few real-world studies, however, have examined sequencing patterns among BTK inhibitors for CLL/SLL and the patient characteristics across different sequences, including social determinants of health (SDOH). The aim of this study is to examine the characteristics, treatment patterns, and SDOH among patients with CLL/SLL who received BTK inhibitors in a large network of community oncology practices. METHODS: This was a retrospective study of adult patients diagnosed with CLL/SLL who were prescribed a BTK inhibitor between 1/1/2020-4/30/2023 in The US Oncology Network. Study data were captured from structured fields in the iKnowMed electronic health record (EHR), with linkage to external sources to evaluate patients' Area Deprivation Index (ADI) scores and rural/urban status. ADI scores were determined by mapping patients' home addresses to a census block group (CBG), which was then linked to the ADI. ADI rankings are based on CBG and determined by the domains of income, education, employment, and housing quality, where high scores indicate increased disadvantage. Low socioeconomic status (SES) was defined as the top 20% of ADI scores on a national and state level (cut-off based on literature review). Rural/urban status was based on the RUCA codes published by the US Department of Agriculture. Insurance coverage was reported “as is” in the claims system with Medicaid an indicator of low SES. Results were assessed by treatment sequence, and SDOH measures results were reported as counts, frequency, and 95% confidence intervals (CI). Chi Square p-values were reported for selected SDOH measures and are shown in text. Data are presented for treatment subgroups with at least 30 eligible patients. RESULTS: In total, 2,082 patients were included in the analysis (median age 73 years; 61.9% male; 73.5% white; 35.0% Rai stage 0-I; median follow-up 14.1 months). The highest proportion of patients received acalabrutinib or ibrutinib without an observed subsequent BTK inhibitor (n=1,159 and n=628, respectively). Patient characteristics by the top 6 treatment sequences are provided in Table 1. Demographic and clinical characteristics across the treatment sequences were similar, including sex, race, and ethnicity distributions, along with Rai stage and ECOG performance status at baseline. Across the subgroups, 8.7% (n=182) were observed to receive a subsequent BTK inhibitor. Among patients who received a BTK inhibitor in 2020 (n=597), 62.3% (n=372) received ibrutinib and a single patient received zanubrutinib. Among the 206 patients who received a BTK inhibitor in 2023, 6.8% (n=14) and 28.6% (n=59) received ibrutinib and zanubrutinib, respectively. In total, 137 patients (6.6%; 95% CI 5.6-7.7) were classified as living in rural locations. Low SES status based on state and national indicators was observed among 361 (17.3%; 95% CI 15.7-19.0) and 125 (6.0%; 95% CI 5.0-7.1) patients, respectively, and was also similar across the subgroups. The highest proportion of patients had Medicare insurance coverage (42.1%; n=877; 95% CI 40-44.3), followed by managed Medicare (24.4%; n=508; 95% CI 22.6-26.3). A statistical difference was found between the treatment regimens for rural/urban ( P<0.01), but not for state ADI ( P=0.52), national ADI ( P=0.36), or Medicaid insurance coverage vs. all others ( P=0.18). The actual values for each regimen are in the Table 1. CONCLUSIONS: The results of this study provide insight into the shifting treatment landscape of BTK inhibitor use among patients with CLL/SLL. During the observation period, the use of ibrutinib decreased while acalabrutinib and zanubrutinib increased. When evaluating measures of SDOH, similarities across the treatment sequence subgroups suggest that patients' SES and Medicaid do not influence prescribing patterns, but rural/urban status show differences. Further real-world research and longitudinal follow-up are needed to examine the impact of SDOH on treatment choice, treatment switching, reasons for switching, and outcomes among users of BTK inhibitors. Additionally, a better understanding of the specific treatment regimen(s) and reasons driving rural/urban differences is needed.

Ibrutinib Added to Standard Conditioning and As Consolidation Therapy Following Autologous Hematopoietic Stem Cell Transplantation (AutoHCT) for Relapsed/Refractory Activated-B-Cell Subtype Diffuse Large B-Cell Lymphoma (ABC-DLBCL): Primary Analysis of the US Intergroup Double-Blind Randomized Phase III Study Alliance A051301/BMT-CTN 1201

Introduction: AutoHCT is an effective therapy for patients (pts) with DLBCL who are refractory or relapse following first-line chemotherapy, but long term outcomes remain suboptimal. The BTK inhibitor ibrutinib has shown promising activity in pts with ABC-DLBCL (Wilson et al, Nat Med 2015). In 2016 we launched a randomized phase III clinical trial to evaluate the addition of ibrutinib to AutoHCT as part of conditioning and as consolidation therapy for pts with relapsed/refractory ABC-DLBCL. Patients and Methods: Following assessment of open-label treatment in a safety cohort of 6 pts, we randomly assigned pts with chemotherapy-sensitive persistent or relapsed ABC-DLBCL to receive ibrutinib 560 mg [Arm A] or placebo [Arm B] concurrently with conditioning on days -6 to -1 of AutoHCT (Cycle 1). Following count recovery and resolution of acute toxicities, pts continued ibrutinib 560 mg in Arm A or placebo in Arm B for 12 additional 28-day cycles. Crossover to Arm A using single agent ibrutinib was allowed for pts progressing on Arm B. Central pathology review was performed for disease confirmation and subtype assignment. Initially, ABC subtype assignment was performed using the Nanostring Lymphoma Subtyping Test (LST) but the study was amended to use the IHC-based Hans classifier for non-GCB on 8/15/19. Other key eligibility criteria included receipt of no more than 3 prior regimens, no active CNS involvement, no need for long-term anticoagulation, and no prior progression on Ibrutinib. Pts were stratified by time to relapse (<=12 mos vs >12 mos), type of conditioning (BEAM or CBV) and prior ibrutinib use. The original design required 296 patients with 82% power to detect a difference in 2-year progression-free survival (PFS) rates of 67% vs. 50% with a two-sided alpha of 0.05. A revised statistical design allowed an interim futility analysis to be conducted after 40 pts were enrolled and followed for 2 years. Even though the study met criteria to continue accrual to a target of 160 pts, we decided to close it early due to declining accrual on 12/20/2022. We hereby present the primary analysis of the evaluable patients enrolled (data as of 07/17/2023). Results: Between 2/6/17 and 8/24/18, we screened 255 pts but enrolled only 34 (13%) largely due to long assay turnaround times and performance characteristics with the LST. Following the switch to the IHC-based Hans classifier (after 8/15/19), 60 out of 110 pts screened were enrolled (54%) in line with our a priori expectation. In total, 45 pts were randomized to Arm A vs. 43 to Arm B, with 39 and 38, respectively, being evaluable for the primary endpoint at this time. Median age was 61 years (range 20-75 years), median number of prior lines of therapy was 2, 46% of the pts were female, 21% were refractory or had early relapse, 94% were planned to receive BEAM conditioning. Overall, 87% of pts in Arm A and 88% in Arm B underwent conditioning while 70% and 67% respectively, started maintenance therapy. The median number of cycles received was 6 in Arm A vs. 5 in Arm B. The primary endpoint of 2-year PFS was 57.6% (95% CI: 42.1%, 78.8%) in Arm A vs. 40.8% (95% CI: 26.5, 62.8%) in Arm B (HR=0.54; 95% CI: 0.26, 1.10; log-rank p = 0.087). Median PFS was 26.5 months (95% CI: 10.2, not reached [NR]) in Arm A vs. 8.1 months (95% CI: 5.4, NR) in Arm B. Only one pt crossed over to Arm A after progression on Arm B. The most common grade 3-4 AEs in each of the arms were: neutropenia (A: 14%, B: 14%), febrile neutropenia (A: 11%, B: 9%), and thrombocytopenia (A: 11%, B: 7%). Rates of any grade atrial fibrillation were similar between arms (12.8% in Arm A vs. 10.5% in Arm B); one patient had grade 3 and one patient had grade 4 atrial fibrillation, both in Arm B. Six pts had reported grade 5 events (Arm A: 2 sepsis, 1 COVID-19, 1 respiratory failure and 1 disease progression and Arm B: 1 disease progression) but only one grade 5 event (sepsis, Arm A) was deemed probably related to treatment. Conclusions: Despite an early high rate of screen failures and declining accruals due to competition with CAR-T cell therapy, the primary analysis suggests that ibrutinib with and following AutoHCT in relapsed/refractory ABC-DLBCL is well-tolerated and may improve PFS in this high-risk patient population. This trial was supported by: U10CA180821, U10CA180882, U24CA196171; U10CA180820, UG1CA233234 (ECOG-ACRIN); U10CA180868 (NRG); U10CA180888 (SWOG) ClinicalTrials.gov Identifier: NCT02443077 https://acknowledgments.alliancefound.org

CTIM-38. NEUROTOXICITY AND MANAGEMENT OF PRIMARY AND SECONDARY CNS LYMPHOMA AFTER ADOPTIVE IMMUNOTHERAPY WITH CD19-DIRECTED CAR T-CELLS

Abstract BACKGROUND Chimeric antigen receptor (CAR) T-cells targeting CD19 have been established as a leading engineered T-cell therapy for systemic B-cell lymphomas; however, efficacy data for patients with CNS involvement are limited. Also, there are concerns about increased neurotoxicities (denoted by the term 'ICANS') when the target antigen is present within the CNS. METHODS We retrospectively report on CNS-specific toxicities, management, and CNS response of 45 consecutive CAR T-cell transfusions for patients with active CNS lymphoma at the Massachusetts General Hospital over a five-year period. RESULTS Our cohort includes 17 patients with primary CNS lymphoma (PCNSL; one patient with two CAR T-cell transfusions) and 27 patients with secondary CNS lymphoma (SCNSL). Mild ICANS (grade 1-2) was observed after 19/45 transfusions (42.2%) and severe ICANS (grade 3-4) after 7/45 transfusions (15.6%). No fatalities were directly attributed to ICANS. A larger increase in C-reactive protein (CRP) levels and higher rates of ICANS were detected in SCNSL. Early fever and baseline C-reactive protein levels were associated with ICANS occurrence. CNS response was seen in 31 cases (68.9%), including a complete response of CNS disease in 18 cases (40.0%) which lasted for a median of 11.4 ± 4.5 months. Similar response rates were seen in both patients with parenchymal and leptomeningeal involvement. Dexamethasone dose at time of lymphodepletion (but not at or after CAR T-cell transfusion) was associated with an increased risk for CNS progression (HR per mg/d: 1.16, p = 0.031). If bridging therapy was warranted, the use of ibrutinib translated into favourable CNS-progression free survival (5 versus 1 month, HR 0.28, CI 0.1-0.7; p = 0.010). CONCLUSION CAR T-cells exhibit promising anti-tumor effects and a favourable safety profile in CNS lymphoma. Further evaluation of the role of bridging regimens and corticosteroids is warranted to boost the success of such therapy.

Abstract 17859: Real World Cardiovascular Events With Next Generation Bruton's Tyrosine Kinase Inhibitors - An Updated Analysis

Introduction: Acalabrutinib and zanubrutinib are next generation Bruton’s tyrosine kinase inhibitors (BTKIs) associated with dramatic efficacy against B cell malignancies. In early trials, these BTKIs show less cardiac activity than ibrutinib. Yet, whether this is seen in longer term follow up is unknown. Methods: Leveraging the US Food and Drug Administration’s Adverse Events Reporting System (FAERS), we identified the relative incidence and predictive factors for atrial fibrillation (AF) after BTKI initiation from 2015-2022. Secondary outcomes were the reporting odds ratios (ROR) of major adverse cardiovascular adverse events (AEs), defined as AF, non-AF atrial arrhythmias, heart failure, conduction blocks, and ventricular arrythymias. In addition, using a registry cohort of 838 hematologic malignancy patients treated with ibrutinib or acalabrutinib from 2012-2020, we assessed the comparative incidence of new AF. Observed incident AF rates were compared with Framingham heart predicted rates, and absolute excess risks of AF were estimated. Multivariable logistic-regression models were used to identify factors associated with AF, other cardiac AEs, and mortality. Results: Among 21,435 events reported to FAERS during BTKI use, 3,453 were cardiovascular AEs. AF was the most reported AE (ROR 8.8, 95% CI, 8.3-9.4; Figure A ). The likelihood (ROR) of cardiac AE reporting in next generation BTKI treated patients was >3.0 ( P <0.05; Figure A ) for AF events. Furthermore, in acalabrutinib treated registry patients, 9.7% developed incident AF over a median follow up of 42 months. In those without prior ibrutinib use, the weighted average incidence was 281 per 10,000 person years compared to the Framingham predicted rate of 103 per 10,000 person years (RR 2.73, P <0.001; AER 178; Figure B ). Conclusions: These data suggest residual AF risk with next generation BTKIs.

Efficacy and safety outcomes of single-agent ibrutinib therapy in chronic lymphocytic leukemia and relapsed/refractory mantle-cell lymphoma

Objectives: We aimed to evaluate patients using ibrutinib for the treatment of chronic lymphocytic leukemia (CLL) and relapsed/refractory mantle-cell lymphoma (MCL), focusing on high-risk subgroups, predictors of efficacy, response levels, and safety profile. Methods: This retrospective cohort study included adult patients diagnosed with CLL and relapsed/refractory MCL who were started on ibrutinib as a single-agent between May 2015 and December 2021 in Bursa Uludag University, Department of Hematology. Results: Of the 45 patients (23 CLL, 22 MCL) started on ibrutinib, the median age was 65 (range: 48-86) years, and 66.7% were male. Del(17p) was present in 47.8% of CLL patients; there was no remarkable difference between del(17p) status and the rates of achieving CR. The median follow-up with ibrutinib treatment in CLL patients was 13.3 (range: 0.3-77.8) months. In univariate analysis, progression-free survival (PFS) and overall survival (OS) were associated with the advanced Eastern Cooperative Oncology Group (ECOG) score (p = 0.003 and p = 0.004, respectively), and > 2 lines treatment regimens before ibrutinib (p = 0.016 and p = 0.050, respectively). In multivariate analysis, the ECOG performance status remained significant for OS. The median use of ibrutinib for MCL patients was 6 (range: 1-48) months, and the proportion of patients who achieved CR was 27.3%. In the univariate analysis of MCL patients, the ECOG performance status for PFS and OS was statistically significant (p = 0.045 and p = 0.016, respectively). Patients' most common non-hematological adverse events were pneumonia and urinary tract infection. Conclusions: Our investigation of patient outcomes treated outside clinical trials confirms ibrutinib's sufficient efficacy and safety profile in CLL and relapsed/refractory MCL.

Real World Experience of Ibrutinib in an Ethnically Diverse Canadian Community Hospital

Chronic Lymphocytic Leukemia (CLL) is an indolent lymphoproliferative disorder commonly managed in community centers. Ibrutinib revolutionized the management of patients with CLL (2). Ibrutinib was initially considered an easy to administer, well tolerated oral medication with excellent efficacy. It was the first clinically available Bruton's Tyrosine Kinase (BTK) inhibitor widely used to treat CLL (3). Recently there have been concerns about cardiovascular toxicities leading to the use of alternative BTK inhibitors (5). Where alternative BTK inhibitors are available these toxicity concerns have led to a decline in the use of ibrutinib to treat CLL. The population served is ethnically diverse consisting of 52% South East Asian with a significant population of African origin. We suspected that the concerns regarding Ibrutinib toxicity were not seen in our patient population prompting a retrospective review of our experience. Ibrutinib therapy A total of 106 CLL patients treated with Ibrutinib were identified from which data was extracted. The mean age was 63.4 years. Patients with CLL treated with Ibrutinib from 2014 to 2021 were identified using OPIS and Meditech and data was extracted manually. Table 1 60% of patient received their initial drug funding through compassionate access, 2% via private insurance and the remaining 38% through the provincial health system. The majority of patients who received funding through compassionate access were eventually transitioned to the provincial health system for drug funding. Toxicity and outcomes Table 2 81% of treated patients never required a dose adjustment of Ibrutinib. The majority of dose reductions were of a temporary nature. We were unable to obtain accurate response data in our retrospective review. 82 of the 106 patients continue on ibrutinib therapy. It is presumed that these patients continue to benefit from therapy without disease progression although response data details were poorly recorded in the medical record. Conclusions There is a lack of data of community real world experience with Ibrutinib particularly in the Canadian setting. Community centers generally are lacking in information technology required to do retrospective audits. Our data shows that ibrutinib therapy for CLL is a reasonable and effective option with good tolerability in a patient population with high cardiovascular risk. The data is limited by the retrospective data collection. The efficacy of therapy is likely comparable to that of the published literature. These data suggest that the tolerability of Ibrutinib therapy seems better than that of the published literature (1) with a low incidence of atrial fibrillation, dose adjustments and low drug discontinuation rate. Of note Richter's transformation was also uncommon in our patient population. This is particularly of interest as our study did capture patients in the early days of ibrutinib therapy when there were concerns that Richter's transformation was more common than seen today. Many of the patients who were treated with ibrutinib would not have received the drug today because of cardiovascular concerns (4). At that time, it was the only available oral targeted agent for the treatment of chronic lymphocytic leukemia. Other agents such as Venetoclax, Acalabrutinib, Zanubrutinib and novel combinations were unavailable at that time or were not funded. These lack of options likely contribute to the persistence of Ibrutinib therapy in our patients. These data suggest that ibrutinib can be used in a high cardiovascular risk population with good efficacy and tolerability. 1.Alloucjery, M., Tomowiak, C., Lombard, T., & et al. (2021). Safety Profile of Ibrutinib: An Analysis of the WHO Pharmacovigilance Database. Front Pharmacology, 12:769315. 2.Byrd, J. C., Brown, J. R., O'Brien, S., & et al. (2014). Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. NEJM, 371(3):213-223. 3.Byrd, J. C., Furman, R. R., & Coutre, S. S. (2013). Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. NEJM, 369(1):32-42. 4.Lovell, A. R., Jammal, N., & Bose, P. (2022). Selecting the optimal BTK inhibitor therapy in CLL: rationale and practical considerations. Therapueltic Advances in Hematology, 13:1177/20406207221116577. 5.Salem, J. E., Manouchehri, A., & Bretagne, M. (2019). Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. J Am Coll Cardiol, 74:1667-1678.

Safety and Efficacy of Axatilimab at 3 Different Doses in Patients with Chronic Graft-Versus-Host Disease (AGAVE-201)

Background: Chronic graft-versus-host disease (cGVHD) is an immune-mediated complication of allogeneic hematopoietic cell transplant (alloHCT) that affects multiple organs with inflammatory and fibrotic pathology, leading to significant patient burden and mortality. Colony-stimulating factor 1 receptor (CSF-1R)-dependent monocytes and macrophages play a key role in cGVHD inflammation and fibrosis. Axatilimab (SNDX-6352) is an investigational, high-affinity anti-CSF-1R monoclonal antibody that targets monocytes and macrophages. We previously demonstrated the biological and clinical activity of axatilimab with organ-specific responses and symptom improvement in a phase 1/2 study (NCT03604692) in patients with cGVHD. Methods: This pivotal phase 2, open-label, randomized, multicenter study evaluated axatilimab at 3 different doses in alloHCT patients with recurrent or refractory cGVHD (AGAVE-201; NCT04710576). Eligible patients were randomized 1:1:1 to receive intravenous (IV) axatilimab at 0.3 mg/kg every 2 weeks (Q2W), 1 mg/kg Q2W, or 3 mg/kg every 4 weeks (Q4W). Randomization was stratified by severity of cGVHD and prior use of ibrutinib, ruxolitinib, or belumosudil. Concomitant use of corticosteroids, calcineurin inhibitors, or mammalian target of rapamycin inhibitors (sirolimus or everolimus) was allowed. Axatilimab treatment could be continued as long as there was clinical benefit as assessed by the investigator. The primary efficacy endpoint was overall response rate (ORR) in the first 6 cycles (24 weeks) as defined by the NIH 2014 consensus criteria; the efficacy boundary of the ORR is based on the lower bound of the 95% CI exceeding 30%. The key secondary endpoint was the proportion of patients reporting a clinically significant reduction of symptoms, as measured by the modified Lee Symptom Scale (mLSS) score with a threshold of ≥7 points. Safety endpoints included frequency and severity of treatment-related adverse events (TRAEs) and treatment-emergent adverse events (TEAEs). Results: A total of 241 patients were enrolled across 121 study sites and 239 (99.2%) patients were treated with axatilimab at the data cutoff of 7 April 2023. Patients were heavily pretreated with a median of 4 prior lines of therapy, including ruxolitinib (74%), belumosudil (23%), and ibrutinib (31%). Demographics and disease characteristics were balanced among the 3 dose cohorts (Table 1). ORR (95% CI) was 74% (63, 83) with 0.3 mg/kg Q2W, 67% (55, 77) with 1 mg/kg Q2W, and 50% (39, 61) with 3 mg/kg Q4W (Table 1). Median duration of response (DOR) has not been reached in any of the cohorts, with 60%, 60% and 53% of patients maintaining response at 12 months in the 0.3 mg/kg Q2W, 1 mg/kg Q2W, and 3 mg/kg Q4W dose cohorts, respectively. Clinical benefit, as measured by reduction in mLSS score, was reported in 55%, 54%, and 36% of patients in the 0.3 mg/kg Q2W, 1 mg/kg Q2W, and 3 mg/kg Q4W cohorts, respectively, in the first 6 cycles. Drug discontinuation owing to TEAEs occurred in 6% of patients with 0.3 mg/kg Q2W, 22% with 1 mg/kg Q2W, and 18% with 3 mg/kg Q4W. The most common TEAEs are summarized in Table 2. Fatal TEAEs occurred in 1.3%, 8.6%, and 7.6% of patients in the 0.3 mg/kg Q2W, 1 mg/kg Q2W, and 3 mg/kg Q4W dose cohorts, respectively. The frequency of TRAEs and grade ≥ 3 TRAEs were dose dependent, consistent with CSF-1R inhibition-mediated macrophage clearance. Most infections were mild, with 3 reported cytomegalovirus infections, including reactivations, in the higher dose cohorts. Conclusions: The AGAVE-201 pivotal trial met its primary endpoint for all doses studied. Axatilimabtreatment of refractory cGVHD in heavily pretreated patients resulted in robust clinical activity and durable responses in all 3 dose cohorts, with the highest ORR and least toxicity at the 0.3 mg/kg Q2W dose. Adverse events consisted primarily of transient laboratory abnormalities and other on-target effects known to be associated with CSF-1R block.

Outcomes of CLL Patients Exposed to Venetoclax+/-R after Ibrutinib in France: The Resist Retrospective Study from the Filo-CLL Group

Background: In chronic lymphocytic leukemia (CLL), despite the fact that Bruton tyrosine kinase inhibitors (BTKi) are increasingly used 1st or 2nd line therapy, and the Bcl-2 inhibitor (Bcl-2i) venetoclax +-rituximab (VEN-R) relapses, based on the good results of the MURANO trial (although it did not include BTKi-exposed patients [pts]), multicentric retrospective studies describing the real world outcomes of BTKi exposed pts under Bcl-2i treatment are still lacking. Most of the data published so far, extracted from USA databases, lack granularity to explain which clinical or biological factors define prognosis in the modern therapeutic era of CLL. Here, results of the experience gathered by 10 FiLO-CLL-affiliated centers in France are presented, monitored by physicians in charge of the pts. The RESIST registry assembled outcomes from 150 pts, among whom 117 are presented here as a first efficacy analysis (the complete set of pts will be presented at the congress). Results: Analysis of these 117 pts shows a predominance of men (68%) and a median age of 59 years (29-85). A median of two previous lines of treatment (range 1-5] was given before initiating VEN, with a majority of immunochemotherapy (FCR) in first line and progressive increase of ibrutinib use. As expected, the rate of complete response (CR) decreased over the lines, yet remained over 30%. Intolerance to ibrutinib was the main cause for discontinuation in 27.4%, and 66.7% were refractory or relapsed patients (45% presenting with BTK mutations before VEN, the other patients stopped due to other causes). At the time of VEN treatment (75% VEN-R), 35.3% of the pts had bulky disease, 63% elevated lactate dehydrogenase and 24.8% a bad performans status (3-4). High risk cytogenetic was found in nearly all patients: 63.8% del(17p) and/or TP53 mutation and 94% unmutated IGHV status. The sequence of VEN therapy was terminated as planned for 56.3% of the pts, while it was stopped for progression/relapse in 27.6% and for intolerance in 16.1%. The most common grade ≥ 3 adverse events observed with VEN, reported in 92 pts, were hematological (30.4%), gastro-intestinal (8.7%), infectious (3.3%) and cutaneous (4.4%). Tumor lysis syndrome during the ramp-up phase was infrequent (grade 1 = 8.4%, grade 2 = 1.9% and grade 3 = 0.9%). At the time of analysis, the best response was CR for 69% of the pts (CR+Cri+PR: 95%). MRD assessment was done in 52 pts, 50% of which obtained MRD undetectable responses. With a median follow-up of 37.7 months (mo; 95% confidence interval [CI] 32.7-40.1), 27.6% of the pts had progressed. The mPFS is 35.9 mo (95%CI 29.8-53), mOS 59.4 mo (95%CI 44-Not Reached) and median time to next treatment (TNTT) 45.9 mo (95%CI 31.7-58.8), while in the 7-year update of the VenR arm of the MURANO trial the latter outcomes were much higher (54.7 mo, not reached, and 63 mo respectively). On univariate and multivariate analyses, only TP53 mutations tended to be significantly associated with worse PFS (HR = 1.83 [0.99; 3.38], p=0.05) and OS (HR = 2.11 [0.91; 4.86], p=0.07). A total of 44 patients relapsed after VEN, with a median time to next treatment-2 of 18.0 mo (95%CI 5.5-21.1). The updated results of this subset of patients will be presented at the congress. Conclusion: Although slightly improved as compared to other real-life series in Italy or in the US, these data indicate that VEN or VEN+R after progression, relapse or intolerance to BTKi is moderately efficient with only about 35.9 months median PFS (in spite of undetectable MRD in 26/52 available patients). TP53 abnormalities were confirmed to be an important risk factor, yet not BTK mutations, or. This work is important to help designing clinical trials aiming at improving the outcomes with next generation BTKi/Bcl-2i, or even CAR-T cells.

Australian data on the utilisation and duration on treatment of ibrutinib with a proton pump inhibitor in patients with relapsed or refractory chronic lymphocytic leukaemia.

In Australia, over half of patients with relapsed/refractory chronic lymphocytic leukaemia treated with ibrutinib use concomitant proton pump inhibitors (PPIs). High gastric pH reduces the bioavailability of some Bruton tyrosine kinase inhibitors. There was no difference in duration on ibrutinib with or without concomitant PPI (unadjusted P = 0.61; adjusted hazard ratio: 1.23, 95% confidence interval: 0.75-2.02, P = 0.411). PPI use does not affect ibrutinib treatment persistence.

P06.11.B NEUROTOXICITY AND MANAGEMENT OF PRIMARY AND SECONDARY CNS LYMPHOMA AFTER ADOPTIVE IMMUNOTHERAPY WITH CD19-DIRECTED CAR T-CELLS

Abstract BACKGROUND Chimeric antigen receptor (CAR) T-cells targeting CD19 have been established as a leading engineered T-cell therapy for systemic B-cell lymphomas; however, data for patients with CNS involvement are limited. Whether CAR T-cells represent a viable therapeutic avenue for such patients remains therefore unclear. MATERIAL AND METHODS We retrospectively searched our institutional database for patients with primary and secondary CNS lymphoma who were treated with CD19-directed CAR T-cells for active CNS disease. Clinical data, CNS-specific toxicities, imaging findings, and outcome were analyzed. RESULTS We identified 45 consecutive CAR T-cell transfusions for active CNS lymphoma at the Massachusetts General Hospital over a five-year period. This cohort includes 17 patients with primary CNS lymphoma (PCNSL; one patient with two CAR T-cell transfusions) and 27 patients with secondary CNS lymphoma (SCNSL). Mild neurotoxicity (grade 1-2) was observed after 19/45 transfusions (42.2%) and severe neurotoxicity (grade 3-4) after 7/45 transfusions (15.6%). A larger increase in C-reactive protein (CRP) levels and higher rates of neurotoxicity were detected in SCNSL. Early fever and baseline C-reactive protein levels predicted neurotoxicity occurrence. CNS response was seen in 31 cases (68.9%), including a complete response of CNS disease in 18 cases (40.0%) which lasted for a median of 11.4 ± 4.5 months. Dexamethasone dose at time of lymphodepletion (but not at or after CAR T-cell transfusion) was associated with an increased risk for CNS progression (HR per mg/d: 1.16, p = 0.031). If bridging therapy was warranted, the use of Ibrutinib translated into favourable CNS-progression free survival (5 versus 1 month, HR 0.28, CI 0.1-0.7; p = 0.010). CONCLUSION CD19-directed CAR T-cells exhibit promising anti-tumor effects and a favourable safety profile in patients with CNS lymphoma. Further evaluation on the role of bridging regimens and corticosteroids is urgently warranted.

Infectious complications among patients receiving ibrutinib for the treatment of hematological malignancies.

Ibrutinib is a Bruton's tyrosine kinase inhibitor used to treat multiple hematologic malignancies and graft-versus-host disease. Though less myelosuppressive than cytotoxic chemotherapy, increased infections, including invasive fungal infections (IFIs), have been reported with ibrutinib use. This study aimed to determine the characteristics and risk factors for infection associated with ibrutinib at our institution. Patients who received ibrutinib between June 2014 and August 2019 were included. Primary endpoints were the incidence of any infection and the incidence of serious infection (defined as hospitalization, parenteral antimicrobial therapy, or pneumonia regardless of hospitalization). Infection risk factors were assessed using logistic regression. One hundred thirty-two patients were identified (78% male; median age, 71 years). The most common indications for ibrutinib were chronic lymphocytic leukemia (67%) and mantle cell lymphoma (12%). Infection and serious infection occurred in 94 (71%) and 47 (36%) patients, respectively; when pneumonia was excluded as a criterion for serious infection, the serious infection rate was 27%. The median time from ibrutinib initiation to first infection was 125 days. Prior allogeneic hematopoietic stem cell transplantation (allo-HSCT) (odds ratio [OR], 4.60; 95% CI, 1.22-17.4) and corticosteroid use (OR, 5.55; 95% CI, 1.52-20.3) were significant risk factors for serious infection. IFIs were diagnosed in 7 patients (5%): 5 had Pneumocystis jirovecii pneumonia and 2 were infected with invasive molds. Serious infection and IFI rates are high but similar to those previously described. Risk factors for serious infection included allo-HSCT and corticosteroid use. Targeted antimicrobial prophylaxis should be evaluated in prospective studies in patients on ibrutinib to reduce serious infections and IFI.

Bleeding risk with concurrent use of anticoagulants and ibrutinib: A population-based nested case-control study.

Data regarding the safety of co-administration of ibrutinib with anticoagulants in real-life settings are scarce. Using a nationwide database, we conducted a nested case-control study in a cohort of new users of ibrutinib to assess the risk of clinically relevant bleeding (CRB) associated with anticoagulation. Cases were patients with a diagnosis of CRB, defined as hospitalization with a diagnosis of bleeding. The date of CRB constituted the index date. Up to four controls were matched on sex, age at index date and duration of follow-up. The risk of CRB associated with anticoagulation in patients receiving ibrutinib was estimated using conditional logistic regression models, providing odds ratios (OR) adjusted for risk factors of bleeding. Among 614 cases and 2407 matched controls, the risk of CRB was significantly higher in patients receiving both ibrutinib and anticoagulants (adjusted OR [aOR] 2.54, confidence interval [CI] 95% [1.94; 3.32]). When considering anticoagulant class, aOR was 1.99 (CI 95% [1.19; 3.33]) for VKA, 2.48 (CI 95% [1.76; 3.47]) for direct oral anticoagulants and 3.40 (CI 95% [2.01; 5.75]) for parenteral anticoagulants. In conclusion, this study found a 2.5-fold increased risk of CRB in patients receiving both ibrutinib and anticoagulants in real-life settings, and similar aOR among oral anticoagulants.

Advancements in the Treatment of CLL: The Rise of Zanubrutinib as a Preferred Therapeutic Option.

Ibrutinib, the first-in-class Bruton's tyrosine kinase inhibitor (BTKi), is a commonly deployed therapeutic option for previously untreated and relapsed/refractory (R/R) patients with chronic lymphocytic leukemia (CLL). The use of ibrutinib is, however, partially limited by off-target side effects. Zanubrutinib (zanu) is a second-generation BTKi with enhanced target selectivity and occupancy of the kinase binding site. The SEQUOIA study showed that zanu significantly prolonged progression-free survival (PFS) when compared to bendamustine-rituximab (BR) in treatment-naive CLL patients. More recently, data from the phase III ALPINE trial, which directly compared zanu with ibrutinib, demonstrated that zanu's advantages include an improved safety profile as well as enhanced clinical efficacy. Based on the results of the SEQUOIA and ALPINE pivotal trials, the Food and Drug Administration (FDA) and European Medicines Agency (EMA) licensed zanu for the treatment of patients with CLL or small lymphocytic lymphoma (SLL) in January 2023. The updated (v2.2023) National Comprehensive Cancer Network (NCCN) guidelines and the most recent German CLL algorithm suggest that zanu may replace first-generation BTKis as a preferred therapeutic option for patients with CLL/SLL due to its increased selectivity for the kinase binding site, improved therapeutic efficacy, and favorable toxicity profile. Some drug class-related characteristics such as drug resistance, low complete remission (CR) rates, and indefinite treatment duration still remain with zanu, and the results from recently completed and ongoing fixed-duration clinical trials, combining zanu with an anti-BCL2 agent, are eagerly awaited with the possible promise of a reduced treatment duration and lower financial burden.

Neurotoxicity and management of primary and secondary central nervous system lymphoma after adoptive immunotherapy with CD19-directed chimeric antigen receptor T-cells.

Chimeric antigen receptor (CAR) T-cells targeting CD19 have been established as a leading engineered T-cell therapy for B-cell lymphomas; however, data for patients with central nervous system (CNS) involvement are limited. We retrospectively report on CNS-specific toxicities, management, and CNS response of 45 consecutive CAR T-cell transfusions for patients with active CNS lymphoma at the Massachusetts General Hospital over a 5-year period. Our cohort includes 17 patients with primary CNS lymphoma (PCNSL; 1 patient with 2 CAR T-cell transfusions) and 27 patients with secondary CNS lymphoma (SCNSL). Mild ICANS (grade 1-2) was observed after 19/45 transfusions (42.2%) and severe immune effector cell-associated neurotoxicity syndrome (ICANS) (grade 3-4) after 7/45 transfusions (15.6%). A larger increase in C-reactive protein (CRP) levels and higher rates of ICANS were detected in SCNSL. Early fever and baseline C-reactive protein levels were associated with ICANS occurrence. CNS response was seen in 31 cases (68.9%), including a complete response of CNS disease in 18 cases (40.0%) which lasted for a median of 11.4 ± 4.5 months. Dexamethasone dose at time of lymphodepletion (but not at or after CAR T-cell transfusion) was associated with an increased risk for CNS progression (hazard ratios [HR] per mg/d: 1.16, P = .031). If bridging therapy was warranted, the use of ibrutinib translated into favorable CNS-progression-free survival (5 vs. 1 month, HR 0.28, CI 0.1-0.7; P = .010). CAR T-cells exhibit promising antitumor effects and a favorable safety profile in CNS lymphoma. Further evaluation of the role of bridging regimens and corticosteroids is warranted.

Toxicity and Outcomes of Ibrutinib in Chronic Lymphatic Leukemia-Real-World Results from the Study of 215 Patients in Argentina

Different pivotal works allowed the approval of ibrutinib as a CLL treatment, both in the first line and in relapsed/refractory patients, the adverse effects differ from conventional chemotherapy, the discontinuation rate was 10%, but in different real-life studies, showed a higher number of complications and medication suspension rates of 40 to 50%. To know the reality of the use of ibrutinib in CLL in our environment, we designed this work with the objectives of evaluating the safety profile of the drug with the description of the adverse effects, their incidence, and their severity. The clinical efficacy will also be studied with the determination of the response achieved, calculation of overall survival (OS) and progression-free survival. Also as an additional objective, the discontinuation rate and its causes will be obtained. A total of 215 patients in 26 centers throughout the country were retrospectively analyzed. 189 patients (88%) had a global response, and the majority 58% achieved a partial response. The 5-year overall survival was 60%, with no difference between patients with different numbers of previous lines. The progression-free survival of the entire group was 5.06 years. 44.7% of the population, presented at least 1 adverse effect. The most frequent ones were: bleeding, thrombocytopenia, pneumonia and diarrhea. Others presented: anemia, neutropenia, infections, AF, HTA, arthralgia, rash, opportunistic infections. Most adverse events were mild to moderate in grade and generally occurred within the first 6 months. The main cause of treatment suspension was the appearance of adverse effects, 37 patients had to suspend it, 27 due to adverse effects (72.97%). In our work, we found that ibrutinib, as a single agent, has outstanding activity in CLL, with a significant percentage of overall responses, even in patients with several lines of prior treatment. Most of the adverse effects were of a mild to moderate degree. The cardiovascular effects of TKI, HBP, and AF, are in percentages similar to those reported in other studies. If we analyze the percentage of treatment discontinuation, which is 17%, mostly due to adverse effects, this finding is similar to pivotal studies. In conclusion, our real-life study confirms the important activity of ibrutinib in patients with CLL, in the first line and relapses, highlighting the low percentage of treatment discontinuation in our environment. We believe our work reflects the real life and daily care of patients with CLL, under treatment with ibrutinib in our environment.

Serositis causing pericardial and pleural effusions after eight years of maintenance ibrutinib for Waldenstrom's macroglobulinemia.

Ibrutinib is a tyrosine kinase inhibitor approved for multiple B-cell malignancies, including Waldenstrom's macroglobulinemia in 2014. Although the drug portends favorable outcomes, it also bears a profile of side effects. Current literature describes only two cases of nonhemorrhagic pericardial effusion associated with ibrutinib use, and here we present the third. This case recounts an episode of serositis causing pericardial and pleural effusions and diffuse edema after eight years of maintenance ibrutinib for Waldenstrom's macroglobulinemia (WM). A 90-year-old male with WM and atrial fibrillation presented to the emergency department for a week of progressive periorbital and upper and lower extremity edema, dyspnea, and gross hematuria, despite increasing at-home diuretic dose. The patient was on 140 mg ibrutinib twice daily. Labs showed stable creatinine, serum IgMs of 97, and negative serum and urine protein electrophoresis. Imaging revealed bilateral pleural effusions and pericardial effusion with impending tamponade. All other workup was unrevealing, diuretics were ceased, pericardial effusion was monitored with serial echocardiograms, and ibrutinib was exchanged for low-dose prednisone. After five days, the effusions and edema dissipated, hematuria resolved, and patient was discharged. Resumption of lower dose ibrutinib one month later led to a subsequent return of edema, which again subsided with cessation. Reevaluation of maintenance therapy continues outpatient. Patients on ibrutinib presenting with dyspnea and edema should be monitored for pericardial effusion; the drug should be held in exchange for anti-inflammatory therapy, and future management should involve cautious, low-dose resumption, or exchange for alternative therapy.

Abstract 3689: Uncovering the metabolic vulnerabilities in activated B cell diffuse large B cell lymphoma

Abstract DLBCL is the most common B cell malignancy in adults accounting for 30-40% of non-Hodgkin lymphoma. Only 60% of these cases are curable, with activated B cell DLBCL (ABC-DLBCL) having inferior outcomes than the germinal center (GCB) DLBCL. The use of ibrutinib to treat non-responsive/relapsed ABC-DLBCL cases has significantly improved the treatment of this disease. However, in more than 40% of ABC-DLBCL cases, the disease progresses or develops resistance to ibrutinib. Thus, there is an urgent unmet need to understand the molecular basis of resistance mechanisms and identify novel therapeutic regimens to treat IR DLBCL. Utilizing high throughput metabolomics, we identified cysteine-methionine metabolism and alanine, aspartate, and glutamate metabolism to be deregulated in IR cells. We further identified interleukin four induced 1 (IL4I1), an L-amino acid oxidase that partakes in cysteine and methionine metabolism by contributing to the methionine salvage pathway. The amino acid cysteine contributes to cancer metabolic remodeling by a), in its free form, in redox control, as a component of the antioxidant glutathione or its involvement in protein s-cysteinylation, b), as a substrate for the production of hydrogen sulfide (H2S), which feeds the mitochondrial electron transfer chain and mediates persulphidation of ATPase and glycolytic enzymes, thereby stimulating cellular bioenergetics; and, c), as a carbon source for epigenetic regulation, biomass production, and energy production. Consistent with this, we show that loss of IL4I1 expression induced aberrant cysteine and methionine metabolism accompanied by metabolic reprogramming to OXPHOS, which collectively enabled increased drug tolerance of DLBCL. This adaptive metabolic mechanism exhibited increased cysteine and cystathionine intracellular levels in IR-DLBCL lacking IL4I1 expression. As cysteine and glutathione are scavengers of free radicals (mainly reactive oxygen species (ROS)), they can nullify the effects of the majority of oxidative or alkylating drugs used in cancer therapy, affording a vital resistance mechanism and disruption of cysteine homeostasis appears to be promising strategy for induction of cancer cell death and provide therapeutic approaches to treat Ibrutinib-resistant-ABC- DLBCL for improved patient care. Citation Format: Satishkumar Singh, Fouad Choueiry, Anuvrat Sircar, Narendranath Epperla, Jiangjiang Zhu, Lalit Sehgal. Uncovering the metabolic vulnerabilities in activated B cell diffuse large B cell lymphoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3689.