Ibrutinib Therapy Research Articles

Long-Term Outcomes in Chronic Lymphocytic Leukemia Treated with Ibrutinib: 10-Year Follow-up of a Phase 2 Study

Background: Targeted agents have replaced conventional chemotherapy in treatment of chronic lymphocytic leukemia (CLL) with substantially improved outcomes in CLL with TP53 alterations (del17p or TP53 mutations). Whereas fludarabine, cyclophosphamide, and rituximab chemoimmunotherapy (CIT) had a median progression-free survival (mPFS) of 11.2 months and median overall survival (mOS) of 33.1 months as frontline therapy in del17p CLL (Fisher et al. Blood 2016), we previously reported a 6-year PFS of 61% and OS of 79% in CLL with TP53 alterations receiving frontline continuous ibrutinib (Ahn et al. NEJM 2020). In a similar patient subset, the CLL14 study demonstrated a mPFS of 51.9 months and a 5-year OS of 60.0% using fixed-duration venetoclax and obinutuzumab (Al-Sawaf et al. EHA 2023; Al-Sawaf et al. Nat. Comm 2023). Although more effective than CIT, long-term outcomes in the era of targeted therapy are not yet fully defined. With a median follow-up of nearly 10 years, we analyzed efficacy, safety, and depth of response in CLL patients treated with long-term ibrutinib therapy in a phase 2 study (NCT01500733). Methods: Eligible patients had high-risk CLL, defined by TP53 alterations or age ≥65 years-old (N = 84 evaluable), and received ibrutinib 420 mg orally once daily until disease progression or intolerable side effects. Response assessments were performed annually with CT scans up to five years and subsequently with physical exam. Minimal residual disease (MRD) was performed annually with peripheral blood flow cytometry. Undetectable MRD (uMRD) was defined as <1 CLL cell per 10,000 leukocytes. For patients discontinuing the study, long-term outcomes were obtained when possible through a separate natural history study (NCT00923507). Results: As of December 31, 2022, a median follow-up of 113 months and 117 months (reverse Kaplan-Meier) was available for calculation of PFS and OS, respectively. The mPFS for all patients was 85.9 months (Table 1). mPFS was significantly shorter in those with TP53 alterations (67.3 months, N = 53) vs. those without (not reached, N = 31) and in relapsed disease (49 months, N = 32) vs. frontline treatment (108 months, N = 52). The OS at 117 months was 58.5% for all patients, 73.8% for treatment-naïve patients, and 54.1% in patients with TP53 alterations. Among patients with TP53 alterations receiving frontline ibrutinib (N = 34), the mPFS was 81 months with an OS of 69.7% at 117 months. Most patients (82.1%, 69/84) had discontinued ibrutinib at the time of analysis with 15 patients (17.9%) remaining on therapy. 37 (44.0%) patients discontinued ibrutinib for progressive disease including 6 cases with histologic transformation. 27 (32.1%) patients discontinued therapy related to treatment-emergent adverse events (AEs) including 8 cardiac AEs (four cases were grade ≥2 atrial fibrillation), 7 second cancers, 4 infections, 3 cases of dementia (ages 78, 80, and 85), 2 pleural effusions, and 3 other AEs. Five patients (5.9%) withdrew from the study with 4 switching to commercial supply of ibrutinib and one changing to CAR-T therapy. uMRD was observed in 15.4% (13/84) of all patients. The median time to uMRD was 5 years (range: 2 - 10 years). There was no enrichment in these patients for Rai stage ≥3-4, unmutated IGHV, TP53 alteration, prior treatment, or age. Most patients achieving uMRD also had a complete response (CR) to therapy (10/13) and remained progression-free at last follow-up (12/13). The one patient with progressive disease achieved uMRD and CR at 24 months, had detectable MRD at 36 months, and had nodal progression at 60 months. Among the progression-free patients, 8 had subsequent MRD assessments demonstrating sustained uMRD for 1-6 years including one patient who had been off any CLL-directed therapy for 4 years. Conclusions: These results further define the long-term prognosis of patients treated with BTK inhibitors for CLL, most notably with substantial improvements in the OS of patients with TP53 alterations over CIT. Additionally, these results may inform discussions of continuous BTK inhibitor therapy versus fixed-duration venetoclax combinations in frontline therapy of high-risk CLL. In a subset of ibrutinib-treated patients, depth of response increased over multiple years to the point of uMRD suggesting the possibility that such patients might safely discontinue therapy, following paradigms established in patients with chronic myelogenous leukemia.

Pituitary macroadenoma apoplexy as a rare complication of Bruton tyrosine kinase inhibitor in chronic lymphoid leukaemia

BackgroundPituitary apoplexy is a neurosurgical emergency and is a known yet rare complication of pituitary macroadenoma. Patients typically present with visual field defects, headache and altered sensorium. There are multiple risk factors for this complication and a thorough drug history is essential to exclude iatrogenic causes of disease. We present an extremely rare case of newly diagnosed pituitary insufficiency unveiled by ibrutinib therapy (a Bruton tyrosine kinase inhibitor). Furthermore, after initial withdrawal of ibrutinib because of the erroneous diagnosis of Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH), its re-administration led to the development of classical pituitary apoplexy 4 months after treatment was restarted.Case presentationA male patient in his 60s with a background of chronic lymphocytic leukaemia (CLL) on ibrutinib and venetoclax presents with acute confusion and deranged electrolytes. He is found to be hyponatraemic and is diagnosed with Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) and treated with fluid restriction. He represents again 3 weeks later with hyponatraemia and further investigations reveal pituitary insufficiency and macroadenoma. He was restarted on ibrutinib and venetoclax at the time of discharge.Four months later, he presents with sudden retro-orbital headache associated with vomiting. Clinical findings include cranial nerve III, IV and XI palsy. Humphrey’s visual field examination revealed a left visual field index (VFI) of only 1% while the right was 64% with temporal hemianopia. Both pupils were mid-dilated and poorly reactive to light. MRI pituitary with contrast showed features of pituitary apoplexy and optic nerve compression. He was urgently referred to the neurosurgical team and underwent an emergency trans-sphenoidal hypophysectomy with circumferential excision of the macroadenoma. Post-operative recovery was uneventful with marked improvement in vision bilaterally.The patient was restarted on ibrutinib and venetoclax 2 weeks post-operatively. Approximately 1 year post-treatment, he remains in radiological, clinical and biochemical remission from CLL and all medications have been withdrawn.ConclusionsThis is a unique and rare case of pituitary macroadenoma apoplexy following the commencement of ibrutinib for CLL. Central nervous system haemorrhage is a rare side effect of ibrutinib due to its platelet dysfunction effects. A thorough assessment is required to assess the risks and benefits of using ibrutinib in patients with pituitary macroadenoma to avoid serious complications.

Incidence of cardiovascular and bleeding events and reasons for discontinuation in patients with chronic lymphocytic leukemia treated with ibrutinib-A retrospective analysis on consecutive patients from a well-defined region.

Ibrutinib treatment is associated with cardiovascular side effects, in particular atrial fibrillation (AF) and hypertension, as well as increased risk of bleeding. Here, we aimed at describing the incidence of these events during long-term follow-up in patients with chronic lymphocytic leukemia treated outside clinical trials as well as identifying clinical factors predictive of developing AF. Additionally, other reasons for treatment withdrawal were analyzed. The study was retrospective, data were collected from medical records. A total of 134 patients were identified. Median follow-up was 32 months (range 3-103) and median duration of ibrutinib treatment was 26 months (range 1-103). Of 110 patients with no prior history of AF, 24.5% were diagnosed during treatment. Newly diagnosed or worsening of pre-existing hypertension occurred in 15.7%. Sixty-six % of the patients experienced bleeding events, of which 7.5% grade 3-4. Treatment discontinuation and dose reduction occurred in 68% and 47% of the patients, respectively, mostly due to toxicity. The incidence of AF was high and at a median follow-up of 2.5 years, two-thirds of the patients discontinued treatment mostly due to bleeding and infections. Treatment-related toxicity of any grade should be regarded as a concern of prolonged ibrutinib therapy.

Hepatitis B virus reactivation in seronegative occult hepatitis B patient receiving ibrutinib therapy

BackgroundIbrutinib is a Bruton’s tyrosine kinase (BTK) inhibitor approved for the treatment for several mature B-cell malignancies. Reactivation of hepatitis B virus (HBV) is a well-described complication in patients with chronic HBV infection or prior HBV exposure undergoing cytotoxic or immunosuppressive chemotherapy for hematologic malignancies. This phenomenon has been frequently reported with rituximab. However, published data on the risk of HBV reactivation induced by ibrutinib are scarce. Cases of HBV reactivation in hematologic patients receiving ibrutinib therapy have recently been described, but limited only to overt hepatitis B patients or seropositive occult hepatitis B patients.Case presentationWe report the first case of HBV reactivation during ibrutinib treatment in an asymptomatic 82-year-old woman with seronegative occult hepatitis B patient (i.e., negative for HBsAg, anti-HBc and anti-HBs). Four months after ibrutinib treatment, her liver function test (LFT) was deranged, with seroconversion to HBsAg positivity. Serum hepatitis B virus DNA was quantified to be 1.92 × 108 IU/ml. Antiviral treatment was initiated, and viral load was gradually suppressed with improvement in LFT.ConclusionsOur case illustrated that in populations with a high incidence of HBV exposure, systematic screening for HBV exposure is essential prior to ibrutinib treatment, followed by serial monitoring of serologic and molecular markers of hepatitis B. There is a need for an international consensus to support the recommendation of antiviral prophylaxis against HBV reactivation in patients using ibrutinib.

Impacts of early therapy response, interval to therapy interruption, and cumulative therapy interruption duration on outcome of ibrutinib therapy in relapsed/refractory chronic lymphocytic leukemia.

To investigate the impact of early response and treatment interruption on the survival of patients with relapsed/refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (r/r CLL/SLL) treated with ibrutinib.This post hoc analysis used data of patients received ibrutinib treatment from an open-label, multicenter phase 3 study comparing ibrutinib with rituximab in patients with r/r CLL/SLL. The association of complete or partial response at 6months, interruption within the first 6months, cumulative interruption durations during the ibrutinib-treated period with progression-free survival (PFS) and overall survival (OS) were evaluated using the adjusted Cox hazard proportional model.The study included 87 patients treated with ibrutinib, of which 74 patients had at least 6months of ibrutinib treatment and were analyzed. The response at 6months did not affect PFS (HR = 0.58, 95%CI: 0.22-1.49) or OS (HR = 0.86, 95%CI: 0.22-3.31). The onset of interruption before or after 6months was not associated with PFS (HR = 0.88, 95%CI: 0.34-2.30) or OS (HR = 0.75, 95%CI: 0.23-2.52). However, a cumulative interruption of more than 35days was independently associated with worse PFS (HR = 2.4, 95%CI: 0.99-5.74) and OS (HR = 2.6, 95%CI: 0.88-7.44). Continuous interruption for more than 14days was associated with a numerically lower 3-year PFS rate (> 14 vs. ≤ 14days: 42% vs. 73%) and 3-year OS rate (> 14 vs. ≤ 14days: 58% vs. 84%, both P > 0.05).Response status at 6months or early therapy interruptions did not affect survival in patients with r/r CLL/SLL treated with ibrutinib. However, a cumulative temporary interruption of more than 35days could potentially impact patient outcomes.

Treatment with idelalisib in patients with chronic lymphocytic leukemia – real world data from the registry of the German CLL Study Group

Idelalisib in combination with rituximab is an efficacious treatment for patients suffering from chronic lymphocytic leukemia (CLL) with known limitations due to toxicities. However, the benefit after prior Bruton tyrosine kinase inhibitor (BTKi) therapy remains unclear. For this analysis, 81 patients included in a non-interventional registry study of the German CLL study group (registered at www.clinicaltrials.gov as # NCT02863692) meeting the predefined criteria of a confirmed diagnosis of CLL and being treated with idelalisib containing regimens outside clinical trials were considered. 11 patients were treatment naïve (13.6%) and 70 patients (86.4%) pretreated. Patients had median of one prior therapy line (range 0–11). Median treatment duration with idelalisib was 5.1 months (range 0–55.0 months). Of 58 patients with documented treatment outcome, 39 responded to idelalisib containing therapy (67.2%). Patients treated with the BTKi ibrutinib as last prior treatment prior to idelalisib responded in 71.4% compared to a response rate of 61.9% in patients without prior ibrutinib. Median event free survival (EFS) was 15.9 months with a 16 versus 14 months EFS in patients with ibrutinib as last prior treatment or not, respectively. Median overall survival was 46.6 months. In conclusion, treatment with idelalisib appears to have a valuable impact in patients being refractory to prior ibrutinib therapy even though there are limitations in our analysis due to the low number of patients included.

B-cell Receptor Pathway Mutations Are Infrequent in Patients with Chronic Lymphocytic Leukemia on Continuous Ibrutinib Therapy.

Acquired mutations in Bruton's tyrosine kinase (BTK) or phospholipase C-γ2 (PLCG2) genes are associated with clinical progressive disease (PD) in patients with chronic lymphocytic leukemia (CLL) treated with BTK inhibitors. Data on mutation rates in patients without PD on ibrutinib treatment are limited. We evaluated frequency and time to detection of BTK and PLCG2 mutations in peripheral blood samples from 388 patients with previously untreated (n = 238) or relapsed/refractory (n = 150) CLL across five clinical trials. With median follow-up of 35 months (range, 0-72) without PD at last sampling, mutations in BTK (3%), PLCG2 (2%), or both genes (1%) were rare in previously untreated patients. With median follow-up of 35 months (range, 1-70) without PD at last sample, mutations in BTK (30%), PLCG2 (7%), or both genes (5%) were more common in patients with relapsed/refractory CLL. Median time to first detection of BTK C481S mutation was not reached in previously untreated patients and was >5 years in patients with relapsed/refractory CLL. Among patients evaluable at PD, previously untreated patients (n = 12) had lower rates than those with relapsed/refractory disease (n = 45) of BTK (25% vs. 49%) and PLCG2 mutations (8% vs. 13%). Time from first detection of BTK C481S mutation to PD was 11.3 months in 1 previously untreated patient and median 8.5 months (range, 0-35.7) among 23 patients with relapsed/refractory CLL. This systematic investigation describes development of mutations over time in patients without PD and informs the potential clinical opportunity to optimize ongoing benefits for such patients.

TRLS-03. IBRUTINIB DISRUPTS BLOOD-TUMOR BARRIER INTEGRITY TO ENHANCE CNS DRUG DELIVERY AND RODENT GLIOMA MODEL SURVIVAL

Abstract BACKGROUND In the setting of malignant glioma, cytotoxic drugs are often inhibited from accessing the tumor site due to the blood-brain-barrier (BBB). Identifying agents that transiently increase BBB permeability would advance glioma treatment. Ibrutinib, an FDA approved lymphoma treatment, has previously impaired aortic endothelial adhesion and in combination with cytotoxic therapy, increased rodent glioma model survival. In this study, we propose ibrutinib inhibits brain endothelial cell junctional expression to disrupt BBB integrity and increase chemotherapy delivery to malignant glioma cells. METHODS Using rat glioma cells, S635, we evaluated treatment effects with doxil (3mg/kg), ibrutinib (25mg/kg) and combination therapy. We measured effects with serial brain MRIs, doxil plasma and brain regional concentrations, along with 3kD dextran permeability. To evaluate the effects of ibrutinib on in vitro brain endothelial cells, we measured changes in cell-cell electrical impedance and rhodamine efflux, as a surrogate of Abcb1 transporter function, over time (0 to 8h) and at varied drug concentrations (1, 5, and 10µM ibrutinib). RESULTS Ibrutinib in combination with doxil, prolonged median survival in rodent glioma models (18 vs. 24days, p<0.05). MRI findings demonstrated a -14 or -53% vs -75% tumor volume change with doxil or ibrutinib alone vs. combination therapy, respectively (p<0.05). Comparing combination therapy vs. doxil alone, ibrutinib increased CNS concentrations of doxil in the tumor injected brain regions with statistical significance (56ng/mL vs. 74.6ng/mL, p<0.05). In in vitro studies, ibrutinib decreased brain endothelial cell-cell impedance maximally at 2 hours, in a dose dependently without affecting cell viability. Additionally, we observed ibrutinib dose dependently inhibit Abcb1 activity in both endothelial and glioma cells. CONCLUSION Our results suggest ibrutinib increases brain endothelial permeability by causing junctional disruption and inhibition of Abcb1, resulting in increased CNS drug entry and prolonged survival in glioma rat models.

BV6, AN ANTAGONIST OF INHIBITOR OF APOPTOSIS PROTEINS, SENSITIZES RESISTANT MANTLE CELL LYMPHOMA CELLS TO VENETOCLAX

Introduction: Although Bruton’s tyrosine kinase inhibitors (BTKi) and CAR T-cell therapy have achieved remarkable efficacy in the treatment of mantle cell lymphoma (MCL), it remains incurable due to the inevitable development of therapeutic resistance. The BCL-2 inhibitor venetoclax is effective in many relapsed MCL patients, including those who progressed on BTKi, but subsequent relapse to venetoclax yields poor clinical outcomes. Hence, novel therapeutics and combination therapies are required to tackle the clinical challenges. Here, we investigated BV6, an antagonist of inhibitor of apoptosis proteins (IAPs), alone and in combination with venetoclax in multiple therapy-resistant MCL models. Methods: We performed single-cell RNA-seq to assess gene expression in ibrutinib-sensitive, ibrutinib-resistant, and dual ibrutinib-/CAR T-resistant MCL patients. Cell lines with acquired resistance to ibrutinib or venetoclax, as well as primary tumor cells from patients who relapsed after multiple therapies, were used as models of MCL resistance. CellTiter-Glo® luminescent assay was used to measure cell viability; annexin V/PI staining was used to measure the induction of apoptosis; and western blotting was used to assess IAP and apoptosis signaling protein expression across MCL cell lines after drug treatment. Results: The single-cell RNA-seq analysis demonstrated that IAP gene expression was not influenced by patient response to ibrutinib and CAR T-cell therapy, and western blotting showed that IAP proteins were broadly expressed across all MCL cell lines. To determine the on-target effects of BV6, we treated JeKo-1, JeKo-IBN-R, Mino, and Mino-VEN-R cells with BV6 and examined the expression of IAPs. BV6 treatment for 4h markedly reduced c-IAP1 and c-IAP2 expression, and moderately reduced XIAP expression. BV6 inhibited cell viability in both ibrutinib- and venetoclax-resistant cell lines, and BV6 treatment for 24 h dose-dependently induced apoptosis in MCL cells, including not only cell lines with acquired resistance but also patient primary cells, independent of their resistance to ibrutinib, venetoclax, and CAR T-cell therapy. We observed a striking and significant synergy in the cell viability assay when ibrutinib- or venetoclax-resistant cells were treated with BV6 combined with venetoclax (combination index < 1), and a dramatic enhancement of apoptosis (p < 0.001). The combination eradicated c-IAP1 and c-IAP2 expression, while XIAP was synergistically diminished. This was accompanied by strong caspase-3 activation and PARP cleavage. This combination therapy is currently under evaluation in venetoclax-resistant mouse model in vivo. Conclusions: Our findings indicate that a combination of IAP antagonists with apoptosis inducers can be exploited as a rational strategy to overcome therapeutic resistance in MCL. This study was supported by philanthropic funds from the Kimmel Research fund and various donor funds. Keywords: Aggressive B-cell non-Hodgkin lymphoma, Combination Therapies, Molecular Targeted Therapies No conflicts of interests pertinent to the abstract.

5‐YEAR (Y) FOLLOW‐UP OF A PHASE 2 STUDY OF IBRUTINIB PLUS FLUDARABINE, CYCLOPHOSPHAMIDE, RITUXIMAB (IFCR) AS INITIAL THERAPY FOR YOUNGER CLL PATIENTS (PTS)

Introduction: This frontline study investigates whether iFCR followed by 2Y ibrutinib (IBR) maintenance (I-M) could provide deep and durable responses in CLL irrespective of IGHV status. We previously reported high rates of bone marrow undetectable minimal residual disease (BM-uMRD) in both IGHV unmutated (U-IGHV, 83%) and mutated (M-IGHV, 82%) pts (Davids et al., Lancet Haematol, 2019). Here, we report updated data at a median follow-up of 63 months. Methods: In this phase 2 investigator-sponsored trial (NCT02251548), eligible pts received up to 6 cycles of iFCR followed by 2Y I-M. Pts with BM-uMRD after 2Y I-M had the option to stop IBR. MRD was assessed with multicolor flow at 10-4. Targeted NGS covering 97 genes was applied to peripheral blood (PB) samples at MRD recurrence. Results: 85 pts with a median age of 55Y (range 38–65) were treated, including 53% with U-IGHV and 6% with del17p and/or TP53MUT. 77 pts (91%) completed 2Y I-M. 20 pts continued IBR beyond 2Y I-M, including 13 with detectable MRD in BM or PB at 2Y. Safety was similar to our previous report; the cumulative incidence of atrial fibrillation was 8%, and second malignancy occurred in 11%, mostly non-melanoma skin cancer. Two pts (2%) had secondary myeloid neoplasms. No new deaths have occurred since the one death reported in the prior publication (sudden cardiac death during I-M). 5Y PFS was 94% (95% CI 89%–100%) and 5Y OS was 99% (95% CI 96%–100%). There was no difference in PFS by IGHV status or duration of I-M (Figure A). Five pts progressed with CLL, all after cessation of IBR. Fourteen pts remained in response on continuous IBR therapy, two of whom had achieved BM-uMRD at 2Y but chose to continue IBR. We longitudinally tracked PB MRD of 69 pts treated with at least 2Y of I-M with available samples and observed high rates of PB-uMRD post-iFCR (75%) and after 2Y I-M (77%). At 4Y after completion of iFCR, 63% of evaluable pts maintained PB-uMRD (Figure B). Thirteen pts (15%) had MRD recurrence without clinical progression, mostly after stopping IBR; 62% of these pts had U-IGHV, 7% del17p, and 15% NOTCH1MUT. BTKMUT was not detected in any of the ten pts analyzed at time of MRD recurrence. One pt had PLCG2MUT at a low allele frequency (2%). Driver gene mutations were commonly detected at MRD recurrence (23% with TP53MUT, 38% with 1–2 other mutations per pt affecting NOTCH1, SF3B1, ATM, XPO1, and/or BRAF). Four of six pts (67%) who received IBR retreatment after MRD recurrence achieved PR. Median duration of IBR retreatment was 34 months. Serial PB MRD data from five pts on IBR retreatment revealed that the MRD growth stabilized but was not eradicated during retreatment. Keywords: chronic lymphocytic leukemia (CLL), minimal residual disease, molecular targeted therapies This study was funded by Pharmacyclics, an AbbVie Company. Conflicts of interests pertinent to the abstract I. E. Ahn Consultant or advisory role: BeiGene D. M. Brander Conflicts of interests pertinent to the abstract Consultant or advisory role: Pfizer, Pharmacyclics, Genentech, TG Therapeutics, ArQule/Merck, AbbVie Research funding: Juno/Celgene/BMS, AstraZeneca/Acerta, CATO/SMS Catapult, NeWave, DTRM, Genentech, BeiGene, MEI Pharma, ArQule/Merck, AbbVie Other remuneration: Ascentage J. Montegaard Consultant or advisory role: Pharmacyclics, Abbvie, AstraZeneca A. Alencar Consultant or advisory role: Amgen, Kite, Seagen, Epizyme, Janssen, BeiGene, Incyte, TG Therapeutics, Genentech, Lilly Research funding: Loxo, BeiGene, Incyte C. A. Jacobson Consultant or advisory role: Kite/Gilead, BMS/Celgene, Novartis, Miltenyi, Abintus Bio, Ipsen, Instil Bio, Daiichi-Sankyo, Morphosys, Caribou Bio, ImmPACT Bio, AztraZeneca Research funding: Kite/Gilead, Pfizer P. Armand Consultant or advisory role: Merck, BMS, Pfizer, Affimed, Adaptive, Infinity, ADC Therapeutics, Celgene, Morphosys, Daiichi Sankyo, Miltenyi, Tessa, GenMab, C4, Enterome, Regeneron, Epizyme, Astra Zeneca, Genentech, Xencor Honoraria: Merck, BMS Research funding: Kite; Research funding (institutional), Merck, BMS, Affimed, Adaptive, Tensha, Otsuka, Sigma Tau, Genentech/Roche, IGM J. Crombie Consultant or advisory role: Incyte, Karyopharm, Kite, ADC therapeutics, Genmab Research funding: Roche, Merck, Abbvie, Bayer A. S. LaCasce Consultant or advisory role: Seagen, Kite Honoraria: Research to practice J. Arnason Consultant or advisory role: BMS E. P. Hochberg Other remuneration: Leuko (Equity) J. S. Abramson Consultant or advisory role: Abbvie, Astra-Zeneca, BeiGene, Bluebird Bio, BMS, Celgene, Epizyme, Incyte, Kymera, Genmab, Genentech, Ono Pharma, Mustang Bio, MorphoSys, Regeneron, Century, Kite Pharma, Lilly, Janssen, Takeda, Caribou Biosciences, Interius, Cellectar J. R. Brown Consultant or advisory role: Abbvie, Acerta/Astra-Zeneca, BeiGene, Genentech/Roche, Grifols Worldwide Operations, Hutchmed, iOnctura, Janssen, Kite, Loxo/Lilly, MEI Pharma, Numab Therapeutics, Pfizer, Pharmacyclics Research funding: BeiGene, Gilead, iOnctura, Loxo/Lilly, MEI Pharma, TG Therapeutics M. S. Davids Consultant or advisory role: AbbVie, Adaptive Biosciences, Ascentage Pharma, AstraZeneca, BeiGene, BMS, Eli Lilly, Genentech, Janssen, Merck, Mingsight Pharmaceuticals, ONO Pharmaceuticals, Secura Bio, TG Therapeutics, Takeda Research funding: AbbVie, AstraZeneca, Ascentage Pharma, Genentech, MEI Pharma, Novartis, Surface Oncology, TG Therapeutics

Comparative arrhythmia patterns among patients on tyrosine kinase inhibitors.

Tyrosine kinase inhibitors (TKIs) are widely used in the treatment of hematologic malignancies. Limited studies have shown an association between treatment-limiting arrhythmias and TKI, particularly ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor. We sought to comprehensively assess the arrhythmia burden in patients receiving ibrutinib vs non-BTK TKI vs non-TKI therapies. We performed a retrospective analysis of consecutive patients who received long-term cardiac event monitors while on ibrutinib, non-BTK TKIs, or non-TKI therapy for a hematologic malignancy between 2014 and 2022. One hundred ninety-three patients with hematologic malignancies were included (ibrutinib = 72, non-BTK TKI = 46, non-TKI therapy = 75). The average duration of TKI therapy was 32months in the ibrutinib group vs 64months in the non-BTK TKI group (p = 0.003). The ibrutinib group had a higher prevalence of atrial fibrillation (n = 32 [44%]) compared to the non-BTK TKI (n = 7 [15%], p = 0.001) and non-TKI (n = 15 [20%], p = 0.002) groups. Similarly, the prevalence of non-sustained ventricular tachycardia was higher in the ibrutinib group (n = 31, 43%) than the non-BTK TKI (n = 8 [17%], p = 0.004) and non-TKI groups (n = 20 [27%], p = 0.04). TKI therapy was held in 25% (n = 18) of patients on ibrutinib vs 4% (n = 2) on non-BTK TKIs (p = 0.005) secondary to arrhythmias. In this large retrospective analysis of patients with hematologic malignancies, patients receiving ibrutinib had a higher prevalence of atrial and ventricular arrhythmias compared to those receiving other TKI, with a higher rate of treatment interruption due to arrhythmias.

The outcome of ibrutinib-based regimens in relapsed/refractory central nervous system lymphoma and the potential impact of genomic variants.

Relapsed/refractory (r/r) central nervous system lymphoma (CNSL) exhibits aggressive behavior and poor outcomes. As an effective bruton tyrosine kinase (BTK) inhibitor, ibrutinib yields benefits in B-cell malignancies. We aimed to explore the efficacy of ibrutinib in treating r/r CNSL patients, and whether genomic variants impact treatment outcomes. The ibrutinib-based regimens in 12 r/r primary CNSL (PCNSL) and 2 secondary CNSL (SCNSL) patients were analyzed retrospectively. The impact of genetic variants on the effects of treatments was examined using whole-exome sequencing (WES) technology. In PCNSL, the overall response rate was 75%, with median overall survival (OS) not reached (NR) and progression-free survival (PFS) of 4 months. Both SCNSL patients responded to ibrutinib, with median OS NR and PFS of 0.5-1.5 months. Infections were common during ibrutinib therapy (42.86%). The PCNSL patients harboring gene mutations in PIM1, MYD88 and CD79B, and the proximal BCR and nuclear factor kappa B (NF-κB) pathways responded to ibrutinib. Patients who harbored simple genetic variants and those with a low tumor mutation burden (TMB; 2.39-5.56/Mb) responded swiftly and maintained remission for more than 10 months. A patient with a TMB of 11/Mb responded to ibrutinib but continued to experience disease progression. In contrast, patients with complex genomic features, especially extremely high TMB (58.39/Mb), responded poorly to ibrutinib. Our study demonstrates that ibrutinib-based therapy is effective and relatively safe for the treatment of r/r CNSL. Patients with less genomic complexity, especially with regard to TMB, might benefit more from ibrutinib regimens.

A Phase 2 Trial of Ibrutinib and Nivolumab in Patients with Relapsed or Refractory Classical Hodgkin's Lymphoma.

Relapsed or refractory classical Hodgkin lymphoma (cHL) remains a difficult treatment challenge. Although checkpoint inhibitors (CPI) have provided clinical benefit for these patients, responses are generally not durable, and progression eventually occurs. Discovering combination therapies which maximize the immune response of CPI therapy may overcome this limitation. We hypothesized that adding ibrutinib to nivolumab will lead to deeper and more durable responses in cHL by promoting a more favorable immune microenvironment leading to enhanced T-cell-mediated anti-lymphoma responses. We conducted a single arm, phase II clinical trial testing the efficacy of nivolumab in combination with ibrutinib in patients ≥18 years of age with histologically confirmed cHL who had received at least one prior line of therapy. Prior treatment with CPIs was allowed. Ibrutinib was administered at 560 mg daily until progression in combination with nivolumab 3 mg/kg IV every 3 weeks for up to 16 cycles. The primary objective was complete response rate (CRR) assessed per Lugano criteria. Secondary objectives included overall response rate (ORR), safety, progression free survival (PFS), and duration of response (DoR). A total of 17 patients from two academic centers were enrolled. The median age of all patients was 40 (range 20-84). The median number of prior lines of treatment was five (range 1-8), including 10 patients (58.8%) who had progressed on prior nivolumab therapy. Most treatment related events were mild (<Grade 3) and expected from the individual side effect profiles of ibrutinib and nivolumab. In the intent to treat population (n = 17), the ORR and CRR were 51.9% (9/17) and 29.4% (5/17), which did not meet the prespecified efficacy endpoint of a CRR of 50%. In patients who received prior nivolumab therapy (n = 10), the ORR and CRR were 50.0% (5/10) and 20.0% (2/10), respectively. At a median follow up of 8.9 months, the median PFS was 17.3 months, and the median DOR was 20.2 months. There was no statistically significant difference in median PFS between patients who received previous nivolumab therapy versus patients who were nivolumab naïve (13.2 months vs. 22.0 months, p = 0.164). Combined nivolumab and ibrutinib led to a CRR of 29.4% in R/R cHL. Although this study did not meet its primary efficacy endpoint of a CRR of 50%, likely due to enrollment of heavily pretreated patients including over half of who had progressed on prior nivolumab treatment, responses that were achieved with combination ibrutinib and nivolumab therapy tended to be durable even in the case of prior progression on nivolumab therapy. Larger studies investigating the efficacy of dual BTK inhibitor/immune checkpoint blockade, particularly in patients who had previously progressed on checkpoint blockade therapy, are warranted.

A real-world study to assess the association of cardiovascular adverse events (CVAEs) with ibrutinib as first-line (1L) treatment for patients with chronic lymphocytic leukaemia (CLL) in the United States.

Ibrutinib, a Bruton's tyrosine kinase inhibitor, is often used as first-line (1L) treatment of chronic lymphocytic leukaemia (CLL); however, it is associated with an increased risk for cardiovascular adverse events (CVAEs). This real-world study adds to existing literature by simultaneously investigating the correlation between pre-existing CV risk factors and the relative cardiotoxicity of ibrutinib vs other therapies in CLL/small lymphocytic lymphoma (SLL). Using a real-world database, the risk of subsequent CVAEs (any CVAE, atrial fibrillation [AF], or hypertension) were compared among patients who received 1L ibrutinib monotherapy or another type of non-ibrutinib therapy, grouped as intensive (IT) or non-intensive therapy (NIT). Each patient's baseline CV risk was estimated using the Framingham risk score. Inverse probability treatment weighting was incorporated into a logistic regression model to reduce baseline imbalance. Results showed ibrutinib was significantly associated with higher risk of CVAEs regardless of baseline CV risk. Compared with IT, odds ratios of any CVAE, hypertension, or AF were 2.61, 3.66, and 3.02, respectively vs 1.88, 2.13, and 2.46, respectively, with NIT. Sensitivity analyses confirmed the findings were robust. These results suggest clinical caution should be taken when selecting ibrutinib for patients with CLL/SLL, especially in those with high baseline CV risk.

Cutaneous Involvement of Angioimmunoblastic T-cell Lymphoma

A 74-year-old man with chronic lymphocytic leukemia and angioimmunoblastic T-cell lymphoma (AITL) of the right lung was undergoing evaluation for initiation of chemotherapy. Bendamustine and rituximab were previously initiated but stopped after one month due to adverse effects. The patient subsequently completed 7 years of ibrutinib therapy, which was halted 3 weeks prior to presentation due to its ineffectiveness and significant hematologic lab abnormalities. Treatment with CHOP (cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, prednisone) was proposed, however the patient had a nodule concerning for cellulitis on the left fifth palmar digit requiring treatment prior to chemotherapy initiation. No improvement was seen after courses of cephalexin and doxycycline. Due to a lack of response to these two antibiotics, dermatology was consulted for further evaluation.&#x0D; On physical exam, there was a 1.3-cm red-violaceous crusted nodule on the palmar aspect of the left fifth digit (Figure 1, panel A). Dermoscopy showed central orange-tan pigmentation with loss of normal acral ridge pattern and surrounding irregular vessels (Figure 1, panel B). The differential diagnosis included Sweet syndrome, drug eruption, infection, and malignancy. A punch biopsy was performed and showed an atypical lymphocytic nodular infiltrate with angioinvasive and angiodestructive features, and immunohistochemical stains suggested AITL. The patient’s clinical stage was changed from stage II to stage IV AITL due to skin involvement, and the patient was started on CHOP treatment.&#x0D; AITL is a peripheral CD4+ follicular T-helper cell-based lymphoma that presents with B symptoms and generally has a poor prognosis after conventional chemotherapies [1]. Though rare, AITL has been reported to present with skin manifestations in up to 50% of cases, which typically present as macular or papular eruptions on the trunk, similar to toxic erythema of chemotherapy, drug eruptions, or viral exanthems [2]. However, there are multiple case reports of AITL mimicking a variety of systemic dermatologic or oncologic entities, including dermatomyositis, systemic lupus erythematosus, vasculitis, and urticaria [3].&#x0D; This case of AITL with cutaneous involvement illustrates an uncommon presentation of this peripheral lymphoma that often has skin manifestations. The presence of skin involvement implies an advanced clinical stage, which confers a poorer prognosis [4]. Due to its variable presentations in the skin, it is often misdiagnosed as a vasculitis or exanthem, particularly when its initial presentation is in the skin without prior diagnosis of internal AITL malignancy [3]. As in this case, most patients are treated for their condition with chemotherapy, starting with anthracycline-based chemotherapy, and often require higher-dose or modified therapy due to the short response duration [4]. Here, we highlight the diagnostic challenge of AITL and the clinical importance of its identification for appropriate staging and treatment of this condition.

CNS-invasive aspergillosis following ibrutinib therapy

Ibrutinib is Bruton’s tyrosine kinase inhibitor that now become the standard of care for the treatment of CLL (chronic lymphocytic leukemia) and other lymphoid cancers. With its increasing usage, oncologists must become more aware of their potential side effect profile. Ibrutinib is typically thought to be less immunosuppressive than standard immunotherapy; however, can still cause devastating side effects. We present a case of CNS-invasive aspergillosis in a patient with Waldenstrom’s macroglobulinemia being managed with ibrutinib. We hypothesize that treatment with ibrutinib can resemble those with X-gammaglobulinemia, thus putting our patient at risk of developing such an invasive fungal infection. Traditional risk factors for CNS-invasive aspergillosis include neutropenia, systemic glucocorticoid treatment, mastoidectomy, spinal anesthesia and paraspinal glucocorticoid injections. Oncologists need to weigh the risks and benefits of ibrutinib therapy in certain populations and more data in the future may suggest potentially adding empiric antifungal coverage with its usage.

Targeting glutaminase is therapeutically effective in ibrutinib-resistant mantle cell lymphoma.

Mantle cell lymphoma (MCL) is an incurable B-cell non-Hodgkin lymphoma characterized by frequent relapses. The development of resistance to ibrutinib therapy remains a major challenge in MCL. We previously showed that glutaminolysis is associated with resistance to ibrutinib. In this study, we confirmed that glutaminase (GLS), the first enzyme in glutaminolysis, is overexpressed in ibrutinib-resistant MCL cells, and that its expression correlates well with elevated glutamine dependency and glutaminolysis. Furthermore, we discovered that GLS expression correlates with MYC expression and the functioning of the glutamine transporter ASCT2. Depletion of glutamine or GLS significantly reduced cell growth, while GLS overexpression enhanced glutamine dependency and ibrutinib resistance. Consistent with this, GLS inhibition by its specific inhibitor telaglenastat suppressed MCL cell growth both in vitro and in vivo. Moreover, telaglenastat showed anti-MCL synergy when combined with ibrutinib or venetoclax in vitro, which was confirmed using an MCL patient-derived xenograft model. Our study provides the first evidence that targeting GLS with telaglenastat, alone or in combination with ibrutinib or venetoclax, is a promising strategy to overcome ibrutinib resistance in MCL.

Tolerability of Acalabrutinib after Prior Ibrutinib Treatment in Patients with CLL: Experience of a Tertiary Cancer Care Center

Introduction: Treatment of chronic lymphocytic leukemia (CLL) has been revolutionized by the introduction of Bruton Tyrosine Kinase inhibitors (BTKi). Ibrutinib (IBR) and acalabrutinib (ACA) are two BTKi approved for the treatment of CLL patients (pts) with both frontline and relapsed disease. Based on its kinome inhibitory properties, IBR has more off-target kinase interactions compared to the second-generation BTKi ACA, including inhibition of ITK, HER2, HER4, and TEC, likely leading to increased off-target toxicity (Estupiñán, 2021 and McMullen, 2014). Results from the first randomized phase III trial comparing ACA to IBR in pts with previously treated CLL found a lower incidence of atrial fibrillation (Afib) with ACA (Byrd, 2021). However, there is lack of information on tolerability of ACA in pts treated outside clinical trials who had received prior IBR treatment. Our study aimed, therefore, to evaluate the real-world tolerability of ACA after IBR therapy in pts with CLL with specific attention to cardiovascular effects. Methods: All pts with CLL treated at our institution between 11/2019 and 5/2021 with ACA after prior IBR therapy were included in this study. Pts with less than 6 months of follow up were excluded unless they died prior to that period. Pts with confirmed Richter's Transformation were also excluded. All data were retrospectively obtained through institutional electronic health records, including demographics, clinical and genetic prognostic factors, toxicities, survival outcomes, duration of ACA therapy and reasons for IBR and ACA discontinuation. All grading of adverse events was completed utilizing the Common Terminology Criteria for Adverse Events (CTCAE), International Society on Thrombosis and Hemostasis (ISTH), or European Organization for Research and Treatment of Cancer (EORTC) definitions, as appropriate. All adverse events considered possibly related to BTKi are reported. A waiver of informed consent was granted for this retrospective study. Results: 52 pts treated with ACA and history of prior IBR treatment were identified (Table 1). The median age was 68 years (range, 40-92 years) and 25% were > 75 years old. ACA was administered for a median of 12.4 months (range, 0.4-43.3 months) with 19 pts (37%) requiring a dose reduction at some point during ACA treatment. The most commonly reported adverse effects during IBR treatment included arthralgia/myalgia (31%), Afib (17%), rash (15%), GI upset (12%), and hypertension (HTN, 10%). The reason for IBR treatment discontinuation was adverse effects in 47 pts (90%), progression in 4 pts (8%) and pts preference in 1 (2%). The most commonly reported adverse effects during ACA treatment included GI upset/GERD (25%), headache (17%), arthralgia/myalgia (12%), Afib (10%) and cytopenias (10%). At the time of data collection, 17 (33%) patients had discontinued ACA treatment. The reason for ACA treatment discontinuation was adverse effects in 14 pts (27%), progression in 2 pts (4%) and pt preference in 1 (2%). Specific attention was given to cardiovascular effects since a significant proportion of pts had a past medical history of cardiac comorbidities prior to ACA treatment, including history of HTN in 33 pts (63%) and Afib in 12 pts (23%). New onset Afib developed in 1 pt (2%) and recurrent Afib was observed in 4 pts (8%) during ACA therapy. The 4 pts with recurrent Afib had history of Afib while on IBR therapy. Median time to Afib events with ACA was 4.4 months (range, 0.5-13.3 months). New or worsening HTN developed in only 1 pt while on ACA therapy. Time to HTN episode was 0.2 months. There were few instances of major bleeding with either IBR (2%) or ACA (6%). Two pts (4%) developed an invasive infection while on IBR, no evidence of invasive infection has been reported in the pts receiving ACA. At the time of data collection, 3 patients have died, causes of death included sepsis, respiratory failure and multiorgan failure that were not deemed treatment-related. Conclusion: This real-world experience shows overall good tolerability of ACA after prior IBR therapy in pts with CLL. We observed a lower incidence of Afib (17% vs. 10%) and HTN (10% vs. 2%) during ACA treatment compared to IBR, even if cardiovascular co-morbidities were common among our pts. With a median follow up of 12.4 months (range, 0.4-43.3 months) since the start of ACA therapy, only 27% of pts discontinued treatment because of toxicity. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Resistance to the Non-Covalent BTK Inhibitor Pirtobrutinib

Pirtobrutinib is a non-covalent BTK inhibitor (BTKi) designed to maintain activity despite the most common resistance mutation to covalent inhibitors, at BTK C481. To investigate mechanisms of disease progression on pirtobrutinib, we evaluated the effect of pirtobrutinib in vitro on the BCR pathway in pre- and post-treatment patient samples (n=5), and on 2 of these patients, we performed whole exome sequencing longitudinally including prior to and at relapse on pirtobrutinib. Phylogenetics and subclonal dynamics associated with resistance were evaluated using the PhylogicNDT and Concerti tools. To investigate the impact of identified BTK mutations on BCR activation, we generated 6 single and 3 double mutants using site directed mutagenesis and expressed them in the BTK null DT40 B cell line. We demonstrate that primary CLL cells from responding patients on the pirtobrutinib trial show reduced BCR signaling, reduced CCL3/CCL4 chemokine secretion, as well as effective induction of apoptosis and inhibition of proliferation, in response to pirtobrutinib. At time of progression, these primary CLL cells show increasing resistance to pirtobrutinib in signaling inhibition and cytokine production, with reduced inhibition of proliferation and induction of apoptosis. In WES analysis, patient #1 had 16 samples evaluated prior to, during, and at relapse on acalabrutinib, vecabrutinib and pirtobrutinib. Clonal analysis of samples collected during acalabrutinib shows steady selection of a clone harboring BTK p.C481S mutation with CCF 92% at relapse but then steadily decreases during pirtobrutinib treatment. Concerti's time-scaled phylogenetic tree shows the birth of a new clone containing the BTK gatekeeper mutation, p.T474I, during acalabrutinib treatment, which then grows rapidly under pirtobrutinib treatment, taking over nearly the entire cancer cell population and replacing the prior p.C481S clone. This complete clonal shift during pirtobrutinib treatment suggests that pirtobrutinib effectively inhibits the p.C481S clone, while the p.T474I gatekeeper clone is likely driving resistance in this patient. We also observed an additional gatekeeper clone BTK p.T474L develop at low levels, as well as another previously undescribed BTK mutation at p.M477I. Manual inspection showed that BTK mutations p.M477I and p.T474I are in cis and therefore in the same clone. Patient #2 had 10 samples evaluated prior to, during and at relapse on ibrutinib and pirtobrutinib. During ibrutinib therapy, we observed a steady increase in a clone with TP53 p.S240G and SF3B1 p.K666N mutations, reaching CCFs >40% at relapse on ibrutinib. We also noted a significant increase in BTK p.C481R (CCF 33%), BTK p.C481S (CCF 11%) and TP53 p.R196* (CCF 5%) at progression on ibrutinib. Under pirtobrutinib treatment the clone carrying BTK p.C481R decreased to CCF 20%, while BTK p.C481S (28%) and TP53 p.R197* (35%) both increased. Concerti's phylogenetic tree captures the birth of a resistant clone, harboring BTK p.L528W which significantly increases to CCF 30% at progression on pirtobrutinib. Functional characterization of the identified BTK mutations demonstrated that only T474I, T474L and C481S mutants showed adequate kinase activity, while all the other mutants including M477I, C48IR and L528W essentially lacked kinase activity as judged by phosphorylation at BTK Y223 and at PLCG2 Y753. As expected, the C481S variant was resistant to ibrutinib, but not to pirtobrutinib, while the T474I/L variants were sensitive to ibrutinib but resistant to pirtobrutinib. Interestingly, phosphorylation of AKT and ERK were retained downstream, even with mutations that failed to activate proximal BCR signaling. Furthermore, phosphorylation of AKT and ERK was also observed in the B7.10 cell line which lacks endogenous BTK, demonstrating significant activation of these pathways independent of BTK. In this study, we demonstrate that ex vivo efficacy of pirtobrutinib declines as patients’ CLL starts to progress, in concert with the development of gatekeeper and alternative site BTK mutations that lead to resistance to pirtobrutinib. Interestingly, many of the second-site BTK mutations fail to activate BTK phosphorylation but are still associated with downstream activation of phospho-AKT and phospho-ERK; the mechanism of this activation remains to be elucidated.

Ibrutinib-Associated Sudden Death in Patients with CLL

INTRODUCTION: Ibrutinib therapy is associated with an increased risk of cardiac arrhythmias. There is currently no standard for cardiac screening or monitoring in patients on ibrutinib and it remains unknown which factors predispose patients to serious or fatal arrhythmias. METHODS: We report a retrospective cohort study of patients with chronic lymphocytic leukemia (CLL) on ibrutinib-based therapies at the NIH Clinical Center from 2012-2022. Electronic medical records were reviewed for cardiac symptoms, cardiac testing, and autopsy reports. Patients with sudden death were analyzed for 41 genes associated with inherited and syndromic conditions involving cardiac arrhythmias (Invitae). Serum concentrations of ibrutinib from stored samples were measured. RESULTS: A total of 131 patients with CLL received ibrutinib-based therapy (128 single-agent ibrutinib and 3 ibrutinib-duvelisib). Five patients (3.82%) had sudden death over an observation period of 624 patient-years. At time of death, 4 patients were receiving ibrutinib monotherapy and 1 was receiving ibrutinib in combination with duvelisib. The median age of sudden death was 62 (range 48-70) and the median duration of ibrutinib treatment at time of death was 21 months (range 0.1-56.2). All patients with sudden death had elevated body mass indices, 4 had pre-existing concurrent hypertension and hyperlipidemia, 2 had cardiac symptoms prior to starting ibrutinib (palpitations, chest pain, dizziness, dyspnea on exertion), and only 1 developed cardiac symptoms while on ibrutinib (palpitations at 33 months). Three patients had documented arrhythmias while on ibrutinib, including 2 with occasional ectopy and bradycardia on resting EKG and 1 with ventricular couplets on exercise stress test. In serum samples collected 0.1-8.1 months prior to death, only 1 patient had an elevated ibrutinib concentration of 278.18 ng/mL, above the expected average Cmax of 190 ng/mL after a 420mg dose of ibrutinib (Advani et al. J Clin Oncol, 2013). Genetic analysis revealed no pathologic variants associated with cardiac arrhythmia genes, but did show 2 different variants of uncertain significance in 2 patients. Autopsies were performed in 3 patients and identified structural cardiac abnormalities in 2 patients: 1 with hypertensive cardiomyopathy and another with cardiovascular dysplasia and fibrotic bundle branches. None of the autopsies showed obstructive coronary artery disease, heart failure, ischemia, embolism, or other apparent cause of sudden death. DISCUSSION: Continuous ibrutinib therapy until disease progression or treatment toxicity is a treatment strategy widely used in CLL. However, limited data are available regarding the relationship between ibrutinib, ventricular arrhythmias, and sudden death. The incidence of sudden death in our study was 801 per 100,000 patient-years, which is similar to a previous estimate of 788 per 100,000 patient-years among ibrutinib-treated patients (Lampson et al. Blood, 2017) and higher than 102 per 100,000 patient-years (95% CI 24-180) in an age-matched cohort (Maruyama et al. BMJ Open, 2012). One patient showed cardiovascular dysplasia and fibrosis at autopsy; interestingly, pre-clinical data in mice showed ibrutinib-induced myocardial fibrosis as a contributing factor to the development of atrial fibrillation (Xiao et al. Circulation, 2020). However, autopsies could not identify a common cause of death between the 3 patients. CONCLUSION: Early identification of cardiac arrhythmias on treatment may prevent serious arrhythmias and sudden death. Recently introduced guidance in the ibrutinib prescribing information describes dose reductions or discontinuation at the first occurrence of grade 2 or higher cardiac failure or arrhythmia in patients with CLL. Further research is warranted to identify risk mitigation strategies.