Cardiovascular events of Bruton's tyrosine kinase inhibitors: A real-world study based on the United States Food and Drug Administration Adverse Event Reporting System database.

AIMS: Bruton's tyrosine kinase inhibitors (BTKIs), including first-generation ibrutinib, second-generation acalabrutinib and zanubrutinib, may be involved in the mechanisms of action related to adverse events (AEs) of the cardiovascular system. We aimed to characterize the cardiovascular AEs of BTKIs reported in the US Food and Drug Administration (FDA) Adverse Event Reporting System, and to compare the cardiovascular risks of BTKIs. METHODS: Across all indications of three FDA-approved BTKIs, primary suspect drugs were extracted over two periods: from January 2013 to December 2022 (after the approval of the first BTKI), and from January 2020 to December 2022 (all three BTKIs on the market). Disproportionality was measured by reporting odds ratios (RORs) and information components. Additional analyses were performed without incorporating patients with underlying cardiovascular disease (CVD). RESULTS: A total of 10 353 cases included the uses of ibrutinib, acalabrutinib and zanubrutinib. Ibrutinib was significantly associated with 47 cardiovascular AEs. Acalabrutinib was associated with new signals, including cardiac failure (ROR = 1.82 [1.13-2.93]), pulmonary oedema (ROR = 2.15 [1.19-3.88]), ventricular extrasystoles (ROR = 5.18 [2.15-12.44]), heart rate irregular (ROR = 3.05 [1.53-6.11]), angina pectoris (ROR = 3.18 [1.71-5.91]) and cardiotoxicity (ROR = 25.22 [17.14-37.10]). In addition, cardiovascular events had an earlier onset in acalabrutinib users. Zanubrutinib was only associated with atrial fibrillation. Acalabrutinib and zanubrutinib had lower ROR values than ibrutinib. The AE signals were generally consistent between the population receiving and not receiving CVD medications. CONCLUSIONS: Potential cardiovascular risks identified in this study were not clearly noted on the label of marketed acalabrutinib. Caution should be paid to the cardiovascular risks of BTKIs having been or being developed.

Mast Cell-Targeting Therapies in Mast Cell Activation Syndromes.

PURPOSE OF REVIEW: Provide an overview of the expanding landscape of mast cell (MC)-targeting treatments in mast cell activation syndromes (MCAS). RECENT FINDINGS: Tyrosine-kinase inhibitors (TKIs) targeting wild-type and mutated KIT can efficiently induce MC depletion. Avapritinib and midostaurin can also temper IgE-mediated degranulation. Avapritinib has been recently approved by the FDA for the treatment of indolent systemic mastocytosis (ISM). Targeting activation pathways and inhibitory receptors is a promising therapeutic frontier. Recently, the anti Siglec-8 antibody lirentelimab showed promising results in ISM. MCAS is a heterogeneous disorder demanding a personalized therapeutic approach and, especially when presenting as anaphylaxis, has not been formally captured as outcome in prospective clinical trials with TKI. Long-term safety of TKI needs to be addressed. New drugs under investigation in diseases in which non-neoplastic MCs play a pivotal role can provide important inputs to identify new efficient and safe treatments for MCAS.

Clinical and therapeutic challenges of smouldering multiple sclerosis.

INTRODUCTION: Assessment of the clinical course, neuroimaging and histopathological changes suggests that multiple sclerosis (MS) should not be defined merely as a focal inflammatory disease of the central nervous system (CNS) because the essence of the disease is due to a diffuse, 'smouldering', pathophysiological process. STATE OF THE ART: Progression independent of relapse activity (PIRA) is the clinical indicator of smouldering MS. Multiple pathomechanical factors determining smouldering MS have been identified, i.e. continuous activation of microglia, which is the source of smouldering inflammation and the failure of remyelination in MS. CLINICAL IMPLICATIONS: Our paper presents new neuroimaging markers, including paramagnetic rim lesions (PRLs) and slowly expanding lesions (SELs), potential methods for clinical evaluation and promising therapeutic options, i.e. Bruton's tyrosine kinase inhibitors that prevent PIRA in smouldering MS. With the duration of MS, the efficacy of the current immunomodulatory treatment is reduced, and its effect is insufficient to control smouldering MS. FUTURE DIRECTIONS: Innovative insights into the pathophysiology and clinical course warrant the need for a holistic approach to MS. The efforts of clinicians should be aimed at indicating subtle neurological deficits in physical performance and cognitive functioning to characterise the disease progression in its early stages. Undoubtedly, a new era for MS is coming in which new resonance markers will be used together with clinical methods to assess smouldering MS, and the treatment will include combination therapy with consideration of drugs that reduce relapse rates and therapy aimed at inhibiting disease progression.

Novel combination approaches with targeted agents in frontline chronic lymphocytic leukemia.

Targeted therapies have revolutionized the frontline treatment landscape for patients with chronic lymphocytic leukemia (CLL) and have largely displaced a reliance on chemoimmunotherapy when treating this disease. Multiple randomized trials have documented the efficacy of oral therapy with the Bruton tyrosine kinase inhibitors ibrutinib and acalabrutinib (and zanubrutinib, pending a supplemental new drug application in CLL), as well as BCL2 inhibition using venetoclax. In this review, the authors highlight novel therapeutic strategies for using these agents in combination, either as doublet therapy or as triplet therapy, with anti-CD20 antibodies. First, the current treatment landscape is outlined, and the data are reviewed for continuous and time-limited therapeutic approaches, which constitute the current standard of care. Then, more recent reports are described from phase 2 and 3 studies exploring different combination strategies of Bruton tyrosine kinase and BCL2 inhibition for treatment-naive patients. In addition, relevant differences are emphasized between patient characteristics (e.g., patient fitness and the presence of high-risk disease features) and study methodology (e.g., dosing schedule, randomization, and assessment of measurable residual disease) across trials. Finally, the authors revisit the currently available data for these approaches in the context of ongoing studies and future planned trials, evaluating their potential impact on the frontline treatment landscape for CLL in the years to come.

Efficacy and safety-related factors of BTK inhibitors as a bridge to CAR-T therapy in R/R FL.

Although anti-CD19 chimeric antigen receptor (CAR) T cell therapy has achieved satisfactory results in relapsed/refractory (R/R) follicular lymphoma (FL), patients with R/R FL and high-risk disease characteristics, previous hematopoietic stem cell transplantation, bulky disease, and progression of disease within 2 years (POD24) had a low complete response (CR). Twenty-seven patients with R/R FL, later disease stages, higher tumor burden, or higher previous treatment lines who had received Bruton tyrosine kinase (BTK) inhibitors before anti-CD19 CAR T cell therapy, or received BTK inhibitors as combination therapy, were included in this study. The clinical response and adverse events (AEs) in anti-CD19 CAR T cell therapy were observed. All patients with R/R FL who received BTK inhibitors combined with anti-CD19-CAR T cell therapy had later disease stages, higher tumor burden, and higher treatment lines than those who did not receive BTK inhibitor combination therapy. However, no difference in the clinical response was found between the two groups. The clinical response in the POD24 group was lower than that in the non-POD24 group; however, no difference in the clinical response was found between the FL and transformed FL (tFL) groups, between the follicular lymphoma international prognostic index (FLIPI) 1 1-2 and FLIPI 1 3-5 groups, and between the FLIPI 2 1-2 and FLIPI 2 3-5 groups. The mean anti-CD19 CAR T cell peak was higher in the CAR-T group with BTK inhibitor than in the CAR-T group without BTK inhibitor. Meanwhile, a higher proportion of patients in the non-POD24 group, FL group, and PR group achieved CR after 2 months. No difference in cytokine secretion was found between the CAR-T group with and without BTK inhibitors. It was higher in the non-POD24 group, FLIPI 1 3-5 group, and FLIPI 2 3-5 group. No difference in cytokine release syndrome and immune effector cell-associated neurotoxic syndrome grades was found between the CAR-T groups with or without BTK inhibitors and between the other groups. Poor prognostic factors, other than POD24, did not affect the clinical response to BTK inhibitors in combination with anti-CD19 CAR T cell therapy in patients with R/R FL. Therefore, BTK inhibitors combined with anti-CD19 CAR-T therapy may be an effective and safe approach for patients with R/R FL and high-risk factors.Trial registration: The study was registered at http://www.chictr.org.cn/index.aspx as ChiCTR-ONN-16009862 and http://www.chictr.org.cn/index.aspx as ChiCTR1800019622.

Molecular-Biology-Driven Frontline Treatment for Chronic Lymphocytic Leukemia: A Network Meta-Analysis of Randomized Clinical Trials.

The treatment of chronic lymphocytic leukemia (CLL) currently relies on the use of chemo-immunotherapy, Bruton's tyrosine kinase inhibitors, or BCL2 inhibitors alone or combined with an anti-CD20 monoclonal antibody. However, the availability of multiple choices for the first-line setting and a lack of direct head-to-head comparisons pose a challenge for treatment selection. To overcome these limitations, we performed a systematic review and a network meta-analysis on published randomized clinical trials performed in the first-line treatment setting of CLL. For each study, we retrieved data on progression-free survival (according to del17/P53 and IGHV status), overall response rate, complete response, and incidence of most frequent grade 3-4 adverse event. We identified nine clinical trials encompassing 11 different treatments, with a total of 5288 CLL patients evaluated. We systematically performed separated network meta-analyses (NMA) to evaluate the efficacy/safety of each regimen in the conditions previously described to obtain the surface under the cumulative ranking curve (SUCRA) score, which was subsequently used to build separated ranking charts. Interestingly, the combination of obinutuzumab with acalabrutinib reached the top of the chart in each sub-analysis performed, with the exception of the del17/P53mut setting, where it was almost on par with the aCD20 mAbs/ibrutinib combination (SUCRA aCD20-ibrutinib and O-acala: 93.5% and 91%, respectively) and of the safety evaluation, where monotherapies (acalabrutinib in particular) gave better results. Finally, considering that NMA and SUCRA work for single endpoints only, we performed a principal component analysis to recapitulate in a cartesian plane the SUCRA profiles of each schedule according to the results obtained in each sub-analysis, confirming again the superiority of aCD20/BTKi or BCL2i combinations in a first-line setting. Overall, here we demonstrated that: (1) a chemotherapy-free regimen, such as the combination of aCD20 with a BTKi or BCL2i, should be the preferred treatment choice despite biological/molecular characteristics (preferred regimen O-acala); (2) there is less and less room for chemotherapy in the first line treatment of CLL.

Bruton's Tyrosine Kinase Inhibitors (BTKIs): Review of Preclinical Studies and Evaluation of Clinical Trials.

In the last few decades, there has been a growing interest in Bruton's tyrosine kinase (BTK) and the compounds that target it. BTK is a downstream mediator of the B-cell receptor (BCR) signaling pathway and affects B-cell proliferation and differentiation. Evidence demonstrating the expression of BTK on the majority of hematological cells has led to the hypothesis that BTK inhibitors (BTKIs) such as ibrutinib can be an effective treatment for leukemias and lymphomas. However, a growing body of experimental and clinical data has demonstrated the significance of BTK, not just in B-cell malignancies, but also in solid tumors, such as breast, ovarian, colorectal, and prostate cancers. In addition, enhanced BTK activity is correlated with autoimmune disease. This gave rise to the hypothesis that BTK inhibitors can be beneficial in the therapy of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), Sjögren's syndrome (SS), allergies, and asthma. In this review article, we summarize the most recent findings regarding this kinase as well as the most advanced BTK inhibitors that have been developed to date and their clinical applications mainly in cancer and chronic inflammatory disease patients.

The safety of Bruton's tyrosine kinase inhibitors in B-cell malignancies: A systematic review.

B-cell malignancies, most notably lymphomas, make up most of the non-Hodgkin lymphomas in the United States. There are limited randomized data comparing first- and second-generation Bruton tyrosine kinase (BTK) inhibitors. Our aim was to compare the safety profiles of first versus second-generation BTK inhibitors. A systematic search was performed from database inception to January 13, 2020. Studies with BTK inhibitor monotherapy for the treatment of B-cell malignancies in the adult population (>18 years old) were utilized and the adverse events (AEs) were extracted. Fifty-five studies that met the inclusion criteria were included in the systematic review with 41 studies with first generation and 14 studies with second generation. The review included both clinical trials and retrospective studies with average time of follow-up of 2 years for the first-generation group and 18 months for the second-generation group. We found that the incidence of cardiovascular AEs was significantly higher in the first-generation group (20.8%) as compared to the second-generation group (6.3%). However, there was a higher incidence of hematologic/oncologic and gastrointestinal side effects in the second-generation group compared to the first (62.3% compared to 39.2% and 36.9% compared to 28.9%). The number of Grade 5 cardiovascular events (death) was same in the first-generation group compared to the second generation. Further research is needed to develop highly selective BTK inhibitors to avoid unwanted AEs by minimizing off-targets.

Acute gout flare of bilateral first metatarsophalangeal joints due to ibrutinib use in chronic lymphocytic leukemia.

INTRODUCTION: Bruton tyrosine kinase inhibitors represent important tools in the therapeutic armamentarium against chronic lymphocytic leukemia (CLL) and other B-lymphoproliferative disorders. CASE REPORT: We describe herein a unique 65-year-old patient who presented with bilateral foot pain four months after starting treatment with ibrutinib for CLL. Of note, the patient had previously been diagnosed with gout, and was taking allopurinol prophylactically at the time of the event. Compliance with allopurinol was in excess of 99%. Yet, he was diagnosed with acute gout flare of bilateral first metatarsophalangeal (MTP) joints.Management & Outcome: Ibrutinib dose was reduced by one third, and the patient's gout flare up was treated with ibuprofen as needed. After symptoms abated, ibrutinib was continued at 2/3rds of the dose, with an excellent CLL control. The patient tolerated this dose without any further adverse effects.Discussion/Conclusions: We have reported a unique side effect of acute bilateral first MTP joint gout flare likely triggered by ibrutinib use for CLL while the patient was taking a xanthine oxidase inhibitor. The mechanism by which ibrutinib caused this phenomenon remains to be elucidated.

Ibrutinib protects T cells in patients with CLL from proliferation-induced senescence.

BACKGROUND: The development of Bruton's tyrosine kinase inhibitors (BTKi) for the treatment of chronic lymphocytic leukaemia (CLL) has provided a highly effective and relatively non-toxic alternative to conventional chemotherapy. Some studies have shown that BTKi can also lead to improvements in T cell immunity in patients despite in vitro analyses suggesting an immunosuppressive effect of BTKi on T cell function. METHODS: In this study, we examined both the in vitro effect and long-term in vivo effect of two clinically available BTKi, ibrutinib and zanubrutinib. Additional in vitro assessments were undertaken for a third BTKi, acalabrutinib. Immune subset phenotyping, cytokine secretion, T cell degranulation and proliferation assays were performed on peripheral blood mononuclear cells isolated from untreated CLL patients, and CLL patients on long-term (> 12 months) BTKi treatment. RESULTS: Similar to prior studies we observed that long-term BTKi treatment normalises lymphocyte subset frequency and reduces PD-1 expression on T cells. We also observed that T cells from patients taken prior to BTKi therapy showed an abnormal hyper-proliferation pattern typical of senescent T cells, which was normalised by long-term BTKi treatment. Furthermore, BTKi therapy resulted in reduced expression of the T cell exhaustion markers PD-1, TIM3 and LAG3 in late generations of T cells undergoing proliferation. CONCLUSIONS: Collectively, these findings indicate that there are critical differences between the in vitro effects of BTKi on T cell function and the effects derived from long-term BTKi exposure in vivo. Overall long-term exposure to BTKi, and particularly ibrutinib, resulted in improved T cell fitness in part due to suppressing the abnormal hyper-proliferation of CLL T cells and the associated development of T cell senescence.

Current and Emerging Treatments for Waldenström Macroglobulinemia.

Waldenström macroglobulinemia (WM) is a rare lymphoplasmacytic lymphoma. The primary goal of therapy is to reduce symptoms related to direct infiltration of the bone marrow and decrease monoclonal IgM-associated complications. Active agents in the management of WM can be broadly classified as rituximab-alkylator combination therapy, proteasome inhibitor-based therapy, and Bruton's tyrosine kinase inhibitor-based therapy. MYD88L265P and CXCR4 genetic status are pivotal for tailoring treatment options. Ibrutinib is a suitable treatment option for both treatment-naïve and relapsing WM patients. Recent advances in the intracellular B cell and cytokine signaling pathways have contributed to the development of novel therapeutic strategies. Current clinical trials are promising and may further advance WM-directed therapy.

Current Treatment of Refractory/Relapsed Chronic Lymphocytic Leukemia: A Focus on Novel Drugs.

Recently, the use of novel targeted drugs has changed the treatment paradigms in chronic lymphocytic leukemia (CLL). Among the several drugs used for the management of relapsed/refractory (R/R) CLL, Bruton tyrosine kinase inhibitors (ibrutinib and acalabrutinib), phosphatidylinositol 3-kinase inhibitors (idelalisib and duvelisib), B-cell lymphoma 2 inhibitor (venetoclax), and novel CD20 monoclonal antibodies have demonstrated the greatest improvements in survival among R/R CLL patients. However, patients with relapsed but asymptomatic CLL do not need immediate alternative treatment and should be observed until evident sign of progression. Among available approved treatments, venetoclax + rituximab for 24 months or ibrutinib as continuous therapy is recommended. Another, less recommended, option is idelalisib in combination with rituximab. The correct treatment selection depends on the type of prior therapy, response to previous treatment and side effects, presence of comorbidities, and the risk of drug toxicity. Allogeneic hematopoietic stem cell transplantation and investigational therapies such as chimeric antigen receptor-T-cell therapy are promising treatment options for high-risk patients, including those progressing after 1 or more targeted therapies. The present review discusses current treatment strategies for patients with R/R CLL.

Sequencing of Novel Therapies for Mantle Cell Lymphoma.

OPINION STATEMENT: There is no standard approach to sequencing novel therapies in mantle cell lymphoma (MCL). For initial treatment, intensive induction chemotherapy followed by autologous stem cell transplant and rituximab maintenance remains our preferred approach in young, fit patients. We consider bendamustine plus rituximab or lenalidomide plus rituximab in patients who are ineligible for intensive chemotherapy-based approaches. Bruton's tyrosine kinase inhibitors are our preferred class of agents to use in the second-line setting. When patients inevitably relapse on one of these agents, we proceed with chimeric antigen receptor T-cell (CAR T) therapy in eligible patients, often with the use of bridging therapy with corticosteroids, lenalidomide, or venetoclax. We treat patients who are ineligible for CAR T or clinic trial with venetoclax, lenalidomide, or proteosome inhibitor-based regimens, although efficacy is expected to be limited in this setting with a shortened duration of response to each subsequent line of therapy. Allogeneic stem cell transplant remains an option for carefully selected patients who progress after autologous stem cell transplant and CAR T. Clinical trials involving combinations of novel agents in early lines of therapy are ongoing, and new compounds with unique mechanisms of action are in development. The results of ongoing clinical trials with novel agents will further change the treatment landscape for patients with MCL in the coming years.

[Successful treatment with silver nitrate chemical cauterization for paronychia and granulation in a patient with chronic lymphocytic leukemia undergoing ibrutinib therapy].

A 72-year-old man with leukocytosis, anemia, and lymphadenopathy was diagnosed with chronic lymphocytic leukemia (CLL) in August 2017 and was carefully monitored in a "watch-and-wait" manner until it became an "active disease." Ibrutinib (IBR) was initiated orally in July 2018 at a dose of 420 mg/day after disease progression due to chromosome 17p deletion (del 17p). The patient showed partial response after transient lymphocytosis while on IBR treatment. IBR induces paronychia and skin disorder due to the disruption of disulfide bonds between cysteine and inhibition of epidermal growth factor receptor due to the off-target effect. This results in reduced quality of life. In February 2019, paronychia (grade 1) developed in the patient's right foot's first toe; hence, topical gentamicin and taping therapy were performed. However, the symptoms persisted without any improvements. In July 2019, paronychia/granulation (grade 2) was aggravated and successfully treated with silver nitrate chemical cauterization and taping therapy. The patient was continuously treated with 420 mg/day IBR without dose reduction or discontinuation, resulting in successful disease control of CLL with del 17p.

Ibrutinib monotherapy outside of clinical trial setting in Waldenström macroglobulinaemia: practice patterns, toxicities and outcomes.

Ibrutinib-related data in Waldenström macroglobulinaemia (WM) remain sparse, particularly outside of trials. We report on 80 patients [previously treated, n = 67 (84%), treatment-naïve, n = 13 (16%)] with WM, evaluated consecutively at Mayo Clinic, who received ibrutinib off-study after its approval in 2015 for WM. Overall response rate (ORR) was 91%; major-response rate (MRR) was 78%. The median time to first response and best response was 2·9 [95% confidence interval (CI): 2-4] and 5·7 (95% CI: 4-12) months, respectively. The median follow-up was 19 (95% CI: 14-21) months; 18-month progression-free survival (PFS) was 82%. The median time on therapy was 12·5 (95% CI: 9·3-16·7) months, and the median duration-of-response was 32 (range: 23-32) months. Twenty-five patients (31%) had discontinued therapy at last follow-up (68% due to treatment-related toxicities) and 18% of patients required dose reduction. Fatigue (12%) and atrial-fibrillation (11%) were common non-haematological toxicities. IgM rebound occurred in 36% of patients who abruptly discontinued ibrutinib. Following ibrutinib discontinuation, 84% of patients received subsequent treatment, achieving an ORR of 57% and MRR of 50%. The median PFS from commencement of subsequent salvage therapy was 18 months. Ibrutinib therapy, outside of clinical trials, is effective in WM, but is associated with toxicities and challenges, including IgM rebound and a high drug discontinuation rate for reasons other than disease progression.

Emerging bruton tyrosine kinase inhibitors for chronic lymphocytic leukaemia: one step ahead ibrutinib.

Introduction: In the last few years, the expansion of therapy with pathway inhibitors has revolutionized the treatment landscape of chronic lymphocytic leukemia (CLL). As a matter of fact, ibrutinib, the first-in-class Bruton tyrosine kinase (BTK) inhibitor, became a milestone in the treatment of both naïve or relapsed/refractory CLL patients. Most patients treated with such an agent achieve durable clinical response; however, a deeper response is rarely reached and continuous treatment is required. Since ibrutinib-resistant CLL clones can develop in about 20% of patients and toxicities, leading to drug discontinuation, occur in about 30% of patients treated with ibrutinib, several new BTK inhibitors have been developed in order to lower off-target effects and overcome ibrutinib resistance.Areas covered: In this review, we summarize the main English publications exploring efficacy and side effects of first and next-generation BTK inhibitors. Results of clinical trials evaluating these novel agents are presented and critically discussed.Expert opinion: Efforts in the development of highly specific second-generation BTK inhibitors and combination strategies provide challenging options to overcome limitations of therapy with ibrutinib. It is also crucial to identify additional risk factors and to understand disease biology underlying clonal evolution of CLL in the context of novel agents.

Ibrutinib in the management of Waldenstrom macroglobulinemia.

Bruton tyrosine kinase plays a critical role in hastening cell proliferation. Bruton tyrosine kinase inhibitors are a class of immunotheraputic agents that disrupt this signaling pathway. Ibrutinib, a novel Bruton tyrosine kinase inhibitor approved by the Food and Drug Administration (FDA) for the treatment of Waldenstrom macroglobulinemia in patients who have failed treatment with other agents, has emerged as an important therapeutic agent in the management of Waldenstrom macroglobulinemia and other plasma cell dyscrasias. Ibrutinib has shown to increase progression free survival and improve overall mortality. We present a review of ibrutinib, beginning with an overview of the Bruton tyrosine kinase pathway and clinically relevant gene mutations impacting treatment and prognosis for patients with Waldenstrom macroglobulinemia, followed by evidence supporting therapeutic indications for ibrutinib, and detailing its safety and efficacy evidence, current clinical guidelines, adverse effects and their management, and finally challenges of drug resistance. We also present findings on newly developed Bruton tyrosine kinase inhibitors in the therapeutic pipeline to provide readers insight into this rapidly evolving corner of oncology pharmacy practice.

Harnessing the Effects of BTKi on T Cells for Effective Immunotherapy against CLL.

B-cell receptor (BCR) signaling and tumor-microenvironment crosstalk both drive chronic lymphocytic leukemia (CLL) pathogenesis. Within the microenvironment, tumor cells shape the T-cell compartment, which in turn supports tumor growth and survival. Targeting BCR signaling using Bruton tyrosine kinase inhibitors (BTKi) has become a highly successful treatment modality for CLL. Ibrutinib, the first-in-class BTKi, also inhibits Tec family kinases such as interleukin-2-inducible kinase (ITK), a proximal member of the T-cell receptor signaling cascade. It is increasingly recognized that ibrutinib modulates the T-cell compartment of patients with CLL. Understanding these T-cell changes is important for immunotherapy-based approaches aiming to increase the depth of response and to prevent or treat the emergence of resistant disease. Ibrutinib has been shown to improve T-cell function in CLL, resulting in the expansion of memory T cells, Th1 polarization, reduced expression of inhibitory receptors and improved immune synapse formation between T cells and CLL cells. Investigating the modulation of BTKi on the T-cell antitumoral function, and having a more complete understanding of changes in T cell behavior and function during treatment with BTKi therapy will inform the design of immunotherapy-based combination approaches and increase the efficacy of CLL therapy.