Richter transformation (RT) represents the development of intrusive lymphoma in individuals previously or concurrently diagnosed with chronic lymphocytic leukemia (CLL) and is characterized by lymph node enlargement. However, cases involving extra-nodal organ involvement as the first symptom are rare. There are no reports of RT with breast lesions as the first symptom. Nonspecific and atypical clinical manifestations represent key challenges in the accurate diagnosis and appropriate treatment of RT. This case report describes an elderly female patient who presented with breast lesions as the first RT symptom. The patient was admitted with a painless mass in the left breast. Examination revealed multiple lymphadenopathies and abnormally high white blood cell levels. The patient was diagnosed with CLL after hematological tests, assessments of bone marrow morphology, and tissue biopsy. Mammography and B-ultrasonography showed solid space-occupying lesions (BI-RADS category 5) in the left breast. Initially, the patient declined a breast biopsy and was therefore prescribed ibrupotinib treatment, which showed limited efficacy. A needle biopsy of the affected breast indicated the presence of diffuse large B-cell lymphoma. Based on auxiliary and pathological examinations and medical history, the final diagnosis was RT with breast involvement. Zanubrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone treatment provided initial control; however, the treatment strategy required adjustment because of the patient\'s fluctuating condition. The current status of the patient is marked as stable, showing an overall achievement of partial alleviation. The patient is in the process of receiving follow-up treatment. We also performed a comprehensive literature review on RT, with particular emphasis on its biological paradigm, prognosis implications, existing therapeutic approaches, and emerging directions in treatment modalities.

Bruton\'s Tyrosine Kinase (BTK) inhibitors have become one of the most vital drugs in the therapy of chronic lymphocytic leukemia (CLL). Inactivation of BTK disrupts the B-cell antigen receptor (BCR) signaling pathway, which leads to the inhibition of the proliferation and survival of CLL cells. BTK inhibitors (BTKi) are established as leading drugs in the treatment of both treatment-naïve (TN) and relapsed or refractory (R/R) CLL. Furthermore, BTKi demonstrate outstanding efficacy in high-risk CLL, including patients with chromosome 17p deletion, TP53 mutations, and unmutated status of the immunoglobulin heavy-chain variable region (IGHV) gene. Ibrutinib is the first-in-class BTKi which has changed the treatment landscape of CLL. Over the last few years, novel, covalent (acalabrutinib, zanubrutinib), and non-covalent (pirtobrutinib) BTKi have been approved for the treatment of CLL. Unfortunately, continuous therapy with BTKi contributes to the acquisition of secondary resistance leading to clinical relapse. In recent years, it has been demonstrated that the predominant mechanisms of resistance to BTKi are mutations in BTK or phospholipase Cγ2 (PLCG2). Some differences in the mechanisms of resistance to covalent BTKi have been identified despite their similar mechanism of action. Moreover, novel mutations resulting in resistance to non-covalent BTKi have been recently suggested. This article summarizes the clinical efficacy and the latest data regarding resistance to all of the registered BTKi.

Cardiovascular adverse events (CVAEs) are common adverse effects of first-generation Bruton tyrosine kinase inhibitors (BTKis) and limit their use considerably. This led to the development of second-generation BTKis-acalabrutinib and zanubrutinib-which are more selective, potent, and presumed to have better safety profiles than the previous group of medications. However, there have been sporadic reports of CVAEs associated with second-generation BTKis in clinical practice. To address this issue, a comprehensive meta-analysis to pool the documented CVAEs was performed, including major hemorrhage, any bleeding, atrioventricular block, atrial fibrillation/flutter, pericardial effusion, pericarditis, heart failure, cardiac arrest, myocardial infarction, hypertension, hypotension, and stroke. This meta-analysis incorporated 8 studies. Among these, 6 were Phase III trials and 2 were Phase II trials. These studies collectively enrolled a total of 2938 patients.
Multiple databases, including PubMed, MEDLINE, Cochrane Library, Scopus, and EMBASE, were systematically searched for relevant clinical trials from inception through January 14, 2023. The effect measure used was odds ratio (OR) and 95% CI.
Of a total of 1774 studies identified during the initial database search, 8 were included in the meta-analysis. The incidence of overall and cardiovascular mortality was comparable between the 2 groups. There were no significant differences observed for cardiovascular mortality (OR = 0.36; 95% CI, 0.08-1.65; n = 2588; I2 = 45%; P = 0.19). Similar results were found for all-cause mortality (OR = 0.85; 95% CI, 0.67-1.07), any bleeding (OR = 1.90; 95% CI, 0.88-4.09), major bleeding (OR = 1.07; 95% CI, 0.65-1.76), atrioventricular block (OR = 0.74; 95% CI, 0.15-3.68), atrial fibrillation/flutter (OR = 0.74; 95% CI, 0.37-1.50), and other CVAEs associated with second-generation BTKis.
Based on the available evidence, there is no indication of worse cardiovascular outcomes or superiority of second-generation BTKis compared with standard treatments in terms of safety profile. However, additional large-scale controlled trials are needed to provide robust support for the superior tolerability of new-generation BTKis.

UNASSIGNED: The pharmacology, pharmacokinetics, pharmacodynamics, clinical efficacy, and safety of zanbrutinib are described.
UNASSIGNED: Mantle cell lymphoma (MCL) is a mature B-cell lymphoma that is typically associated with unfavorable outcomes, and virtually all patients with MCL have refractory or relapsed disease despite aggressive treatment. The treatment paradigm for MCL has transformed dramatically over the past decade owing to rapid advancements in immunotherapy and molecular-targeted therapies. Zanubrutinib, a second-generation Bruton\'s tyrosine kinase inhibitor (BTKI) designated for mature B-cell non-Hodgkin\'s lymphoma (NHL), has drastically improved the survival outcomes in relapsed/refractory (R/R) MCL patients. This selective BTKI is a small molecule that functions by forming a covalent bond in the active site of BTK. The inhibition of BTK activity is essential for the signaling of B-cell antigen receptor (BCR) and cytokine receptor pathways. In a preclinical study, zanubrutinib inhibited malignant B-cell proliferation and reduced tumor growth. Zanubrutinib was granted FDA-accelerated approval based on the results of Phase I and II trials. The investigator-assessed overall response rate was 83.7%, of which 78% of patients achieved complete response. The median duration of response was 19.5 months, and the median progression-free survival was 22.1 months. The most common (≥20%) all-grade adverse events were low neutrophil count (46.5%), upper respiratory tract infection (38.4%), rash (36.0%), low white blood cell count (33.7%), and low platelet count (32.6%).
UNASSIGNED: Zanubrutinib is a selective, next-generation, orally active, irreversible BTK inhibitor. The selectivity of zanubrutinib and its superior efficacy, with a well-tolerated safety profile, have proven to be attractive options for other malignancies.

Over the past decade, the treatment landscape of chronic lymphocytic leukemia (CLL) has dramatically changed, shifting from cytotoxic chemotherapy to targeted therapies. Bruton\'s tyrosine kinase (BTK) inhibitors have revolutionized the treatment of CLL and are increasingly applied in many other malignancies. However, ibrutinib, the first BTK inhibitor approved, is associated with serious toxicities, including atrial fibrillation in up to 38% of patients, ventricular arrhythmias, and other cardiovascular toxicities. Emerging data suggest several newer BTK inhibitors (eg, acalabrutinib, zanubrutinib) are still associated with cardiotoxic risks. This review examines the current state of evidence, including incidence rates, risk factors, mechanisms, and management strategies of cardiovascular toxicities with BTK inhibitors and other CLL therapies. We specifically focus on atrial fibrillation, ventricular arrhythmias/sudden death, hypertension, heart failure, bleeding, and stroke. We also touch on other emerging BTK therapies (eg, pirtobrutinib). Finally, we highlight key unanswered questions and future directions of research.

Zanubrutinib is a Bruton tyrosine kinase (BTK) inhibitor used in B cell malignancy treatment and is generally well tolerated in most patients. Zanubrutinib-induced aseptic meningitis is currently not reported. Herein, we present the first case of zanubrutinib-induced aseptic meningitis. A 33-year-old woman was diagnosed with relapsed/refractory follicular lymphoma and subsequently developed aseptic meningitis after receiving zanubrutinib treatment. We reviewed the literature and uncovered the lack of current reports on zanubrutinib or other BTK inhibitor-induced aseptic meningitis. Moreover, we summarized cases on aseptic meningitis induced by common chemotherapy and targeted drugs used for hematological diseases. Drug-induced aseptic meningitis (DIAM) is a drug-induced meningeal inflammation. The possible pathogenesis is the direct stimulation of the meninges via intrathecal injection of chemotherapy drugs and immune hypersensitivity response caused by immunosuppressive drugs. It is more common in women with immune deficiency and mainly manifests as persistent headache and fever. Cerebrospinal fluid examinations mainly demonstrate a significant increase in cells and proteins. DIAM diagnosis needs to exclude bacterial, fungal, viral, and tuberculosis infections; neoplastic meningitis; and systemic diseases involving the meninges. The prognosis of DIAM is usually favorable, and physicians should detect and stop the causative drug. In conclusion, zanubrutinib-induced aseptic meningitis is a rare but serious complication, and physicians should be promptly aware of this adverse event to avoid serious consequences.

Waldenström macroglobulinemia (WM) is a rare form of non-Hodgkin B-cell lymphoma with a variable clinical presentation that can impact a patient\'s quality of life by causing anemia, peripheral neuropathy, serum hyperviscosity, extramedullary disease, and other symptoms. There are several safe and effective treatment regimens for patients with WM, and the choice of therapy should be made in a personalized fashion considering the patient\'s symptoms, comorbidities, and genomic profile. Bruton tyrosine kinase (BTK) inhibitors are a new option to treat patients with WM. Zanubrutinib is a next-generation covalent BTK inhibitor designed to have fewer off-target effects than previous BTK inhibitors. This review summarizes the pharmacokinetic and pharmacodynamic properties of zanubrutinib as well as safety and efficacy findings. Then, it explores the health economic and outcomes research associated with the costs of treating patients with WM and the reasons why zanubrutinib may be a more cost-effective treatment option compared with ibrutinib, a first-generation BTK inhibitor. Future directions for the treatment of WM focus on the use of zanubrutinib in combination therapy. Combinations based on effective ibrutinib or acalabrutinib treatments may be effectively applied with zanubrutinib given the similar mechanism of action for these BTK inhibitors. Combination therapies could also help prevent the development of disease resistance, minimize toxicity, and support treatment regimens of finite duration.

Zanubrutinib, a next-generation non-covalent Bruton\'s tyrosine kinase (BTK) inhibitor, shows great efficacy in the treatment of B cell malignancies. Some patients may experience a series of side effects after the treatment of zanubrutinib. Grade 4 dermatological toxicities are rare, which present as severe rash and skin infection. Herein, we retrospectively reported the grade 4 dermatological toxicities of zanubrutinib in three consecutive patients. They were treated with zanubrutinib 160 mg twice daily orally. One patient was diagnosed with Primary Breast Diffuse Large B-cell Lymphoma(PB-DLBCL) and two patients were diagnosed with Chronic Lymphocytic Leukemia(CLL). Within one month after zanubrutinib treatment, all three patients developed grade 4 dermatological toxicities, including bruising, maculopapular rash, petechiae, ecchymosis, hemorrhagic blister, acne-Like rash, papulopustular rash, and skin infections. Zanubrutinib was discontinued in two patients due to unacceptable dermatological toxicities. Safety data from pre-licensing clinical trials showed that zanubrutinib-related side effects were frequent but well tolerated. To date, no severe dermatological toxicities were reported. The majority of patients can be relieved with symptomatic treatment, but a very small percentage of patients may face discontinuation of the drug.

UNASSIGNED: The bleeding risk associated with Bruton\'s tyrosine kinase inhibitor (BTKi) monotherapy remains to be understood. This systematic review aims to evaluate BTKi monotherapy related bleeding risk.
UNASSIGNED: PubMed, Embase, and CENTRAL were searched up to 5 December 2021. We included randomized controlled trials (RCTs) comparing BTKi monotherapy with control drugs, or comparing different BTKi monotherapies.
UNASSIGNED: 10 studies with 3139 patients were included. Ibrutinib (vs. control drugs) significantly increased the risk of overall bleeding and major bleeding (RR = 2.22, 95% CI 1.80-2.75, P < 0.00001; RR = 1.80, 95% CI 1.02-3.18, P = 0.04, respectively). Acalabrutinib (vs. control drugs) had a significantly increased overall bleeding risk (RR = 3.45, 95% CI 2.39-4.99, p < 0.00001). A significant difference was found in overall bleeding between ibrutinib and acalabrutinib (RR = 1.35, 95% CI 1.11-1.64, P = 0.002). Compared to zanubrutinib, ibrutinib tended to increase the risk of major bleeding (RR = 1.55, 95% CI 0.57-4.18, P = 0.39).
UNASSIGNED: Ibrutinib and acalabrutinib (vs. control drugs) have a higher risk of bleeding and overall bleeding, respectively. Limited evidence suggests that ibrutinib (vs. acalabrutinib) significantly increases overall bleeding risk, but the differences are not observed in other comparisons.

The availability of Bruton tyrosine kinase (BTK) inhibitors has brought about a paradigm shift in the treatment of patients with B-cell lymphomas and chronic lymphocytic leukemia. BTK was clinically validated as a target by the efficacy of the first-in-class inhibitor ibrutinib. The extended survival conferred by BTK inhibitors has brought long-term tolerability to the foreground. To minimize toxicities thought to be attributable to off-target kinase inhibition, a next generation of BTK inhibitors with greater selectivity was developed. In the United States, zanubrutinib, a next-generation BTK inhibitor, has been approved for treating adults with mantle cell lymphoma who have received at least one prior therapy, for adults with Waldenström macroglobulinemia, and for adults with relapsed or refractory marginal zone lymphoma who have received at least one anti-CD20-based therapy. Because few head-to-head comparative trials of BTK inhibitors have so far been reported, no BTK \'inhibitor of choice\' can be identified. Zanubrutinib has promising efficacy in its approved indications and appears to have reduced cardiac toxicities, particularly atrial fibrillation, which may influence the choice of BTK inhibitor treatment by prescribers. Further studies are needed to inform on optimal treatment sequencing of zanubrutinib and its combination with other agents. Here, we summarize existing clinical evidence for its efficacy and safety in mantle cell lymphoma, Waldenström macroglobulinemia, marginal zone lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, and other B-lymphoproliferative indications.
UNASSIGNED: Zanubrutinib is a drug that was shown to effectively treat cancer of B cells without causing excessive serious side effects Patients with certain B-cell malignancies (cancers of white blood cells) benefit from treatment with Bruton tyrosine kinase (BTK) inhibitors, drugs that block the BTK protein and keep cancer from growing and spreading. Patients experience extended survival with ibrutinib, the first-generation BTK inhibitor approved by US Food and Drug Administration (FDA); however, one in five patients quit treatment because of harmful side effects. Ibrutinib-related side effects such as increased risk of bleeding, atrial fibrillation (abnormal heart rhythm), and high blood pressure are thought to be caused by ibrutinib blocking other proteins besides the intended target protein BTK. To reduce these side effects, zanubrutinib, a next-generation BTK inhibitor, was designed to block BTK more specifically than ibrutinib. Results of clinical studies on zanubrutinib treatment appear promising in patients with several types of B-cell malignancies, including mantle cell lymphoma (MCL), Waldenström macroglobulinemia (WM), marginal zone lymphoma (MZL), chronic lymphocytic leukemia, and small lymphocytic lymphoma. There are not yet enough clinical data to determine which BTK inhibitor is most effective in treating B-cell malignancies without causing harmful side effects. Early data from the phase 3 ALPINE clinical study suggest that zanubrutinib works better than ibrutinib, and fewer patients experience side effects and quit treatment. Zanubrutinib is currently approved for use for treatment of adult patients with MCL who have received at least one prior therapy, for adults with WM, and for adults with MZL who have received at least one anti-CD20-based therapy.