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Zanubrutinib is an orally administered second-generation covalent inhibitor of Bruton tyrosine kinase that was recently approved by the US Food and Drug Administration for the treatment of chronic lymphocytic leukemia and small lymphocytic leukemia. It has been associated with significant major and minor bleeding events, including intracranial and GI hemorrhage and hematuria, with or without concurrent antiplatelet or anticoagulation therapy. We report a case of a 65-year-old man with relapsing chronic lymphocytic leukemia. He presented to us with repeated episodes of worsening dyspnea secondary to hemorrhagic pleural effusion 2 months after the initiation of zanubrutinib with concomitant apixaban use. On discontinuation of zanubrutinib after the second episode, he remained asymptomatic on further follow-up examination. Previously only described with the first-generation Bruton tyrosine kinase inhibitor, our case focuses attention on a rare adverse event and a first reported incidence, to our knowledge, of recurrent hemorrhagic pleural effusion associated with zanubrutinib in a patient with relapsing chronic lymphocytic leukemia. [ABSTRACT FROM AUTHOR]

Summary Idiopathic multicentric Castleman disease (iMCD) is a rare and heterogeneous lymphoproliferative disorder that lacks standardised treatment options for patients with refractory or relapsed (r/r) disease. Blocking Bruton's tyrosine kinase (BTK) has emerged as a promising therapeutic approach for iMCD without depleting B cells. This single‐centre, retrospective study enrolled 10 patients with r/r iMCD who were treated with orelabrutinib, a novel, next‐generation BTK inhibitor. The median age at orelabrutinib initiation was 48 (range: 31–58) years. The overall response rate was 70% (7/10 patients, 95% CI: 34.8–93.3), with 20% (n = 2) achieving complete response and 50% (n = 5) achieving partial response. The median time to response was 9.8 (range: 5.9–20.5) months. Patients in the non‐responder group also demonstrated a continuous improvement in haemoglobin (91–105 g/L) and albumin (32–38 g/L) levels at month 12 of treatment despite not fulfilling response criteria. No grade 3 or higher adverse events occurred during the median time to the next treatment of 29.0 (range: 15.0–36.2) months. No patient mortality was recorded during the median follow‐up duration of 32.8 (range: 15.0–36.9) months. In conclusion, orelabrutinib is a safe and effective regimen for r/r iMCD. [ABSTRACT FROM AUTHOR]

Abstract Follicular lymphoma (FL) is an indolent, germinal center B cell–derived lymphoid neoplasm, for which recent advances in treatment have substantially improved patient survival. However, FL remains an incurable and heterogeneous disease, with groups of patients experiencing early disease progression, histologic transformation, or a high risk of treatment-related toxicity. Additionally, FL is a continually relapsing disease, and response rates and disease-control intervals decrease with each subsequent line of therapy. In this review, we explore the current treatment landscape for relapsed or refractory FL and promising therapies in development, highlighting the efficacy and potential risks of each treatment. We provide a real-world perspective on the unmet needs of patients with FL. Novel therapeutic approaches in development offer a wide array of options for clinicians when treating relapsed or refractory FL. A nuanced approach is required to address the needs of individual patients, taking into consideration both the risks and benefits of each treatment option, as well as patient preferences.

• The update covers the approval of time-limited ibrutinib–venetoclax in first line and new data on MRD-driven treatment. • It also covers the approval of the BTKi zanubrutinib in both treatment-naive and relapsed or refractory CLL. • Additional evidence on the time-limited combination of venetoclax plus an anti-CD20 antibody in the first line are included. • Options for later-line treatments based on the type of prior lines of treatment are also included. • Recommendations are based on available scientific data and the authors' collective expert opinion. [ABSTRACT FROM AUTHOR]

Follicular lymphoma (FL) is an indolent, germinal center B cell–derived lymphoid neoplasm, for which recent advances in treatment have substantially improved patient survival. However, FL remains an incurable and heterogeneous disease, with groups of patients experiencing early disease progression, histologic transformation, or a high risk of treatment-related toxicity. Additionally, FL is a continually relapsing disease, and response rates and disease-control intervals decrease with each subsequent line of therapy. In this review, we explore the current treatment landscape for relapsed or refractory FL and promising therapies in development, highlighting the efficacy and potential risks of each treatment. We provide a real-world perspective on the unmet needs of patients with FL. Novel therapeutic approaches in development offer a wide array of options for clinicians when treating relapsed or refractory FL. A nuanced approach is required to address the needs of individual patients, taking into consideration both the risks and benefits of each treatment option, as well as patient preferences. [ABSTRACT FROM AUTHOR]

One of the most successful and highly developed drug targets in cancer is Bruton's tyrosine kinase (BTK). Remarkable basic and translational studies have led to the clinical approval of several generations of small-molecule BTK inhibitors. Recent discovery of kinase-deficient BTK inhibitor resistance mutations sheds light on still undiscovered roles of BTK in B cell receptor signaling. Noncovalent BTK inhibitors represent potential future frontline treatment options in chronic lymphocytic leukemia (CLL). New dual-binding BTK inhibitors and BTK degraders represent the future of BTK targeting. Successful development of BTK inhibitors in cancer has led to new applications in other conditions such as autoimmune disease. Bruton's tyrosine kinase (BTK) inhibitors have revolutionized the treatment landscape for B cell lymphomas such as chronic lymphocytic leukemia (CLL). The first-in-class BTK inhibitor ibrutinib has recently been succeeded by covalent BTK inhibitors that are safer but still face challenges of resistance mutations. The noncovalent BTK inhibitor pirtobrutinib was recently approved for relapsed and refractory CLL, and whether noncovalent BTK inhibitors will supplant covalent BTK inhibitors as upfront treatment options either alone or in combination will be determined. Meanwhile, newer BTK inhibitors and BTK degraders are vying for their place in the potential future landscape of B cell cancers as well as autoimmune diseases. This review will cover the latest progress in BTK inhibitor development and where the field is moving in light of these recent discoveries. [ABSTRACT FROM AUTHOR]

Dermatological adverse events (AEs) are generally mild during therapy with Bruton’s tyrosine kinase inhibitor (BTKi), and it is often unnecessary to adjust the BTKi dosage or discontinue treatment. However, in this study, we present the cases of two patients diagnosed with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who experienced severe dermatological AEs during BTKi treatment and subsequently had to discontinue it. The first patient, who previously suffered from rashes, experienced rashes again along with fever when exposed to BTKi. The subsequent dermatological biopsy revealed necrotizing vasculitis. The second patient suffered from skin ulcers concurrently with cough and fever. The BTKi treatment was permanently discontinued when the histopathological biopsy revealed a fungal infection. Therefore, clinicians should pay attention to atypical rashes during BTKi treatment and skin biopsies are necessary for further diagnosis and intervention.

To explore the optimal treatment for young patients with untreated mantle cell lymphoma (MCL), we compared the efficacy and safety of R-CHOP/R-DHAP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone/rituximab, dexamethasone, cytarabine and cisplatin) and R-BAP (rituximab, bendamustine, cytarabine, and prednisone) plus BTK (Bruton's tyrosine kinase) inhibitors in newly diagnosed patients. Eighty-three young patients (≤ 65 years old) with newly diagnosed MCL admitted to the First Affiliated Hospital of Zhengzhou University from January 1, 2014, to June 1, 2023, using R-CHOP/R-DHAP or R-BAP plus BTK inhibitor were assessed in this study. The median age at presentation was 60 (42–65) years in 83 patients, including 64 males and 19 females; 59 were treated with R-CHOP/R-DHAP regimen chemotherapy, and 24 were treated with R-BAP in combination with the BTK inhibitor regimen. The median follow-up was 17 months (2–86 months) in 83 patients, and the median PFS (progression-free survival) time was not reached. The CRR (complete response rate) of the R-BAP group was higher than that of the R-CHOP/R-DHAP group (87.5% vs. 54.2%, P = 0.005). The ORR (overall response rate) was not significantly different between the two groups (ORR: 91.7% vs. 84.7%, P = 0.497). The PFS (progression-free survival) of the R-BAP group was longer than that of the R-CHOP/R-DHAP group (P = 0.013), whereas OS was not significantly different between the two groups (P = 0.499). The most common adverse effect in both groups was hematotoxicity, with a higher incidence of grade 3–4 lymphopenia and grade 3–4 thrombocytopenia in the R-BAP group than in the R-CHOP/R-DHAP group (P = 0.015 and P = 0.039). Male sex (HR = 4.257, P = 0.013), LDH (lactate dehydrogenase) ≥ 245 U/L (HR = 3.221, P = 0.012), pleomorphic-blastoid (HR = 2.802, P = 0.043) and R-CHOP/R-DHAP regimen (HR = 7.704, P = 0.047) were independent risk factors for PFS. Ki67 ≥ 30% (HR = 8.539, P = 0.005) was an independent risk factor for OS. First-line treatment with R-BAP in combination with BTK inhibitor improved CRR and prolonged PFS in young patients with mantle cell lymphoma and adverse events were tolerable. [ABSTRACT FROM AUTHOR]

Simple Summary: Discussed here is a review of the changing landscape in the treatment of mantle cell lymphoma (MCL) regarding the emergence and use of targeted therapy. Targeted therapy is the use of small molecules designed to interrupt specific mechanisms within the cancer cell to exert anti-tumor efficacy. Targeting such mechanisms relies upon our understanding of what makes a cancer cell malignant. MCL is a difficult-to-treat lymphoid cancer that relies heavily upon constitutive intracellular signaling, promoting its growth and survival. The mainstay of MCL treatment has been to treat it with cytotoxic chemotherapy; however, targeted therapies have allowed for improved treatment outcomes and continue to change the way we manage this disease. This review aims to describe what targeted therapies are being utilized in MCL treatment and their mechanisms of action, safety, and efficacy, as well as future directions for their use in MCL treatment. Mantle cell lymphoma (MCL) is a rare, heterogeneous B-cell non-Hodgkin's lymphoma. The standard front-line treatment utilizes chemotherapy, often followed by consolidation with an autologous hematopoietic cell transplant; however, in most patients, the lymphoma will recur and require subsequent treatments. Additionally, mantle cell lymphoma primarily affects older patients and is frequently chemotherapy-resistant, which has further fostered the necessity for new, chemotherapy-free treatment options. In the past decade, targeted therapies in mantle cell lymphoma have been practice-changing as the treatment paradigm shifts further away from relying primarily on cytotoxic agents. Here, we will review the pathophysiology of mantle cell lymphoma and discuss the emergence of targeted, chemotherapy-free treatments aimed at disrupting the abnormal biology driving its lymphomagenesis. Treatments targeting the constitutive activation of NF-kB, Bruton's Tyrosine Kinase signaling, and anti-apoptosis will be the primary focus as we discuss their clinical data and toxicities. Our review will also focus primarily on the emergence and use of targeted therapies in the relapsed/refractory setting but will also discuss the emergence of their use in front-line therapy and in combination with other agents. [ABSTRACT FROM AUTHOR]

Chronic lymphocytic leukemia (CLL) is a monoclonal B-cell lymphoproliferative disease with a high annual incidence in Western countries. As B-cell receptor (BCR) signaling and intrinsic apoptotic resistance play critical roles in the development and survival of CLL cells, therapeutic approaches targeting these pathways have been extensively investigated to tackle this incurable disease. Over the last decade, several Phase 3 trials have confirmed the superior efficacy of covalent Bruton tyrosine kinase inhibitors (cBTKis) and venetoclax, a selective B-cell lymphoma 2 (BCL2) inhibitor, over chemoimmunotherapy. This has been demonstrated in both the treatment-naïve and relapsed/refractory (RR) settings and includes patients with high-risk molecular features. However, these drugs are not curative, with patients continuing to relapse after treatment with both cBTKis and BCL2is, and the optimal treatment strategy for these patients has not been defined. Several novel agents with distinct mechanisms have recently been developed for CLL which have demonstrated efficacy in patients who have previously received cBTKis and BCL2i. In particular, novel BCR-signaling targeting agents have shown promising efficacy in early-phase clinical trials for RR-CLL. Furthermore, cancer immunotherapies such as bispecific antibodies and chimeric antigen receptor T-cells have also shown anti-tumor activity in patients with heavily pretreated RR-CLL. Personalised approaches with these novel agents and combination strategies based on the understanding of resistance mechanisms have the potential to overcome the clinical challenge of what to do next for a patient who has already had a cBTKi and venetoclax. [ABSTRACT FROM AUTHOR]

Abstract Background Bruton’s tyrosine kinase (Btk) is an enzyme expressed in leukocytes other than T lymphocytes and plasma cells and involved in B-cell receptor- and Fcγ receptor (FcγR)-mediated signal transduction. Btk inhibitors potentially suppress autoantibody production due to the expected inhibitory ability of B lymphocyte differentiation into antibody-producing plasma cells and reduce FcγR-mediated neutrophil activation, including the release of neutrophil extracellular traps (NETs). Microscopic polyangiitis (MPA) is a systemic small-vessel vasculitis characterized by the pathogenic autoantibody, antineutrophil cytoplasmic antibody (ANCA) that reacts with myeloperoxidase (MPO). MPO and MPO-ANCA immune complex (IC)-induced FcγR-mediated NETs are critically involved in MPA pathogenesis. This study aimed to demonstrate the therapeutic efficacy of the Btk inhibitor tirabrutinib on MPA. Methods Various doses of tirabrutinib or vehicle were orally administered to Sprague–Dawley rats daily. Four weeks later, the number of peripheral B lymphocytes was counted, and Btk phosphorylation in B lymphocytes was evaluated by flow cytometry. Human peripheral blood neutrophils were stimulated by MPO and anti-MPO antibody ICs (MPO and anti-MPO-ICs), and Btk and its downstream Vav phosphorylation were assessed by western blotting. The effects of tirabrutinib on MPO and anti-MPO-IC-induced NET formation were examined in vitro. Wistar Kyoto rats were immunized with human MPO to induce experimental MPA and given drug-free or tirabrutinib-containing feed (0.0037% or 0.012%) from day 0 or 28. All rats were euthanized on day 42 for serological and histological evaluation. Results Tirabrutinib inhibited Btk phosphorylation without decreasing B lymphocytes in vivo. Neutrophil Btk and Vav were phosphorylated when stimulated with MPO and anti-MPO-ICs. Tirabrutinib suppressed MPO and anti-MPO-IC-induced NET formation in vitro and ameliorated experimental MPA in a dose-dependent manner in vivo. Although MPO-ANCA production was not affected, NET-forming neutrophils in the blood were significantly reduced by tirabrutinib. Conclusions The Btk inhibitor tirabrutinib suppressed MPO and anti-MPO-IC-induced NET formation in vitro and ameliorated experimental MPA by reducing NET-forming neutrophils but not decreasing MPO-ANCA titer in vivo. This study suggests that Btk is a possible therapeutic target in MPA.

Abstract Background The treatment landscape for chronic lymphocytic leukemia (CLL) continues to undergo considerable evolution. Optimal selection of initial therapy from multiple effective options provides a major challenge for clinicians, who need to consider both disease and patient factors in conjunction with a view to sequencing available therapies in event of disease relapse. Review We explore the most topical clinically relevant unresolved questions through discussion of important available pertinent literature and propose expert opinion based on these data. (1) Shrinking role of chemoimmunotherapy (CIT); while novel therapies are generally superior, we highlight the utility of FCR for IGHV-mutated CLL. (2) Choosing between inhibitors of Bruton’s tyrosine kinase (BTKi); while efficacy between agents is likely similar there are important differences in toxicity profiles, including the incidence of cardiac arrhythmia and hypertension. (3) BTKi with or without anti-CD20 monoclonal antibodies (mAb); while obinutuzumab-acalabrutinib (AO) may confer superior progression-free survival to acalabrutinib (Acala), this is not true of rituximab (Ritux) to ibrutinib (Ib)—we highlight that potential for increased side effects should be carefully considered. (4) Continuous BTKi versus time-limited venetoclax-obinutuzumab (VenO); we propose that venetoclax (Ven)-based therapy is generally preferable to BTKi with exception of TP53 aberrant disease. (5) BTKi-Ven versus VenO as preferred time-limited therapy; we discuss comparable efficacies and the concerns about simultaneous 1L exposure to both BTKi and Ven drug classes. (6) Utility of triplet therapy (BTKi-Ven-antiCD20 mAb) versus VenO; similar rates of complete response are observed yet with greater potential for adverse events. (7) Optimal therapy for TP53 aberrant CLL; while limited data are available, there are likely effective novel therapy combinations for TP53 aberrant disease including BTKi, BTKi-Ven ± antiCD20 mAb. Conclusion Frontline therapy for CLL should be selected based on efficacy considering the patient specific biologic profile of their disease and potential toxicities, considering patient comorbidities and preferences. With the present paradigm of sequencing effective agents, 1L combinations of novel therapies should be used with caution in view of potential adverse events and theoretical resistance mechanism concerns in the absence of compelling randomized data to support augmented efficacy.

BTK inhibitors (BTKi) are highly effective in B-cell malignancies. Acalabrutinib and zanubrutinib have exhibited favorable safety profiles when compared with ibrutinib. We identified all published/ presented randomized trials comparing a second-generation BTKi with ibrutinib and reconstructed individual patient-level, censored time-to-event data for adverse events to evaluate the impact of second-generation BTKi on safety outcomes including atrial fibrillation/flutter [AF], hypertension, bleeding, diarrhea, and infection. 1386 pts from ELEVATE-RR (n=533), ALPINE (n=652), and ASPEN (n=201) trials were included in the analyses. Acalabrutinib or zanubrutinib were associated with significant reductions in cumulative event rates of AF (HR 0.28, 95% CI 0.18–0.42, p<0.001), bleeding (HR 0.65, 95% CI 0.52–0.81, p<0.001), diarrhea (HR 0.61, 95% CI 0.47–0.78, p<0.001), hypertension (HR 0.40, 95% CI 0.27–0.61, p<0.001), and infections (HR 0.83, 95% CI 0.70-0.98, p=0.032). In summary, zanubrutinib and acalabrutinib have a favorable safety profile among pts with r/r B-cell malignancies. These data support use of acalabrutinib or zanubrutinib as preferred BTK inhibitors for approved indications. [ABSTRACT FROM AUTHOR]

This paper describes the development of a relatively feasible, economic, and safe method for the multigram-scale synthesis of BIIB068, an efficient reversible BTK inhibitor. The new process is highlighted by an economical construction of a 2-amino-4 substituted pyrimidine employing a simple nucleophilic substitution reaction and a green reduction of the cyano group. The developed process provided an overall yield of 32%, with an HPLC purity of 99%. The structure of BIIB068 was confirmed by MS, IR, 1H-NMR, and 13C-NMR, and the structures of some intermediates were confirmed by MS and 1H-NMR. [ABSTRACT FROM AUTHOR]

Purpose of Review: The discovery of recurring somatic mutations, in particular MYD88 and CXCR4 mutations, in Waldenström macroglobulinemia (WM), a rare B-cell lymphoproliferative disorder, led in the last decade to the development of several therapeutic agents with high efficacy. This review aims to provide an overview of available treatments in WM and novel agents, focusing on studies published over recent years. Recent Findings: There is no international consensus on the best first-line option in treatment-naïve patients. Randomized clinical trials are rare in WM and there has been no prospective comparison of chemoimmunotherapy and BTK inhibitors in the frontline setting. Summary: Chemoimmunotherapy and BTK inhibitors, the two feasible and most widely used treatments in first-line treatment, represent very different options in terms of duration of therapy, route of administration, cost, and adverse effect. In addition to tumor genotype and patient comorbidities, choice of therapy in WM should take into account these parameters. Results of ongoing and future clinical trials evaluating fixed-duration combinations with BTK inhibitors and novel agents are awaited. [ABSTRACT FROM AUTHOR]

Objective: Richter syndrome (RS) occurs in approximately 2–10% of chronic lymphocytic leukemia (CLL) patients, more often during the disease course than at diagnosis, with a diffuse large B-cell Lymphoma (DLBCL) histology in 95% of cases. Despite great advances in the treatment of CLL in recent years, RS also develops in patients treated with novel agents, as summarized in our case report and review. Methods: We summarized 3 patients with RS treated with immunochemotherapy combined with BTK inhibitor (BTKi) or BCL2 inhibitor (BCL2i) and reviewed the literature. Results: Three RS patients were summarized. Patient 1 was transformed into DLBCL during dose reductions in ibrutinib and achieved bone marrow (BM) minimal residual disease (MRD)-negative complete response (CR) after rituximab etoposide, dexamethasone, doxorubicin, cyclophosphamide, and vincristine (R-EDOCH) combined with BTKi treatment and sustained progression-free survival (PFS) for more than 2 years. Patient 2, who transformed at the time of diagnosis, progressed after being treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), followed by PD1 antibody combined with cytosine, arabinoside, cisplatin and dexamethasone (DHAP) treatment and PD1 antibody combined with ifosfamide, carboplatin, and etoposide (ICE) treatment. Patient 2 achieved CR after treatment with rituximab, gemcitabine, and oxaliplatin (R-GemOx) combined with BTKi. Patient 3, who transformed at the time of diagnosis with CARD11, TP53, and ATM mutations, progressed after being treated with R-EDOCH combined with BTKi and achieved MRD-negative CR after treatment with R-GemOx and venetoclax, which has continued for 3 months. We summarized new protocols utilizing targeted therapy, such as BTKi acalabrutinib, and checkpoint inhibition, and the potential role of precision medicine in future trials of RS treatment. The efficacy of these protocols as single agents or in combination with immunochemotherapy is currently being evaluated. Conclusion: In our study, immunochemotherapy combined with BTKi or BCL2i achieved favorable efficacy in the treatment of RS. The treatments should be optimized by the combination of both chemotherapies and targeted therapy to develop a specific individual approach for each patient, according to previous treatment and biological characteristics. [ABSTRACT FROM AUTHOR]

Bruton's tyrosine kinase inhibitor (BTKi) has revolutionized the treatment of B-cell lymphomas. However, BTKi-related hematological toxicity hinders treatment continuity and may further affect clinical efficacy. To identify risk factors and predict the likelihood of BTKi-related hematological toxicities, we constructed and validated a prediction model for severe hematological toxicity of BTKi. Approved by the hospital medical science research ethics committee (No. M2022427), we collected real-world data in patients treated with BTKi from a Lymphoma Research Center in China. The outcome of interest was severe hematological toxicity caused by BTKi. 36 candidate variables were categorized into demographics, diagnostic and treatment information, laboratory data, and medical history. The study sample was randomly divided into training (70%) and validation (30%) sets. We developed and compared the performance of various modelling methods, including decision tree (DT), random forest (RF), gradient boosting decision tree (GBDT), extreme gradient boosting (XGBoost), light gradient boosting machine (LightGBM), and logistic regression (LR). Finally, we constructed a Web-calculator of the optimal model to estimate the risk of hematological toxicity. This study was designed, conducted and reported strictly in compliance with the TRIPOD checklist. Data from a total 121 patients were included [median age, 65 years (range, 56–73 years); 74 (61.15%) men; 47 (38.84%) severe hematological toxicity]. The XGBoost model demonstrated better overall properties than other models, achieving high discrimination (AUC: 0.671; accuracy: 0.730; specificity: 0.913) and clinical benefit. The following 10 variables were used to develop the XGBoost model: white blood cell count (WBC), neutrophil count (Neut), red blood cell count (RBC), platelet count (PLT), fibrinogen (Fib), total protein (TP), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), gender and type of BTKi. SHAP values demonstrated insightful associations between these variables and hematological toxicity. Finally, to facilitate clinical and research use, we also deploy the XGBoost model on a web-calculator for free access. The XGBoost model with promising accuracy was developed to predict the severe hematological toxicity of BTKi. It helps to strengthen the proactive monitoring and management of patients with hematological toxicity, and thus achieve long-term continuous BTKi treatment. [ABSTRACT FROM AUTHOR]

Purpose of Review: This research paper aims to provide an overview of evidence-based sequencing of therapies in relapsed/refractory chronic lymphocytic leukemia (CLL) in the era of targeted drugs. Recent Findings: In the absence of data from randomized clinical trials comparing novel agents head-to-head, growing evidence suggests that patients with late relapse (> 2 years) after fixed-duration therapies benefit from identical retreatment, whereas a class switch is favorable in those with short-lived remissions or progressive disease on continuous drug intake. Treatment of patients previously exposed to both covalent inhibitors of BTK and BCL2 remains an unmet medical need. Novel drugs, in particular noncovalent BTKI, show promising efficacy in this difficult-to-treat subgroup in early clinical trials. Summary: The optimal sequencing of therapies in CLL requires consideration of individual patient factors and disease characteristics. Double-refractory disease continuous to pose a clinical challenge with a focus on participation in clinical trials whenever possible. [ABSTRACT FROM AUTHOR]

Purpose of Review: There have been significant advances in the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL) over the past two decades. However, the intention of treatment remains control of the disease and delay of progression rather than a cure which remains largely elusive. Considering that CLL is mostly seen in older patients, there are multiple factors that play a role in the selection of CLL beyond the frontline treatment. Here, we review the concept of relapsed CLL, factors that predispose to relapse, and therapeutic options available to this patient population. We also review investigational therapies and provide a framework for selection of therapies in this setting. Recent Findings: Targeted therapies with continuous BTK inhibitors (BTKi) or fixed duration venetoclax plus anti-CD20 monoclonal antibody therapy have established superiority over chemoimmunotherapy in relapsed CLL and have become the preferred standard of care treatment. The second-generation more selective BTK inhibitors (acalabrutinib and zanubrutinib) have shown improved safety profile compared to ibrutinib. However, resistance to the covalent BTK inhibitors may emerge and is commonly associated with mutations in BTK or other downstream enzymes. The novel non-covalent BTK inhibitors such as pirtobrutinib (Loxo-305) and nemtabrutinib (ARQ 531) are showing promising activities for relapsed CLL refractory to prior covalent BTKi. Other novel therapies such as chimeric antigen receptor (CAR) T cell therapy have also shown significant activities for relapsed and refractory CLL. Measurable residual disease (MRD) assessment has a growing importance in venetoclax-based limited-duration therapy and there is mounting evidence that MRD negativity improves outcomes. However, it remains to be seen if this will become an established clinically significant endpoint. Further, the optimal sequence of various treatment options remains to be determined. Summary: Patients with relapsed CLL now have more options for the treatment of the disease. The choice of therapy is best individualized especially in the absence of direct comparisons of targeted therapies, and the coming years will bring more data on the best sequence of use of the therapeutic agents. [ABSTRACT FROM AUTHOR]

Waldenström macroglobulinemia (WM) is a rare, non-Hodgkin lymphoma that remains incurable. Rituximab, an anti-CD20 monoclonal antibody has been the cornerstone of treatment against WM, and its combination with an alkylator, bendamustine, achieves durable remission in treatment-naive patients with symptomatic WM. However, novel “druggable” targets that have been identified within the clonal lymphoplasmacytic cells in WM have resulted in a rapid development of targeted therapies in both the frontline and relapsed and refractory (R/R) settings. Several agents directed against the known targets have shown promising efficacy, with mostly manageable toxicities. The class of Bruton’s tyrosine kinase (BTK) inhibitors has transformed the therapeutic landscape for patients with WM, given their convenient oral dosing and strong efficacy, with high rates of attainment of very good partial response (VGPR). The tolerability of the next-generation BTK inhibitors appears to be superior to that of the first-in-class agent, ibrutinib. Targeted therapies from other classes have also demonstrated efficacy in both single-agent and combination regimens. Inhibitors of proteasome BCL-2, mTOR and PI-3 kinase have demonstrated efficacy in WM. Emerging therapies under investigation will continue to further shape the management paradigm, especially in the R/R setting. These include bispecific antibodies, radiotherapeutic agents and chimeric antigen receptor T-cell (CART) cell therapies. This review outlines the current literature and future direction of targeted therapies in WM.

Introduction: Cytotoxic CD8+ T cell (CTL) exhaustion is a dysfunctional state of T cells triggered by persistent antigen stimulation, with the characteristics of increased inhibitory receptors, impaired cytokine production and a distinct transcriptional profile. Evidence from immune checkpoint blockade therapy supports that reversing T cell exhaustion is a promising strategy in cancer treatment. Ibrutinib, is a potent inhibitor of BTK, which has been approved for the treatment of chronic lymphocytic leukemia. Previous studies have reported improved function of T cells in ibrutinib long-term treated patients but the mechanism remains unclear. We investigated whether ibrutinib directly acts on CD8+ T cells and reinvigorates exhausted CTLs. Methods: We used an established in vitro CTL exhaustion system to examine whether ibrutinib can directly ameliorate T cell exhaustion. Changes in inhibitory receptors, transcription factors, cytokine production and killing capacity of ibrutinibtreated exhausted CTLs were detected by flow cytometry. RNA-seq was performed to study transcriptional changes in these cells. Btk deficient mice were used to confirm that the effect of ibrutinib was independent of BTK expression. Results: We found that ibrutinib reduced exhaustion-related features of CTLs in an in vitro CTL exhaustion system. These changes included decreased inhibitory receptor expression, enhanced cytokine production, and downregulation of the transcription factor TOX with upregulation of TCF1. RNA-seq further confirmed that ibrutinib directly reduced the exhaustion-related transcriptional profile of these cells. Importantly, using btk deficient mice we showed the effect of ibrutinib was independent of BTK expression, and therefore mediated by one of its other targets. Discussion: Our study demonstrates that ibrutinib directly ameliorates CTL exhaustion, and provides evidence for its synergistic use with cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Opinion Statement: Treatment of relapsed and refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) has changed dramatically over the past decade due to the development of oral targeted agents in several therapeutic classes, including BTK inhibitors (such as ibrutinib, acalabrutinib, zanubrutinib, and the non-covalent BTK inhibitor pirtobrutinib), the first in class BCL2 inhibitor venetoclax, PI3K inhibitors (idelalisib and duvelisib), and monoclonal antibodies in monotherapy and in combination. My approach to treatment of the R/R patient draws heavily on prior therapies, such that a patient with no exposure to prior novel therapies would be offered either a BTK or BCL2-based regimen, whereas patients with prior BTK inhibitor exposure would likely receive a BCL2 inhibitor and vice versa. For patients who are intolerant to a BTK inhibitor but are otherwise responding, an alternate BTK inhibitor may be considered. For those patients who have received a fixed-duration BCL2 inhibitor-based regimen and have maintained a response for greater than 12–24 months, re-treatment with a BCL2 inhibitor-based regimen at progression may be considered based on limited data, recognizing that robust prospective clinical trials are lacking in this space. For those patients who are "double refractory" and have progressed on both a BTK inhibitor and a BCL2 inhibitor-based regimen, clinical trials are strongly preferred. In absence of a clinical trial, these patients can be challenged with PI3K inhibitors, though responses are usually not durable, and toxicity is high. Combination cytotoxic chemotherapy with novel agents, allogeneic hematopoietic stem cell transplant, and cellular therapy may be considered for very high-risk populations, such as patients with Richter's transformation, though novel approaches are urgently needed and clinical trial enrollment is highly encouraged. [ABSTRACT FROM AUTHOR]

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Introduction: Bruton tyrosine kinase inhibitor (BTKi) has demonstrated substantial efficacy in treating B-cell lymphoproliferative diseases (BLPD). Nonetheless, the significant discontinuation rates due to toxicity or financial reasons cannot be overlooked. In China, empirical evidence on the usage of BTKi remains scarce. Methods: To address this, a retrospective cohort study was conducted focused on 673 Chinese patients with BLPD who underwent at least one month of BTKi therapy. Results: Median age at BTKi initiation was 60 years. The median duration on BTKi treatment of the whole cohort was 36.4 months. The median post-BTK survival was not reach. BTKi-based treatment was permanently discontinued in 288 (43.8%) patients during follow-up, mostly attributed to progressive disease. Within the first 6 months of BTKi treatment, 76 patients (26.3%) had early treatment discontinuation. Patients with early discontinuation had extreme worse outcome with a median post-discontinuation survival of only 6.9 months. On multivariate analysis, withdrawal BTKi by toxicity and withdrawal BTKi within 6 months retained to be independent predictors of post-BTK survival, after taking account of the response depth, lines of therapy and baseline cytogenetics including 17p deletion. The decision between BTKi monotherapy and combination therapy, along with the preference for first or secondgeneration BTKi, exerted no significant impact on survival. Discussions: These observations contribute valuable real-world insights into the utilization of BTKi in China. We concluded that BTKi is an effective and welltolerated treatment for long-term use in Chinese patient population. However, it is imperative to stress that a proportion of patients discontinue BTKi early, leading to suboptimal outcomes. This study underscores the importance of adherence to BTKi therapy for improved clinical outcomes in real-world patients. [ABSTRACT FROM AUTHOR]

Background: The treatment landscape for chronic lymphocytic leukemia (CLL) continues to undergo considerable evolution. Optimal selection of initial therapy from multiple effective options provides a major challenge for clinicians, who need to consider both disease and patient factors in conjunction with a view to sequencing available therapies in event of disease relapse. Review: We explore the most topical clinically relevant unresolved questions through discussion of important available pertinent literature and propose expert opinion based on these data. (1) Shrinking role of chemoimmunotherapy (CIT); while novel therapies are generally superior, we highlight the utility of FCR for IGHV-mutated CLL. (2) Choosing between inhibitors of Bruton's tyrosine kinase (BTKi); while efficacy between agents is likely similar there are important differences in toxicity profiles, including the incidence of cardiac arrhythmia and hypertension. (3) BTKi with or without anti-CD20 monoclonal antibodies (mAb); while obinutuzumab-acalabrutinib (AO) may confer superior progression-free survival to acalabrutinib (Acala), this is not true of rituximab (Ritux) to ibrutinib (Ib)—we highlight that potential for increased side effects should be carefully considered. (4) Continuous BTKi versus time-limited venetoclax-obinutuzumab (VenO); we propose that venetoclax (Ven)-based therapy is generally preferable to BTKi with exception of TP53 aberrant disease. (5) BTKi-Ven versus VenO as preferred time-limited therapy; we discuss comparable efficacies and the concerns about simultaneous 1L exposure to both BTKi and Ven drug classes. (6) Utility of triplet therapy (BTKi-Ven-antiCD20 mAb) versus VenO; similar rates of complete response are observed yet with greater potential for adverse events. (7) Optimal therapy for TP53 aberrant CLL; while limited data are available, there are likely effective novel therapy combinations for TP53 aberrant disease including BTKi, BTKi-Ven ± antiCD20 mAb. Conclusion: Frontline therapy for CLL should be selected based on efficacy considering the patient specific biologic profile of their disease and potential toxicities, considering patient comorbidities and preferences. With the present paradigm of sequencing effective agents, 1L combinations of novel therapies should be used with caution in view of potential adverse events and theoretical resistance mechanism concerns in the absence of compelling randomized data to support augmented efficacy. [ABSTRACT FROM AUTHOR]

Katarzyna Malarz,1,&ast; Julia Korzuch,2,&ast; Tainah Dorina Marforio,3 Katarzyna Balin,1 Matteo Calvaresi,3 Anna Mrozek-Wilczkiewicz,1 Robert Musiol,2 Maciej Serda2 1A. Che&lstrok;kowski Institute of Physics, University of Silesia in Katowice, Chorzów, Poland; 2Institute of Chemistry, University of Silesia in Katowice, Katowice, Poland; 3Department of Chemistry “Giacomo Ciamician”, University of Bologna, Bologna, Italy&ast;These authors contributed equally to this workCorrespondence: Maciej Serda; Katarzyna Malarz, Email maciej.serda@us.edu.pl; katarzyna.malarz@us.edu.plIntroduction: Thanks to recent advances in synthetic methodology, water-soluble fullerene nanomaterials that interfere with biomolecules, especially DNA/RNA and selected proteins, have been found with tremendous potential for applications in nanomedicine. Herein, we describe the synthesis and evaluation of a water-soluble glycine-derived [60]fullerene hexakisadduct (HDGF) with Th symmetry, which is a first-in-class BTK protein inhibitor.Methods: We synthesized and characterized glycine derived [60]fullerene using NMR, ESI-MS, and ATR-FT-IR. DLS and zeta potential were measured and high-resolution transmission electron microscopy (HRTEM) observations were performed. The chemical composition of the water-soluble fullerene nanomaterial was examined by X-ray photoelectron spectrometry. To observe aggregate formation, the cryo-TEM analysis was carried out. The docking studies and molecular dynamic simulations were performed to determine interactions between HDGF and BTK. The in vitro cytotoxicity was evaluated on RAJI and K562 blood cancer cell lines. Subsequently, we examined the induction of cell death by autophagy and apoptosis by determining the expression levels of crucial genes and caspases. We investigated the direct association of HDGF on inhibition of the BTK signalling pathway by examining changes in the calcium levels in RAJI cells after treatment. The inhibitory potential of HDGF against non-receptor tyrosine kinases was evaluated. Finally, we assessed the effects of HDGF and ibrutinib on the expression of the BTK protein and downstream signal transduction in RAJI cells following anti-IgM stimulation.Results: Computational studies revealed that the inhibitory activity of the obtained [60]fullerene derivative is multifaceted: it hampers the BTK active site, interacting directly with the catalytic residues, rendering it inaccessible to phosphorylation, and binds to residues that form the ATP binding pocket. The anticancer activity of produced carbon nanomaterial revealed that it inhibited the BTK protein and its downstream pathways, including PLC and Akt proteins, at the cellular level. The mechanistic studies suggested the formation of autophagosomes (increased gene expression of LC3 and p62) and two caspases (caspase-3 and − 9) were responsible for the activation and progression of apoptosis.Conclusion: These data illustrate the potential of fullerene-based BTK protein inhibitors as nanotherapeutics for blood cancer and provide helpful information to support the future development of fullerene nanomaterials as a novel class of enzyme inhibitors.Graphical Abstract: Keywords: fullerenes, BTK inhibitor, anticancer agent, autophagy, apoptosis

Summary: Waldenström macroglobulinaemia (WM) is characterized by the presence of a MYD88L265P mutation. This mutation promotes growth and survival of malignant cells through Bruton tyrosine kinase (BTK) activation. Ibrutinib was the first BTK inhibitor approved for WM. Intolerance to ibrutinib frequently leads to dose reductions, though the impact of reducing ibrutinib dosing has not been systematically studied. We performed a retrospective study to determine the frequency and impact of reducing ibrutinib dosing in WM patients. With a median treatment time of 64 months, 96 (27%) of 353 WM patients required a dose reduction due to adverse events such as musculoskeletal symptoms, cardiac events, dermatologic symptoms, cytopenias, and gastrointestinal symptoms. The median time to initial dose reduction was 9.3 months (range, 0.5–74). Dose reductions were more common in those 65 years of age or older versus under 65 [hazard ratio (HR) 2.46, 95% confidence interval (CI) 1.55–3.90; p < 0.001], and in females versus males (HR 2.20, 95% CI 1.41–3.28, p < 0.001). Most patients (65%) had improvement or resolution of adverse effects after initial dose reduction. With a median follow‐up of three years from dose reduction, hematologic response sustained or deepened in 79% of patients. These data suggest that dose reduction of ibrutinib is a reasonable treatment approach for patients with intolerable side effects. [ABSTRACT FROM AUTHOR]

Ibrutinib has dramatically changed the treatment landscape for chronic lymphocytic leukemia (CLL) since its availability in British Columbia (BC), Canada in 2014. We analyzed patterns of use and real-world survival outcomes in 370 patients who received ibrutinib for first-line (1 L, n = 35) and relapsed/refractory (R/R, n = 335) CLL between 2014–2018 in BC. Dose reductions and interruptions were frequent in 32% and 27%, respectively. With a median follow-up of 27.6 months, 35% of patients discontinued ibrutinib, primarily for adverse events (AEs) rather than progressive disease. Over the course of treatment, 87% of patients experienced at least one adverse event. The 2-year overall survival (OS) and event-free survival (EFS) were excellent at 83.9% and 76.1%, respectively, with medians not reached. However, patients who discontinued ibrutinib had a median OS of 32.5 months and median EFS of only 3.8 months from time of discontinuation, highlighting the need to minimize toxicity in the real-world. [ABSTRACT FROM AUTHOR]

Waldenström macroglobulinemia (WM) is a rare, non-Hodgkin lymphoma that remains incurable. Rituximab, an anti-CD20 monoclonal antibody has been the cornerstone of treatment against WM, and its combination with an alkylator, bendamustine, achieves durable remission in treatment-naive patients with symptomatic WM. However, novel "druggable" targets that have been identified within the clonal lymphoplasmacytic cells in WM have resulted in a rapid development of targeted therapies in both the frontline and relapsed and refractory (R/R) settings. Several agents directed against the known targets have shown promising efficacy, with mostly manageable toxicities. The class of Bruton's tyrosine kinase (BTK) inhibitors has transformed the therapeutic landscape for patients with WM, given their convenient oral dosing and strong efficacy, with high rates of attainment of very good partial response (VGPR). The tolerability of the next-generation BTK inhibitors appears to be superior to that of the first-in-class agent, ibrutinib. Targeted therapies from other classes have also demonstrated efficacy in both single-agent and combination regimens. Inhibitors of proteasome BCL-2, mTOR and PI-3 kinase have demonstrated efficacy in WM. Emerging therapies under investigation will continue to further shape the management paradigm, especially in the R/R setting. These include bispecific antibodies, radiotherapeutic agents and chimeric antigen receptor T-cell (CART) cell therapies. This review outlines the current literature and future direction of targeted therapies in WM. [ABSTRACT FROM AUTHOR]

Small molecule Bruton's tyrosine kinase (BTK) inhibitors have been developed for the treatment of various haemato-oncological diseases, and ibrutinib was approved as the first BTK inhibitor for anticancer therapy in 2013. Previous reports proved the receptor kinase human epidermal growth factor receptor 2 (HER2) to be a valid off-target kinase of ibrutinib and potentially other irreversible BTK inhibitors, as it possesses a druggable cysteine residue in the active site of the enzyme. These findings suggest ibrutinib as a candidate drug for repositioning in HER2-positive breast cancer (BCa). This subtype of breast cancer belongs to one of the most common classes of breast tumours, and its prognosis is characterized by a high rate of recurrence and tumour invasiveness. Based on their similar kinase selectivity profiles, we investigated the anticancer effect of zanubrutinib, evobrutinib, tirabrutinib and acalabrutinib in different BCa cell lines and sought to determine whether it is linked with targeting the epidermal growth factor receptor family (ERBB) pathway. We found that zanubrutinib is a potential inhibitor of the HER2 signalling pathway, displaying an antiproliferative effect in HER2-positive BCa cell lines. Zanubrutinib effectively inhibits the phosphorylation of proteins in the ERBB signalling cascade, including the downstream kinases Akt and ERK, which mediate key signals ensuring the survival and proliferation of cancer cells. We thus propose zanubrutinib as another suitable candidate for repurposing in HER2-amplified solid tumours. [ABSTRACT FROM AUTHOR]

Leukapheresis is a resource-intensive and high-risk treatment with unclear benefits when used for leukostasis syndrome in hematologic malignancies. In this case report and literature review we discuss the pathophysiology of leukostasis syndrome associated with chronic lymphocytic leukemia (CLL) and the rapidly evolving paradigm of CLL treatment through the lens of a 51-year-old man who was diagnosed with CLL. He presented with clinical manifestations of leukostasis syndrome with an absolute lymphocyte count of 522.6×109/L. We identified 15 additional cases of CLL-associated leukostasis syndrome in our literature review. Pulmonary and neurologic manifestations of leukostasis were most common. In combination with pharmacologic cytoreduction, leukapheresis was used successfully in most cases with few reports of complications. In the context of greater adoption of first line therapies for CLL that are known to induce transient leukocytosis, we explore leukapheresis as an adjunctive therapy that can rapidly reduce the lymphocyte count and in select instances possibly mitigate the effects of Bruton's tyrosine kinase inhibitor-induced hyperleukocytosis.

Background: Waldenström macroglobulinemia (WM) is a rare subtype of B-cell lymphoma. Rituximab-based combination therapy and Bruton’s tyrosine kinase (BTK) inhibitors have greatly improved the prognosis of WM. Despite the high response rate and good tolerance of BTK inhibitors in treatment of WM, a proportion of patients still experience disease progression.Case presentation: We report a 55-year-old man with relapsed WM. The patient achieved partial remission after six courses of CHOP chemotherapy and multiple plasma exchanges in initial treatment. He was admitted to the hospital with abdominal distension, and was diagnosed with relapsed WM and subsequently started on zanubrutinib. Disease progression and histological transformation occurred during treatment. We performed liquid biopsies on transformed plasma, tumor tissue and ascites at the same time and found high consistency between ascites and tissues. Moreover, we detected resistance mutations of BTK inhibitors (BTK, PLCG2) in ascites that were not detected in plasma or tissue. Eventually, the patient died during the 15-month follow-up after relapse.Conclusion: We describe a rare case of WM transformation to DLCBCL treated with chemoimmunotherapy and BTK inhibition. We analyzed tumor DNA obtained at different anatomic sites and circulating tumor DNA (ctDNA) derived from plasma and ascites specimens, with apparent significant temporal and spatial heterogeneity. The case specifically highlights the clinical value of ctDNA of ascites supernatant from WM patients, which is a more convenient and relatively noninvasive method compared with traditional invasive tissue biopsy.

Summary: Antibody titres in 462 patients with haematological malignancies after the second (D2) and third (D3) SARS‐CoV‐2 vaccine were compared with those of healthy controls (HCs). Significant decay of antibody titre was observed pre D3, but titre surged post D3. The number of seronegative patients decreased from 79 (17.1%) to 44 (9.5%) from post D2 to post D3, and patients with adequate antibody titre increased from 204 (44.2%) to 358 (77.5%). Of the patients who received B‐cell‐targeted therapy, 80% were seronegative and 71% remained seronegative after D3. CD19+, CD4+, CD8+ cell counts, and immunoglobulin G (IgG) levels were identified as independent predictors for adequate serologic response. [ABSTRACT FROM AUTHOR]

Mantle cell lymphoma (MCL) is a heterogenous disease that is one of the most challenging blood cancers due to its poor prognosis, high risk of relapse and drug resistance. Recent researches have brought significant changes in MCL patients outcomes and new clinical. Bruton's Tyrosine Kinase (BTK), a key kinase in the B-cell antigen receptor (BCR) signaling pathway, is a clinical research hot spot and plays a major role in the survival and spread of malignant B cells. The first generation of BTK inhibitors, led by ibrutinib, have shown promising results in targeted treatment. Meanwhile, several inhibitors have entered clinical studies and demonstrated outstanding therapeutic activity in clinical trials for MCL, indicating a good prospect for development. Despite these encouraging findings, the duration of response is limited, and resistance to BTK inhibitors develops in a portion of individuals. This review summarizes the pathogenesis of MCL and targeted BTK inhibitors and provides an overview of the mutations that can lead to resistance to BTK inhibitors. The purpose of this article is to review the literature describing these selective therapies and provides perspectives for their further development. [ABSTRACT FROM AUTHOR]

Aberrant activity of histone deacetylases (HDACs) is frequently detected in B‐cell lymphomas, which indicated the therapeutic implications of HDAC inhibitors for B‐cell malignancies. We have discovered that lymphoma cells treated with HDAC inhibitor presented with activation of Bruton tyrosine kinase (BTK) which played an important role in the development of B‐cell malignancies. Therefore, our study intended to explore whether the addition of ibrutinib (BTK inhibitor) to chidamide (HDAC inhibitor) could generate combined anti‐tumor effects in B‐cell lymphomas. Using cell viability assay, cell cycle and apoptosis kit, we demonstrated an evident synergistic action of ibrutinib and chidamide in inhibiting tumor cell proliferation and motility. Consistent with in vitro data, the synergistic anti‐tumor effects were also observed in multiple tumor‐bearing mice models. By performing RNA‐seq and flow cytometry of tumor tissue, the enhancement of anti‐tumor immunity was observed with the co‐treatment of chidamide and ibrutinib. Together, these mechanistic insights indicated that simultaneously targeting BTK and HDAC could be a promising clinical therapy for B‐cell lymphomas. [ABSTRACT FROM AUTHOR]

Treatment with covalent Bruton tyrosine kinase inhibitors (BTKi) represents an important advance in the management of relapsed or refractory mantle cell lymphoma, but these treatments are not curative and many patients ultimately relapse. Pirtobrutinib, a highly selective, non covalent (reversible) BTKi, inhibits both wild type and C481-mutant BTK with equal low nM potency, and has favorable oral pharmacology that enables continuous BTK inhibition throughout the dosing interval regardless of intrinsic rate of BTK turnover. Pirtobrutinib is well tolerated and has demonstrated promising efficacy in patients with poor prognosis B-cell malignancies following prior therapy, including covalent BTKi. This phase III, head-to-head, randomized study (NCT04662255) will evaluate whether pirtobrutinib is superior to investigator's choice of covalent BTKi in patients with previously treated, BTKi-naive mantle cell lymphoma. [ABSTRACT FROM AUTHOR]

This work investigates the synergistic potential of the nanostructured lipid carrier (NLC) gel of Ibrutinib with Curcumin as a repurposing strategy to treat psoriasis. In the present work, various components such as liquid lipid, solid lipid, and surfactant were selected and optimized based on the solubility of each drug, size, and polydispersity index. The optimized NLC consists of Capryol PGMC as liquid lipid, Glyceryl Mono Stearate as solid lipid, and Pluronics-F-127 as a surfactant. The prepared NLCs have a particle size of 95.12 ± 3.39 nm with PDI of 0.285 ± 0.009, exhibiting high entrapment efficiency (86.04 ± 2.86% for IBR and 87.25 ± 2.14% for CUR) with spherical geometry. CI value of 0.283 suggests synergism. Carbopol 940 was used as a gelling agent and has shown improved flux compared to plain drug gel. Anti-psoriatic studies in BALB/c mice indicated negligible skin irritation and improved histopathological features of psoriasis. Moreover, a reduced amount of inflammatory markers (TNF-alpha, IL-6, IL-22, and IL-23), and psoriasis severity score was observed with prepared gel than the IMQ group. The study suggested integrated benefits of repurposing Ibrutinib with Curcumin as NLC topical gel and it could possibly reduce remission of Psoriasis like inflammation and merit additional investigation. [ABSTRACT FROM AUTHOR]

Current therapeutic strategies for central nervous system (CNS) relapse of diffuse large B-cell lymphoma (DLBCL) are extremely limited. Secondary central nervous system lymphoma (SCNSL) also shows a grave prognosis and high mortality. This report describes a young female patient with DLBCL and CNS relapse who received low-dose CD19-directed chimeric antigen receptor T (CAR-T) cell therapy followed with Bruton's tyrosine kinase inhibitor and programmed cell death protein 1 antibody after several lines of chemotherapy. However, limited reports on CAR-T cell therapy are applied for SCNSL, particularly those in combination with targeted agents. The current treatment combination for this case provides a new regimen for CNS relapse from DLBCL. [ABSTRACT FROM AUTHOR]

Antihistamine refractory chronic spontaneous urticaria (CSU) has a prevalence of up to 50%. Anti-immunoglobulin E (IgE) therapies have revolutionized management of CSU, yet refractory cases persist, suggesting a role for biologic agents that impact alternative routes of mast cell stimulation independent of cross-linking at FcεR1. This review addresses anti-IgE and Th2-targeted therapies in the management of CSU. In addition, we explore novel treatments targeting alternative pathways of mast cell activation including MAS-related G protein-coupled receptor-X2 and sialic acid-binding immunoglobulin-like lectin-6, inhibiting intracellular signaling via Bruton's tyrosine kinase, and disrupting KIT activation by SCF., Competing Interests: Disclosure J.S. Bernstein has no conflicts of interest to disclose. J.A. Bernstein has served as PI and consultant for Sanofi Regeneron, Novartis, Genentech, Amgen, GSK, Celldex, Jasper, Escient, Astra-Zeneca, Allakos, Blueprint, Cogent, Telios, CSL Behring, Takeda/Shire, Pharming, Biocryst, Kalvista, Ionis, Biomarin, GSK, and Merck. Serves on AAAAI BOD, WAO BOD, Interasma BOD, UCARE COE, and AIM COE as well as on the editorial boards for Journal of Allergy and Clinical Immunology, Journal of Allergy and Clinical Immunology: In Practice, Annals of Allergy, Asthma and Clinical Immunology, Allergy and Asthma Proceedings. D.M. Lang has served as a consultant for, received honoraria from, and/or has carried out clinical research with AstraZeneca, Blueprint, Celldex, Genentech, Novartis, Sanofi-Regeneron, serves as Guest Editor for Journal of Allergy and Clinical Immunology in Practice, and also on the Editorial Boards of Allergy and Asthma Proceedings and DynaMed, and Delegate to National Quality Forum representing the American Academy of Allergy, Asthma, and Immunology., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Bruton's tyrosine kinaseinhibitors (BTKis) changed the trajectory of upfront and relapsed/refractory chronic lymphocytic leukemia (CLL) treatment. However, BTKis are plagued by a spectrum of toxicities. Zanubrutinib was developed to circumvent challenges with prolonged tolerability by increasing BTK selectivity and maximizing efficacy through pharmacokinetic/pharmacodynamic optimization. However, with the availability of ibrutinib, acalabrutinib, and zanubrutinib, limited data exists to guide sequencing of BTKi therapy in the relapsed/refractory setting., Areas Covered: We review the first head-to-head trial (ALPINE) of zanubrutinib versus ibrutinib for the treatment of relapsed/refractory CLL and compare zanubrutinib's clinical efficacy and toxicities, including in patients with del(17p) and/or TP53 mutations to ibrutinib and acalabrutinib., Expert Opinion: Zanubrutinibrepresents one of the new standards of care for relapsed/refractory CLL based on superior progression-free survival and response rates over ibrutinib. Whilezanubrutinib is associated with fewer cardiac toxicities, similar rates of neutropenia and hypertension are noted. Ongoing studies are pushing the envelope, utilizing targeted drug combinations and minimal residual disease markers as well as receptor tyrosine kinase-like orphan receptor 1 inhibitors, chimeric antigen receptor T-cells, and novel BTK degraders. However, zanubrutinibrepresents a strong contender in the arsenal of treatment options for relapsed/refractory CLL.

Background: Anti-myelin-associated-glycoprotein (MAG) neuropathy is a distal, predominantly demyelinating, sensory or sensory-motor polyneuropathy most often developing in the context of an IgM-type monoclonal gammopathy due to monoclonal gammopathy of undetermined significance or lymphoplasmacytic lymphoma. Rituximab is considered standard therapy for treatment naïve patients, but optimal treatment methods for relapsed/refractory patients have not been established. Case presentation: We demonstrate that tirabrutinib, a second-generation Burton kinase inhibitor, led to drastic improvements of polyneuropathy that were affirmed by nerve conduction studies in a rituximab-refractory anti-MAG neuropathy patient. Tirabrutinib continues to give excellent disease control with no apparent adverse events at 11 months since initiation, and the patient remains free of plasmapheresis sessions which were originally mandatory. Conclusion: Tirabrutinib is an extremely promising treatment option for anti-MAG neuropathy.

Despite recent improvements in multiple myeloma (MM) treatment, MM remains an incurable disease and most patients experience a relapse. The major reason for myeloma recurrence is the persistent stem cell-like population. It has been demonstrated that overexpression of Bruton's tyrosine kinase (BTK) in MM stem cell-like cells is correlated with drug resistance and poor prognosis. We have developed a novel small BTK inhibitor, KS151, which is unique compared to other BTK inhibitors. Unlike ibrutinib, and the other BTK inhibitors such as acalabrutinib, orelabrutinib, and zanubrutinib that covalently bind to the C481 residue in the BTK kinase domain, KS151 can inhibit BTK activities without binding to C481. This feature of KS151 is important because C481 becomes mutated in many patients and causes drug resistance. We demonstrated that KS151 inhibits in vitro BTK kinase activities and is more potent than ibrutinib. Furthermore, by performing a semi-quantitative, sandwich-based array for 71-tyrosine kinase phosphorylation, we found that KS151 specifically inhibits BTK. Our western blotting data showed that KS151 inhibits BTK signaling pathways and is effective against bortezomib-resistant cells as well as MM stem cell-like cells. Moreover, KS151 potentiates the apoptotic response of bortezomib, lenalidomide, and panobinostat in both MM and stem cell-like cells. Interestingly, KS151 inhibits stemness markers and is efficient in inhibiting Nanog and Gli1 stemness markers even when MM cells were co-cultured with bone marrow stromal cells (BMSCs). Overall, our results show that we have developed a novel BTK inhibitor effective against the stem cell-like population, and potentiates the response of chemotherapeutic agents. [ABSTRACT FROM AUTHOR]

The advent of novel targeted therapies, including B-cell receptor (BCR) pathway and B-cell lymphoma 2 (BCL2) inhibitors, has substantially changed the treatment paradigm for chronic lymphocytic leukemia (CLL). Although targeted therapies have improved outcomes compared to traditional chemoimmunotherapy in the front-line and relapsed or refractory settings, they are associated with resistance mutations and suboptimal outcomes in certain high-risk patients. Additionally, targeted therapies are associated with drug interactions and unique adverse effect profiles which can be challenging for patients and clinicians to manage. Ongoing studies continue to address questions regarding optimal sequencing of therapies, the role of treatment combinations, and the efficacy of next-generation novel agents. This review provides a comprehensive overview regarding the clinical management of targeted therapies for CLL and applies current literature to clinical practice. [ABSTRACT FROM AUTHOR]

Despite recent improvements in multiple myeloma (MM) treatment, MM remains an incurable disease and most patients experience a relapse. The major reason for myeloma recurrence is the persistent stem cell-like population. It has been demonstrated that overexpression of Bruton’s tyrosine kinase (BTK) in MM stem cell-like cells is correlated with drug resistance and poor prognosis. We have developed a novel small BTK inhibitor, KS151, which is unique compared to other BTK inhibitors. Unlike ibrutinib, and the other BTK inhibitors such as acalabrutinib, orelabrutinib, and zanubrutinib that covalently bind to the C481 residue in the BTK kinase domain, KS151 can inhibit BTK activities without binding to C481. This feature of KS151 is important because C481 becomes mutated in many patients and causes drug resistance. We demonstrated that KS151 inhibits in vitro BTK kinase activities and is more potent than ibrutinib. Furthermore, by performing a semi-quantitative, sandwich-based array for 71-tyrosine kinase phosphorylation, we found that KS151 specifically inhibits BTK. Our western blotting data showed that KS151 inhibits BTK signaling pathways and is effective against bortezomib-resistant cells as well as MM stem cell-like cells. Moreover, KS151 potentiates the apoptotic response of bortezomib, lenalidomide, and panobinostat in both MM and stem cell-like cells. Interestingly, KS151 inhibits stemness markers and is efficient in inhibiting Nanog and Gli1 stemness markers even when MM cells were co-cultured with bone marrow stromal cells (BMSCs). Overall, our results show that we have developed a novel BTK inhibitor effective against the stem cell-like population, and potentiates the response of chemotherapeutic agents.

Abivertinib, a third-generation tyrosine kinase inhibitor, is originally designed to target epidermal growth factor receptor (EGFR)-activating mutations. Previous studies have shown that abivertinib has promising antitumor activity and a well-tolerated safety profile in patients with non-small-cell lung cancer. However, abivertinib also exhibited high inhibitory activity against Bruton's tyrosine kinase and Janus kinase 3. Given that these kinases play some roles in the progression of megakaryopoiesis, we speculate that abivertinib can affect megakaryocyte (MK) differentiation and platelet biogenesis. We treated cord blood CD34+ hematopoietic stem cells, Meg-01 cells, and C57BL/6 mice with abivertinib and observed megakaryopoiesis to determine the biological effect of abivertinib on MK differentiation and platelet biogenesis. Our in vitro results showed that abivertinib impaired the CFU-MK formation, proliferation of CD34+ HSC-derived MK progenitor cells, and differentiation and functions of MKs and inhibited Meg-01-derived MK differentiation. These results suggested that megakaryopoiesis was inhibited by abivertinib. We also demonstrated in vivo that abivertinib decreased the number of MKs in bone marrow and platelet counts in mice, which suggested that thrombopoiesis was also inhibited. Thus, these preclinical data collectively suggested that abivertinib could inhibit MK differentiation and platelet biogenesis and might be an agent for thrombocythemia. [ABSTRACT FROM AUTHOR]

The use of Bruton's tyrosine kinase (BTK) inhibitors has changed the management of patients with B-cell lymphoid malignancies. BTK is an important molecule that interconnects B-cell antigen receptor (BCR) signaling. BTK inhibitors (BTKis) are classified into three categories, namely covalent irreversible inhibitors, covalent reversible inhibitors, and non-covalent reversible inhibitors. Ibrutinib is the first covalent, irreversible BTK inhibitor approved in 2013 as a breakthrough therapy for chronic lymphocytic leukemia patients. Subsequently, two other covalent, irreversible, second-generation BTKis, acalabrutinib and zanubrutinib, have been developed for lymphoid malignancies to reduce the ibrutinib-mediated adverse effects. More recently, irreversible and reversible BTKis have been under development for immune-mediated diseases, including autoimmune hemolytic anemia, immune thrombocytopenia, multiple sclerosis, pemphigus vulgaris, atopic dermatitis, rheumatoid arthritis, systemic lupus erythematosus, Sjögren's disease, and chronic spontaneous urticaria, among others. This review article summarizes the preclinical and clinical evidence supporting the role of BTKis in various autoimmune, allergic, and inflammatory conditions. [ABSTRACT FROM AUTHOR]

Aims: Examine relationships between the systemic exposure of acalabrutinib, a highly selective, next‐generation Bruton tyrosine kinase inhibitor, and its active metabolite (ACP‐5862) vs. efficacy and safety responses in patients with B‐cell malignancies who received acalabrutinib as monotherapy or in combination with obinutuzumab. Methods: For exposure–efficacy analyses, patients with untreated chronic lymphocytic leukaemia were assessed for best overall response, progression‐free survival and tumour regression. For exposure–safety analyses, incidences of grade ≥2 adverse events (AEs), grade ≥3 AEs and grade ≥2 events of clinical interest were assessed in patients with B‐cell malignancies. Acalabrutinib and ACP‐5862 pharmacokinetic (PK) parameter estimates were obtained from population PK modelling. Exposure calculations were based on study dosing regimens. Total active moieties were calculated to account for contributions of ACP‐5862 to overall efficacy/safety. Results: A total of 573 patients were included (exposure–efficacy analyses, n = 274; exposure–safety analyses, n = 573). Most patients (93%) received acalabrutinib 100 mg twice daily. Median total active area under the concentration–time curve (AUC24h,ss) and total active maximal concentration at steady‐state (Cmax,ss) were similar for patients who received acalabrutinib as monotherapy or in combination with obinutuzumab, and for responders and nonresponders. No relationship was observed between AUC24h,ss/Cmax,ss and progression‐free survival or tumour regression. Acalabrutinib AUC24h,ss and Cmax,ss were generally comparable across groups regardless of AE incidence. Conclusion: No clinically meaningful correlations between acalabrutinib PK exposure and efficacy and safety outcomes were observed. These data support the fixed acalabrutinib dose of 100 mg twice daily in the treatment of patients with B‐cell malignancies. [ABSTRACT FROM AUTHOR]

Bruton's Tyrosine Kinase (BTK) is considered crucial in the activation and survival of both physiological and malignant B-cells. In recent years, ibrutinib, an oral BTK inhibitor, became a breakthrough therapy for hematological malignancies, such as chronic lymphocytic. However, ibrutinib's feasibility might not end there. Several other kinases with established involvement with solid malignancies (i.e., EGFR, HER2) have been found to be inhibited by this agent. Recent discoveries indicate that BTK is a potential anti-solid tumor therapy target. Consequently, ibrutinib, a BTK-inhibitor, has been studied as a therapeutic option in solid malignancies. While most preclinical studies indicate ibrutinib to be an effective therapeutic option in some specific indications, such as NSCLC and breast cancer, clinical trials contradict these observations. Nevertheless, while ibrutinib failed as a monotherapy, it might become an interesting part of a multidrug regime: not only has a synergism between ibrutinib and other compounds, such as trametinib or dactolisib, been observed in vitro, but this BTK inhibitor has also been established as a radio- and chemosensitizer. This review aims to describe the milestones in translating BTK inhibitors to solid tumors in order to understand the future potential of this agent better. [ABSTRACT FROM AUTHOR]