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Abstract Introduction Multiple sclerosis (MS) is a chronic neurodegenerative disease that leads to impaired cognitive function and accumulation of disability, with significant socioeconomic burden. Serious unmet need in the context of managing MS has given rise to ongoing research efforts, leading to the launch of new drugs planned for the near future, and subsequent concerns about the sustainability of healthcare systems. This study assessed the changes in the Italian MS market and their impact on the expenditures of the Italian National Healthcare Service between 2023 and 2028. Methods A horizon-scanning model was developed to estimate annual expenditure from 2023 to 2028. Annual expenditure for MS was calculated by combining the number of patients treated with each product (clinical inputs) and the yearly costs of therapy (economic inputs). Baseline inputs (2020–2022) were collected from IQVIA® real-world data, while input estimation for the 5-year forecast was integrated with analog analyses and the insights of clinicians and former payers. Results The number of equivalent patients treated in 2028 in Italy was estimated at around 67,000, with an increase of 10% versus 2022. In terms of treatment pattern evolution, first-line treatments are expected to reduce their shares from 47% in 2022 to 27% in 2028, and Bruton tyrosine kinase inhibitors are expected to reach 23% of patient shares. Overall, expenditure for MS is estimated to decrease from €721 million in 2022 to €551 million in 2028, mainly due to losses of exclusivity and renegotiation of drug prices. Conclusion Despite the increase in the number of patients treated for MS and the launch of new molecules that will reach high market penetration, the model confirmed sustainability for the Italian National Healthcare Service.

Abstract Bruton’s tyrosine kinase (BTK), a nonreceptor tyrosine kinase, plays a remarkable role in the transmission and amplification of extracellular signals to intracellular signaling pathways. Various types of cells use the BTK pathway to communicate, including hematopoietic cells particularly B cells and T cells. The BTK pathway plays a role in controlling the proliferation, survival, and functions of B cells as well as other myeloid cells. First, second, and third-generation BTK inhibitors are currently being evaluated for the treatment of immune-mediated diseases in addition to B cell malignancies. In this article, the available evidence on the action mechanisms of BTK inhibitors is reviewed. Then, the most recent data obtained from preclinical studies and ongoing clinical trials for the treatment of autoimmune diseases, such as pemphigus vulgaris, pemphigus foliaceus, bullous pemphigoid, systemic lupus erythematosus, Sjögren’s disease, rheumatoid arthritis, systemic sclerosis, multiple sclerosis, myasthenia gravis, and inflammatory diseases such as psoriasis, chronic spontaneous urticaria, atopic dermatitis, and asthma are discussed. In addition, adverse effects and complications associated with BTK inhibitors as well as factors predisposing patients to BTK inhibitors complications are discussed.

Introduction: Multiple sclerosis (MS) is a chronic neurodegenerative disease that leads to impaired cognitive function and accumulation of disability, with significant socioeconomic burden. Serious unmet need in the context of managing MS has given rise to ongoing research efforts, leading to the launch of new drugs planned for the near future, and subsequent concerns about the sustainability of healthcare systems. This study assessed the changes in the Italian MS market and their impact on the expenditures of the Italian National Healthcare Service between 2023 and 2028. Methods: A horizon-scanning model was developed to estimate annual expenditure from 2023 to 2028. Annual expenditure for MS was calculated by combining the number of patients treated with each product (clinical inputs) and the yearly costs of therapy (economic inputs). Baseline inputs (2020–2022) were collected from IQVIA® real-world data, while input estimation for the 5-year forecast was integrated with analog analyses and the insights of clinicians and former payers. Results: The number of equivalent patients treated in 2028 in Italy was estimated at around 67,000, with an increase of 10% versus 2022. In terms of treatment pattern evolution, first-line treatments are expected to reduce their shares from 47% in 2022 to 27% in 2028, and Bruton tyrosine kinase inhibitors are expected to reach 23% of patient shares. Overall, expenditure for MS is estimated to decrease from €721 million in 2022 to €551 million in 2028, mainly due to losses of exclusivity and renegotiation of drug prices. Conclusion: Despite the increase in the number of patients treated for MS and the launch of new molecules that will reach high market penetration, the model confirmed sustainability for the Italian National Healthcare Service. [ABSTRACT FROM AUTHOR]

Background: Bruton's tyrosine kinase inhibitors (BTKi) and the B‐cell lymphoma 2 (BCL2) inhibitor venetoclax have significantly improved outcomes and achieved durable remission in patients with chronic lymphocytic leukemia (CLL). BTKi/venetoclax‐treated patients with exposure to both novel agents (regardless of the reason for discontinuation) are classified as "double‐exposed," and often have poor prognoses. This study aims to assess the efficacy and effectiveness of treatments in double‐exposed CLL patients. Methods: PubMed, Embase, and Web of Science databases were searched until December 2023. Results: We retrieved 3948 articles for screening and included 13 publications covering nine distinct studies. Three clinical trials reported a median PFS of 16.8 months with pirtobrutinib, 13 months with lisocabtagene maraleucel, and 10.1 months with nemtabrutnib. ORR ranged from 58% with nemtabrutinib and 80% with lisocabtagene maraleucel. In observational studies, PFS ranged from 3 months with chemoimmunotherapy to 12 months with BTKi, and ORR ranged from 31.8% with chemoimmunotherapy to 85.7% with chimeric antigen receptors (CAR) T‐cell therapy. Conclusion: This study highlights the limited clinical data on efficacy outcomes for double‐exposed CLL/SLL patients. Pirtobrutinib, lisocabtagene maraleucel, and a combination of ibrutinib and venetoclax have shown promising effects. However, the scarcity of treatment options and efficacy data for patients who have failed BTKi and venetoclax underscores a significant unmet medical need. [ABSTRACT FROM AUTHOR]

Abstract Background First generation Bruton tyrosine kinase inhibitors (BTKi) such as ibrutinib have been associated with cardiovascular toxicities. Newer generation BTKi (e.g.,acalabrutinib and zanabrutinib) have been associated with lower incidence of cardiotoxicity in clinical trials. Objective Given paucity in real-world data on the overall cardiac risk factor profile, especially with the newer BTKi, our study evaluated the incidence of cardiotoxicity with various BTKi among a large, commercially insured population of patients. Methods We performed a retrospective cohort analysis of all adults with a diagnosis of B-cell malignancy undergoing treatment with BTKi acalabrutinib and ibrutinib between January 2018 and June 2020 using Optum’s de-identified Clinformatics® Data Mart Database. We then identified patients who had pre-existing cardiac disease one year prior to starting BTKi. New incidence of atrial fibrillation/flutter, hypertension, bleeding, ventricular tachycardia/fibrillation and sudden cardiac death from the time of index presciption were compared with standard Chi Square or Student t-test where appropriate. Multivariate logistic regression models were also estimated to evaluate for confounding. Results A total of 1691 patients were included in the final analysis. 1595 (94%, median age 75 (19–90) years, 61% male gender) patients received ibrutinib, and 96 (6%, median age 73.5 (32–90) years, 62.5% male gender) patients received acalabrutinib. The median duration of drug exposure of ibrutinib was 238 (2-1084) days vs. 150 (30–870) days for acalabrutinib. There was lower new incidence of atrial fibrillation/flutter (4.6%-vs-17%, p = 0.013), hypertension (6.3%-vs-25%, p = NS), sudden cardiac arrest/death (0% vs. 1.5%, p = NS) in the acalabrutinib group compared to ibrutinib, of which only the lower incidence of atrial fibrillation/flutter was statistically significant. This was despite the finding of a higher prevalence of atrial fibrillation/flutter at baseline in patients receiving acalabrutinib. Conclusions There was lower incidence of new atrial fibrillation/flutter with acalabrutinib when compared to ibrutinib in a real-world cohort of patients.

ABSTRACT Background Bruton's tyrosine kinase inhibitors (BTKi) and the B‐cell lymphoma 2 (BCL2) inhibitor venetoclax have significantly improved outcomes and achieved durable remission in patients with chronic lymphocytic leukemia (CLL). BTKi/venetoclax‐treated patients with exposure to both novel agents (regardless of the reason for discontinuation) are classified as “double‐exposed,” and often have poor prognoses. This study aims to assess the efficacy and effectiveness of treatments in double‐exposed CLL patients. Methods PubMed, Embase, and Web of Science databases were searched until December 2023. Results We retrieved 3948 articles for screening and included 13 publications covering nine distinct studies. Three clinical trials reported a median PFS of 16.8 months with pirtobrutinib, 13 months with lisocabtagene maraleucel, and 10.1 months with nemtabrutnib. ORR ranged from 58% with nemtabrutinib and 80% with lisocabtagene maraleucel. In observational studies, PFS ranged from 3 months with chemoimmunotherapy to 12 months with BTKi, and ORR ranged from 31.8% with chemoimmunotherapy to 85.7% with chimeric antigen receptors (CAR) T‐cell therapy. Conclusion This study highlights the limited clinical data on efficacy outcomes for double‐exposed CLL/SLL patients. Pirtobrutinib, lisocabtagene maraleucel, and a combination of ibrutinib and venetoclax have shown promising effects. However, the scarcity of treatment options and efficacy data for patients who have failed BTKi and venetoclax underscores a significant unmet medical need.

Objectives: Ibrutinib, a first-generation covalent Bruton's tyrosine kinase inhibitor (BTKi) was found to be a risk factor for the occurrence of invasive fungal complications. Acalabrutinib is a second-generation covalent BTKi used to treat B-cell malignancies. Healthy donor neutrophils incubated ex vivo with acalabrutinib lose ability to control Aspergillus conidia germination. In patients receiving acalabrutinib, the potential effect on neutrophil antifungal activity is unknown. Furthermore, only two cases of invasive aspergillosis have been reported during treatment with acalabrutinib, outside of a few cases in a clinical trial. Methods: We describe three new cases of invasive aspergillosis occurring within the first months of acalabrutinib therapy in patients with chronic lymphocytic leukemia. We used videomicroscopy and flow cytometry approaches to investigate the basic functional responses against Aspergillus of neutrophils from acalabrutinib-treated patients. Results: We showed an alteration in the anti-Aspergillus response after 1 month of acalabrutinb therapy: neutrophils lost their capacities of killing Aspergillus fumigatus germinating conidia and decreased their reactive oxygen species production when stimulated by Aspergillus. Conclusions: It is important to follow-up patients treated with acalabrutinib for the risk of aspergillosis as well as those treated with ibrutinib.

The dysregulation of the immune system in Chronic Lymphocytic Leukemia (CLL) often allows for the development of immune-mediated diseases. Among them, autoimmune cytopenias are the most common, but cases of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) have been reported. We herein report on a patient who developed a CIDP while undergoing ibrutinib treatment for CLL, prompting drug discontinuation. Steroid treatment and a rituximab course proved to be ineffective at obtaining long-term control of CIDP, but therapy with venetoclax and rituximab, which was started due to CLL progression, led to the progressive amelioration of the symptoms up to complete remission of the neurological disease.

Background: Inhibition of Bruton's tyrosine kinase (BTK) is an emerging multiple sclerosis (MS) therapy. BTK inhibitors (BTKi) cross the blood-brain barrier and modulate B cells and microglia, major cellular players in active and chronic active lesions. Objective: To assess potential lesional and cellular targets of BTKi, we examined BTK expression in different type of MS white matter (WM) lesions, in unmanipulated CNS resident cells, and in a degenerative MS model associated with microglia activation in vivo. Methods: We examined BTK expression by next-generation RNA-sequencing in postmortem 25 control WM, 19 NAWM, 6 remyelinating, 18 active, 13 inactive and 17 chronic active lesions. Presence of B cells and microglia were examined by immunohistochemistry. CNS resident cells were isolated from the mouse brain by magnetic sorting. BTK expression was examined by quantitative PCR in isolated cells and dissected corpus callosum from mice treated with cuprizone (CPZ). Results: BTK expression was significantly increased in active and chronic active lesions with upregulated complement receptors and Fcg receptors. Active lesions contained high number of perivascular B cells, microglia, and macrophages. Chronic active lesions were characterized by microglia/macrophages in the rim. Microglia expressed BTK at high level (120-fold) in contrast to other CNS cell types (2-4-fold). BTK expression was increasing during CPZ treatment reaching significance after stopping CPZ. Conclusion: Considering BTK expression in MS lesions and resident cells, BTKi may exert effect on B cells, microglia/macrophages in active lesions, and limit microglia activation in chronic active lesions, where tissue damage propagates. [ABSTRACT FROM AUTHOR]

Abstract Waldenström macroglobulinemia (WM) is a rare, incurable low grade lymphoma following a relapsing trajectory. Management strategies have evolved with the introduction of targeted therapy including new classes of Bruton tyrosine kinase inhibitor (BTKi). Treatment may however be limited particularly at relapse by a lack of drug availability and tolerability. We assessed the real‐world efficacy and tolerability of bortezomib‐containing regimens in patients with WM at frontline and relapse including those with prior BTKi resistance. Forty‐one patients were identified with 44 bortezomib‐containing regimens administered (n = 12 frontline, n = 32 relapse). Of patients treated at relapse, the median prior lines of therapy was 3 (range 1–7). 24% (10/41) of the cohort were refractory or intolerant to BTKi prior to bortezomib delivery. The median follow‐up after bortezomib administration was 34 months (range 0‐131). Overall response rate was 88%; 2‐year overall survival and progression‐free survival were 90% (95% confidence interval [CI] 73–96) and 76% (95% CI 55–87), respectively. Median time‐to‐next‐treatment was 66 months. Neuropathy (grade 1–2) occurred in 24% (8/34) and did not result in treatment cessation in any case. Gastrointestinal disturbance occurred in 7% (3/41). Treatment discontinuations were rare (1/44; 2%), suggesting a manageable safety profile. Major response rate was comparable in those with prior BTKi compared with those without (75% [6/8] vs 84% [27/32], p = 0.61). Bortezomib should be considered as a treatment modality particularly in those who are refractory to BTKi.

Primary central nervous system lymphoma (PCNSL) is a highly aggressive brain tumor with poor prognosis if no treatment. The activation of the NF-kB (nuclear factor kappa-B) is the oncogenic hallmark of PCNSL, and it was driven by B cell receptor (BCR) and Toll-like receptor (TLR) signaling pathways. The emergence of Bruton's tyrosine kinase inhibitors (BTKis) has brought the dawn of life to patients with PCNSL. This review summarizes the management of PCNSL with BTKis and potential molecular mechanisms of BTKi in the treatment of PCNSL. And the review will focus on the clinical applications of BTKi in the treatment of PCNSL including the efficacy and adverse events, the clinical trials currently being carried out, the underlying mechanisms of resistance to BTKi and possible solutions to drug resistance. [ABSTRACT FROM AUTHOR]

Mantle cell lymphoma (MCL) is a challenging B-cell non-Hodgkin lymphoma with a poor prognosis and frequent relapses. While treatment advancements such as rituximab and Bruton tyrosine kinase inhibitors (BTKi) like ibrutinib have improved outcomes, novel treatments are continually sought. Zanubrutinib, a second-generation BTKi, promises reduced side effects due to its high selectivity and reduced off-target inhibition. This paper presents a novel case of simultaneous radiotherapy and zanubrutinib treatment in a patient with MCL. We describe a 76-year-old female with a history of MCL treated with zanubrutinib. The patient presented with a metastatic lesion in the parotid gland, which emerged from a previously treated spinocellular carcinoma. She underwent parotidectomy followed by adjuvant radiotherapy while continuing zanubrutinib. The combination was well-tolerated with minimal side effects, including grade 1 dermatitis and grade 2 mucositis, neither of which progressed significantly. Hematological parameters monitored during treatment showed delayed, transient lymphopenia and neutropenia, which resolved post-therapy. No dose adjustment was necessary. The safety and efficacy of concurrent radiotherapy and zanubrutinib treatment in MCL patients are largely unexplored in clinical literature. This case represents the first documented instance of concurrent radiotherapy and zanubrutinib treatment. Our case suggests a favorable safety profile with manageable adverse effects, contrasting with concerns about increased toxicity with other tyrosine kinase inhibitors and radiotherapy combinations. These results indicate the feasibility of this approach with minimal adverse effects. Future studies should explore the broader applicability and efficacy of this treatment strategy, focusing on long-term outcomes and the interplay between BTKi therapy and radiotherapy response., Competing Interests: Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Fabi et al.)

Bruton's tyrosine kinase (BTK) is an important protein belonging to the tyrosine kinase family that plays a key role in the intracellular signaling and proliferation, migration, and survival of normal and malignant B-lymphocytes and myeloid cells. Understanding the role of BTK in the B-cell signaling pathway has led to the development of BTK inhibitors (BTKi) as effective therapies for malignancies of myeloid origin and exploration as a promising therapeutic option for other cancers. Given its central function in B-cell receptor signaling, inhibition of BTK is an attractive approach for the treatment of a wide variety of autoimmune diseases that involve aberrant B-cell function including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and multiple sclerosis (MS). Here, we review the role of BTK in different cell signaling pathways, the development of BTKi in B-cell malignancies, and their emerging role in the treatment of MS and other autoimmune disorders. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) resulting in demyelination and neurodegeneration. The therapeutic strategy is now largely based on reducing inflammation with immunosuppressive drugs. Unfortunately, when disease progression is observed, no drug offers neuroprotection apart from its anti-inflammatory effect. In this review, we explore current knowledge on the assessment of neurodegeneration in MS and look at putative targets that might prove useful in protecting the axon from degeneration. Among them, Bruton's tyrosine kinase inhibitors, anti-apoptotic and antioxidant agents, sex hormones, statins, channel blockers, growth factors, and molecules preventing glutamate excitotoxicity have already been studied. Some of them have reached phase III clinical trials and carry a great message of hope for our patients with MS. [ABSTRACT FROM AUTHOR]

• Invasive aspergillosis may occur within the first months of acalabrutinib therapy. • Antifungal neutrophil activities are impaired in patients on acalabrutinib therapy. • Our series suggests 4.3% of invasive aspergillosis in patients on acalabrutinib. Ibrutinib, a first-generation covalent Bruton's tyrosine kinase inhibitor (BTKi) was found to be a risk factor for the occurrence of invasive fungal complications. Acalabrutinib is a second-generation covalent BTKi used to treat B-cell malignancies. Healthy donor neutrophils incubated ex vivo with acalabrutinib lose ability to control Aspergillus conidia germination. In patients receiving acalabrutinib, the potential effect on neutrophil antifungal activity is unknown. Furthermore, only two cases of invasive aspergillosis have been reported during treatment with acalabrutinib, outside of a few cases in a clinical trial. We describe three new cases of invasive aspergillosis occurring within the first months of acalabrutinib therapy in patients with chronic lymphocytic leukemia. We used videomicroscopy and flow cytometry approaches to investigate the basic functional responses against Aspergillus of neutrophils from acalabrutinib-treated patients. We showed an alteration in the anti- Aspergillus response after 1 month of acalabrutinb therapy: neutrophils lost their capacities of killing Aspergillus fumigatus germinating conidia and decreased their reactive oxygen species production when stimulated by Aspergillus. It is important to follow-up patients treated with acalabrutinib for the risk of aspergillosis as well as those treated with ibrutinib. [ABSTRACT FROM AUTHOR]

Drug repositioning is a promising and powerful innovative strategy in the field of drug discovery. In this study, we screened a compound-library containing 800 Food and Drug Administration approved drugs for their anti-leukemic effect. All screening activities made use of human peripheral blood mononuclear cells (PBMCs), isolated from healthy or leukemic donors. Compounds with confirmed cytotoxicity were selected and classified in three groups: i) anti-neoplastic compounds which are drugs used in leukemia treatment, ii) compounds known to have an anti-cancer effect and iii) compounds demonstrating an anti-leukemic potential for the first time. The latter group was the most interesting from a drug repositioning perspective and yielded a single compound, namely Isoprenaline which is a non-selective β-adrenergic agonist. Analysis of the cytotoxic effect of this drug indicated that it induces sustainable intracellular ATP depletion leading, over time, to necrotic cell death. We exploited the Isoprenaline-induced intracellular ATP depletion to sensitize primary leukemic cells to fludarabine (purine analogue) and Ibrutinib (Bruton's tyrosine kinase inhibitor) treatment. In-vitro treatment of primary leukemic cells with a combination of Isoprenaline/fludarabine or Isoprenaline/Ibrutinib showed a very high synergistic effect. These combinations could constitute a new efficient regimen for CLL treatment following successful evaluation in animal models and clinical trials. [ABSTRACT FROM AUTHOR]

Competing Interests: None disclosed.

Background: The ONO-4059-02 phase 1/2 study showed favorable efficacy and acceptable safety profile of tirabrutinib, a second-generation Bruton's tyrosine kinase inhibitor, for relapsed/refractory primary central nervous system lymphoma (PCNSL). Here, we report the long-term efficacy and safety after a 3-year follow-up., Methods: Eligible patients were aged ≥ 20 years with histologically diagnosed PCNSL and KPS of ≥ 70. Patients received oral tirabrutinib once daily at 320 or 480 mg, or 480 mg under fasted conditions., Results: Between October 19, 2017, and June 13, 2019, 44 patients were enrolled: 33 and 9 had relapsed and refractory, respectively. The 320, 480, and 480 mg fasted groups included 20, 7, and 17 patients, respectively. The median follow-up was 37.1 months. The overall response rate was 63.6% (95% CI: 47.8-77.6) with complete response (CR), unconfirmed CR, and partial response in 9, 7, and 12 patients, respectively. The median duration of response (DOR) was 9.2 months, with a DOR rate of 19.8%; the median progression-free survival (PFS) and median overall survival (OS) were 2.9 months and not reached, respectively, with PFS and OS rates of 13.9% and 56.7%, respectively. Adverse events occurred in 38 patients (86.4%): grade ≥ 3 in 23 (52.3%) including 1 patient with grade 5 events. KPS and quality of life (QoL) scores were well maintained among patients receiving long-term treatment., Conclusions: The results demonstrated the long-term clinical benefit of tirabrutinib, with deep and durable response in a subset of patients and acceptable safety profile, while KPS and QoL scores were maintained., Competing Interests: All authors received support for developing the manuscript, which includes funding, medical writing, and article processing charge. HY reports honoraria from Ono, Chugai, Fujifilm, and Novocure global. YN reports grants from Chugai, Sumitomo Pharma, Eisai, Otsuka, SBI, AbbVie, Daiichi Sankyo, Stella Pharma, and Meiji Seika; honoraria from Chugai, Sumitomo Pharma, Eisai, Otsuka, SBI, AbbVie, Daiichi Sankyo, Stella Pharma, and Meiji Seika. MN reports grants from Chugai, MSD, Nippon Kayaku, Bristol Myers Squibb, Pfizer, Takeda, Shionogi, Kyowa Kirin, Teijin Pharma, Asahi Kasei Medical, HOYA Technosurgical, AbbVie, Eisai, Daiichi Sankyo, Otsuka, Astellas, Tsumura, Sanofi, Mitsubishi Tanabe Pharma, Sanei, CSF Behring, and Ono; consulting fees from Ono, Nippon Shinyaku, and Novocure; honoraria from Chugai, MSD, Nippon Kayaku, UCB Japan, Sumitomo Pharma, Ono, Ohara, AbbVie, Eisai, Daiichi Sankyo, Novocure, Bristol Myers Squibb, and Kyowa Kirin; support for attending meetings and/or travel from Ono, Eisai, Denka, Kyowa Kirin, and Nippon Kayaku; Participation on a Data Safety Monitoring Board or Advisory Board in Novocure; and medical writing support from Ono and Chugai. KM reports grants from Chugai, Eisai, Gunze Medical, Otsuka, Nihon Medi-Physics, Gunze, Stryker Japan, Kyowa Kirin, MSD, Teijin Pharma, AbbVie, Daiichi Sankyo, Novocure, HOYA Technosurgical, Ohara, and CSL Behring; and honoraria from Ono and Chugai. YA reports grants from Philips, Otsuka, Chugai, Nihon Medi-Physics, Daiichi Sankyo, Stryker, Eisai, Japan Blood Products Organization, Ono, Taiho, Sumitomo Pharma, Astellas, Incyte Biosciences, and Servier; and honoraria for lectures from Nippon Kayaku, Novocure, UCB Japan, Ono, Brainlab, Merck, Chugai, Eisai, Daiichi Sankyo, Carl Zeiss, and Nihon Medi-Physics. KA reports honoraria and support for attending meetings and/or travel from Ono. NF reports grants from Ono, Bayer, Chugai, Celgene, and Genmab and Incyte; honoraria from AstraZeneca, Bristol Myers Squibb, Chugai, CSL Behring, Sumitomo Pharma, Eisai, Janssen, Kyowa Kirin, Nippon Shinyaku, Novartis, Ono, Otsuka, Sanofi, SymBio, Takeda, and Zenyaku; and participation on a data safety monitoring board in Huya Japan and an advisory board in AstraZeneca, AbbVie, Eli Lilly, Genmab, and Novartis. KS reports honoraria from Daiichi Sankyo, Eisai, Meiji Seika Pharma, Bristol Myers Squibb, Novartis, Ono, and Nobel Pharma. AA is employed in Ono and holds stocks of Ono. RN reports grants from MSD, Eisai, AbbVie, and Chugai; and consulting fee from Novocure; honoraria from AbbVie, Chugai, Daiichi Sankyo, Eisai, Novocure, and Ono., (© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Chikungunya virus (CHIKV) is transmitted by Aedes mosquitoes and causes prolonged arthralgia in patients. After crossing the mosquito midgut barrier, the virus disseminates to tissues including the head and salivary glands. To better understand the interaction between Aedes albopictus and CHIKV, we performed RNASeq analysis on pools of mosquito heads and parts of the thorax 8 days post infection, which identified 159 differentially expressed transcripts in infected mosquitos compared to uninfected controls. After validation using RT-qPCR (reverse transcriptase-quantitative polymerase chain reaction), inhibitor of Bruton’s tyrosine kinase (BTKi), which has previously been shown to be anti-inflammatory in mammals after viral infection, was further evaluated for its functional significance. Knockdown of BTKi using double-stranded RNA in a mosquito cell line showed no significant difference in viral RNA or infectivity titer. However, BTKi gene knocked-down cells showed increased apoptosis 24 hours post-infection compared with control cells, suggesting involvement of BTKi in the mosquito response to viral infection. Since BTK in mammals promotes an inflammatory response and has been shown to be involved in osteoclastogenesis, a hallmark of CHIKV pathogenesis, our results suggest a possible conserved mechanism at play between mosquitoes and mammals. Taken together, these results will add to our understanding of Aedes Albopictus interactions with CHIKV.

Aim: To evaluate the safety and efficacy of pirtobrutinib in previously treated patients (pts) with MCL. Method: BRUIN is a multicenter phase 1/2 study (NCT03740529) of oral pirtobrutinib monotherapy in pts with advanced B-cell malignancies who have received >2 prior therapies. The primary objective for phase 1 was to determine the RP2D. The primary objective of phase 2 was ORR. Secondary objectives included DoR, PFS, OS, safety and tolerability, and pharmacokinetics. Results: As of 27 Sept 2020, 323 pts (170 CLL/SLL, 61 MCL, 26 WM, 26 DLBCL, 13 MZL, 12 FL, 9 RT and 6 other NHL) were treated on 7 dose levels (25-300 mg QD). Among the 61 MCL pt, median number of prior lines of therapy was 3 (1-8). No DLTs were reported and MTD was not reached (n = 323). 200mg QD was selected as the RP2D. Fatigue (20%), diarrhea (17%) and contusion (13%) were the most frequent TEAEs regardless of attribution or grade seen in >10% pts. The most common AE of grade ≥3 was neutropenia (10%). Treatment-related hemorrhage/hypertension occurred in 5 (2%)/4 (1%) pts. 5 (1%) pts discontinued due to TEAEs. 52 prior BTKi treated MCL pts were efficacy evaluable with an ORR of 52% (95% CI 38-66; 13 CR (25%), 14 PR (27%), 9 SD (17%), 11 PD (21%) and 5 (10%) discontinued prior to first response assessment). Median follow up was 6 months (0.7-18.3+). Responses were observed in 9/14 pts (64%) with prior autologous or allogeneic stem cell transplant, and 2 of 2 with prior CAR-T cell therapy. Conclusion: Pirtobrutinib demonstrated promising efficacy in heavily pretreated, poor-prognosis MCL following multiple prior lines of therapy. Pirtobrutinib was well tolerated and exhibited a wide therapeutic index. Updated data, including approximately 60 new pts with MCL and an additional 10 months since the prior data cut will be presented. [ABSTRACT FROM AUTHOR]

Primary central nervous system lymphoma (PCNSL) is a highly aggressive brain tumor with poor prognosis if no treatment. The activation of the NF-κB (nuclear factor kappa-B) is the oncogenic hallmark of PCNSL, and it was driven by B cell receptor (BCR) and Toll-like receptor (TLR) signaling pathways. The emergence of Bruton's tyrosine kinase inhibitors (BTKis) has brought the dawn of life to patients with PCNSL. This review summarizes the management of PCNSL with BTKis and potential molecular mechanisms of BTKi in the treatment of PCNSL. And the review will focus on the clinical applications of BTKi in the treatment of PCNSL including the efficacy and adverse events, the clinical trials currently being carried out, the underlying mechanisms of resistance to BTKi and possible solutions to drug resistance., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Shen and Liu.)

Aim: To evaluate the safety and efficacy of pirtobrutinib in previously treated CLL/SLL. Method: BRUIN is a phase 1/2 multicenter study (NCT03740529) of oral pirtobrutinib monotherapy in pts with advanced B-cell malignancies who have received >2 prior therapies. Primary objective for phase 1: determine the RP2D. Primary objective of phase 2: ORR. Secondary objectives included DoR, PFS, OS, safety and tolerability and pharmacokinetics. Results: As of 27 Sept 2020, 323 pts with B-cell malignancies (170 CLL/SLL, 61 MCL, 26 WM, 26 DLBCL, 13 MZL, 12 FL, 9 RT and 6 other) were treated on 7 dose levels (25-300 mg QD). Median number of prior lines of therapies = 3 (1-11). No DLTs were reported and MTD was not reached (n = 323). 200 mg QD was selected as RP2D. Fatigue (20%), diarrhea (17%) and contusion (13%) were the most frequent TEAEs regardless of attribution or grade seen in >10% pts. Most common AE of grade ≥3 was neutropenia (10%). 139 CLL/SLL pts were efficacy-evaluable with a median follow up time of 6 months (0.16-17.8+). ORR was 63% (95% CI 55-71) with 69 PRs (50%), 19 PR-Ls (14%), 45 SDs (32%) and 1 PD (1%), and 5 (4%) discontinued prior to first response assessment. Among 121 BTKi pretreated pts, ORR was 62% (95% CI 53-71). Responses deepened over time with an ORR of 86% among pts with >10 months follow-up. ORR was similar in pts who discontinued prior BTKi due to progression (67%), or adverse events or other reasons (52%). Of 88 responding pts, all except 5 remained on therapy. Conclusion: Pirtobrutinib demonstrated promising efficacy in heavily pretreated CLL/SLL pts. Pirtobrutinib was well tolerated and exhibited a wide therapeutic index. Updated data, including approximately 100 new pts with CLL and an additional 10 months since the prior data cut will be presented. Previously at ASH -- 63rd Annual Meeting. [ABSTRACT FROM AUTHOR]

Waldenström macroglobulinemia (WM) is a rare, incurable low grade lymphoma following a relapsing trajectory. Management strategies have evolved with the introduction of targeted therapy including new classes of Bruton tyrosine kinase inhibitor (BTKi). Treatment may however be limited particularly at relapse by a lack of drug availability and tolerability. We assessed the real-world efficacy and tolerability of bortezomib-containing regimens in patients with WM at frontline and relapse including those with prior BTKi resistance. Forty-one patients were identified with 44 bortezomib-containing regimens administered ( n = 12 frontline, n = 32 relapse). Of patients treated at relapse, the median prior lines of therapy was 3 (range 1-7). 24% (10/41) of the cohort were refractory or intolerant to BTKi prior to bortezomib delivery. The median follow-up after bortezomib administration was 34 months (range 0-131). Overall response rate was 88%; 2-year overall survival and progression-free survival were 90% (95% confidence interval [CI] 73-96) and 76% (95% CI 55-87), respectively. Median time-to-next-treatment was 66 months. Neuropathy (grade 1-2) occurred in 24% (8/34) and did not result in treatment cessation in any case. Gastrointestinal disturbance occurred in 7% (3/41). Treatment discontinuations were rare (1/44; 2%), suggesting a manageable safety profile. Major response rate was comparable in those with prior BTKi compared with those without (75% [6/8] vs 84% [27/32], p = 0.61). Bortezomib should be considered as a treatment modality particularly in those who are refractory to BTKi., Competing Interests: SDS reports speaker fees and research funding from Janssen, BeiGene and Sanofi. JK, EU, RB, KT, AR, RG, IP and CK have no conflict of interest to declare., (© 2022 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Simple Summary: Richter transformation is a significant and devastating complication of chronic lymphocytic leukemia. While its pathogenesis has been well-studied in terms of genetic and molecular changes and its diagnosis has been made easier by imaging and pathological techniques, its treatment is still an issue. Most patients are resistant to chemo-immunotherapy, and even novel agents do not seem to improve the prognosis in a significant way. Therefore, new combinations and novel drugs are currently being tested. In the current review, we summarize new data about the pathophysiology, biological, and clinical basis of Richter transformation, as well as the different treatments of this condition. Richter transformation (RT) is a poorly understood complication of chronic lymphocytic leukemia (CLL) with a dismal prognosis. It is associated with a switch in histopathology and biology, generally with a transformation of the original CLL clone to diffuse large B-cell lymphoma (DLBCL) or less frequently to Hodgkin's variant of Richter transformation (HVRT). It occurs in 2–10% of CLL patients, with an incidence rate of 0.5–1% per year, and may develop in treatment-naïve patients, although it is more common following therapy. In recent years, there has been a deeper understanding of the molecular pathogenesis of RT that involves the inactivation of the TP53 tumor suppressor gene in 50–60% of cases and the activation of aberrations of NOTCH1 and MYC pathways in about 30% of cases. Compared to the preceding CLL, 80% of cases with DLBCL-RT and 30% of HVRT harbor the same IGHV-D-J rearrangements, indicating a clonal evolution of the disease, while the remaining cases represent de novo lymphomas that are clonally unrelated. Despite advances in understanding the molecular variations and the pathogenesis of the disease, there is still no significant improvement in patient outcomes. However, if no clinical trials were designed for patients with RT in the past, now there many studies for these patients that incorporate new drugs and novel combinations that are being explored. In this review, we summarize the new information accumulated on RT with special emphasis on results involving the novel therapy tested for this entity, which represents an unmet clinical need. [ABSTRACT FROM AUTHOR]

Chikungunya virus (CHIKV) is transmitted by Aedes mosquitoes and causes prolonged arthralgia in patients. After crossing the mosquito midgut barrier, the virus disseminates to tissues including the head and salivary glands. To better understand the interaction between Aedes albopictus and CHIKV, we performed RNASeq analysis on pools of mosquito heads and parts of the thorax 8 days post infection, which identified 159 differentially expressed transcripts in infected mosquitos compared to uninfected controls. After validation using RT-qPCR (reverse transcriptase-quantitative polymerase chain reaction), inhibitor of Bruton's tyrosine kinase ( BTKi ), which has previously been shown to be anti-inflammatory in mammals after viral infection, was further evaluated for its functional significance. Knockdown of BTKi using double-stranded RNA in a mosquito cell line showed no significant difference in viral RNA or infectivity titer. However, BTKi gene knocked-down cells showed increased apoptosis 24 hours post-infection compared with control cells, suggesting involvement of BTKi in the mosquito response to viral infection. Since BTK in mammals promotes an inflammatory response and has been shown to be involved in osteoclastogenesis, a hallmark of CHIKV pathogenesis, our results suggest a possible conserved mechanism at play between mosquitoes and mammals. Taken together, these results will add to our understanding of Aedes Albopictus interactions with CHIKV.