Modified R-BAC plus BTK inhibitor regimen in newly diagnosed young patients with mantle cell lymphoma: a real-world retrospective study.

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.

Chimeric TIM-4 receptor-modified T cells targeting phosphatidylserine mediates both cytotoxic anti-tumor responses and phagocytic uptake of tumor-associated antigen for T cell cross-presentation.

To leverage complementary mechanisms for cancer cell removal, we developed a novel cell engineering and therapeutic strategy co-opting phagocytic clearance and antigen presentation activity into T cells. We engineered a chimeric engulfment receptor (CER)-1236, which combines the extracellular domain of TIM-4, a phagocytic receptor recognizing the "eat me" signal phosphatidylserine, with intracellular signaling domains (TLR2/TIR, CD28, and CD3ζ) to enhance both TIM-4-mediated phagocytosis and T cell cytotoxic function. CER-1236 T cells demonstrate target-dependent phagocytic function and induce transcriptional signatures of key regulators responsible for phagocytic recognition and uptake, along with cytotoxic mediators. Pre-clinical models of mantle cell lymphoma (MCL) and EGFR mutation-positive non-small cell lung cancer (NSCLC) demonstrate collaborative innate-adaptive anti-tumor immune responses both in vitro and in vivo. Treatment with BTK (MCL) and EGFR (NSCLC) inhibitors increased target ligand, conditionally driving CER-1236 function to augment anti-tumor responses. We also show that activated CER-1236 T cells exhibit superior cross-presentation ability compared with conventional T cells, triggering E7-specific TCR T responses in an HLA class I- and TLR-2-dependent manner, thereby overcoming the limited antigen presentation capacity of conventional T cells. Therefore, CER-1236 T cells have the potential to achieve tumor control by eliciting both direct cytotoxic effects and indirect-mediated cross-priming.

[Update on treatment strategies for mantle cell lymphoma].

Mantle cell lymphoma (MCL) is a type of lymphoid malignancy that is rare in Japan. MCL is refractory to conventional chemotherapy and has dismal outcomes. Nonetheless, the prognosis of MCL has gradually improved with the advent of autologous stem cell transplantation and BTK inhibitors. First-line therapies incorporating BTK inhibitors are currently under development, and are expected to further improve the prognosis. Nevertheless, subsets with poor prognosis have been identified, including p53 abnormalities (TP53 mutations or deletions), blastoid variant, high MIPI-c, and POD24, and these show resistance to conventional treatments including BTK inhibitors. To overcome these challenges, novel therapies such as CAR-T therapy and combination therapy with BTK and BCL2 inhibitors are being developed, and should soon become clinically available in Japan. The therapeutic landscape for MCL is evolving dynamically, and this article will discuss the future of MCL treatment strategies in Japan.

Long-term outcomes in patients with chronic lymphocytic leukemia treated with ibrutinib: Focus on hypertension and cardiovascular toxicity.

BACKGROUND: Continuous ibrutinib administration is needed to maintain efficacy in patients with chronic lymphocytic leukemia (CLL) and, as such, long-term toxicity is a concern. The authors report the 5-year follow-up of patients with CLL who received treatment with ibrutinib with a focus on hypertension and cardiovascular toxicities. METHODS: Patient characteristics were assessed, including blood pressure, cardiovascular disease, disease progression, and death. Univariate logistic regression analysis assessed the relation of patient characteristics and the development of new or worsened hypertension. The incidence of hypertensive outcomes was evaluated using competing risk. Survival was estimated using the Kaplan-Meier method. RESULTS: Three hundred patients with CLL who were treated with ibrutinib on clinical trials were included. The median patient age at study enrollment was 65 years (range, 29-83 years). Seventy percent of patients were men, and 88% were Caucasian. Sixty-nine percent of patients had hypertension at baseline, and 47% were on antihypertensive medication. Eighty-eight percent had relapsed or refractory CLL. New-onset and worsening hypertension were common, occurring in 68.5% and 38% of patients, respectively. Systolic blood pressure ≥160 mm Hg or diastolic blood pressure ≥100 mm Hg was observed in 16.9% of patients. Hypertension was reversible after ibrutinib discontinuation. Older age, male sex, tobacco use, and chronic kidney disease were associated with ibrutinib-related hypertension. Baseline hypertension was not associated with major adverse cardiovascular events in ibrutinib-treated patients nor with event-free or overall survival. CONCLUSIONS: Hypertension is a common toxicity in patients with CLL who receive ibrutinib but is manageable in most patients. Other than chronic kidney disease, baseline cardiovascular disease did not affect ibrutinib-related hypertension nor was hypertension associated with major adverse cardiovascular events or survival. PLAIN LANGUAGE SUMMARY: Ibrutinib is an effective treatment for patients with chronic lymphocytic leukemia. Ibrutinib is a well tolerated therapy, however hypertension can develop or worsen in patients receiving ibrutinib and other cardiovascular events are significant challenges to the use of this drug. This may be particularly true in patients with heart disease. Short-term side effects may worsen heart disease, but the long-term impact is unknown. The long-term results of ibrutinib on heart disease and hypertension are described.

Dose reductions in patients with Waldenström macroglobulinaemia treated with ibrutinib.

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.

Antibody status following booster vaccination against SARS-CoV-2 virus in patients with haematologic malignancies.

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.

Anticancer effect of zanubrutinib in HER2-positive breast cancer cell lines.

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.

A prediction model for severe hematological toxicity of BTK inhibitors.

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.

Advances in Treatment of Waldenström Macroglobulinemia.

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. 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.

Next-Generation Sequencing-Optimal Sequencing of Therapies in Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL).

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. 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.

Current Treatment Options in Relapsed and Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: a Review.

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.

Ibrutinib combined with low-dose histone deacetylases inhibitor chidamide synergistically enhances the anti-tumor effect in B-cell lymphoma.

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.

Treatment strategies for a rapidly evolving landscape in chronic lymphocytic leukemia management.

With the advent of targeted therapies for chronic lymphocytic leukemia (CLL), treatment choice has expanded and patients are living longer. Careful consideration is needed regarding treatment duration and sequence, how best to meet patients' needs, balancing toxicities while improving long-term survival and maximizing depth of response. This review addresses these considerations and discusses current targeted treatment dilemmas. Targeted therapies have dramatically transformed the CLL treatment landscape. Two treatment paradigms have emerged using B-cell lymphoma 2 inhibitors (BCL2i) and Bruton's tyrosine kinase (BTK): (i) fixed duration and (ii) continuous treatment. The BCL2i venetoclax can attain deep remissions with a fixed-duration approach, resulting in high rates of undetectable minimal residual disease (uMRD) in treatment-naïve and relapsed/refractory (R/R) patients with CLL. BTKis such as ibrutinib and acalabrutinib achieve high objective response rates and long-term disease control, although they rarely attain complete response or uMRD status as monotherapy. Numerous studies are evaluating the clinical utility of BTKi and BCL2i as combination therapies, where deep remissions have been found to occur. MRD status may also be a useful marker for deciding when to stop continuous therapy, and randomized trials on MRD-guided treatment strategies are currently ongoing. The current treatment choice between continuous or fixed-duration therapy should be based on comorbidities, risks, preferences, and treatment goals, whilst areas of emerging clinical interest include the potential utility of BTKi-BCL2i combination therapies, as well as an MRD-guided treatment strategies in the future.

Exposure-response analysis of acalabrutinib and its active metabolite, ACP-5862, in patients with B-cell malignancies.

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.

BRUIN MCL-321: phase III study of pirtobrutinib versus investigator choice of BTK inhibitor in BTK inhibitor naive mantle cell lymphoma.

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, noncovalent (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.

MCL is an uncommon type of B-cell non-Hodgkin lymphoma, a cancer of the immune system. It starts in the part of the lymph node called the mantle zone, where unusual B cells gather and crowd out healthy B cells in the lymph nodes, spleen, bone marrow and/or other organs. MCL can be caused by inappropriate cell signaling. BTK has been identified as a key driver of unusual cell signaling and blocking BTK has been shown to help kill the cancer cells. Covalent (not reversible) BTK inhibitors have advanced the treatment of MCL, but the effectiveness of these treatments is limited by side effects and treatment resistance. Pirtobrutinib, a noncovalent (reversible) BTK inhibitor, has been shown to have manageable side effects and to be effective in patients with MCL following previous treatment, including treatment with covalent BTK inhibitors. The BRUIN MCL-321 study compares pirtobrutinib with three currently approved covalent BTK inhibitors (ibrutinib, acalabrutinib or zanubrutinib), in patients with MCL who have never received any form of BTK inhibitor. This trial will look at how many people live with the disease without it getting worse. Like other cancer treatments, pirtobrutinib may affect both healthy cells and tumor cells, which can result in side effects that will also be looked at in this study. This study is active and currently recruiting new patients who have received at least one previous therapy for MCL and have never been treated with a BTK inhibitor. Clinical Trial Registration: NCT04662255 (ClinicalTrials.gov).

Discovery of pyrrolo[1,2-a]quinoxalin-4(5H)-one derivatives as novel non-covalent Bruton's tyrosine kinase (BTK) inhibitors.

Bruton's tyrosine kinase (BTK) is a promising target in the treatment of B cell malignancies and autoimmune disorders. Developing selective non-covalent BTK inhibitors is an important strategy to overcome the side effects and drug resistance induced by covalent BTK inhibitors. In this article, we designed and synthesized pyrrolo[1,2-a]quinoxalin-4(5H)-one and imidazo[1,2-a]quinoxalin-4(5H)-one based selective noncovalent BTK inhibitors via scaffold hopping from BMS-986142 and investigated their biological activities. Among the synthesized compounds, pyrrolo[1,2-a]quinoxalin-4(5H)-one derivatives 2 and 4 showed great BTK inhibition potency with IC50 value at 7.41 nM and 11.4 nM, respectively. Besides, they showed equivalent or even better potency in U937 and Ramos cells than BMS-986142. The kinase selectivity profiling study illustrated the excellent selectivity of compound 2 against a panel of 468 kinases. In U937 xenograft models, compound 2 could significantly inhibit tumor growth with TGI = 65.61%. In all, we provided a new scaffold as non-covalent selective BTK inhibitors and the representative compounds exhibited potency both in vitro and in vivo.

Real-world management of targeted therapies in chronic lymphocytic leukemia.

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.

Topical delivery of Bruton's tyrosine kinase inhibitor and curcumin-loaded nanostructured lipid carrier gel: Repurposing strategy for the psoriasis management.

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.

The role of Bruton's tyrosine kinase in the immune system and disease.

Bruton's tyrosine kinase (BTK) is a TEC kinase with a multifaceted role in B-cell biology and function, highlighted by its position as a critical component of the B-cell receptor signalling pathway. Due to its role as a therapeutic target in several haematological malignancies including chronic lymphocytic leukaemia, BTK has been gaining tremendous momentum in recent years. Within the immune system, BTK plays a part in numerous pathways and cells beyond B cells (i.e. T cells, macrophages). Not surprisingly, BTK has been elucidated to be a driving factor not only in lymphoproliferative disorders but also in autoimmune diseases and response to infection. To extort this role, BTK inhibitors such as ibrutinib have been developed to target BTK in other diseases. However, due to rising levels of resistance, the urgency to develop new inhibitors with alternative modes of targeting BTK is high. To meet this demand, an expanding list of BTK inhibitors is currently being trialled. In this review, we synopsize recent discoveries regarding BTK and its role within different immune cells and pathways. Additionally, we discuss the broad significance and relevance of BTK for various diseases ranging from haematology and rheumatology to the COVID-19 pandemic. Overall, BTK signalling and its targetable nature have emerged as immensely important for a wide range of clinical applications. The development of novel, more specific and less toxic BTK inhibitors could be revolutionary for a significant number of diseases with yet unmet treatment needs.

Ibrutinib for central nervous system lymphoma: the Australasian Lymphoma Alliance/MD Anderson Cancer Center experience.

Primary and secondary central nervous system lymphomas (PCNSL/SCNSL) are aggressive rare malignancies with dismal outcomes. Encouraging data have emerged from Phase I/II clinical trials treating relapsed/refractory PCNSL/SCNSL with ibrutinib. We analysed 33 patients who received ibrutinib, alone or with other therapies, for PCNSL (n = 9) or SCNSL (n = 24). The objective response rate was 58% (complete response 55%). The median progression-free survival and overall survival for patients with PCNSL were both 3·1 months; for SCNSL, 10·2 and 11·5 months respectively. Only one invasive fungal infection was observed, despite concurrent or recent use of dexamethasone 8-16 mg daily in 14 patients (42%). Ibrutinib has encouraging activity in these aggressive malignancies.