Treatment of CLL has changed remarkably in the last decade and novel agents are the standard therapy in various jurisdictions. However, the biology of CLL still plays an important part in the treatment choice and disease outcomes. In this post chemo-immunotherapy era for CLL, number of biological factors have lost their clinical significance and most patients will benefit from continuous or time-limited therapy. However, TP53 and IGHV mutation status still retains clinical significance in determining outcomes with various therapeutic approaches. New emerging biological markers including drug-specific mutations are adding to the complexity of decision making in relapsed CLL. End of treatment minimal residual disease analysis (MRD) adds prognostic information to the outcomes with time-limited therapy. MRD-guided duration of treatment may improve further outcomes, but longer clinical follow-up is needed before this approach is incorporated in clinical guidelines. The review gives an update on the impact of biological markers on outcomes with novel agents.

Recent years have brought a much-needed paradigm shift to the management and treatment of mature B-cell lymphomas. Pathophysiologic and clinical heterogeneity within the various subtypes have historically contributed to treatment challenges and differences in outcomes. Novel genomic tools and therapeutic modalities give promise for improved patient outcomes, but are also making treatment planning increasingly complex. To bridge the gaps between therapeutic advancements and clinical practice, an assembly of multidisciplinary hematologic oncology faculty convened to deliberate on the prevailing challenges, knowledge gaps, and controversies in B-cell lymphoma and chronic lymphocytic leukemia management. Many controversies and questions were identified regarding treatment selection, sequencing, and high-risk subtypes. There is a need for head-to-head trials in this therapeutic area to help answer some of these questions. The insights explored and the gaps in knowledge identified by this panel will inform a follow-up conference in 2025 that will employ the modified Delphi method to develop and publish formal consensus recommendations that can provide actionable guidance to practicing clinicians.

In recent years, chronic lymphocytic leukemia (CLL) treatment has changed dramatically. Chemoimmunotherapy with fludarabine/cladribine, cyclophosphamide, and rituximab have been almost completely replaced by targeted therapies with small molecules, such as Bruton's tyrosine kinase inhibitors or B-cell lymphoma 2 (BCL-2) antagonists. However, few studies have assessed the impact of novel therapies on patient quality of life (QoL).

This article reviews the safety profile of new therapeutic options and their impact on the QoL of CLL patients. The MEDLINE database was searched for English language publications from 2010 through June 2024, including the Proceedings of the American Society of Hematology from over the past 5 years.

CLL is a clinically heterogenous disease predominantly affecting elderly patients. The variable clinical course of disease requires personalization and individualized treatment to achieve the optimal survival outcome and acceptable safety profile, especially in the case of poor prognosis. Clinical trials performed in the past decade indicate that novel drugs, used as a single agent or as part of a conventional chemotherapy, offer promise in minimalizing relapse rates, and may allow more effective and safer treatment options by reducing the risk of adverse events, especially cytopenias and infections.

Chronic lymphocytic leukemia (CLL) remains an incurable disease, except in rare cases treated with allogeneic stem-cell transplantation or favorable-risk CLL treated with chemoimmunotherapy. Treatment initiation follows the Rai and Binet staging systems, but the International Workshop on Chronic Lymphocytic Leukemia criteria emphasize active disease rather than stage alone. Early treatment in asymptomatic, high-risk patients has not shown an overall survival benefit, even with targeted therapies such as Bruton's tyrosine kinase and BCL2 inhibitors. The watch-and-wait strategy remains standard, although future trials may refine early treatment indications for specific high-risk groups.

Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in adults, characterized by the accumulation of dysfunctional lymphocytes. Ibrutinib, a first-generation Bruton tyrosine kinase (BTK) inhibitor, has significantly improved CLL treatment but is associated with adverse cardiovascular events such as atrial fibrillation (AF) and hypertension (HTN). Second-generation BTK inhibitors (BTKi) such as acalabrutinib were developed to have greater selectivity for BTK to reduce off-target effects and improve safety. Comparative real-world data between ibrutinib and second-generation BTKi are limited. This study analyzed data from the TriNetX Global Collaborative Network to compare cardiovascular outcomes in CLL patients who received ibrutinib or acalabrutinib. The two groups were well-balanced using propensity score matching. The outcomes examined included new-onset AF, HTN, reported heart failure, ventricular arrhythmias, bleeding, and all-cause mortality. The incidence of AF/flutter was lower for acalabrutinib compared to ibrutinib [5.8% vs. 11.7%; HR 0.59 (95% CI 0.43-0.83); p = 0.002]. The incidence of HTN was also lower in the acalabrutinib cohort [15% vs. 26.3%; HR 0.65 (95% CI 0.53-0.81); p < 0.05]. The incidence of heart failure, ventricular arrhythmia, bleeding events, or all-cause mortality did not differ after 3 years of treatment with acalabrutinib or ibrutinib, respectively. Our findings indicate that acalabrutinib has a more favorable cardiovascular toxicity profile compared to ibrutinib; therefore, validating the ELEVATE-RR trial in a real-world setting.

This post-marketing surveillance evaluated the safety and effectiveness of tirabrutinib in patients with relapsed/refractory primary central nervous system lymphoma (r/r PCNSL) in a real-world setting in Japan.

All patients with r/r PCNSL who started treatment with tirabrutinib between May 20 and 31 October 2020, were registered. Adverse drug reactions (ADRs) and effectiveness were assessed over 52-weeks from the start of tirabrutinib treatment.

Of the 189 patients assessed for safety, 52.4% were male, the median age was 70.0 years (range 30-88), and 49.2% of patients had a Karnofsky performance status score of ≤60. ADRs of any grade and grade ≥3 were observed in 55.6% and 24.3% of patients, respectively. The most common ADRs were rash (11.6%), neutrophil (10.1%) and platelet (5.3%) count decreased. Most of the ADRs corresponding to infections, clinically significant skin disorders, myelosuppression, hypersensitivity, interstitial lung diseases, hepatic function disorders, and hemorrhages resolved or were in the process of resolving. Among the 121 patients assessed for effectiveness, the overall response rate evaluated by the treating physicians was 61.2%, and the 365-day survival rate was 69.8%.

This surveillance confirmed the tolerability and effectiveness of tirabrutinib in patients with r/r PCNSL in the real-world setting.

Japan Registry of Clinical Trials: jRCT2011210002.

Over the past two decades, there has been a continuous improvement in outcome for patients with indolent lymphoma (iNHL) resulting in a gradual accumulation of survivors. While life expectancy in the current era approaches that of the lymphoma-free population, patients continue to experience lifelong complications of the disease and its treatment affecting general health, emotional, psychological and social wellbeing, relationships, employment, finances, and fitness. Contemporary care models while suited to the management of lymphoma are often lacking when it comes to identification and management of these additional needs. Given improvements in physical survival achieved over the past decades, it is timely for us to focus on other issues affecting patient wellbeing including immunodeficiency and infection, second cancers, cardiovascular disease, bone health, psychological wellbeing, and sexual health. Many of these aspects are in the domain of the primary care physician; however, there is limited guidance on how these issues should be addressed. It is now time for us to engage our patients, their caregivers, and other healthcare providers in care aspects beyond the lymphoma diagnosis, so they can anticipate a rich and full life, free from both direct and indirect consequences of the lymphoma diagnosis.

The combination of ibrutinib plus venetoclax (IV) in chronic lymphocytic leukemia (CLL) treatment leverages their complementary mechanisms of action. Studies investigating IV typically begin with a short initial course of ibrutinib, followed by venetoclax introduction for a limited duration, typically 12 months. The Swiss Group for Clinical Cancer Research (SAKK) 34/17 study is a single-arm, multicenter, phase 2 trial evaluating the effectiveness of a modified IV schedule in patients with relapsed/refractory (R/R) CLL. No prior exposure to BTK or BCL2 inhibitors was allowed. The lead-in phase with ibrutinib was extended to 6 months to reduce the tumor burden and related tumor lysis syndrome (TLS) risk. Additionally, the treatment phase with IV is prolonged to a minimum of 24 months to enhance the undetectable minimal residual disease (uMRD; 10-4) rate. The primary end point was the rate of complete response or complete response with incomplete bone marrow recovery (CR/CRi) with uMRD in both bone marrow (BM) and peripheral blood (PB). Secondary end points included assessing the proportion of patients transitioning to a low-risk category for TLS after receiving ibrutinib lead-in. Of the 30 enrolled patients with R/R CLL, 40.0% achieved uMRD CR/CRi by intention-to-treat analysis, and 53.3% showed uMRD in the BM and PB. After the lead-in period with ibrutinib, 57.1% of patients achieved a low risk of TLS. At cycle 31, the progression-free survival rate was 89.9%. These results contribute to the increasing body of evidence supporting the idea that a longer IV duration is beneficial for enhancing therapeutic effectiveness. This trial was registered at www.clinicaltrials.gov as #NCT03708003.

Limited treatment options for primary central nervous system lymphoma (PCNSL) highlight the need for alternative therapies. This study evaluated orelabrutinib (O) and rituximab (R), plus high-dose methotrexate (M) (ORM), as a potential induction therapy for newly diagnosed PCNSL.

Patients received six cycles of 150 mg/day orelabrutinib, 375 mg/m2 rituximab, plus 3.5 g/m2 methotrexate every 3 weeks, followed by autologous hematopoietic stem cell transplantation and orelabrutinib maintenance. The primary endpoint was the overall response rate (ORR) at the end of induction therapy. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety.

From October 21, 2020, to October 22, 2024, 28 patients were treated and evaluated for efficacy and safety analyses. At the end of induction therapy, the ORR was 71.4% (95% CI, 51.3-86.8), including 16 (57.1%) complete and 4 (14.3%) partial responses. At a median follow-up of 21.6 months, the median PFS was 35.3 months (95% CI, 8.4-not evaluable), and the median OS was not reached, with PFS and OS rates of 64.3% and 96.3% at 1 year, 64.3% and 90.9% at 2 years, and 45.9% and 82.7% at 3 years, respectively. All 28 (100%) patients experienced treatment-related adverse events (TRAEs) of any grade. Grade 3 TRAEs occurred in seven (25.0%) patients, including five (17.9%) leukopenia, one (3.6%) thrombocytopenia, and one (3.6%) diarrhea. No other Bruton's tyrosine kinase inhibitor-related off-target toxicities (e.g., atrial fibrillation/flutter) or TRAE-related deaths were observed.

The ORM induction regimen showed anti-tumor activity with a favorable safety profile, offering a potential therapeutic strategy for newly diagnosed PCNSL.

 ClinicalTrials.gov: NCT05600660.

Cancer is one of the leading causes of death worldwide. Recent advances in precision oncology have enabled many specific cancer patient populations to respond well and achieve longer survival with small-molecule kinase inhibitors, which have become a new therapeutic strategy for tumors. Since 2001, the Food and Drug Administration has approved 108 and 63 new anticancer drugs for treating solid tumors and hematological malignancies, respectively, 89 of which belong to the large group of small-molecule kinase inhibitors (SMKIs). Compared to conventional chemotherapeutic agents such as cyclophosphamide, doxorubicin, and 5-FU, SMKIs offer better efficacy with fewer toxic side effects. Nevertheless, with the development of more novel SMKIs and their wider clinical application to a larger population of cancer patients, variable degrees of cardiotoxic adverse events have emerged for some SMKIs during cancer therapy. This review comprehensively summarizes the most updated progress in the cardiotoxicity of SMKIs in cancer therapy and discusses the new findings and mechanisms, which will provide emerging strategies for the prevention of cardiotoxicity caused by small molecule targeted drugs and the design of the next generation of low cardiotoxicity targeted drugs.

The advent of Bruton tyrosine kinase inhibitor (BTKi) therapy with ibrutinib introduced a highly effective targeted therapy in the management of chronic lymphocytic leukemia (CLL). However, due to the adverse effect profile some patients cannot tolerate this novel therapy. Newer, more potent and targeted BTK inhibitors such as acalabrutinib have been developed. Acalabrutinib is an irreversible and second generation BTKi that covalently inhibits BTK with greater selectivity than ibrutinib. As novel BTKis are developed, a greater understanding of their efficacy and adverse effect rates can assist clinicians and patients in the shared clinical decision-making process. A search was conducted using the PICOS model and PRISMA guidelines. PubMeb, Embase, and Cochrane Library databases were searched using the keywords: Acalabrutinib, Acalabrutinib Monotherapy, Tyrosine Kinase Inhibitor, and Relapsed/Refractory (R/R) CLL. After initial literature review 12 studies were chosen for evaluation in this meta-analysis. Meta-analysis and follow up meta-regression models were completed. The results were as follows: ORR 82% (95% CI 74%-90%, I2 = 84.14%, p < 0.01), CR 4% (95% CI 2%-6%, I2 = 0.00%, p = 0.99), mortality rate 12% (95% CI 6%-19%, I2 = 87.23%, p < 0.01), mortality rate due to adverse effect 7% (95% CI 3%-10%, I2 = 67.67%, p = 0.01), mortality due to pneumonia 2% (95% CI 1%-3%, I2 = 0.00%, p = 0.43), mortality due to CLL progression 4% (95% CI 2%-6%, I2 = 61.03%, p = 0.04), neutropenia (≥ grade 3) 18% (95% CI 15%-20%, I2 = 0.00%, p = 0.70), thrombocytopenia (≥ grade 3) 7% (95% CI 4%-11%, I2 = 54%, p = 0.09), anemia (≥ grade 3) 9% (95% CI 6%-12%, I2 = 36.93%, p = 0.18), pneumonia (≥ grade 3) 10% (95% CI 6%-14%, I2 = 66.37%, p = 0.02) and atrial fibrillation 7% (95% CI 3%-11%, I2 = 80.13%, p = 0.00). The results demonstrate that acalabrutinib shows efficacy in the treatment of R/R CLL with tolerable adverse reaction rates.

Prognostic assessment in chronic lymphocytic leukemia (CLL) is essential for delivery of timely, personalized therapy. TP53 status, karyotype, IGHV mutational status, minimal residual disease (MRD), gene mutations and markers of cell proliferation were important prognostic tools in the era of chemo-immunotherapy (CIT). With BCL2 inhibitors (BCL2i), outcome is still impacted by IGHV status, TP53 status, complex karyotype, and achievement of undetectable MRD. On the other hand, BTK inhibitors (BTKi) are agnostic to IGHV status, rarely cause MRD negative remissions and are less clearly impacted by TP53 status. Although based on less mature data, outcomes with BCL2i/BTKi combinations are likely influenced by TP53 and IGHV status. Responses to non-covalent BTKI (ncBTKI) are impacted by the mechanism of resistance to previous covalent BTKi. Finally, responses to chimeric antigen receptor T cell therapy (CAR-T) appear independent of TP53 status, but dependent on overall T- cell fitness.

Bruton's tyrosine kinase (BTK) is a therapeutically validated drug target. Small-molecule inhibitors of BTK have changed the treatment paradigms of multiple B-cell malignancies and evolved over three generations to overcome clinical challenges. Four drugs are now approved by the FDA, including the first-in-class drug ibrutinib and successively approved acalabrutinib, zanubrutinib, and pirtobrutinib. The third-generation drug pirtobrutinib, which binds non-covalently to BTK, is expected to overcome resistance mutations at the covalent binding Cys481 residue of the first and second-generation drugs that covalently bind to BTK. However, some newly identified non-Cys481 resistance mutations to pirtobrutinib have shown their co-resistance to some of the covalent inhibitors, and this leaves a major unmet need that is promoting the development of next-generation BTK-targeted therapeutics. More non-covalent BTK inhibitors with differentiated binding modes are under development, and the ongoing development focus of next-generation therapeutics involves new and alternative directions to target BTK using dual-binding inhibitors and degraders of BTK, as well as its allosteric inhibitors. Recent exploration of the differentiated features of BTK inhibitors in various aspects has shown the possible link between their different features and different functional and therapeutic consequences. This review summarizes the key differentiated features of the BTK inhibitors approved by the FDA and others under development to add knowledge for their therapeutic application and future development. Long-term follow-up updates of clinical outcomes of the earlier developed drugs are also included, together with direct and indirect comparisons of efficacy and safety between the different generations of drugs. The ongoing development status of next-generation BTK-targeted therapeutics is described, with a discussion on their therapeutic potential and some limitations.

Treatment of chronic lymphocytic leukemia (CLL) has been revolutionized with the introduction of small molecule inhibitors targeting both the B-cell receptor (BCR) signaling pathway and B-cell lymphoma-2 (BCL-2) family of proteins. Inhibitors of Bruton's tyrosine kinase (BTK) and the BH3 mimetic venetoclax are bothcurrently used as the standard of care for patients in the frontline and relapsed/refractory setting of CLL. With the clinical success of both these classes of therapies, sequencing of these agents has become a major challenge in treatment of CLL. In this review we will discuss the current data available for both classes of agents in the front-line and relapsed/refractor setting, considerations when giving these agents, and how we can continue to improve the treatment landscape for CLL.

The Bruton tyrosine kinase inhibitor (BTKi) has emerged as a key treatment for B-cell lymphomas. Despite its efficacy in the treatment of malignancies, numerous cases of invasive fungal infections (IFI) have been reported in patients receiving ibrutinib, a first-generation BTKi. Cases of invasive aspergillosis have also been reported with acalabrutinib and zanubrutinib.

The objective of this study was to provide an overview of the pathogens involved, the time of onset of infections and factors influencing survival.

Data sources: PubMed, Embase and Web of Science databases were used, and the results were reported according to Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines.

Case reports, case series, clinical trials and cohort studies were included.

All reported cases of IFI in patients treated with BTKi were analysed. For case reports/case series, demographic, microbiological and outcome data were retrieved. Assessment of risk of bias: Given the significant heterogeneity in clinical trials/cohort studies, only epidemiological analysis was performed, without formal incidence analysis. Methods of data synthesis: Epidemiologic data were presented as descriptive statistics.

In total, 25 215 patients from 92 retrospective and prospective clinical trials/cohort studies and 211 patients from 115 case reports/case series were included. Among clinical trials/cohorts, 736 IFI were reported, including 234 candidiasis (31.8%), 227 aspergillosis (30.8%) and 124 Pneumocystis jirovecii pneumonia (PJP) (16.8%). Among the case reports/case series, 155 (73.5%) had chronic lymphocytic leukaemia, and 56 (26.5%) had other malignancies. The main IFI were aspergillosis (n = 107, 50.7%), cryptococcosis (n = 33, 15.6%), PJP (n = 26, 12.3%) and mucormycosis (n = 23, 10.9%). The median delay between the initiation of BTKi and IFI was 2.3, 4.0, 3.0 and 3.0 for aspergillosis, cryptococcosis, PJP and mucormycosis, respectively. The survival rate improved when BTKi was discontinued during infection.

Targeted therapies in lymphocytic malignancies raised new issues concerning infectious complications. Monitoring IFI in patients receiving second- and third-generation BTKi is crucial for improving the management of these manifestations.

The fixed-duration combination of ibrutinib and venetoclax (IV) has emerged as a highly effective therapeutic strategy for treating chronic lymphocytic leukemia (CLL), marking a significant shift in the treatment paradigm for this disease. Preclinical studies have demonstrated the synergistic anti-leukemic effects of the elements of this regimen and therefore provide a strong rationale for their combined use in the clinical setting. Clinical trial data of IV has demonstrated substantial improvements in progression-free survival (PFS) rates across both treatment-naïve and relapsed/refractory CLL. Notably, a considerable proportion of patients have achieved undetectable measurable residual disease (uMRD), a key marker of deep remission. However, several critical questions remain unanswered, including the optimal duration of IV and the prognostic significance of uMRD, particularly in high-risk CLL subsets. Whilst uMRD is widely considered a surrogate for deep remission, the precise correlation of this parameter with long-term survival outcomes in IV-treated patients requires further clarification. Moreover, emergent evidence suggests that a prolonged duration of IV therapy, beyond that currently employed, may enhance MRD clearance. Future research should focus on the optimization of BTKi/venetoclax fixed-duration regimens, particularly for elderly and medically unfit patients. In this context, the development of more selective BTKis that minimize adverse events whilst maintaining effective disease control will be crucial.

The first-generation Bruton tyrosine kinase (BTK) inhibitor ibrutinib is effective in patients with CLL but is associated with considerable cardiac toxicity. The more selective second-generation BTK inhibitor acalabrutinib has demonstrated a more favorable cardiovascular safety profile with fewer atrial fibrillation events versus ibrutinib. We performed a comprehensive analysis of cardiac outcomes with acalabrutinib versus active comparators, including ibrutinib, in patients with and without baseline cardiovascular disorders.

Data from three phase 3 trials in CLL (ELEVATE-RR, ELEVATE-TN, ASCEND) were used. Exposure-adjusted incidence rates (EAIR; events/100 person-months) were reported for system organ class "cardiac disorders" in patients overall and by number of baseline cardiovascular disorders. All analyses were descriptive. No statistical comparisons were performed.

In total, 1362 patients were included; 404 (29.7%) had ≥1 baseline cardiovascular disorder. The overall EAIR of any-grade cardiac disorder events was lower for acalabrutinib versus active comparator in each trial, and acalabrutinib did not increase cardiac events in patients with ≥1 baseline cardiovascular disorder. The EAIR of de novo cardiac disorder events (ie, among patients without baseline cardiovascular disorders) was also lower for acalabrutinib versus active comparator across trials (ELEVATE-RR: 0.34 vs. 0.67 [acalabrutinib vs. ibrutinib], ELEVATE-TN: 0.28 and 0.25 vs. 0.59 [acalabrutinib plus obinutuzumab and acalabrutinib vs. chlorambucil + obinutuzumab], ASCEND: 0.28 vs. 0.44 and 0.54 [acalabrutinib vs. idelalisib plus rituximab and bendamustine plus rituximab]).

The EAIRs of cardiac disorder events was relatively low overall with acalabrutinib versus comparators, regardless of the presence of baseline cardiovascular disorders.

Bruton tyrosine kinase inhibitors (BTKi) are utilized in the front-line setting as well as for relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). However, there are some uncertainties regarding the risk of infections, especially pneumonia, from different BTKi with varied immunomodulatory effects on the innate and adaptive immune system. The newer second-generation BTKi, acalabrutinib and zanubrutinib, have reduced off-target effects compared to ibrutinib. We identified clinical trials from MEDLINE, Embase, and CENTRAL databases from the inception to 30 June 2023 and the number of cases with any grade and grade ≥ 3 pneumonia, pneumocystis pneumonia (PJP), and other fungal pneumonia, along with the total number of patients in the arms with BTKi monotherapy were extracted. The meta-analysis was performed using the inverse variance method and the random-effects model. After two rounds of review, 18 clinical trials containing 20 arms of BTKi monotherapy were eligible for the meta-analysis. The pooled incidences of any grade and grade ≥ 3 pneumonia in patients with CLL on BTKi therapy were 13% and 8%, respectively. There were no differences in the incidences of any grade (p = 0.61) or grade ≥ 3 pneumonia (p = 0.30) among patients treated with different BTKi. However, the pooled incidences of any grade and grade ≥ 3 pneumonia were greater in R/R CLL patients compared to those who were treatment-naïve (15% vs 7%, p < 0.01 and 10% vs 5%, p = 0.04, respectively). The pooled incidences of PJP and other fungal pneumonia were 1% (I2 = 10%) and 1% (I2 = 0%), respectively. Our study showed no significant differences in the incidence of pneumonia of any grade or grade ≥ 3 among patients treated with second-generation BTKi or first-generation BTKi. The risk of pneumonia may not be a factor in choosing among BTKi. Of note, the incidence of pneumonia was higher in R/R CLL patients on BTKi therapy when compared to treatment-naïve CLL. Fungal pneumonia, including PJP, is uncommon in CLL, and the subgroup analyses were not able to distinguish any differences among different BTKi.

Recent advancements in chronic lymphocytic leukemia (CLL) treatment emphasize fixed-duration (FD) strategies, notably venetoclax with obinutuzumab or ibrutinib, now endorsed by ESMO guidelines. The AMPLIFY phase 3 trial highlights acalabrutinib-venetoclax combinations, demonstrating superior progression-free survival and manageable safety.1 These findings support FD regimens as a paradigm shift, optimizing efficacy, safety, and patient convenience in frontline CLL therapy.

Uncovering a drug's mechanism of action and possible adverse effects are critical components in drug discovery and development. Moreover, it provides evidence for why some drugs prove more effective than others and how to design better drugs altogether. Here, we demonstrate the utility of a high-throughput in vitro screening platform along with a comprehensive panel to aid in the characterization of 15 Bruton's tyrosine kinase (BTK) inhibitors that are either approved by the FDA or presently under clinical evaluation. To compare the potency of these drugs, we measured the binding affinity of each to wild-type BTK as well as a clinically relevant resistance mutant of BTK (BTK C481S). In doing so, we discovered a considerable difference in the selectivity and potency of these BTK inhibitors to the wild-type and mutant proteins. Some of this potentially contributes to the adverse effects experienced by patients undergoing therapy using these drugs. Overall, noncovalent BTK inhibitors showed stronger potency for both the wild-type and mutant BTK when compared with that of covalent inhibitors, with the majority demonstrating a higher specificity and less off-target modulation. Additionally, we compared biological outcomes for four of these inhibitors in human cell-based models. As expected, we found different phenotypic profiles for each inhibitor. However, the two noncovalent inhibitors had fewer off-target biological effects when compared with the two covalent inhibitors. This and similar in-depth preclinical characterization of drug candidates can provide critical insights into the efficacy and mechanism of action of a compound that may affect its safety in a clinical setting.

Bruton tyrosine kinase (Btk) has long been known to play a key role in chronic lymphatic leukaemia, Waldenström macroglobulinaemia and other B-cell proliferative disorders. An impressive programme of drug discovery and clinical development led to the approval of covalent and non-covalent Btk inhibitors that became pillars of treatment of such malignancies. However, both a risk of cardiovascular events and the emergence of an elusive mutational landscape seem to complicate the clinical use of each Btk inhibitor. In this plain language mini-review, we show that the search for better Btk inhibitors is challenged by the ancestral origin of Btk, its homology with innocent kinases in cardiovascular system and unique phylogenetic-like modalities with which Btk can mutate upon exposure to one inhibitor or another. Whereas basic and clinical pharmacology is already at work to explore new avenues of Btk inhibition, phylogeny remains behind the curtain to steer achievements and failures in this field.

Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in adults. Although treatment has shifted from immunochemotherapy to novel targeted drugs over the last 10 years, novel therapies remain under investigation, particularly in relapsed and refractory patients.

This review describes the use of approved targeted drugs and novel therapies in treatment-naïve and relapsed or refractory CLL. Particular attention is paid to the management of double-refractory patients, and the discovery of novel drugs in the last five years.

Targeted drugs are effective and well-tolerated in the treatment of CLL. In the last five years, several novel agents have been investigated in preclinical studies and clinical trials, including combinations of approved drugs, novel BTK and BCL2 inhibitors, BTK degraders, bispecific antibodies and CAR-T cells. It is anticipated that some should be approved in the near future.

The mechanism by which ibrutinib, a Bruton's tyrosine kinase inhibitor, can elevate the risk of arrhythmias is not fully elucidated. In this study, we explored how inhibition of off-target kinases can contribute to this phenomenon.

We performed a Mendelian randomization analysis to examine the causal associations between genetically proxied inhibition of six putative ibrutinib drug targets (ErbB2/HER2, CSK, JAK3, TEC, BLK, and PLCG2) and the atrial fibrillation (AF) risk, proarrhythmic ECG indices, and cardiometabolic traits and diseases. Inverse-variance weighted random-effects models and Wald ratio were used to examine the associations between genetically proxied inhibition of these drug targets and the risk of outcomes. Colocalization analyses were employed to examine the robustness of the causally significant findings. ELISAs were used to measure ErbB2 levels in intracardiac plasma samples.

Genetically proxied ErbB2 inhibition was associated with an increased AF risk, higher P wave terminal force, and prolonged QTc interval. Patients with AF had significantly higher intracardiac ErbB2 levels compared with patients with paroxysmal supraventricular tachycardia. CSK inhibition prolonged the QRS duration, decreased the QTc interval, and was potentially linked to conduction blocks. PLCG2 inhibition led to decreased P wave terminal force, shorter QTc interval, and increased risk of left bundle branch block. BLK inhibition shortened the QTc interval and was also associated with atrioventricular block.

The off-target effects and downstream targets of ibrutinib, including CSK, PLCG2, ERBB2, TEC, and BLK, may lead to cardiac electrical homeostasis imbalances and lethal cardiovascular diseases. Using drugs that inhibit these targets should be given extra caution.

The effectiveness of Bruton tyrosine kinase (BTK) inhibitors is influenced by the level of BTK occupancy in target tissues. In randomized phase 3 studies, progression-free survival (PFS) with zanubrutinib was superior to ibrutinib, whereas acalabrutinib was noninferior to ibrutinib in previously treated chronic lymphocytic leukemia. To establish a link between numerical differences in BTK occupancy and differentiated efficacy profiles among three covalent BTK inhibitors, quantitative systems pharmacology (QSP) modeling was employed. The model was developed to describe available clinical BTK occupancy data in patients with B-cell malignancies. Simulations of BTK occupancy were conducted for various clinical scenarios (e.g., dose interruption) and for bone marrow (BM), for which routine measurements are difficult. This model describes pharmacokinetics of BTK inhibitors; intracellular concentration of BTK inhibitors in peripheral blood mononuclear cells (PBMCs), BM, and lymph nodes (LNs); binding of BTK inhibitors with BTK; and BTK turnover rate. The model was validated using available clinical BTK occupancy data. Consistent with observed clinical data, the model predicted that zanubrutinib 160 mg twice daily resulted in higher median trough BTK occupancy in PBMCs, LNs, and BM compared with ibrutinib and acalabrutinib. Although the BTK occupancy differences at trough were relatively small between the BTK inhibitors, the differences were more pronounced after dose interruption. The current work underscores the importance of maintaining high BTK occupancy at steady-state trough and during treatment interruption to ensure maximal efficacy and provides an example of combining in vitro and clinical data to model receptor occupancy in tissues where measurements are challenging.

Over the past decade, Bruton's tyrosine kinase (BTK) has emerged as a pivotal therapeutic target for B-cell malignancies and autoimmune diseases, given its essential role in B-cell development and function. Dysregulation of BTK signalling is implicated in a range of hematologic cancers, including Waldenström's macroglobulinaemia (WM), mantle cell lymphoma (MCL), and chronic lymphocytic leukaemia (CLL). The development of BTK inhibitors (BTKIs), starting with ibrutinib, has revolutionized the treatment of these malignancies by inhibiting B-cell receptor (BCR) signalling and inducing apoptosis in malignant B-cells. Despite the impressive clinical efficacy of ibrutinib, challenges such as resistance mutations and off-target effects remain. To address these issues, next-generation BTKIs, including acalabrutinib, orelabrutinib, zanubrutinib, and pirtobrutinib, have been developed, offering improved specificity and reduced toxicity profiles. This review highlights the therapeutic potential of BTK-targeted therapies in treating B-cell malignancies, discusses recent advancements with FDA-approved BTKIs, and explores the latest clinical outcomes from ongoing trials of novel inhibitors.

Chronic lymphocytic leukemia, characterized by an accumulation of monoclonal B lymphocytes, is the most common adult leukemia. The disease predominantly affects older adults, with a significant proportion being asymptomatic at diagnosis. This manuscript provides a comprehensive review of chronic lymphocytic leukemia, including its epidemiology, clinical presentation, diagnostic criteria, and treatment strategies. Prognostic factors, particularly IGHV mutation status and chromosomal abnormalities, are discussed as critical determinants of disease behavior and treatment response. Recent advances in targeted therapies, such as Bruton's tyrosine kinase inhibitors (BTKi) and B-cell lymphoma 2 inhibitors (BCL-2i), have changed the treatment landscape by demonstrating superior efficacy to chemoimmunotherapy. However, disparities in access to care, particularly in low- and middle-income countries such as Brazil, highlight the need for equitable treatment approaches. The discussion of measurable residual disease (MRD) assessment for prognostication and treatment planning is also highlighted. This review highlights the need for continued research and integration of novel therapies to optimize patient outcomes in chronic lymphocytic leukemia.

Ibrutinib treatment is often complicated by cardiovascular side effects (CVSEs). The objective of this retrospective pharmacogenetic study is to replicate a previously reported association of 'high-risk' patients, who are homozygous carriers of at least two of GATA4 rs804280 AA, KCNQ1 rs163182 GG, and KCNQ1 rs2237895 AA, with increased risk of hypertension or atrial fibrillation, and explore associations for other pharmacogenes (e.g. CYP3A4 , CYP3A5 , CYP2D6 , and ABCB1 ) with ibrutinib CVSEs. Univariate associations with P  < 0.05 were adjusted for significant pretreatment cardiovascular conditions. In total 57 patients were included in the analysis. In the primary analysis, 'high-risk' patients were not more likely to experience hypertension or atrial fibrillation (70 vs. 41%, chi-square P value = 0.06). In secondary analyses, 'high-risk' patients were more likely to experience any CVSE during treatment (75 vs. 41%, P  = 0.013), develop a cardiac rhythm or function disorder (65 vs. 24%, P  = 0.008), and have a treatment modification due to CVSE (45 vs. 8%, P  = 0.004). Additionally, high-risk homozygous variant genotypes of KCNQ1 rs163182 GG and rs2237895 AA were each associated with an increased likelihood of treatment modifications due to CVSE (40 vs. 11%, P  = 0.021 and 45 vs. 9%, P  = 0.004, respectively) and cardiac rhythm or function disorders (60 vs. 27%, P  = 0.037 and 60 vs. 27%, P  = 0.037). This study found supportive evidence that 'high-risk' genotype was associated with increased ibrutinib CVSEs. Validation of these associations is necessary before prospective trials testing whether personalized ibrutinib treatment approaches improve clinical outcomes.

Few studies have explored physician and patient preferences for the treatment of chronic lymphocytic leukemia (CLL) related to treatment efficacy, adverse events (AEs), and treatment duration. Thus, this observational, mixed-methods study investigated patients' and physicians' preferences for CLL first-line treatments.

An online discrete choice experiment in five countries among 192 patients and 259 physicians in the US, the UK, Germany, France, and Australia examined the importance of outcomes and treatment attributes.

Increasing 5-year progression-free survival (5-year PFS) was most important to patients and physicians, with a relative importance (RI) of 30.3% among patients and 37.8% among physicians, followed by reducing the risks of common side effects (RI 21.6% among patients, 22.9% among physicians) and adverse events (AEs) leading to treatment discontinuation (RI 22.1% among patients, 20.6% among physicians). Patients strongly preferred time limited treatment regimen over treatment to progression (TTP). Specifically, patients and physicians would require a 6.4% vs 2.3% increase in 5-year PFS, a 19.4% vs 8.9% decrease in the risk of common all grades side effects, and a 7.5% vs 3.7% decrease in the risk of treatment discontinuation due to AEs, respectively, to compensate for a daily oral medication taken indefinitely vs daily oral medication taken for 24 months.

Overall, patients and physicians favor time-limited treatment regimens over TTP and value treatments with greater PFS benefits followed by lower side effects. Patients and physicians were both willing to trade-off switching from time-limited treatment to TTP for a better 5-year PFS, decrease side effects, and risk of treatment discontinuation due to AEs.

Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in adults in Western countries, with a median age at diagnosis of 72 years. This guide, developed by the Spanish Group for Chronic Lymphocytic Leukemia (GELLC), addresses the most relevant aspects of CLL, with the objectives of facilitating and aiding the diagnostic process, establishing therapeutic recommendations for choosing the best treatment for each type of patient, as well as standardizing the management of CLL and ensuring equity across different hospitals in terms of the use of the various available treatment regimens.

The references obtained were classified according to the level of evidence and following the criteria established by the Agency for Health Research and Quality, and the recommendations were classified according to the criteria of the National Comprehensive Cancer Network (NCCN).

The diagnosis of CLL requires the presence of 5 × 109/l clonal B lymphocytes with the characteristic phenotype (CD19, CD5, CD20, CD23, and kappa or lambda chain restriction) demonstrated by flow cytometry in peripheral blood and maintained for at least 3 months. The presence of cytopenia caused by a typical bone marrow infiltrate establishes the diagnosis of CLL, regardless of the number of circulating lymphocytes or existing lymph node involvement. CLL and small lymphocytic lymphoma (SLL) are the same disease with different presentations, so they should be treated the same way. Current international guidelines recommend FISH with the 4 probes as a mandatory test in clinical practice to guide the prognosis of patients. They also recommend determining the mutational status of the immunoglobulin heavy chain variable region (IGHV) before the first treatment and detecting TP53 mutations before the first and subsequent relapses.

Treatment should be initiated in symptomatic patients with criteria for active disease according to iwCLL. The first aspect to highlight is the prioritization of targeted therapies over immunochemotherapy. In first-line treatment, for patients with del(17p) and/or TP53 mutation, the best therapeutic option is a second-generation covalent Bruton's tyrosine kinase inhibitor (BTKi) administered indefinitely, while in cases without del(17p) or TP53 mutation with mutated IGHV, time-limited therapy with a combination including a BCL2 inhibitor (BCL2i) should be considered as the first therapeutic option. For patients with unmutated IGHV, both continuous BTKi and finite therapy with BCL2i are valid options that should be individually evaluated considering potential toxicities, drug interactions, patient preference, and logistical aspects. In very frail patients, supportive treatment should be considered. In relapse/refractory patients, prior treatment, the biological risk of CLL, the duration of response (if prior finite treatment), or the reason for stopping BTKi (if prior continuous treatment) should be considered.

Ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, is used in the treatment of B-cell malignancies (e.g., chronic lymphocytic leukemia [CLL]). Initial risk stratification of ibrutinib-associated atrial fibrillation (IAAF) may inform atrial fibrillation (AF) surveillance strategies. The performance of existing AF risk scores to predict incident AF among patients newly treated with ibrutinib is unknown.

We conducted a single-center retrospective study of all patients without a history of AF who were treated with ibrutinib (2012-2016). Patient demographics were compared between cohorts by the presence of IAAF within 24 months of treatment initiation. First, the predictive ability of established AF risk models was assessed. Secondly, univariate and multivariate analyses were used to create a new IAAF risk model which was compared to established AF risk models by area under the curve (AUC) analysis.

Of 167 patients (66 ± 11 years, 70% male), 24 (14.4%) developed incident IAAF (mean time to IAAF, 7.1 ± 6.3 months). Univariate analysis showed that hypertension (HTN), diabetes (DM), systolic heart failure (HFrEF), and obstructive sleep apnea (OSA) were associated with IAAF. Logistic regression analysis of variables of interest and those with p < 0.1 on univariate analysis demonstrated that left atrial diameter (LAD) > 43 mm and obstructive sleep apnea were independently associated with IAAF. Existing AF risk scores had reasonable performance (AUC, 0.68-0.72). A new simple clinical risk score was developed: OSA 5 points, HFrEF 3 points, DM 2 points, and hyperlipidemia 2 points. This simple IAAF risk score achieved a numerically greater AUC than that of established risk models (AUC = 0.77). There was no statistically significant difference in the AUC performance between risk scores.

Among 167 ibrutinib naïve patients, risk factors for incident AF development resemble those of the general population. However, common AF risk models have moderate predictive ability. Large validation studies are needed to confirm the superior IAAF predictive ability of this simple risk score and investigate the incremental predictive value of echocardiographic variables.

Richter's syndrome (RS) or transformation of chronic lymphocytic leukemia (CLL) into a more aggressive lymphoma (e.g., diffuse large B cell lymphoma, DLBCL) is a distinct disease that portends an overall poor prognosis and remains a challenge for clinicians to identify and treat effectively. This review of the current literature focuses on the pathology, diagnosis, and management of Richter's syndrome. Clonally related RS has been found to have a worse prognosis than unrelated disease and the genomic profile of DLBCL-RS differs from that of de novo DLBCL. The standard of care therapy for RS has historically been chemoimmunotherapy; consolidative stem cell transplants have a role in improving durability of disease response. Given generally poor response rates to chemotherapy, there have been recent investigations into combination treatments with immune checkpoint inhibitors and small molecule targeted therapies, which have had mixed results. Additional studies are evaluating the use of bispecific antibodies, chimeric antigen receptor T cell therapy, and antibody drug conjugates. RS remains difficult to manage; however, advancements in the understanding of the underlying pathology of transformation and continued investigations into new therapies demonstrate promise for the future.

Over the past decade, treatment recommendations for patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) have shifted from traditional chemoimmunotherapy to targeted therapies. Multiple new therapies are commercially available, and, in many cases, a lack of randomized clinical trial data makes selection of the optimal treatment for each patient challenging. Additionally, many patients continue to receive chemoimmunotherapy in the United States, suggesting a gap between guidelines and real-world practice. The Lymphoma Research Foundation convened a workshop comprising a panel of CLL/SLL experts in the United States to develop consensus recommendations for selection and sequencing of therapies for patients with CLL/SLL in the United States. Herein, the recommendations are compiled for use as a practical clinical guide for treating providers caring for patients with CLL/SLL, which complement existing guidelines by providing a nuanced discussion relating how our panel of CLL/SLL experts in the United States care for patients in a real-world environment.

Bruton tyrosine kinase inhibitors (BTKis) are an established standard of care in chronic lymphocytic leukemia. The covalent BTKis ibrutinib, acalabrutinib, and zanubrutinib bind to BTK C481 and are all susceptible to the C481S mutation. Noncovalent BTKi, including pirtobrutinib, overcome C481S resistance but are associated with multiple variant (non-C481) BTK mutations, including those associated with resistance to acalabrutinib and zanubrutinib (T474 codon and L528W mutations). We review the current knowledge on variant BTK mutations, discuss their clinical implications, and consider their impact on clinical trials.

Cisplatin-induced nephrotoxicity and testicular injury pose significant challenges during chemotherapy.

The current study evaluates the efficacy of acalabrutinib (ACB), a Bruton's tyrosine kinase inhibitor, in mitigating cisplatin-induced damage in renal and testicular tissues in mice.

Testicular and renal toxicity was induced by a single I.P. injection of cisplatin (25 mg/kg). Mice were randomized into four groups: Normal (treated with vehicle), Cis (cisplatin + vehicle), Cis + ACB (6 mg/kg), and Cis + ACB (12 mg/kg). ACB was administered orally for three consecutive days, starting at Day 0 (1  h before single I.P. injection of cisplatin) and continued for Day 1 and Day 2.

ACB treatment (6 mg/kg and 12 mg/kg) significantly improved renal function by reducing serum creatinine, BUN, and KIM-1 levels, while also attenuating inflammation and apoptosis, as evidenced by decreased NLRP3, CD68, and caspase-3 expression. Additionally, it mitigated molecular damage by downregulating mTOR, AMPK, and GSDMD-N. In testicular tissues, ACB preserved structure, restored spermatogenesis, and improved sperm viability and testosterone levels. The protective effects were associated with reduced inflammation, apoptosis, and pyroptosis, indicated by lower levels of cathepsin L, NLRP3, and GSDMD-N.

These findings suggest that ACB offers a promising therapeutic approach to reduce the adverse effects of cisplatin, potentially enhancing the overall efficacy and safety of chemotherapy regimens.

This multicenter, open-label, phase Ib study (ACE-LY-106) assessed the safety and efficacy of acalabrutinib, bendamustine, and rituximab (ABR) in treatment-naïve (TN) and relapsed or refractory (R/R) mantle cell lymphoma (MCL). Patients received acalabrutinib from cycle 1 until disease progression or treatment discontinuation, bendamustine on days 1 and 2 of each cycle for up to 6 cycles, and rituximab on day 1 of each cycle for 6 cycles, continuing every other cycle from cycle 8 for 12 additional doses (TN cohort). Eighteen patients enrolled in the TN cohort and 20 in the R/R cohort. Median duration of exposure to acalabrutinib was 34.0 and 14.6 months in the TN and R/R cohorts, respectively. No new safety risks were identified, and most adverse events (AE) were grades 1 or 2. Thirteen patients from the TN cohort (72.2%) and 17 patients from the R/R cohort (85.0%) reported grade 3-4 AE, most commonly neutropenia (TN: 38.9%; R/R: 50.0%). AE leading to death were pneumonitis (N=1, TN cohort), COVID-19, and cerebrospinal meningitis (N=1 each, R/R cohort). Overall response was 94.4% and 85.0% in the TN and R/R cohorts, respectively; complete response rates were 77.8% and 70.0%, respectively. After a median follow-up of 47.6 months, median progression-free survival (PFS) and overall survival (OS) were not reached in the TN cohort. After a median follow-up of 20.4 months, median PFS was 28.6 months and OS was not reached in the R/R cohort. Results indicate that ABR was safe and efficacious, supporting further study in patients with TN MCL.

Acalabrutinib, a second-generation Bruton's tyrosine kinase inhibitor (BTKi), offers an improved safety profile compared to first-generation inhibitors like ibrutinib. While BTKi guidelines exist, practical differences between BTKis-such as drug interactions and tolerance-are not fully addressed. Therefore, a consensus on acalabrutinib use would benefit the medical community. This 2-round Delphi study involved hematologists, pharmacists, cardiologists, dermatologists, and nurse practitioners throughout France to establish consensus-based practical guidance on managing adverse events (AEs) associated with acalabrutinib in chronic lymphocytic leukemia. Key findings highlighted the need for a hospital pharmacist to analyze drug interactions before starting acalabrutinib. Additionally, the experts' opinion was to avoid the concomitant use of acalabrutinib with strong CYP3A inhibitors due to an increased risk of toxicity and with strong CYP3A inducers due to potential efficacy concerns. Importantly, our study did not find contraindications for acalabrutinib in patients with current or previous atrial fibrillation. The panel emphasized the importance of measuring blood pressure at every clinical visit for patients treated with acalabrutinib and opposed the initiation of acalabrutinib in patients on both aspirin and clopidogrel. For invasive dermatological or dental procedures, acalabrutinib should be discontinued 4 days prior and resumed 48 hours postprocedure in the absence of bleeding. Additionally, patients should be informed about the risk of headaches, particularly during the first month of treatment, and paracetamol use in combination with caffeine is recommended for managing grade ≥ 2 headaches under acalabrutinib treatment. This Delphi study underscored the effectiveness of a collaborative process in enhancing the management of acalabrutinib-associated AEs.

The AMPLIFY trial recently established fixed-duration acalabrutinib, venetoclax, and obinutuzumab (AVO) as a new standard-of-care option for patients with previously untreated chronic lymphocytic leukemia (CLL) with wild-type TP53; however, due to the chemoimmunotherapy control arm, AMPLIFY excluded patients with high-risk TP53 aberration, for whom current standards of care are continuous Bruton tyrosine kinase inhibitor therapy or alternatively fixed-duration venetoclax-based doublets. AVO has not previously been evaluated in patients with CLL with TP53 aberration.

This investigator-sponsored, multicenter, phase II study enrolled patients with treatment-naïve CLL enriched for high-risk CLL, defined by TP53 aberration (ClinicalTrials.gov identifier: NCT03580928). Patients received acalabrutinib, obinutuzumab, and then venetoclax, with each treatment introduced sequentially and in combination, with the duration guided by measurable residual disease (MRD). Patients who achieved undetectable MRD (uMRD) after either 15 or 24 cycles could discontinue treatment. The primary end point was complete remission (CR) with bone marrow uMRD (BM-uMRD) at the start of cycle 16.

Seventy-two patients were accrued, including 45 patients with TP53 aberration. The CR with BM-uMRD rates at the start of cycle 16 were 42% in patients with TP53 aberration and 42% in all-comers, and the BM-uMRD rates were 71% and 78%, respectively. Hematologic toxicities were mainly low grade, and cardiovascular toxicities and bleeding complications were infrequent. After a median follow-up of 55.2 months, 10 patients had progressed, including four with transformation, and three patients died. Four-year progression-free survival and overall survival for patients with or without TP53 aberration were 70%/96% and 88%/100%, respectively.

AVO was highly active and well tolerated in patients with previously untreated high-risk CLL, supporting its use as a new standard-of-care treatment option.

Targeted therapies, consisting of Bruton tyrosine kinase inhibitors (BTKis) or BCL-2 inhibitors, are the mainstay of contemporary treatments for chronic lymphocytic leukemia (CLL). The most common adverse effects (AEs) of BTKis are fatigue, bruising, infection, hematological and cardiovascular AEs. While AEs during treatment are usually mild (grades 1 and 2), grade 3 and 4 AEs have been detected in some patients, necessitating additional medical care and temporary or permanent drug discontinuation. In this review, we analyzed the cardiovascular effects associated with BTKi therapy for CLL and the essential practical aspects of multidisciplinary management of patients who develop cardiovascular toxicity during treatment. We particularly focus on the data and strategies for controlling cardiovascular risks associated with ibrutinib and newer BTKis (acalabrutinib, zanubrutinib and pirtobrutinib), including the development of atrial fibrillation, hypertension, ventricular arrhythmias, sudden death, heart failure, bleeding, and ischemic complications (stroke and myocardial infarction). This review highlights hematological insights underlying cardiotoxicity, an area that has received limited attention in comparison to the predominantly cardiological perspective. This review synthesizes emerging evidence on hematological biomarkers, cardiotoxic mechanisms, and therapeutic interventions, linking hematology and cardiology to enhance understanding and guide comprehensive prevention and management strategies.