While pirtobrutinib is established in Bruton tyrosine kinase inhibitor (BTKi)-refractory disease, its role in BTKi-naïve relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) remains unclear because of the absence of direct comparative trials with second-generation covalent BTKis. We conducted a systematic literature review and Bayesian network meta-analysis of randomized controlled trials (ELEVATE-RR, ALPINE, BRUIN-CLL-314) linked by a common comparator (ibrutinib). Across 814 patients, pirtobrutinib demonstrated efficacy comparable to acalabrutinib and zanubrutinib, with no significant differences in progression-free survival (PFS) (vs acalabrutinib: HR 0.73, 95% CrI 0.44-1.20 vs zanubrutinib: HR 1.12, 95% CrI 0.67-1.89), overall survival (OS), or overall response rate (ORR). Subgroup analyses by genomic risk were inconclusive. Safety profiles were broadly similar; however, pirtobrutinib was associated with a lower risk of cardiovascular adverse events compared with zanubrutinib (OR 0.52, 95% CrI 0.31-0.88) and similar risk relative to acalabrutinib (OR 1.09, 95% CrI 0.62-1.92). In conclusion, pirtobrutinib demonstrated efficacy and tolerability comparable to those of second-generation covalent BTKis, with a potential cardiovascular safety advantage over zanubrutinib in patients with R/R BTKi-naive CLL. However, given the indirect nature of the comparison, the limited evidence base, and between-study heterogeneity, these findings should be considered exploratory.

Covalent Bruton tyrosine kinase inhibitor (cBTKi)-based regimens have redefined therapy for chronic lymphocytic leukemia (CLL). However, continuous treatment with BTKis can select for therapy resistance, typically associated with BTK C481 mutations and fosfolipasi C gamma 2 (PLCγ2) activation. In addition, continuous BTKi therapy poses challenges for treatment interruptions and dose modifications, with implications for clinical outcomes. Pirtobrutinib, a highly selective, reversible (noncovalent) BTKi, inhibits BTK independently of C481 and maintains sustained target engagement. In patients with cBTKi-pretreated relapsed/refractory (R/R) CLL, the BRUIN-CLL-321 trial demonstrated improved progression-free survival (PFS) and time to next treatment (TTNT) compared with idelalisib/rituximab or bendamustine/rituximab, accompanied by a favorable tolerability profile. Data from randomized phase III BRUIN-CLL-313 and BRUIN-CLL-314 trials demonstrate the superiority of pirtobrutinib over chemoimmunotherapy in untreated patients and non-inferiority to ibrutinib in untreated patients or in patients with R/R disease who had no prior exposure to cBTKis. These data are not sufficient to justify a change in clinical practice; however, they lay the groundwork for a potential future repositioning of pirtobrutinib from the treatment of R/R CLL to earlier lines of therapy. In this review, we address a range of current and prospective aspects of pirtobrutinib-based therapies: (1) the strengths and limitations of the trial datasets; (2) the biological rationale for frontline noncovalent BTK inhibition; (3) sequencing trade-offs; and (4) prospective scenarios, including combination strategies and time-limited regimens.

To re-evaluate chronic lymphocytic leukaemia (CLL) epidemiology in the era of modern therapy, data were extracted from the English National Cancer Registration Dataset (NCRD). A total of 34 427 consecutive diagnoses of CLL were recorded (2014-2022), the largest European dataset on record. In addition to known associations with age, gender-ethnicity, multivariable analysis showed incidence rate ratio (IRR) variations with government region (IRR ranging from 0.78 to 0.94 vs. London), socioeconomic deprivation (1.06 [95% confidence interval (CI) 1.02-1.10] for most vs. least deprived quintile) and IRR fall in successive calendar years (0.70 [95% CI 0.67-0.73] for 2022 vs. 2014). With a median follow-up of 74.4 months, 36.9% of patients had died, including 13.6% from blood cancer. 1-, 3- and 5-year overall survival (OS)/net survival rates were 90%/94%, 78%/87% and 67%/81%, respectively. Age, male gender, comorbidity and socioeconomic deprivation were independently associated with shorter OS and cause-specific survival (CSS), with OS-hazard ratio (HR) of 1.42 (95% CI 1.34-1.50) and CSS-HR of 1.28 (1.16-1.41) for the most versus least deprived quintiles. In addition, government region was independently associated with CSS, with HRs relative to London ranging from 0.84 (0.74-0.96) to 1.12 (0.99-1.27). Our findings reveal previously unreported disparities in CLL incidence and survival based on place of residence.

Abstract Clinical trials indicate that acalabrutinib, a second-generation Bruton tyrosine kinase inhibitor, is safe and effective for treating patients with chronic lymphocytic leukemia (CLL), but real-world evidence on its clinical effectiveness is limited. This ongoing multicenter retrospective chart review included UK adults with previously untreated CLL who received acalabrutinib monotherapy as part of a UK-wide early access program. These patients received their first dose of acalabrutinib between 1 April 2020 and 1 April 2021. Data from 282 patients (male patients, n = 156 [55%]) collected from 29 sites across the United Kingdom revealed a median age of 73.9 years (interquartile range [IQR], 68.6-79.4) at acalabrutinib initiation (index date) and a median time of 3.0 years (IQR, 1.2-5.7; n = 281) from CLL diagnosis to treatment. The median follow-up was 48.9 months (IQR, 45.0-52.3). At the 3-year landmark, real-world progression-free survival was 82.5% (95% confidence interval [CI], 78.2-87.1), and real-world overall survival was 84.3% (95% CI, 80.2-88.7). Additionally, 72.3% of patients (95% CI, 67.3-77.8) remained on acalabrutinib treatment. The most common reasons for acalabrutinib discontinuation were adverse events (AEs; 31/87 [36%]), death (16/87 [18%]), and disease progression (14/87 [16%]). Of the 270 patients with recorded information, 99 patients (37%) experienced ≥1 prespecified AE, of which the most frequent were upper respiratory tract infection (n = 21 patients [8%]), rash (n = 13 [5%]), and neutropenia (n = 12 [4%]). This study adds to a body of clinical trial and further postmarketing evidence demonstrating the effectiveness and safety of acalabrutinib within routine UK clinical practice.

The advent of targeted therapies has profoundly altered the prognostic landscape of chronic lymphocytic leukemia (CLL), demanding a reassessment of established predictive models. Initial frameworks, such as the CLL International Prognostic Index (CLL-IPI), primarily relied on clinical and genetic parameters. However, the growing clinical utility of targeted agents highlights the ongoing need to refine these prognostic tools. Although the CLL-IPI remains a valuable metric for progression-free survival (PFS), its capacity to accurately predict overall survival (OS) has been attenuated by the evolution of therapeutic approaches. Novel prognostic models hold promise by leveraging advanced technologies, sophisticated statistical methods, and computational analytics to improve risk stratification. These innovations address the inherent limitations of conventional models, enabling more precise and individualized prognostic assessments. To maintain clinical utility, however, these models must continuously adapt alongside the rapidly advancing therapeutic landscape of CLL. Optimizing patient outcomes requires a fundamental paradigm shift that integrates a broader and more dynamic array of patient-specific data into prognostic evaluations.

Chronic lymphocytic leukemia (CLL) treatment has undergone a significant evolution with a shift from historical chemotherapeutic regimens to targeted therapies such as Bruton tyrosine kinase (BTK) and BCL-2 inhibitors. These advancements have been associated with a notable improvement in survival rates with a transformation of CLL into a chronic and manageable condition for most persons with this disease. However, as a consequence of improved outcomes, long-term CLL survivors now face emergent challenges which include a risk of infections, cardiovascular complications, and secondary malignancies. In this changed scenario, holistic models of care are essential to address emergent health risks. Such models of care for CLL patients require a multidisciplinary approach that integrates CLL treatment with the proactive management of frailty, comorbidities, and psychosocial well-being to enhance both survival and quality of life (QoL). CLL predominantly affects older persons, many of whom present with concurrent frailty and comorbidities that may complicate CLL treatment and impact QoL. Comprehensive geriatric assessments (GA) may play a critical role in the identification of persons at a heightened risk of treatment-related toxicity and may help guide rational therapy selection, particularly in very frail persons. In addition to the assessment of hematological responses, the prospective assessment of patient-reported outcomes (PROs) and frailty metrics may offer a more nuanced understanding of the global treatment benefits. A survivorship-focused care model is crucial to address the multifaceted needs of CLL patients with the extension of patient care into the broader domain of long-term health maintenance with associated improvements in QoL.

Bruton's tyrosine kinase inhibitors (BTKis) have reshaped the management of chronic lymphocytic leukemia (CLL). The first-generation BTKi ibrutinib demonstrated significant efficacy, leading to the development of second-generation agents (acalabrutinib, zanubrutinib) with improved selectivity and safety. However, resistance-most often driven by BTK mutations at the cysteine residue at position 481 (C481S)-remains a major therapeutic limitation. Noncovalent BTKis, such as pirtobrutinib, offer effective options for patients relapsing after covalent BTKi therapy. However, the emergence of novel resistance mutations continues to limit durable responses. As insights into the molecular basis of BTK resistance evolve, routine mutation testing is poised to become integral to personalized treatment in CLL. Future clinical trials are expected to adopt mutation-driven stratification to guide therapeutic sequencing. Ultimately, overcoming BTKi resistance will require innovative strategies, including BTK degraders, bispecific antibodies, and T cell-engaging immunotherapies.

Abnormal uterine bleeding (AUB) describes any bleeding from the uterus that deviates from the norm in terms of regularity, duration, or volume. AUB is a common condition that can significantly affect quality of life. Although inherited bleeding disorders (IBDs) can cause heavy menstrual bleeding, there is no clear consensus on how AUB is best managed in those patients. This study aimed to address this knowledge gap using evidence based on clinical findings to define the best management of AUB in patients with IBD by conducting a systematic review of the literature. Searches were conducted for articles published from January 1, 2000, until May 6, 2024 in the Embase (PubMed), Medline, Scopus, Cochrane library, Google Scholar, and Cumulative Index to Nursing and Allied Health Literature complete via the Elton B. Stephens Company databases. In total, 244 studies were assessed for eligibility based on inclusion and exclusion criteria. Included studies were appraised for risk of bias and quality assurance using the Newcastle Ottawa Scale, after which data was systematically coded to generate descriptive and analytical themes. Thirteen studies were included in the thematic synthesis, encompassing over 893 participants. Thematic synthesis identified hormonal treatments, such as the levonorgestrel-releasing intrauterine system (LNG-IUS), to be largely effective in the symptom management of AUB in IBDs. Treatment of AUB patients with LNG-IUS, followed by tranexamic acid or 1-deamino-8-d-arginine vasopressin (DDAVP) commonly led to amenorrhea. The use of LNG-IUS as first-line therapy is recommended for those with AUB, followed by the use of combination therapy such as tranexamic acid and desmopressin. We identified the need to strengthen communication between specialists involved in the care of those with AUB and IBDs.

Introduction: We have previously reported improved survival in patients (pts) with recurrent gene mutations following treatment with ibrutinib and rituximab (IR) compared to fludarabine, cyclophosphamide and rituximab (FCR). In this study we assessed the impact of baseline gene aberrations on Progression-Free Survival (PFS) in patients receiving MRD-guided ibrutinib plus venetoclax (I+V) compared to those treated (tx) with ibrutinib (I & IR) or FCR in the FLAIR trial. We also report on treatment outcomes based on Immunoglobulin Heavy Chain Variable region (IGHV) Somatic Hypermutation (SHM) and stereotyped subset #2 (S#2) status. Method: FLAIR (ISRCTN01844152) is an ongoing phase III, multicentre, randomised, controlled, open label trial comparing IR and FCR in patients with untreated CLL requiring therapy according to IWCLL criteria. It was subsequently adapted to compare I+V and I alone with FCR. Chromosomal abnormalities were detected using Fluorescent In Situ Hybridization (FISH) with targeted probes for chromosomes 11q and 17p. Pts with >20% 17p deletion (del) were excluded from the trial. Extracted DNA was sequenced using Illumina MiSeq and analysed using an in-house pipeline. Amplicon based targeted sequencing of 33 recurrently mutated (mut) genes was performed in parallel. Detected variants were reported down to minimum variant allele fraction of 3% at 100X coverage. SHM status was determined by PCR amplification of IGHV-IGHD-IGHJ gene rearrangements using IGHV leader/FR1 primers. Bidirectional Sanger sequencing was analysed using IMGT V-Quest and ARResT/AssignSubsets. Cox's proportional hazards was used to estimate Hazard Ratios (HR). Log-rank test was used to estimate p-value where HR was zero (zero progression events in one or more treatment arms). Results: 1172 patients were randomly assigned to receive I+V (n=260), I&IR (n=263 & 386 resp.) or FCR (n=263). Somatic gene mutations were assessed in 1161/1172 (99.1%) pts at baseline and mutations were detected in 715/1161 (61.6%). The frequency of these mutations in pts ranged from 0.2-16.7% with mutations in SF3B1 (16.7%), ATM (14%), NOTCH1 (11.6%), RPS15 (5.1%), MYD88 (5%), TP53 (4.7%), BIRC3 (4.7%), POT1 (4.5%), and BRAF (4.2%) being the most frequent. Del(11q) was detected by FISH in 187/1150 pts (16.3%). IGHV SHM status was available for 1077/1172: 620 (57.6%) IGHV Unmutated (IGHV-UM; >98% of nucleotide identity to germline), 457 (42.4%) IGHV Mutated (IGHV-M). 77/1077 pts were assigned to CLL S#2 (7.1%, n=42 IGHV-M, n=35 IGHV-UM). A significant improvement in PFS was observed between TP53mut pts tx with I+V compared to I&IR and FCR (p=0.04 and 0.009 resp.). The 5yr PFS for TP53mut pts was 100% for I+V (n=11), 70% for I&IR (n=31) and 62.3% for FCR (n=12). Similar improvements in PFS were also observed for del(11q), ATMmut, SF3B1mutand NOTCH1mut pts tx with I+V compared to I&IR and FCR (p=0.001 and <0.001; HR:0.1 p=0.02 and HR:0.03 p<0.001; HR:0.21 p=0.03 and HR:0.07 p<0.001; HR:0.22 p=0.04 and HR:0.09 p=0.002 resp.). For RPS15mut pts a significant improvement in the PFS was seen between pts tx with I+V compared to FCR (p=0.001) but not I&IR (p=0.24). The 5yr PFS for pts tx with I+V, I&IR or FCR was 100%, 82% and 43.5% for del(11q); 97.6%, I&IR 79.7% and 39.2% for ATMmut; 94.1%, 79.5% and 48.3% for SF3B1mut; 97.0%, 75.2% and 54.6% for NOTCH1mut and 100%, 90.2% and 31.7% for RPS15mutpts resp. For IGHV-UM pts (excl. S#2) a significant improvement in PFS was observed when tx with I+V compared to I&IR and FCR (HR:0.20 p<0.001 and HR:0.07 p<0.001 resp.). The 5yr PFS was 94.9% for I+V, 79.3% for IR&I and 49.7% for FCR. A similar improvement was also observed for IGHV-M pts (excl. S#2) tx with I+V compared to FCR but not IR (HR:0.37 p=0.007 and HR:0.64 p=0.188 resp.). The 5yr PFS was 90.1% for I+V, 84.7% for I&IR and 75.2% for FCR. For S#2 pts tx with I+V PFS was significantly improved compared to FCR but not I&IR (p=0.002 and 0.119 resp.). The 5yr PFS was 100% for I+V, 88.9% for I&IR and 52.7% for FCR.Conclusions: Our results from theFLAIR trial demonstrate that targeted treatment is highly effective at mitigating the poor outcome previously associated with unmutated IGHV-UM SHM status, CLL S#2 and recurrent gene aberrations when treated with chemoimmunotherapy. Notably, we report exceptional responses following MRD-guided I+V treatment compared to both the Ibrutinib and FCR arms of the trial, especially in pts with TP53, ATM or NOTCH1 aberrations.