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The article presents a case study of 55-year-old male with untreated chronic lymphocytic leukemia (CLL), and 67-year-old male with CLL with urticaria. It notes the CLL patient treated with ibrutinib monotherapy in a clinical study, using acalabrutinib for the other patient, whose urticaria had reduced after the treatment.

The article presents a study on the level of polyreactive antibodies in the sera of chronic lymphocytic leukemia (CLL) patients with un-mutated (U-CLL) and mutated (M-CLL) immunoglobulin heavy genes (IGHV) and the quantity of polyreactive antibodies secreted by cultured CLL cells stimulated with the toll-like receptor 9 (TLR9) ligand CpG. Topics include comparison of the titer of polyreactive antibodies in CLL patients to the control group and the beneficial effect of ibrutinib.

MLL (mixed‐lineage leukemia)‐fusion genes induce the development of leukemia through deregulation of normal MLL target genes, such as HOXA9 and MEIS1. Both HOXA9 and MEIS1 are required for MLL‐fusion gene‐induced leukemogenesis. Co‐expression of HOXA9 and MEIS1 induces acute myeloid leukemia (AML) similar to that seen in mice in which MLL‐fusion genes are over‐expressed. p27kip1 (p27 hereafter), a negative regulator of the cell cycle, has also been defined as an MLL target, the expression of which is up‐regulated in MLL leukemic cells (LCs). To investigate whether p27 plays a role in the pathogenesis of MLL‐leukemia, we examined the effects of p27 deletion (p27−/−) on MLL‐AF9 (MA9)‐induced murine AML development. HOXA9/MEIS1 (H/M)‐induced, p27 wild‐type (p27+/+) and p27−/− AML were studied in parallel as controls. We found that LCs from both MA9‐AML and H/M‐AML can be separated into three fractions, a CD117‐CD11bhi differentiated fraction as well as CD117+CD11bhi and CD117+CD11blo, two less differentiated fractions. The CD117+CD11blo fraction, comprising only 1–3% of total LCs, expresses higher levels of early hematopoietic progenitor markers but lower levels of mature myeloid cell markers compared to other populations of LCs. p27 is expressed and is required for maintaining the quiescent and drug‐resistant states of the CD117+CD11blo fraction of MA9‐LCs but not of H/M‐LCs. p27 deletion significantly compromises the leukemogenic capacity of CD117+CD11blo MA9‐LCs by reducing the frequency of leukemic stem cells (LSCs) but does not do so in H/M‐LCs. In addition, we found that p27 is highly expressed and required for cell cycle arrest in the CD117‐CD11bhi fraction in both types of LCs. Furthermore, we found that c‐Myc expression is required for maintaining LCs in an undifferentiated state independently of proliferation. We concluded that p27 represses the proliferation of LCs, which is specifically required for maintaining the quiescent and drug‐resistant states of a small subset of MA9‐LSCs in collaboration with the differentiation blockage function of c‐Myc. Highlights: p27 is specifically expressed in a small subset of MLL‐AF9 LSC but not in HOXA9/MEIS1 LSC.The niche‐generated factors Flt3L and SCF induce p27 expression in MLL‐AF9 LSC but not in HOXA9/MEIS1 LSC.p27 restricts proliferation and maintains resistance to chemotherapeutic agents in MLL‐AF9 LSC.Over‐expression of p27 in HOXA9/MEIS1 LSC leads to quiescence and resistance to chemotherapeutic agents. [ABSTRACT FROM AUTHOR]

B-cell receptor (BCR) signaling and tumor–microenvironment crosstalk both drive chronic lymphocytic leukemia (CLL) pathogenesis. Within the microenvironment, tumor cells shape the T-cell compartment, which in turn supports tumor growth and survival. Targeting BCR signaling using Bruton tyrosine kinase inhibitors (BTKi) has become a highly successful treatment modality for CLL. Ibrutinib, the first-in-class BTKi, also inhibits Tec family kinases such as interleukin-2–inducible kinase (ITK), a proximal member of the T-cell receptor signaling cascade. It is increasingly recognized that ibrutinib modulates the T-cell compartment of patients with CLL. Understanding these T-cell changes is important for immunotherapy-based approaches aiming to increase the depth of response and to prevent or treat the emergence of resistant disease. Ibrutinib has been shown to improve T-cell function in CLL, resulting in the expansion of memory T cells, Th1 polarization, reduced expression of inhibitory receptors and improved immune synapse formation between T cells and CLL cells. Investigating the modulation of BTKi on the T-cell antitumoral function, and having a more complete understanding of changes in T cell behavior and function during treatment with BTKi therapy will inform the design of immunotherapy-based combination approaches and increase the efficacy of CLL therapy. [ABSTRACT FROM AUTHOR]

The authors discuss a study by E. M. Hartmann and colleagues regarding the interplay between chemokine (C-C motif) ligand 3 (CCL3) and non-leukemic cells of the lymph node. The authors states that the study authors performed immunohistochemistry on lymph node biopsies for cellular components of the microenvironment and CCL3 protein expression. They mentions that CCL3 has both biological and prognostic relevance in chronic lymphocytic leukemia (CLL).

Purpose: To summarize complication rates, reoperation rates, length-of-stay (LOS), patient-reported outcome measures (PROMs), and range of motion following total shoulder arthroplasty (TSA) in patients with preexisting psychiatric disorders (PDs) compared to controls., Methods: Three databases (MEDLINE, PubMed, and EMBASE) were searched from inception to 4 March 2024 to identify studies comparing outcomes between patients undergoing anatomic (aTSA) or reverse TSA (rTSA) with or without a preexisting psychiatric condition. The authors adhered to the preferred reporting items for systematic reviews and meta-analyses and revised assessment of multiple systematic review guidelines. Data on demographics, as well as postoperative complication rates, reoperation rates, LOS, PROMs, and range of motion were extracted from included studies. PROMs included the American Shoulder and Elbow Surgeons (ASESs) score, and visual analogue scale (VAS) pain score. Meta-analyses were conducted for outcomes reported by multiple studies, with odds ratios (ORs) and mean differences (MDs) as effect measures for continuous and dichotomous outcomes, respectively., Results: Thirteen studies were included in this review, comprising a total of 820,831 TSA patients. The PD group (71.0% female) consisted of 150,432 patients (mean age: 67.6 ± 9.9) with a mean follow-up time of 34.1 ± 30.1 months. The control group (58.1% female) consisted of 670,399 patients (mean age: 69.4 ± 10.7) with a mean follow-up time of 39.1 ± 36.0 months. The PD group had significantly higher rates of complications and reoperation. The PD group also reported significantly lower postoperative ASES scores, higher postoperative VAS scores, and inferior postoperative abduction. There were no significant differences in postoperative LOS, forward flexion, internal rotation, or external rotation., Conclusion: Patients with preexisting PDs may have a one-and-a-half times higher odds of postoperative complication or reoperation, as well as significantly worse postoperative pain and PROMs. Identification of at-risk individuals with preexisting psychiatric conditions and preoperative referral to a mental health specialist to optimize psychiatric conditions may benefit this patient cohort ahead of their shoulder arthroplasty procedure., Level of Evidence: IV., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2025.)

Cardiovascular (CV) toxicities of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib may limit use of this effective therapy in patients with chronic lymphocytic leukemia (CLL). Acalabrutinib is a second-generation BTK inhibitor with greater BTK selectivity. This analysis characterizes pooled CV adverse events (AE) data in patients with CLL who received acalabrutinib monotherapy in clinical trials (clinicaltrials gov. Identifier: NCT02029443, NCT02475681, NCT02970318 and NCT02337829). Acalabrutinib was given orally at total daily doses of 100-400 mg, later switched to 100 mg twice daily, and continued until disease progression or toxicity. Data from 762 patients (median age: 67 years [range, 32-89]; median follow-up: 25.9 months [range, 0-58.5]) were analyzed. Cardiac AE of any grade were reported in 129 patients (17%; grade ≥3, n=37 [5%]) and led to treatment discontinuation in seven patients (1%). The most common any-grade cardiac AE were atrial fibrillation/flutter (5%), palpitations (3%), and tachycardia (2%). Overall, 91% of patients with cardiac AE had CV risk factors before acalabrutinib treatment. Among 38 patients with atrial fibrillation/flutter events, seven (18%) had prior history of arrhythmia or atrial fibrillation/flutter. Hypertension AE were reported in 67 patients (9%), 43 (64%) of whom had a preexisting history of hypertension; no patients discontinued treatment due to hypertension. No sudden cardiac deaths were reported. Overall, these data demonstrate a low incidence of new-onset cardiac AE with acalabrutinib in patients with CLL. Findings from the head-to-head, randomized trial of ibrutinib and acalabrutinib in patients with highrisk CLL (clinicaltrials gov. Identifier: NCT02477696) prospectively assess differences in CV toxicity between the two agents.

Vaccinations effectively prevent infections; however, patients with chronic lymphocytic leukemia (CLL) have reduced antibody responses following vaccinations. Combined humoral and cellular immune responses to novel adjuvanted vaccines are not well characterized in CLL. In an open-label, single-arm clinical trial, we measured the humoral and cellular immunogenicity of the recombinant zoster vaccine (RZV) in CLL patients who were treatment naïve (TN) or receiving Bruton tyrosine kinase inhibitor (BTKi) therapy. The primary endpoint was antibody response to RZV (≥fourfold increase in anti-glycoprotein E [anti-gE]). Cellular response of gE-specific CD4+ T cells was assessed by flow cytometry for upregulation of ≥2 effector molecules. The antibody response rate was significantly higher in the TN cohort (76.8%; 95% confidence interval [CI], 65.7-87.8) compared with patients receiving a BTKi (40.0%; 95% CI, 26.4-53.6; P = .0002). The cellular response rate was also significantly higher in the TN cohort (70.0%; 95% CI, 57.3-82.7) compared with the BTKi group (41.3%; 95% CI, 27.1-55.5; P = .0072). A concordant positive humoral and cellular immune response was observed in 69.1% (95% CI, 56.9-81.3) of subjects with a humoral response, whereas 39.0% (95% CI, 24.1-54.0) of subjects without a humoral response attained a cellular immune response (P = .0033). Antibody titers and T-cell responses were not correlated with age, absolute B- and T-cell counts, or serum immunoglobulin levels (all P > .05). RZV induced both humoral and cellular immune responses in treated and untreated CLL patients, albeit with lower response rates in patients on BTKi therapy compared with TN patients. This trial was registered at www.clinicaltrials.gov as #NCT03702231., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)