Search

Type II cryoglobulinemia is a rare disorder characterized by abnormal immunoglobulins (Igs) precipitating in the blood at low temperatures and redissolving upon warming. Sjogren's disease (SjD) is an autoimmune disorder involving secretory gland malfunction that leads to persistent dryness of the mouth and eyes. Here, we report the case of a 61-year-old woman with a 7-year history of SjD who was diagnosed with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). However, her complicated clinical features could not be sufficiently explained by this disease alone. Immunofixation electrophoresis revealed monoclonal IgM-κ and polyclonal IgG-κ. The presence of precipitated cryoglobulin and elevated rheumatoid factor levels confirmed a diagnosis of type II cryoglobulinemia for this patient. To the best of our knowledge, this case represents the first report of a patient with CLL/SLL, SjD, and type II cryoglobulinemia, which increased our understanding of immune system-related disorders. Because certain similar mechanisms are involved in the pathogenesis of these three diseases, a combination treatment of rituximab, ibrutinib, and dexamethasone resulted in a favorable prognosis for this patient., Competing Interests: Declaration of conflicting interestThe authors declare that there is no conflict of interest.

Introduction: In the last decade, BTK inhibitors and the BCL-2 inhibitor venetoclax have replaced immunochemotherapy in the treatment of CLL., Areas Covered: This review describes the use of BTK inhibitors and BCL2 inhibitors in the treatment of naive and relapsed or refractory CLL, with particular attention to the mechanisms of resistance. It also addresses the management of double-refractory patients, and the discovery of novel drugs. The corpus of papers was obtained by a search of the PubMed and Google Scholar databases for articles in English., Expert Opinion: Covalent BTK inhibitors and venetoclax are commonly recommended for previously-untreated and relapsed/refractory CLL. However, resistance to both drug classes can develop over time. As such, double-refractory patients are difficult to manage and novel approaches are urgently needed.

B-cell activating factor belonging to the TNF family (BAFF), also known as B-lymphocyte stimulator (BLyS), plays a crucial role in B-cell development. It has multiple receptors, including BCMA, TACI, and BAFF-R, with diverse roles in different cell types. BAFF induces B-cell proliferation and immunoglobulin secretion, and acts as a survival factor for immature, naive, and activated B cells. Consequently, BAFF-deficient mice often show suppressed humoral responses, while BAFF-overexpressing mice show the higher number of mature B cells and may develop autoimmune-like manifestations and B-cell lymphoproliferative diseases. Elevated BAFF levels are also associated with various hematological malignancies, and its expression correlates with disease progression in some cases. Therefore, BAFF-targeted therapies, such as belimumab, atacicept, and tabalumab, are being explored in clinical trials for conditions like chronic lymphocytic leukemia (CLL) and multiple myeloma. Belimumab, an anti-BAFF monoclonal antibody, is being investigated in combination with rituximab/venetoclax for CLL. Atacicept, a decoy receptor for BAFF and APRIL, showed tolerability in a phase 1b trial for CLL. Tabalumab, another monoclonal antibody targeting BAFF, did not demonstrate significant efficacy in a phase 2 study for relapsed/refractory multiple myeloma. BAFF ligand-based CAR-T cells are designed to target BAFF receptors and show promise in preclinical studies, particularly for B-cell malignancies. The review emphasizes the importance of understanding the roles of BAFF and its receptors in the microenvironment of hematologic malignancies. Targeting BAFF and its receptors presents potential therapeutic avenues, and ongoing clinical trials provide valuable insights., (© 2024. The Author(s).)

This report focuses on part 3 of a multicenter, open-label, phase 1 study (NCT03198650) assessing the safety, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of acalabrutinib plus obinutuzumab in Japanese patients with treatment-naive (TN) chronic lymphocytic leukemia (CLL). Ten patients were included; median age was 68 years. With a median treatment duration of 27.2 months, treatment-emergent adverse events (AEs) occurred in all patients (grade ≥3, 70%), and the most common AEs were anemia and headache (40% each). One patient had a grade 4 AE of neutropenia (the only dose-limiting toxicity). PK results suggested no marked effects of concomitant obinutuzumab treatment on the exposure of acalabrutinib. PD assessment indicated that combination therapy provided >98% Bruton tyrosine kinase (BTK) occupancy. Overall response rate (ORR) was 100% with median duration of response (DoR) and median progression-free survival (PFS) not reached. Treatment with acalabrutinib plus obinutuzumab was generally safe and efficacious in adult Japanese patients with TN CLL.

The overall value of treatments for chronic lymphocytic leukemia (CLL) depends on several factors, including preferences of the general population, who contributes to the financing of health systems. This study investigated societal preferences for attributes of CLL treatments in Italy. An online large-scale survey was designed using a discrete choice experiment (DCE) methodology and delivered to the Italian adult general population. Ten treatment attributes were identified, covering efficacy, safety, operational aspects and (hypothetical) out-of-pocket cost. DCE data were analyzed using a mixed logit regression model, estimating the willingness-to-pay for attribute levels' change. The general population significantly preferred more effective treatments, with shorter duration, administered orally rather than orally + intravenously. Changes in therapy duration, frequency of checkups and organ damage risk had the greatest impact on preferences. The integration of societal preferences in the value judgments of CLL therapies may help health authorities in establishing priority setting and taking pricing-reimbursement decisions.

Bruton tyrosine kinase (BTK) inhibitors play an important role in targeted treatment of B-cell lymphoproliferative disorders. However, adverse events may limit the proper course of treatment in many patients. The purpose of this study is to compare the risk of cardiovascular and non-cardiovascular adverse events in patients with chronic lymphocytic leukemia (CLL) or small cell lymphocytic lymphoma (SLL) treated with the first-generation BTK inhibitor ibrutinib versus second-generation acalabrutinib, using real-world data from a collaborative multinational network. We used data from the network (TriNetX), which encompasses more than 100 healthcare organizations worldwide. We queried the database for patients aged ≥ 18 years with chronic lymphocytic leukemia or small-cell lymphomas treated with ibrutinib or acalabrutinib in the past ten years before the analysis. We used propensity score matching to balance the cohorts. The 3-year cumulative incidences and hazard ratios for the following outcomes were calculated: atrial flutter or fibrillation, other arrhythmias, heart failure, ischemic stroke or peripheral embolism, acute coronary syndrome, bleeding, and sepsis. We compared 2,107 patients in each group. Atrial fibrillation or flutter occurred in 150 (7.1%) patients with acalabrutinib and 310 (14.7%) patients with ibrutinib during the 3-year follow-up (hazard ratio, 0.68, 95% CI 0.55-0.84). New-onset hypertension occurred in 342 (16.3%) patients in the acalabrutinib group and 584 (27.7%) patients in the ibrutinib group (hazard ratio 0.81, 95% CI 0.66-0.98). Sepsis was diagnosed in 136 (6.5%) patients in the acalabrutinib group versus 239 (11.3%) patients in the ibrutinib group (hazard ratio 0.77, 95 CI 0.60-0.98). The two groups had no significant differences concerning the other adverse events. In a large retrospective cohort using real-world data from electronic medical registers, patients with CLL or SLL treated with acalabrutinib had a better cardiovascular and non-cardiovascular safety profile than those treated with ibrutinib, with lower risks of atrial flutter or fibrillation, new-onset arterial hypertension, and sepsis., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

This real-world retrospective cohort study using Australian Pharmaceutical Benefits Scheme (PBS) 10% investigated changes in chronic lymphocytic leukemia (CLL) treatment by line of therapy, time-to-next-treatment, treatment duration, and overall survival (OS). Overall, 803 patients received their first PBS-reimbursed CLL medication between 1 January 2011 to 31 July 2021 (median age: 70 years; 64.6% male), 289 post-1 August 2020. In 2011, most first-line (1 L) prescribing was fludarabine, cyclophosphamide, and rituximab (FCR). By 2021, common 1L were chlorambucil ± CD20 (26.1%), Bruton Tyrosine Kinase inhibitor (BTKi) (26.1%), and CD20 monotherapy (23.9%). In 2011, relapsed/refractory (R/R) CLL treatment was CD20 monotherapy or FCR. By 2021, BTKi (57.7%) and venetoclax ± CD20 (26.1%) were most common. Compared to FCR, 1 L treatment duration (Hazard Ratio) was shorter for CD20 monotherapy (1.7) or chlorambucil ± CD20 (2.5). In R/R CLL, median duration was 24 (ibrutinib) and 19 months (venetoclax). Median OS was 127 months. CLLtreatment pattern shave greatly changed in Australia since the introduction of novel therapies.

Objective: This article examined the cost-effectiveness of zanubrutinib and ibrutinib for managing relapsed and refractory chronic lymphocytic leukemia from the viewpoint of payers in China and the US., Methods: Markov models were employed to conduct comparisons. Baseline characteristics and clinical data were extracted from the ALPINE study. The cost-effectiveness outcome indicators encompassed cost, quality-adjusted life years, and the incremental cost-effectiveness ratio., Results: The Markov model analysis revealed that the zanubrutinib group incurred an incremental cost per patient of $-24,586.53 compared to the ibrutinib group. The zanubrutinib group exhibited an incremental utility per capita of 0.28 quality-adjusted life years, resulting in an incremental cost-effectiveness ratio of $-88,068.16 per quality-adjusted life year, which is lower than the payment threshold in China. The willingness-to-pay value in China for 2022 was three times the country's gross domestic product per capita. In the US, patients in the zanubrutinib group experienced per capita incremental costs of $-79,421.56, per capita incremental utility of 0.28 quality-adjusted life years, and an incremental cost-effectiveness ratio of $-284,485.45 per quality-adjusted life year., Conclusion: For Chinese payers, zanubrutinib exhibited superior cost-effectiveness compared to ibrutinib. Zanubrutinib proved to be a more affordable option for US payers when considering the payment threshold.

Venetoclax was approved for relapsed/refractory chronic lymphocytic leukemia (R/R CLL) and small lymphocytic leukemia (SLL) in Japan in September 2019; however, clinical data in Japanese patients are limited. This all-case post-marketing surveillance assessed efficacy and safety in Japanese patients with R/R CLL/SLL who started venetoclax treatment between November 2019 and August 2020. Overall, the safety and efficacy analysis sets included 129 and 114 patients, respectively. The overall response rate (ORR) was 57.0%; ORRs were higher in patients with versus without concomitant rituximab (65.4% vs. 54.7%), and in patients with 1 versus ≥ 2 prior lines of therapies (72.5% vs. 44.4%). Adverse events (AEs) were reported in 66.7% of patients (86/129); the most common AEs were neutrophil count decreased (22.5%), white blood cell count decreased (7.8%), and tumor lysis syndrome (TLS; 6.2%). AEs of special interest (TLS, myelosuppression, and infection) were manageable in clinical practice in Japan. Venetoclax is efficacious and safe for R/R CLL/SLL patients in the real-world setting in Japan. ClinicalTrials.gov ID: NCT04198415., (© 2024. The Author(s).)

Abstract: In the CLL14 study, patients with previously untreated chronic lymphocytic leukemia (CLL) and coexisting conditions were randomized to 12 cycles of venetoclax-obinutuzumab (Ven-Obi, n = 216) or chlorambucil-obinutuzumab (Clb-Obi, n = 216). Progression-free survival (PFS) was the primary end point. Key secondary end points included time-to-next-treatment (TTNT), rates of undetectable minimal residual disease (uMRD), overall survival (OS), and rates of adverse events. Patient reported outcomes of time until definitive deterioration (TUDD) in quality of life (QoL) were analyzed. At a median observation time of 76.4 months, PFS remained superior for Ven-Obi compared with Clb-Obi (median, 76.2 vs 36.4 months; hazard ratio [HR], 0.40; 95% confidence interval [CI], 0.31-0.52; P < .0001). Likewise, TTNT was longer after Ven-Obi (6-year TTNT, 65.2% vs 37.1%; HR, 0.44; 95% CI, 0.33-0.58; P < .0001). In the Ven-Obi arm, presence of del(17p), unmutated immunoglobulin heavy-chain variable region, and lymph node size of ≥5 cm were independent prognostic factors for shorter PFS. The 6-year OS rate was 78.7% in the Ven-Obi and 69.2% in the Clb-Obi arm (HR, 0.69; 95% CI, 0.48-1.01; P = .052). A significantly longer TUDD in global health status/QoL was observed in the Ven-Obi than in the Clb-Obi arm (median, 82.1 vs 65.1 months; HR, 0.70; 95% CI, 0.51-0.97). Follow-up-adjusted second primary malignancies incidence rates were 2.3 and 1.4 per 1000 patient-months in the Ven-Obi and Clb-Obi arm, respectively. The sustained long-term survival and QoL benefits support the use of 1-year fixed-duration Ven-Obi in CLL. This trial was registered at www.ClinicalTrials.gov as #NCT02242942., (© 2024 American Society of Hematology. Published by Elsevier Inc. 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.)

Objectives: This is a protocol for a Cochrane Review (intervention). The objectives are as follows: Primary objective: to assess the benefits and harms of currently recommended regimens as the first-line therapy in high-risk people with chronic lymphocytic leukemia, using network meta-analysis Secondary objectives: to assess whether the benefits and harms of the recommended regimens differ according to sex, Rai stage, or genetic mutation status to estimate the ranking of treatments for overall survival, progression-free survival, objective response rate, complete response rate, minimal residual disease, and serious adverse events to estimate the overall rate of adverse events and serious adverse events., (Copyright © 2024 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Antibody-directed targeting of chemotherapeutic nanoparticles to primary human cancers holds promise for improving efficacy and reducing off-target toxicity. However, clinical responses to targeted nanomedicines are highly variable. Herein, we prepared and examined a matrix of 9 particles (organic and inorganic particles of three surface chemistries with and without antibody functionalization) and developed an ex vivo model to study the person-specific targeting of nanoparticles in whole blood of 15 patients with chronic lymphocytic leukemia (CLL). Generally, anti-CD20-functionalized poly(ethylene glycol) (PEG) nanoparticles efficiently targeted CLL cells, leading to low off-target phagocytosis by granulocytes and monocytes in the blood. However, there was up to 164-fold patient-to-patient variability in the CLL targeting. This was further exemplified through using clinically relevant PEGylated doxorubicin-encapsulated liposomes, which showed high interpersonal differences in CLL targeting (up to 234-fold differences) and off-target phagocytosis (up to 65- and 112-fold differences in granulocytes and monocytes, respectively). Off-target phagocytosis led to almost all monocytes being killed within 24 h of treatment. Variance of the off-target association of PEGylated liposomes with granulocytes and monocytes significantly correlated to anti-PEG immunoglobulin G levels in the blood of CLL patients. A negative correlation between CLL targeting of PEG particles and anti-PEG immunoglobulin M levels was found in the blood. Taken together, our study identifies anti-PEG antibodies as key proteins in modulating patient-specific targeting of PEGylated nanoparticles in human leukemia blood. Other factors, such as the antigen expression of targeted cells and fouling properties of nanoparticles, also play an important role in patient-specific targeting. The human leukemia blood assay we developed provides an ex vivo model to evaluate interpersonal variances in response to targeted nanomedicines.

Background: The diffuse large B-cell lymphoma (DLBCL) variant of Richter transformation (DLBCL-RT) is typically chemoresistant with poor prognosis. Aiming to explore a chemotherapy-free treatment combination that triggers anti-tumour immune responses, we conducted a phase 2 study of atezolizumab (a PD-L1 inhibitor) in combination with venetoclax and obinutuzumab in patients with DLBCL-RT., Methods: This was a prospective, open-label, multicentre, single-arm, investigator-initiated, phase 2 study in 15 hospitals in Italy and Switzerland. Eligible patients had a confirmed diagnosis of chronic lymphocytic leukaemia or small lymphocytic lymphoma as per the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria with biopsy-proven transformation to DLBCL; had not previously received treatment for DLBCL-RT, although they could have received chronic lymphocytic leukaemia therapies; were aged 18 years or older; and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. No previous treatment with any of the drugs in the triplet combination was allowed. Patients received 35 cycles of 21 days of intravenous obinutuzumab (100 mg on day 1, 900 mg on day 2, 1000 mg on day 8 and day 15 of cycle 1; 1000 mg on day 1 of cycles 2-8) and intravenous atezolizumab (1200 mg on day 2 of cycle 1 and 1200 mg on day 1 of cycles 2-18), and continuous oral venetoclax (ramp-up from 20 mg/day on day 15 of cycle 1 according to chronic lymphocytic leukaemia schedule, then 400 mg/day from day 1 of cycle 3 to day 21 of cycle 35). The primary endpoint was overall response rate at day 21 of cycle 6 in the intention-to-treat population. We considered an overall response rate of 67% or more to be clinically active, rejecting the null hypothesis of a response of 40% or less. The study is registered with ClinicalTrials.gov, NCT04082897, and has been completed., Findings: Between Oct 9, 2019, and Oct 19, 2022, 28 patients were enrolled (12 [43%] male patients and 16 [57%] female patients). Median follow-up was 16·8 months (IQR 7·8-32·0). At cycle 6, 19 of 28 patients showed a response, yielding an overall response rate of 67·9% (95% CI 47·6-84·1). Treatment-emergent adverse events that were grade 3 or worse were reported in 17 (61%; 95% CI 40·6-78·5) of 28 patients, with neutropenia being the most frequent (11 [39%; 21·5-59·4] of 28 patients). Serious treatment-emergent adverse events were reported in eight (29%; 14·2-48·7) patients, which were most commonly infections (five [18%; 6·1-36·9] of 28 patients). There were two (7%) deaths attributable to adverse events during the study: one from sepsis and one from fungal pneumonia, which were not considered as directly treatment-related by the investigators. Six (21·4%) patients had immune-related adverse events, none of which led to discontinuation. No tumour lysis syndrome was observed., Interpretation: The atezolizumab, venetoclax, and obinutuzumab triplet combination was shown to be active and safe, suggesting that this chemotherapy-free regimen could become a new first-line treatment approach in patients with DLBCL-RT., Funding: Roche., Competing Interests: Declaration of interests AT reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Janssen, Beigene, and Abbvie; support for attending meetings or travel from Abbvie, Janssen, and Beigene; and participation on a data safety monitoring board or advisory board from Janssen, Abbvie, Beigene, Lilly, and AstraZeneca. AMF reports consulting fees from Janssen; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Janssen, Beigene, and AstraZeneca; support for attending meetings or travel from Abbvie, Janssen, Beigene, and AstraZeneca; and participation on a data safety monitoring board or advisory board from Janssen, Beigene, and AstraZeneca. ACo reports grants or contracts from Gilead, BMS, Beigene, Abbvie, Janssen-Cilag, and AstraZeneca; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca, Abbvie, and Janssen-Cilag; support for attending meetings or travel from Janssen; and participation on a data safety monitoring board or advisory board from BMS. MC reports grants or contracts from Johnson & Johnson and Abbvie; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Abbvie and AstraZeneca; support for attending meetings or travel from Johnson & Johnson, Abbvie, and AstraZeneca; and participation on a data safety monitoring board or advisory board from Johnson & Johnson, Abbvie, AstraZeneca, Beigene, and GSK. RC reports support for the present manuscript from the US National Institutes of Health and National Cancer Institute (R01CA196703–01). PLZ reports consulting fees and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Takeda, BMS, MSD, Roche, Gilead, Novartis, Abbvie, Beigene, Kyowa Kirin, and Janssen. MMot reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events; support for attending meetings or travel; and participation on a data safety monitoring board or advisory board from Abbvie, Janssen, and AstraZeneca. GG reports grants from Associazione Italiana per la Ricerca sul Cancro and Piano Nazionale di Ripresa e Resilienza; consulting fees from Abbvie, AstraZeneca, Beiene, Hikma, and Johnson & Johnson; and participation on a data safety monitoring board or advisory board from Abbvie, AstraZeneca, Beigene, Hikma, Johnson & Johnson, and Lilly. LS reports consulting from Abbvie, Beigene, Lilly, AstraZeneca, Janssen, and Merck; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Abbvie, Beigene, Lilly, Octapharma, AstraZeneca, Janssen, and Merck; support for attending meetings or travel from AstraZeneca, Janssen, and Beigene; and participation on a data safety monitoring board or advisory board from Merck. RCa reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Abbvie, Gilead, Gentilipharma, Pierre Fabre, Celgene, and Menarini stemline; support for attending meetings or travel from Pierre Fabre, Beigene, and Servier; and participation on a data safety monitoring board or advisory board from Celgene, Abbvie, Gentilipharma, and Daichi Samkio. TZ report consulting fees and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Roche, Novartis, Gilead, Janssen, AstraZeneca, Lilly, and Abbvie. EZ reports consulting fees from Abbvie, Beigene, BMS, Cures, Elly and Lilly, Incyte, Ipsen, Merck, Miltenyibiomedicine, and Roche; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Abbvie, AstraZeneca, Beigene, and Gilead; support for attending meetings or travel from Abbvie; and participation on a data safety monitoring board or advisory board from Merck. DR reports support for the present manuscript from Adaptive; grants or contracts, consulting fees, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Abbvie, AstraZeneca, Beigene, BMS, Janssen, and Lilly. All other authors declare no competing interests. No honoraria or payments were made for authorship., (Copyright © Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Introduction: In the era of chemo-immunotherapy, high-risk factors unequivocally predicted inferior outcomes for patients with CLL. The widespread adoption of BTK inhibitors has challenged the practical implications of such testing, as many patients have improved outcomes despite the presence of high-risk features. The impact of adverse prognostic factors, such as unmutated IGHV , on survival has been ameliorated by continuous treatment with BTK inhibitors, but not by finite-duration therapy with venetoclax-based combinations. Furthermore, TP53 abnormalities continue to be associated with worse outcomes in the era of novel agents. New treatment modalities, such as pirtobrutinib, lisocabtagene maraleucel, and ongoing studies combining BTK inhibitors with venetoclax, raise new questions on the significance of prognostic factors of survival for patients with CLL., Areas Covered: Herein, we summarized the available literature on patients with CLL harboring high-risk biomarkers, with a focus on data from key clinical trials., Expert Opinion: Testing for prognostic biomarkers will remain relevant to identify patients who may have increased benefit from novel therapeutic strategies, such as combination therapies and novel agents. Patients with high-risk disease should be encouraged to participate in clinical trials.

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) has different epidemiology in Chinese vs. Western patients, but there are few studies of CLL/SLL in large populations of Chinese patients. ALPINE is a global phase 3 trial investigating Bruton tyrosine kinase inhibitors zanubrutinib vs. ibrutinib to treat relapsed/refractory (R/R) CLL/SLL. Here we report results from the subgroup of Chinese patients. Adults with R/R CLL/SLL were randomized 1:1 to receive zanubrutinib (160 mg twice-daily) or ibrutinib (420 mg once-daily) until disease progression or unacceptable toxicity. Endpoints included overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. Data were analyzed descriptively. Ninety patients were randomized in China (zanubrutinib, n = 47; ibrutinib, n = 43). Baseline characteristics were balanced between groups, with fewer male patients in the zanubrutinib vs. ibrutinib group (55.3% vs. 69.8%). Median age was 60.5 years, 11% had del(17p) mutation, and 32% had tumor protein 53 (TP53) mutation. With median 25.3 months follow-up, ORR was 80.9% with zanubrutinib vs. 72.1% with ibrutinib. PFS was improved with zanubrutinib vs. ibrutinib (HR = 0.34 [95% CI, 0.15, 0.77]), and the HR for OS was 0.45 (95% CI, 0.14, 1.50). Rates of Grade ≥ 3 treatment-emergent adverse events (TEAEs; 64.4% vs. 72.1%), AEs leading to discontinuation (6.4% vs. 14.0%), and serious TEAEs (35.6% vs. 51.2%) were lower with zanubrutinib vs. ibrutinib. Zanubrutinib demonstrated improved ORR, PFS, and OS vs. ibrutinib and a more favorable safety profile in patients with R/R CLL/SLL in China. These results are consistent with the full global population of ALPINE. ClinicalTrials.gov: NCT03734016, registered November 7, 2018., (© 2024. The Author(s).)

Objective: The objective was to evaluate the efficacy/safety of pirtobrutinib in the treatment of B-cell malignancies and distinguish it from other available Bruton's tyrosine kinase (BTK) inhibitors., Data Sources: A literature search of PubMed (January 2021 through November 2023) and Clinicaltrials.gov was conducted using terms pirtobrutinib, Jaypirca , and LOXO 305. Licensing trials of available BTK inhibitors were also reviewed., Study Selection and Data Extraction: Relevant English-language clinical trials were evaluated., Data Synthesis: Pirtobrutinib was approved by the US Food and Drug Administration for the treatment of relapsed/refractory mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) based largely on a phase 1/2 study in B-cell malignancies. Pirtobrutinib demonstrated a 73% overall response rate (ORR) in the CLL population and 58% in MCL. Pirtobrutinib has activity in patients resistant to earlier-generation, covalent BTK inhibitors. In fact, the ORRs were similar in BTK-pretreated and naïve patients. Adverse effects include fatigue, diarrhea, bleeding, and infection. Atrial fibrillation, a class effect of BTK inhibitors, may be less common with pirtobrutinib., Relevance to Patient Care and Clinical Practice in Comparison With Existing Drugs: Compared with earlier-generation BTK inhibitors, pirtobrutinib is more selective for BTK and binds noncovalently to the receptor. Ongoing studies are evaluating pirtobrutinib's use in multiple B-cell malignancies and comparing it with other BTK inhibitors., Conclusion: The characteristics of pirtobrutinib render it useful in the treatment of B-cell malignancies no longer responding to a previous BTK inhibitor, and results from ongoing clinical trials may support future expanded use., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The treatment of CLL has evolved from traditional chemoimmunotherapy (CIT) to an increasing number of targeted and biologic approaches. Randomized trials have demonstrated superiority of covalent bruton tyrosine kinase inhibitors (cBTKis) over CIT, and second-generation compounds such as acalabrutinib and zanubrutinib appear to have a more favorable efficacy/safety profile than ibrutinib. The noncovalent BTKi, pirtobrutinib, has shown impressive activity after failure of the cBTKis and is quite tolerable. The Bcl-2 inhibitor venetoclax plus a CD20, generally obinutuzumab, provides a high level of efficacy as initial treatment or after failure on a cBTKi, with many patients achieving a state of undetectable minimal residual disease. Promising novel approaches include BTK degraders, bispecific antibodies, and chimeric antigen receptor T-cell (CAR-T)-cell therapy. What is clear is that CIT is archaic, and current and future targeted approaches will continue to improve the outcome for patients with chronic lymphocytic leukemia.

Background: Bruton's tyrosine kinase inhibitors (BTKis) and the BCL-2 inhibitor venetoclax in combination with obinutuzumab (VEN-O) are both recommended as frontline therapy in chronic lymphocytic leukemia (CLL). However, VEN-O is a 12-month fixed-duration therapy generating durable remissions whereas BTKis are continuous treat-to-progression treatments., Objective: To examine costs before and after the fixed-duration treatment period for VEN-O relative to that observed for BTKis in a national sample of older US adults with CLL in the frontline setting., Methods: This retrospective analysis used Medicare Parts A, B, and D claims from 2016 to 2021. Fee-for-service Medicare beneficiaries aged 66 years or older initiating frontline CLL treatment with VEN-O or a BTKi treatment between June 1, 2019, and June 30, 2020 (index date = first prescription fill date), were included in the sample. Mean cost measures were captured for both groups over 2 fixed time periods calculated from the index date: Month 0 to 12 (proxy for VEN-O on-treatment period) and Month 13 to 18 (proxy for VEN-O off-treatment period). A difference-in-difference approach was used. Multivariate generalized linear models estimated changes in adjusted mean monthly costs during Month 0 to 12 vs Month 13 to 18, for the VEN-O group relative to the BTKi group., Results: The final sample contained 193 beneficiaries treated with VEN-O and 1,577 beneficiaries treated with BTKis. Risk-adjusted all-cause monthly total costs were similar for VEN-O patients ($13,887) and BTKi patients ($14,492) between Month 0 and 12. Moreover, during Month 13 to 18, the mean monthly all-cause total costs declined by 67% for VEN-O ($13,887 to $4,462) but only by 10% for BTKi ($14,492 to $13,051). Hence, the relative reduction in costs across the 2 periods was significantly larger for VEN-O (-$9,425) vs BTKi (-$1,441) patients (ie, difference in difference = -$7,984; P < 0.001). Similar patterns were observed for CLL-related costs, with the substantially larger reductions in CLL-related total monthly costs (-$9,880 VEN-O vs -$1,753 BTKi; P < 0.001) for the VEN-O group primarily driven by the larger reduction in CLL-related monthly prescription costs (-$9,437 VEN-O vs -$2,020 BTKi; P < 0.001)., Conclusions: This real-world study of older adults with CLL found a large reduction in monthly Medicare costs in the 6 months after completion of the fixed-duration treatment period of VEN-O, largely driven by the reduction in CLL-related prescription drug costs. A similar decline in costs was not observed among those treated with BTKis. Our study highlights the substantial economic benefits of fixed-duration VEN-O relative to treat-to-progression therapies like BTKis in the first-line CLL setting.

Lenalidomide (LEN) and rituximab (RTX) have independently improved progression-free survival (PFS) in CLL, leading to interest in use of LEN + RTX (R2) following induction chemoimmunotherapy. Patients with previously untreated CLL received bendamustine + RTX (BR) for 6 cycles, then 24 cycles of R2. LEN dosing was 5-10 mg daily; RTX was given odd cycles (12 doses). The primary endpoint is PFS; secondary endpoints are response and overall survival. Thirty-six patients enrolled, median age 64.5 years. Twenty-nine received R2; 12 completed a full course R2 (33.3%), 5 completed R2 with premature discontinuation of LEN. Dose reductions/holds were most often for neutropenia. Complete response was achieved in 33.3%. After median >4 years follow-up, 2-year and 3-year PFS were 86.1% and 69.4%. Five-year overall survival was 92.3%. R2 maintenance may improve PFS after BR induction, and a lower dose of 5 mg/day and ≤1 year of R2 may be most tolerable (NCT00974233).

Background: Immunodeficiency is a shared feature of B cell malignancies. The risk of infections and their prognostic significance after diagnosis are well characterized, but, conversely, less is known about prediagnostic infections in these domains., Methods: In matched case-control analyzes, using Danish nationwide registers, we assessed the rate of prediagnostic infections in chronic lymphocytic leukemia (CLL), diffuse large B cell lymphoma (DLBCL), multiple myeloma (MM), follicular lymphoma (FL), marginal zone lymphoma (MZL), and lymphoplasmacytic lymphoma (LPL). Survival analyzes of data from clinical registers were then used to determine the effect of infections in the year preceding diagnosis on overall survival. To yield results for as many patients as possible, antimicrobial prescriptions were used as surrogates for infections., Results: The nationwide and clinical registers comprised 30,389 patients, accumulating 213,649 antimicrobial prescriptions, and 18,560 patients accumulating 107,268 prescriptions, respectively. The relative risk of infections was increased up to 15 years prior to diagnosis of malignancy and markedly increased in the year just prior to diagnosis. More than two antimicrobials within one year prior to diagnosis were associated with significantly shorter overall survival, independently of known prognostic factors., Conclusion: Patients with B cell-derived malignancies exhibit marked immunodeficiency several years prior to diagnosis such that different disease subtypes demonstrate both overlapping and distinct trends in infection risk preceding diagnosis. Moreover, multiple infections within the year preceding diagnosis are independently associated with shorter overall survival for all the examined malignancies., (© 2024. The Author(s).)

Despite significant progress in treating chronic lymphocytic leukaemia (CLL), resistance to therapy remains challenging. NOTCH1 activation, common in CLL, confers adverse prognosis. This study explores the impact of NOTCH1 signalling on venetoclax sensitivity in vitro. Although NOTCH1 activation minimally impaired the susceptibility of CLL cells to venetoclax, ex vivo cell competition studies reveal that cells with constitutive NOTCH1 activation outgrew their wild-type counterparts in the presence of ongoing venetoclax exposure. Our findings suggest that while NOTCH1 activation is insufficient to confer venetoclax refractoriness, there is enhanced potential for cells with NOTCH1 activation to escape and thus become fully resistant to venetoclax., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

The management of small lymphocytic lymphoma (SLL) as chronic lymphocytic leukemia (CLL) or an indolent non-Hodgkin lymphoma is highly debated. In this single-center, real-life study, 38 SLL patients managed between 2008 and 2022 were evaluated. Overall, 26/38 cases (68.4%) needed treatment and all but one received CLL concordant therapy, including BR (9/38 cases), fludarabine, cyclophosphamide, rituximab (5/38 cases), rituximab and chlorambucil (4/38 cases), BTK inhibitors (7/38 cases) and steroid (1 case with immune thrombocytopenia). Patients treated between 2008 and 2018 were more likely to receive chemoimmunotherapy compared to patients treated in 2019-2022, that were more likely to receive BTK inhibitors. The median PFS was 54 months and 3-y PFS was 58%, while the median OS was not reached, with a 3-y OS of 84%. We confirm a wide heterogeneity in SLL management and we suggest prospective studies are needed to improve the knowledge of its biology and harmonize its treatment.

Real-world evidence comparing clinical outcomes between venetoclax and Bruton tyrosine kinase inhibitors (BTKis) in patients with frontline (1 L) chronic lymphocytic leukaemia (CLL) is lacking. We compared treatment effectiveness of 1 L venetoclax plus obinutuzumab (VenO) versus BTKi-based regimens. This retrospective observational study using Optum Clinformatics Data Mart® included adult patients with CLL (≥2 outpatient or ≥1 inpatient claim) who received VenO or BTKi-based regimens in 1 L (1/2019-9/2022). Baseline characteristics were balanced using stabilised inverse probability weighting. Outcomes included duration of therapy (DoT), persistence, time to next treatment or death (TTNT-D), and time off-treatment. Among 1506 eligible patients (VenO: 203; BTKi: 1303), the median follow-up duration was 12.6 (VenO) and 16.2 months (BTKi). Median DoT for VenO was 12.3 months; persistence remained higher in VenO versus BTKi through expected 1 L fixed treatment duration. Median TTNT-D was not reached for VenO; however, more VenO- versus BTKi-treated patients had not switched therapies/experienced death through Month 12 (87.1% vs. 75.3%). Among patients that discontinued, median time to discontinuation was 11.7 vs. 5.9 months for VenO versus BTKi and median time off-treatment was 11.3 vs. 4.3 months. In this real-world study, VenO was associated with better effectiveness outcomes than BTKi-based regimens in 1 L CLL., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Introduction: Bruton's tyrosine kinaseinhibitors (BTKis) changed the trajectory of upfront and relapsed/refractory chronic lymphocytic leukemia (CLL) treatment. However, BTKis are plagued by a spectrum of toxicities. Zanubrutinib was developed to circumvent challenges with prolonged tolerability by increasing BTK selectivity and maximizing efficacy through pharmacokinetic/pharmacodynamic optimization. However, with the availability of ibrutinib, acalabrutinib, and zanubrutinib, limited data exists to guide sequencing of BTKi therapy in the relapsed/refractory setting., Areas Covered: We review the first head-to-head trial (ALPINE) of zanubrutinib versus ibrutinib for the treatment of relapsed/refractory CLL and compare zanubrutinib's clinical efficacy and toxicities, including in patients with del(17p) and/or TP53 mutations to ibrutinib and acalabrutinib., Expert Opinion: Zanubrutinibrepresents one of the new standards of care for relapsed/refractory CLL based on superior progression-free survival and response rates over ibrutinib. Whilezanubrutinib is associated with fewer cardiac toxicities, similar rates of neutropenia and hypertension are noted. Ongoing studies are pushing the envelope, utilizing targeted drug combinations and minimal residual disease markers as well as receptor tyrosine kinase-like orphan receptor 1 inhibitors, chimeric antigen receptor T-cells, and novel BTK degraders. However, zanubrutinibrepresents a strong contender in the arsenal of treatment options for relapsed/refractory CLL.

Objective: To investigate the frequency and clinical features of intraocular paraneoplastic sarcoid-like reaction (SLR) in patients with chronic lymphocytic leukemia (CLL)., Methods: Retrospective review of patients with CLL from January 1, 1980, to December 31, 2020. Eye examinations were searched for 22 keywords suggestive of SLR, and charts were manually reviewed., Results: Of 4209 unique patients with CLL, 1021 (24%) had at least 1 eye examination on record, and 324 (8%) had 1 or more keyword eye examination findings. After manual review, 12 patients (<1%) were identified as having probable SLR with characteristic features (n = 7), possible but not classic (n = 1), or suspect but less likely (n = 4). All patients (n = 8) with probable or possible SLR were White, and half (n = 4) were male. Intraocular SLR was diagnosed a mean of 49.7 months after the CLL diagnosis (n = 7) or preceded the CLL diagnosis by 1 month (n = 1). Involvement was bilateral in 5 patients, with 13 total affected eyes and mean presenting Snellen visual acuity of 20/50. Common characteristic features on initial examination included vitreous cell (n = 13), anterior-chamber cell (n = 10), keratic precipitates (n = 9), posterior synechiae (n = 6), chorioretinal lesions (n = 5), and vitreous haze (n = 5). Treatment included topical corticosteroids alone (n = 5), with sub-Tenon corticosteroids (n = 1), or with steroid-sparing immunosuppressive agents (n = 1) or oral corticosteroids alone (n = 1). After a mean follow-up of 19.8 months, final mean visual acuity was 20/30., Conclusion: Intraocular SLRs affect fewer than 1% of patients with CLL. SLR should be on the differential diagnosis list for any CLL patient with ocular complaints, and most patients can be managed successfully with corticosteroids., (Copyright © 2023 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved.)

Abstract: Pirtobrutinib is a highly selective, noncovalent (reversible) Bruton tyrosine kinase inhibitor (BTKi). Patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) were treated with fixed-duration pirtobrutinib plus venetoclax (PV) or pirtobrutinib plus venetoclax and rituximab (PVR) in this phase 1b trial. Prior covalent BTKi therapy was allowed, but not prior treatment with venetoclax. Patients were assigned to receive PV (n = 15) or PVR (n = 10) for 25 cycles. Most patients (68%) had received prior covalent BTKi therapy. At the data cutoff date, the median time on study was 27.0 months for PV and 23.3 months for PVR. Overall response rates were 93.3% (95% confidence interval [CI], 68.1-99.8) for PV and 100% (95% CI, 69.2-100.0) for PVR, with 10 complete responses (PV: 7; PVR: 3). After 12 cycles of treatment, 85.7% (95% CI, 57.2-98.2) of PV and 90.0% (95% CI, 55.5-99.7) of PVR patients achieved undetectable minimal residual disease (<10-4) in peripheral blood. Progression-free survival at 18 months was 92.9% (95% CI, 59.1-99.0) for PV patients and 80.0% (95% CI, 40.9-94.6) for PVR patients. No dose-limiting toxicities were observed during the 5-week assessment period. The most common grade ≥3 adverse events (AEs) for all patients included neutropenia (52%) and anemia (16%). AEs led to dose reduction in 3 patients and discontinuation in 2. In conclusion, fixed-duration PV or PVR was well tolerated and had promising efficacy in patients with R/R CLL, including patients previously treated with a covalent BTKi. This trial was registered at www.clinicaltrials.gov as #NCT03740529., (© 2024 American Society of Hematology. Published by Elsevier Inc. 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.)

Abstract: Covalent Bruton tyrosine kinase inhibitors (cBTKis), which bind to the BTK C481 residue, are now primary therapeutics for chronic lymphocytic leukemia (CLL). Alterations at C481, primarily C481S, prevent cBTKi binding and lead to the emergence of resistant clones. Pirtobrutinib is a noncovalent BTKi that binds to both wild-type (WT) and C481S-mutated BTK and has shown efficacy in BTK-WT and -mutated CLL patient groups. To compare baseline clinical, transcriptomic, and proteomic characteristics and their changes during treatment in these 2 groups, we used 67 longitudinal peripheral blood samples obtained during the first 3 cycles of treatment with pirtobrutinib from 18 patients with CLL (11 BTK-mutated, 7 BTK-WT) enrolled in the BRUIN (pirtobrutinib in relapsed or refractory B-cell malignancies) trial. Eastern Cooperative Oncology Group performance status, age, and Rai stage were similar in both groups. At baseline, lymph nodes were larger in the BTK-mutated cohort. All patients achieved partial remission within 4 cycles of pirtobrutinib. Lactate dehydrogenase and β2-microglobulin levels decreased in both cohorts after 1 treatment cycle. Expression analysis demonstrated upregulation of 35 genes and downregulation of 6 in the BTK-mutated group. Gene set enrichment analysis revealed that the primary pathways enriched in BTK-mutated cells were involved in cell proliferation, metabolism, and stress response. Pathways associated with metabolism and proliferation were downregulated in both groups during pirtobrutinib treatment. Proteomic data corroborated transcriptomic findings. Our data identified inherent differences between BTK-mutated and -WT CLL and demonstrated molecular normalization of plasma and omics parameters with pirtobrutinib treatment in both groups., (© 2024 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.)

Abstract: Chronic lymphocytic leukemia (CLL) progression during Bruton tyrosine kinase (BTK) inhibitor treatment is typically characterized by emergent B-cell receptor pathway mutations. Using peripheral blood samples from patients with relapsed/refractory CLL in ELEVATE-RR (NCT02477696; median 2 prior therapies), we report clonal evolution data for patients progressing on acalabrutinib or ibrutinib (median follow-up, 41 months). Paired (baseline and progression) samples were available for 47 (excluding 1 Richter) acalabrutinib-treated and 30 (excluding 6 Richter) ibrutinib-treated patients. At progression, emergent BTK mutations were observed in 31 acalabrutinib-treated (66%) and 11 ibrutinib-treated patients (37%; median variant allele fraction [VAF], 16.1% vs 15.6%, respectively). BTK C481S mutations were most common in both groups; T474I (n = 9; 8 co-occurring with C481) and the novel E41V mutation within the pleckstrin homology domain of BTK (n = 1) occurred with acalabrutinib, whereas neither mutation occurred with ibrutinib. L528W and A428D comutations presented in 1 ibrutinib-treated patient. Preexisting TP53 mutations were present in 25 acalabrutinib-treated (53.2%) and 16 ibrutinib-treated patients (53.3%) at screening. Emergent TP53 mutations occurred with acalabrutinib and ibrutinib (13% vs 7%; median VAF, 6.0% vs 37.3%, respectively). Six acalabrutinib-treated patients and 1 ibrutinib-treated patient had emergent TP53/BTK comutations. Emergent PLCG2 mutations occurred in 3 acalabrutinib-treated (6%) and 6 ibrutinib-treated patients (20%). One acalabrutinib-treated patient and 4 ibrutinib-treated patients had emergent BTK/PLCG2 comutations. Although common BTK C481 mutations were observed with both treatments, patterns of mutation and comutation frequency, mutation VAF, and uncommon BTK variants varied with acalabrutinib (T474I and E41V) and ibrutinib (L528W and A428D) in this patient population. The trial was registered at www.clinicaltrials.gov as #NCT02477696., (© 2024 American Society of Hematology. Published by Elsevier Inc. 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.)

Patients on B cell immunosuppressive treatments have been shown to have persistent infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this report, a woman treated with ibrutinib for chronic lymphocytic leukemia experienced more than 40 days of coronavirus disease 2019 (COVID-19) infection. Unexpectedly, her peripheral blood experiments showed a normal SARS-CoV-2-specific antibody level and a relatively elevated percentage of CD19 + B cells, while an obvious decrease in the percentages of NK cells, CD4 + T cells and CD8 + T cells. Further SARS-CoV-2-specific T cell analysis in this patient indicated a significant decrease in the percentage of SARS-CoV-2-specific IFN-γ, TNF-α or IL-2 producing CD4 + T or CD8 + T cells. Most notably, ten days after the cease of ibrutinib, the PCR for SARS-CoV-2 turned negative and the reduced proportions of peripheral CD4 + T cells and CD8 + T cells recovered. Our research predicted that the depleted B-cell function therapies may play considerable role in the development of long COVID-19 and the abnormal T-cell subset distribution might be the underlying mechanism., (© 2024. The Author(s).)

Background: Bruton's tyrosine kinase inhibitors (BTKi) and the B-cell lymphoma 2 (BCL2) inhibitor venetoclax have significantly improved outcomes and achieved durable remission in patients with chronic lymphocytic leukemia (CLL). BTKi/venetoclax-treated patients with exposure to both novel agents (regardless of the reason for discontinuation) are classified as "double-exposed," and often have poor prognoses. This study aims to assess the efficacy and effectiveness of treatments in double-exposed CLL patients., Methods: PubMed, Embase, and Web of Science databases were searched until December 2023., Results: We retrieved 3948 articles for screening and included 13 publications covering nine distinct studies. Three clinical trials reported a median PFS of 16.8 months with pirtobrutinib, 13 months with lisocabtagene maraleucel, and 10.1 months with nemtabrutnib. ORR ranged from 58% with nemtabrutinib and 80% with lisocabtagene maraleucel. In observational studies, PFS ranged from 3 months with chemoimmunotherapy to 12 months with BTKi, and ORR ranged from 31.8% with chemoimmunotherapy to 85.7% with chimeric antigen receptors (CAR) T-cell therapy., Conclusion: This study highlights the limited clinical data on efficacy outcomes for double-exposed CLL/SLL patients. Pirtobrutinib, lisocabtagene maraleucel, and a combination of ibrutinib and venetoclax have shown promising effects. However, the scarcity of treatment options and efficacy data for patients who have failed BTKi and venetoclax underscores a significant unmet medical need., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Introduction: Chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), characterized by its monoclonal lymphoproliferative nature, is an indolent but incurable malignancy. The treatment landscape of CLL/SLL has drastically transformed in the last decade since the introduction of targeted therapy and immune-effector T-cell therapy. The paradigm shift from chemoimmunotherapy to targeted and cellular therapies was largely driven by improved efficacy and safety. With the success of targeted therapies, novel agents and combinations are rapidly emerging on the horizon., Areas Covered: In this review, we will summarize clinical evidence supporting current and emerging therapies with emphasis on investigational therapies and novel combinations of commercial agents. Clinical trials were identified via clinicaltrials.gov, and a PubMed literature search was last performed in June 2024., Expert Opinion: With the availability of more effective and better-tolerated treatments for CLL/SLL, the role of early intervention should be further investigated due to its potential to alter disease course, delay progression, and improve overall survival rates. With many highly effective agents and combinations expected to become commercially available, attention to safety profiles and careful selection of patients for each treatment will be critical, with consideration of comorbidities, logistical issues, and financial burden of treatment.

Circular RNAs (circRNAs) are single-stranded RNAs that have received much attention in recent years. CircRNAs lack a 5' head and a 3' poly-A tail. The structure of this type of RNAs make them resistant to digestion by exonucleases. CircRNAs are expressed in different cells and have various functions. The function of circRNAs is done by sponging miRNAs, changing gene expression, and protein production. The expression of circRNAs changes in different types of cancers, which causes changes in cell growth, proliferation, differentiation, and apoptosis. Changes in the expression of circRNAs can cause the invasion and progression of tumors. Studies have shown that changes in the expression of circRNAs can be seen in acute lymphoid leukemia (ALL) and chronic lymphoid leukemia (CLL). The conducted studies aim to identify circRNAs whose expression has changed in these leukemias and their more precise function so that these circRNAs can be identified as biomarkers, prediction of patient prognosis, and treatment targets for ALL and CLL patients. In this study, we review the studies conducted on the role and function of circRNAs in ALL and CLL patients. The results of the studies show that there is a possibility of using circRNAs as biomarkers in the identification and treatment of patients in the future., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Richter transformation usually presents as an aggressive diffuse large B-cell lymphoma, occurs in up to 10% of patients with chronic lymphocytic leukaemia, has no approved therapies, and is associated with a poor prognosis. Pirtobrutinib has shown promising efficacy and tolerability in patients with relapsed or refractory B-cell malignancies, including those who progress on covalent Bruton tyrosine kinase (BTK) inhibitors. This study aims to report the safety and activity of pirtobrutinib monotherapy in a subgroup of patients with Richter transformation from the multicentre, open-label, phase 1/2 BRUIN study., Methods: This analysis included adult patients (aged ≥18 years) with histologically confirmed Richter transformation, an Eastern Cooperative Oncology Group performance status score of 0-2, and no limit of previous therapies, with patients receiving first-line treatment added in a protocol amendment (version 9.0, Dec 15, 2021). Pirtobrutinib 200 mg was administered orally once a day in 28-day cycles. The primary endpoint of phase 1 of the BRUIN trial as a whole, which has been previously reported, was to establish the recommended phase 2 dose for pirtobrutinib monotherapy and the phase 2 primary endpoint was overall response rate. Safety and activity were measured in all patients who received at least one dose of pirtobrutinib monotherapy. This BRUIN phase 1/2 trial was registered with ClinicalTrials.gov and is closed to enrolment (NCT03740529)., Findings: Between Dec 26, 2019, and July 22, 2022, 82 patients were enrolled, of whom five were enrolled during phase 1 and 77 during phase 2. All but one patient received a starting dose of 200 mg pirtobrutinib once a day as the recommended phase 2 dose. The remaining patient received 150 mg pirtobrutinib once a day, which was not escalated to 200 mg. The median age of patients was 67 years (IQR 59-72). 55 (67%) of 82 patients were male and 27 (33%) were female. Most patients were White (65 [79%] of 82). 74 (90%) of 82 patients received at least one previous Richter transformation-directed therapy. Most patients (61 [74%] of 82) had received previous covalent BTK inhibitor therapy for chronic lymphocytic leukaemia or Richter transformation. The overall response rate was 50·0% (95% CI 38·7-61·3). 11 (13%) of 82 patients had a complete response and 30 (37%) of 82 patients had a partial response. Eight patients with ongoing response electively discontinued pirtobrutinib to undergo stem-cell transplantation. The most common grade 3 or worse adverse event was neutropenia (n=19). There were no treatment-related deaths., Interpretation: Pirtobrutinib shows promising safety and activity among patients with Richter transformation, most of whom received previous Richter transformation-directed therapy, including covalent BTK inhibitors. These data suggest that further investigation is warranted of pirtobrutinib as a treatment option for patients with relapsed or refractory Richter transformation after treatment with a covalent BTK inhibitor., Funding: Loxo Oncology., Competing Interests: Declaration of interests WGW reports research funding from Numab Therapeutics, Loxo Oncology–Lilly, Janssens Biotech, NIH P30 CA016672/MDACC Cancer Center Support Grant, GlaxoSmithKline, AbbVie, Cyclacel, Nurix Therapeutics, Juno Therapeutics, Bristol Myers Squibb (Juno & Celgene), AstraZeneca–Acerta Pharma Miragen, Oncternal Therapeutics, Janssens Biotech, Accutar Biotechnology, Sunesis, KITE Pharma, Gilead Sciences, Genentech, Pharmacyclics, GlaxoSmithKline–Novartis; consultancy fees from AbbVie, Cyclacel Nurix Therapeutics, Bristol Myers Squibb (Juno & Celgene), AstraZeneca–Acerta Pharma; a non-relevant financial relationship with the National Comprehensive Cancer Network; support from the National Institutes of Health and National Cancer Institute under award number P30 CA016672; and use of MDACC Cancer Center Support Grant shared resources. NNS reports consultancy fees from Umoja, Janssen, Bristol Myers Squibb–Juno, LOXO Oncology–Lilly, TG therapeutic, Novartis, Seattle Genetics, Gilead–Kite, Incyte, AbbVie, Lilly Oncology, and Miltenyi Biotec; research funding from Miltenyi Biotec and Lilly Oncology; having stock options in a privately-held company with Tundra Therapeutics; and travel support from Epizyme and Miltenyi Biotec. CYC reports consultancy fees, honoraria, and having an advisory role for Roche, Janssen, Gilead, AstraZenecca, Eli Lilly, BeiGene, AbbVie, Menarini, Daizai, and Genmab, and research funding from Roche, MSD, Eli Lilly, Bristol Myers Squibb, and AbbVie. DL reports consultancy fees from Kite, BeiGene, Roche, Eli Lilly, and Janssen and membership on an entity's board of directors or advisory committees with Kite, BeiGene, Roche, Eli Lilly, and Janssen. MSH reports consultancy fees and honoraria from Pharmacyclics. CCC reports consultancy fees from LOXO Oncology–Eli Lilly, BeiGene, AstraZeneca, Genentech, AbbVie, Octapharma, Allogene, Janssen, TG Therapeutics, MEI Pharma, and Mingsight; honoraria from LOXO Oncology–Eli Lilly, BeiGene, AstraZeneca, Genentech, AbbVie; research funding paid to an institution from LOXO Oncology–Eli Lilly, AbbVie, and CarnaBio; membership on an entity's board of directors or advisory committees with BeiGene, AstraZeneca, Genentech, and AbbVie; being an equity holder in a publicly-traded company with Bluebird Bio, Geron, and Pfizer; and receiving travel support from LOXO Oncology–Eli Lilly. NL reports consultancy fees from Genentech, Pharmacyclics, BeiGene, AstraZeneca, AbbVie, Adaptive Biotechnologies, Janssen, and research funding from Genentech, TG Therapeutics, BeiGene, AstraZeneca, AbbVie, MingSight, LOXO Oncology–Eli Lilly, Oncternal, and Octapharma. SM reports consultancy fees from AstraZeneca, Juno–Bristol Myers Squibb, AbbVie, Genentech, Janssen Pharmaceuticals, BeiGene; membership on a board of directors or advisory committee with AstraZeneca, Juno–Bristol Myers Squibb, Janssen Pharmaceuticals, Eli Lilly, Loxo Oncology, and BeiGene; research funding from AstraZeneca, Juno–Bristol Myers Squibb, AbbVie, Janssen Pharmaceuticals, Eli Lilly–Loxo Oncology, BeiGene; and speakers bureau with AstraZeneca, Eli Lilly–Loxo Oncology, and BeiGene. DJ reports research funding from Seagen, Trillium Pharmaceuticals, Regeneron Pharmaceuticals, MEI Pharma, Loxo Oncology, Debio Pharma, ATARA Biotherapeutics, AstraZeneca and membership on a board of directors or advisory committees with Affimed and Daiichi Sankyo. TM reports consultancy fees from BeiGene, Alexion, Sobi, Roche, AstraZeneca, Janssen, and AbbVie; honoraria from BeiGene, Alexion, Sobi, Roche, AstraZeneca, Janssen, and AbbVie; membership on a board of directors or advisory committees on BeiGene, Alexion, Sobi, Roche, AstraZeneca, Janssen, Abbvie; research Funding from Janssen, AbbVie; and speakers bureau for BeiGene, Alexion, Sobi, Roche, AstraZeneca, Janssen, and AbbVie. YW reports research funding from Incyte, InnoCare, LOXO Oncology, Eli Lilly, MorphoSys, Novartis, Genentech, Genmab, and AbbVie; membership on an advisory board with Eli Lilly, LOXO Oncology, TG Therapeutics, Incyte, InnoCare, Kite, Jansen, BeiGene, AstraZeneca, and Genmab; consultancy fees from Innocare and AbbVie; and honoraria from Kite. TAE reports membership on an entity's Board of Directors or advisory committees from Loxo Oncology, Incyte, BeiGene, AstraZeneca, KITE, AbbVie, Roche, Gilead, Secura Bio; speakers bureau from Loxo Oncology, Eli Lilly, Incyte, BeiGene, AstraZeneca, KITE, AbbVie, Loxo Oncology, Roche, Medscape, Janssen, Gilead, PeerView; research funding from BeiGene and AstraZeneca; consultancy fees from Eli Lilly, Incyte, Beigene, Autolus, AstraZeneca, KITE, AbbVie, Loxo Oncology, Roche, Janssen, and Gilead; and honoraria from Eli Lilly, BeiGene, AstraZeneca, KITE, AbbVie, Loxo Oncology, Roche, Janssen, and Gilead. JMR reports consultancy fees from Pharmacyclics, Jannsen, Genentech, GenMab, AstraZeneca, Morphosys, ADC Therapeutics, Epizyme, BeiGene, and AbbVie; research funding from Pharmacyclics, Velosbio, Loxo Oncology, Acerta, Oncternal Pharmaceuticals, Epizyme, and AbbVie; and honoraria from SeaGen. MM reports consultancy from Bayer, ADC therapeutics, Epizyme, Genentech, F Hoffmann-La Roche, and Incyte; research funding from BeiGene, Janssen, F Hoffmann-La Roche– Genentech, Celgene–Bristol Myers Squibb, and Incyte; and speakers bureau with ADC therapeutics, BeiGene, and Kite–Gilead. CT reports honoraria from Loxo Oncolgy. WJ reports consultancy fees from AbbVie, AstraZeneca, BeiGene, Eli Lilly, Pfizer, Roche, SOBI, and Takeda and research funding from AbbVie, AstraZeneca, Bayer, BeiGene, Celgene, Janssen, Eli Lilly, Roche, SOBIm, and Takeda. KI reports honoraria from Eli Lilly, SymBio Pharmaceuticals, Meiji Seika, Nihon Kayaku, Takeda, AstraZeneca, Janssen, Genmab, MSD, Pfizer, AbbVie, Ono Pharmaceuticals, Daiichi Sankyo, Novartis, Bristol Myers Squibb, Chugai Pharma, and Kyowa Kirin; consultancy fees from Takeda, AstraZeneca, Genmab, AbbVie, Otsuka, Eisai, Ono Pharmaceuticals, Nippon Shinyaku, Mitsubishi Tanabe Pharma, and Zenyaku Kogyo; and research funding from AstraZeneca, Genmab, MSD, Pfizer, AbbVie, Otsuka, Eisai, Regeneron, Loxo Oncology, BeiGene, Daiichi Sankyo, Yakult, Novartis, Bristol Myers Squibb, Incyte, Astellas Amgen, Chugai Pharma, Kyowa Kirin. AA reports membership on a board of directors or advisory committees with Genentech, Eli Lilly and Company, Amgen, TG Therapeutics, Incyte, BeiGene, Epizyme, Janssen, and SeaGen; research funding from Eli Lilly, Incyte, and BeiGene; and honoraria from Dr Reddy. MP reports consulting fees from Kura, Accutar, Mitsubishi; participating on a data safety monitoring board or advisory board with lema, Nurix, Daiichi, Kura, and Janssen; leadership with ION Pharma; honoraria from Janssen Oncology; and participating in a consulting or advisory role with Olema Pharmaceuticals, Daiichi Sankyo–UCB Japan, Kura Oncology, Accutar Biotech, and Kura. JFS reports honoraria from Hoffmann-La Roche, AbbVie, AstraZeneca, Janssen, Bristol Myers Squibb, Gilead, and BeiGene; consultancy fees from Hoffmann-La Roche, TG Therapeutics, Bristol Myers Squibb; participating on a data safety monitoring board or advisory board with Genor Bio, Hoffmann-La Roche, AbbVie, AstraZeneca, Janssen, Bristol Myers Squibb, Gilead, and BeiGene; speakers bureau with Hoffmann-La Roche, AbbVie, and BeiGene; and research funding from F Hoffmann-La Roche and AbbVie. JAW reports consultancy from Newave, Loxo Oncology, BeiGene, AstraZeneca, AbbVie, Janssen, and Pharmacyclics and research funding from Schrodinger, Morphosys, Karyopharm, Janssen, and Pharmacyclics. PAT reports consultancy and honoraria from AbbVie, Adaptive Biotechnologies, Ascentage AstraZeneca, BeiGene, Genentech, Genmab, Janssen, Lilly, Merck, Pharmacyclics; speakers bureau from AbbVie, Adaptive Biotechnologies, AstraZeneca, Janssen, and Merck; research funding from AbbVie, Pharmacyclics, Genentech, Lilly, and Adaptive Biotechnologies; and travel support from Merck. PA is a current employee of and equity holder in Eli Lilly. CH reports being an equity holder in Eli Lilly and Foundation Medicine and travel support from Eli Lilly. SCM reports current employment with, being an equity holder in, and travel support from Eli Lilly. NM reports being a current equity holder in Eli Lilly and current employment with Loxo Oncology. BN, CW, BCN, and DET reports current employment with and current equity holder in Eli Lilly. ASR reports current employment with and being equity holder in Eli Lilly and consultancy work with Telios Pharma. HL reports current employment with Loxo Oncology. LER reports serving as a consultant for AbbVie, Ascentage, AstraZeneca, BeiGene, Janssen, Loxo Oncology, Pharmacyclics, Pfizer, and TG Therapeutics; membership of a data safety monitoring committee for Ascentage; serving as a CME speaker for DAVA, Curio, Medscape, and PeerView; holding minority ownership interest in Abbott Laboratories; having received travel support from LOXO Oncology; and having received research funding (paid to the institution) from Adaptive Biotechnologies, AstraZeneca, Genentech, AbbVie, Pfizer, Loxo Oncology, Aptose Biosciences, Dren Bio, and Qilu Puget Sound Biotherapeutics. PG reports consultancy, fees, honoraria, and research funding from Janssen, Eli Lilly–Loxo Oncology, MSD, Roche, AbbVie, BMS, BeiGene, and AstraZeneca., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Eosinophilic dermatosis of hematologic malignancy (EDHM) is a cutaneous manifestation seen in patients with hematoproliferative and lymphoproliferative disorders, most commonly chronic lymphocytic leukemia. This systematic review aimed to summarize the therapeutic interventions of EDHM. A comprehensive search yielded 71 studies, predominantly case reports and series. The most frequently reported modalities were systemic and topical corticosteroids, as well as treatment of the underlying malignancy. Responses to these treatments varied. Targeted therapies, including dupilumab and omalizumab, showed promise, as did other modalities such as montelukast, dapsone, doxycycline, and phototherapy. Higher-quality studies should be conducted to facilitate higher-quality management recommendations for EDHM., (© 2024 the International Society of Dermatology.)

This systematic literature review (CRD42023393903) and a Bayesian network meta-analysis (NMA) aimed to assess the relative safety profile of first-line targeted therapies (acalabrutinib, ibrutinib, obinutuzumab, ofatumumab, pirtobrutinib, ublituximab, umbralisib, venetoclax, zanubrutinib) in chronic lymphocytic leukaemia (CLL) patients with advanced age and/or comorbidities. The NMA revealed that zanubrutinib was the safest treatment option in terms of the overall safety profile (e.g., serious adverse events [AEs] grade 1-5), followed by venetoclax-obinutuzumab, which showed an advantage in terms of AEs grade 1-5. The use of Bruton's tyrosine kinase inhibitor (BTKi) monotherapy was more favourable in terms of the risk of haematological AEs, but chemoimmunotherapy showed advantages in terms of cardiovascular, gastrointestinal, and infectious AEs. The risk of secondary cancers was similar between treatments. In conclusion, targeted therapies are associated with variable and clinically relevant AEs. The therapies appear to be safer when used as monotherapy rather than in combination with immunological agents in naïve CLL patients with advanced age and/or comorbidities., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: informCLL is the largest US-based prospective, observational registry of patients with chronic lymphocytic leukemia (CLL) initiating FDA-approved treatment in the era of targeted therapy., Patients and Methods: Patients were enrolled between October 2015 and June 2019. Data were collected for baseline characteristics, treatment patterns, outcomes, and safety., Results: In total, 1459 eligible patients were enrolled (first line, n = 854; relapsed/refractory, n = 605). The most common index treatments were ibrutinib (first line, 45%; relapsed/refractory, 49%) and chemoimmunotherapy (first line, 43%; relapsed/refractory, 20%). With median follow-up of 31.8 and 30.9 months in first-line and relapsed/refractory cohorts, respectively, median time to next treatment (TTNT) in patients who received any index treatment was not reached (NR) and 48.6 months; estimated proportions without next-line therapy at 48 months were 64% and 50%. Median overall survival (OS) was NR for both cohorts; estimated 48-month OS rates were 81% and 64% in first-line and relapsed/refractory cohorts, respectively. In match-adjusted analyses, TTNT was improved with first-line ibrutinib versus chemoimmunotherapy (median NR vs. 56.5 months; hazard ratio, 0.74; 95% CI, 0.56-0.98). Exposure-adjusted rates of AEs leading to discontinuation and serious AEs were lower with ibrutinib versus chemoimmunotherapy. Estimated 36-month OS rates were similar in Black versus White patients who received any index treatment (first line, 87% vs. 83%; relapsed/refractory, 74% vs. 74%) or ibrutinib (first line, 97% vs. 85%; relapsed/refractory, 81% vs. 77%)., Conclusion: In this prospective, large, real-world CLL registry, first-line ibrutinib was associated with longer TTNT than chemoimmunotherapy, with sustained benefit up to 4 years of follow-up., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Bruton tyrosine kinase inhibitors (BTKi) and the BCL-2 inhibitor venetoclax have significantly improved the prognosis of patients with chronic lymphocytic leukemia (CLL). However, the incidence of severe infections in patients receiving these agents needs to be better understood. Our review aimed to provide an overview of grade ≥3 infections in patients with CLL who received BTKi and venetoclax-based therapy in prospective trials. Infection rates were influenced by the age of patients and the duration of follow-up. For treatment-naive (TN) patients receiving BTKi, infection rates ranged between 11.4 % and 27.4 % and were close to 30 % in relapsed/refractory (R/R) patients. TN and R/R patients receiving fixed-duration venetoclax-based treatments showed variable rates, with maximum values around 20 %. Opportunistic and fatal infections were uncommon. In conclusion, infections remain a concern in patients with CLL receiving targeted agents. A better definition of factors increasing infection vulnerability could help identify those patients who require infection prophylaxis., Competing Interests: Declaration of Competing Interest F.R.M.: Funding for research and educational projects from Abbvie, Takeda, Janssen. Member of Advisory Board for AbbVie, Beigene, AstraZeneca, Janssen. A.M.F.: Member of Advisory Board for Janssen, Beigene, AstraZeneca, Abbvie. A.V.: Member of Advisory Board for AbbVie, Beigene, AstraZeneca, Janssen, CSL Behring, Takeda. C.V.: Consultancy fees from Abbvie and Astra Zeneca. M.B.: speaker/advisor fees from MSD, BioMérieux, Gilead, AstraZeneca, Advanz, and Pfizer, all outside the submitted work. C.O.: None. E.Z.: None. M.M.: grant from Gilead paid to the Institution; speaker/advisor fees from Allovir, BioMérieux, Gilead, Janssen, Moderna, Mundipharma and Pfizer, all outside the submitted work., (Copyright © 2024. Published by Elsevier B.V.)

Importance: Measurable residual disease (MRD) refers to the presence of disease at low levels not detected by conventional pathologic analysis. The association of MRD status as a surrogate end point of clinical outcome in chronic lymphocytic leukemia (CLL) has not been established in the era of targeted agents. Assessing the association of MRD with progression-free survival (PFS) may improve its role as a surrogate marker and allow its use to accelerate drug development., Objective: To assess the association between MRD and PFS in CLL using data from prospective clinical trials that studied targeted agents or obinutuzumab-based treatment., Data Sources: Clinical studies on CLL were identified via searches of PubMed, Embase, Scopus, and Web of Science from inception through July 31, 2023., Study Selection: Prospective, single-arm, and randomized clinical trials that assessed targeted agents or obinutuzumab-based treatment and reported PFS by MRD status were included. Studies with insufficient description of MRD information were excluded., Data Extraction and Synthesis: Study sample size, median patient age, median follow-up time, line of treatment, MRD detection method and time points, and survival outcomes were extracted., Main Outcomes and Measures: Analyses of survival probabilities and hazard ratios (HRs) were conducted for PFS according to MRD status. Meta-analyses were performed using a random-effects model., Results: A total of 11 prospective clinical trials (9 randomized and 2 nonrandomized) including 2765 patients were analyzed. Achieving undetectable MRD (uMRD) at 0.01% was associated with an HR of 0.28 (95% CI, 0.20-0.39; P < .001) for PFS. Median PFS was not reached in both groups (uMRD vs MRD), but the estimated 24-month PFS was better in the uMRD group (91.9% [95% CI, 88.8%-95.2%] vs 75.3% [95% CI, 64.7%-87.6%]; P < .001). The association of uMRD with PFS was observed in subgroup analyses in the first-line treatment setting (HR, 0.24; 95% CI, 0.18-0.33), relapsed or refractory disease setting (HR, 0.34; 95% CI, 0.16-0.71), and trials using time-limited therapy (HR, 0.28; 95% CI, 0.19-0.40)., Conclusions and Relevance: The findings of this systematic review and meta-analysis suggest that assessing MRD status as an end point in clinical trials and as a surrogate of PFS may improve trial efficiency and potentially allow for accelerated drug registration.