Diagnosis Of Chronic Lymphocytic Leukemia Research Articles

MiR-155 and miR-223 as markers of biological and clinical features of chronic lymphocytic leukemia

Introduction. Chronic lymphocytic leukemia (CLL) is a disease characterized by large individual differences both in the clinical course and in molecular patterns of expression of genes and regulatory RNAs, which can influence pathological changes. The involvement of regulatory microRNAs miR-155 and miR-223 in the pathogenesis of CLL is fairly well known, but there is insufficient information about possible fluctuations in the expression of miR-155 and miR-223 depending on the time course of pathology development and on parameters of medical treatment. Purpose – to investigate the expression of miR-155 and miR-223 in patients having CLL with different biological and clinical features and different characteristics of treatment in terms of peripheral-blood substrates (plasma, lymphocytes, and extracellular vesicles) and bone marrow. Material and Methods. This work involved samples of peripheral blood and bone marrow from 38 patients with a diagnosis of CLL from the City Hematology Center at the government-funded healthcare institution (Novosibirsk Oblast) City Clinical Hospital No. 2 from the years 2016 to 2017. Assessment of miR-155 and miR-223 expressions was carried out by reverse-transcription real-time PCR according to the TaqMan principle. Significance of differences between groups was evaluated either by the nonparametric Mann–Whitney test or by the nonparametric Kruskal–Wallis test with subsequent pairwise comparisons via the Mann–Whitney test. Results. High variation of the analyzed parameters was found. The expression levels of miR-155 and miR-223 in microvesicles of patients with unfavorable chromosomal anomalies were lower than those in patients with the chromosomal aberrations (or the normal karyotype) associated with a moderate effect on CLL prognosis. The expression level of miR-223 in peripheral blood lymphocytes of untreated patients with CLL was higher than that observed in treated patients. Conclusion. differences in the expression levels of miR-155 and miR-223 were identified depending on chromosomal aberrations and polychemotherapy. Our preliminary results will provide the basis for future larger studies on levels of microRNAs in CLL patients having specific features of the development, clinical course, and treatment of the disease.

The Looming Cancer: A Qualitative Study on the Experience of Living with Chronic Lymphocytic Leukemia (CLL) before the Initiation of Treatment

Purpose. This study aimed to study the challenges and ways of coping with living with chronic lymphocytic leukemia (CLL) before the initiation of treatment. Methods. Semistructured interviews were carried out with 8 people living with CLL (4 males and 4 females) who had never received any treatment. Interpretative phenomenological analysis was utilized for the analysis of the data. Results. The following three themes were developed: (1) “Still waters run deep” highlights the contrast between living with minimal symptoms while experiencing high anxiety for the future, (2) “Surviving uncertainty” portrays participants’ supportive networks, communication challenges, and internal coping mechanisms to face the threatening overtones of CLL, and (3) “Turning over a new leaf” delineates participants’ realization of life’s finiteness and the way this acts as a nudge for psychological growth. Conclusion. Despite the limited physical discomfort, the CLL diagnosis and the watch-and-wait phase bring about psychological distress, which drives meaning-making efforts and an array of coping mechanisms, potentially leading to posttraumatic growth processes for people living with CLL.

Outcomes with ibrutinib in patients with chronic lymphocytic leukaemia: Results from the German multicentre REALITY study.

To assess treatment adherence, effectiveness and safety outcomes of patients with chronic lymphocytic leukaemia (CLL) receiving ibrutinib in a real-world setting. Patients enrolled in REALITY were ≥18 years with a confirmed diagnosis of CLL and were receiving ibrutinib as a first-line (1L), 2L or ≥3L therapy. Treatment retention, adherence, progression-free survival (PFS), overall survival (OS) and time to next therapy were assessed at 1 and 2 years overall, by typology and by cytogenetic subgroups. PFS and OS were analysed using Kaplan-Meier methods. Exactly 302 patients were enrolled across 57 sites in Germany, from January 2017 to July 2021. One-year retention rates were 69.9% overall (primary endpoint), 77.9% for 1L patients, and 77.6%/78.8% for high-risk patients with del17p/TP53. At 2 years, PFS/OS rates were 77.8%/90.7% overall (1L, 82.7%/90.4%), and were consistent across cytogenetic subgroups. PFS rates were higher for 1L versus ≥3L patients. Patients with the low-acceptance/low-control typology at baseline were less likely to retain treatment at 1 year versus the high-acceptance/high-control typology. No new safety signals were observed. The REALITY study provides further evidence of the effectiveness and safety of ibrutinib in patients with CLL in a real-world setting, particularly in earlier treatment lines.

Prediction of severe infections in chronic lymphocytic leukemia: a simple risk score to stratify patients at diagnosis

Chronic Lymphocytic Leukemia (CLL) is well-known for increasing susceptibility to infections. Factors such as immune dysregulation, IGHV status, hypogammaglobulinemia, and patient comorbidity and treatment, contribute to higher infection rates and mortality. However, the impact of hypogammaglobulinemia on infection rates is controversial. We aimed to identify clinical and biological parameters linked to the risk of severe infectious events. Additionally, we set up a straightforward risk infection score to stratify CLL patients at diagnosis, thereby enabling the development of suitable infection prevention strategies. We retrospectively evaluated 210 unselected CLL patients diagnosed between 1988 and 2018. This evaluation encompassed demographics, Binet stage, immunoglobulin (Ig) levels, treatment history, comorbidities, and IGHV mutational status at diagnosis. The frequency and severity of infectious events were recorded. Analysis revealed that age, IGHV mutational status, Binet stage, and hypogammaglobulinemia were statistically associated with the Time to First Infection (TTFI) in univariate and multivariate analyses. Using hazard ratios from the multivariate analysis, we finally devised a risk scoring system that integrated age, IGHV mutational status, immunoglobulin levels, and Binet stage to stratify patients at diagnosis based on their specific infection risk. In our cohort, disease progression and infections were the leading cause of death. These findings pointed out the clinical need for a screening process strategic for defining infectious risk at the time of CLL diagnosis, with a significant enhancement in the clinical management of these patients.

Expression of ZAP 70 in Chronic Lymphocytic Leukemia (CLL) and its Correlation with Clinical Stages

Objective: To ascertain the levels of ZAP-70 expression within the context of Chronic Lymphocytic Leukemia (CLL) patients and to subsequently analyze the potential correlations between ZAP-70 expression and the clinical staging of the disease. Study Design & Setting: Cross-sectional, descriptive study. Department of Hematology, Armed Forces Institute of Pathology (AFIP), Rawalpindi from July 2021 to December 2021. Methodology: We included 73 CLL patients of various ages and both genders. and patients having lymphoproliferative disorders other than CLL were excluded. Sysmex XN-3000 was used to do complete blood counts. Diagnosis of CLL was confirmed immunophenotypically by flow cytometry. Samples were processed by standard methods for ZAP70 analysis. Descriptive statistics were expressed in terms of mean ± standard deviation (SD). A Chi-square test was conducted, with a significance level of p-value =0.05 being considered significant. Results: Among 73 patients, 24 were females (32.9%) and 49 were males (67.1%). Females had a mean age of 69.00±9.47 years, whereas males had a mean age of 65.73±11.12 years. ZAP-70 expression was positive in 8 (11%) and negative in 65 (89.0%) cases. The expression of ZAP-70 in CLL and its correlation with Binet Stages was significant (p=0.002). ZAP- 70 expression in males and females showed no significant difference (p 0.059). ZAP-70 analysis showed no significant difference in patients with age more than 60 years from = 60 years of age (p= 0.275) Conclusion: ZAP-70 gene expression should be used in routine laboratory settings and can be correlated with the clinical stages of CLL

IMMUNOPHENOTYPE OF LEUKEMIC CELLS IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS WITH NOTCH1 AND SF3B1 GENE MUTATIONS.

The typical chronic lymphocytic leukemia (CLL) immunophenotype is vital for diagnosis, but the expression of some antigens varies and has prognostic value. There are data that reduced CD20 expression is associated with NOTCH1 and SF3B1 gene mutations. To determine a high-risk group of CLL patients for prediction of unfavorable NOTCH1 and SF3B1 gene mutations based on immunophenotyping of leukemic cells. Flow cytometric and molecular-genetic analysis (mutations of NOTCH1, SF3B1, and TP53 genes using the polymerase chain reaction followed by direct sequencing) was performed in a group of 86 previously untreated CLL patients. The immunophenotype of leukemic cells of all examined patients met the criteria of CLL diagnosis. NOTCH1 gene mutations were found in 21 patients (24.4%), and SF3B1 gene mutations - in 7 patients (8.1%). There were no TP53 gene mutations among the examined patients. A decreased number of CD20+CD5+ cells and a downward trend in the relative index of mean fluorescence intensity (iMFI) of CD20+ cells were found in patients with NOTCH1 and SF3B1 gene mutations. Based on the iMFI level (higher and/or lower than 3.0) and the number of CD20+CD5+ cells among all B-cells (higher and/or lower than 50%), we distinguished CLL cases with low and relatively high levels of CD20 antigen expression. Using ROC analysis and the parameter of low CD20 antigen expression, we could predict the presence of NOTCH1 and SF3B1 gene mutations in 73.3 ± 0.06% of patients (p = 0.001). The risk of NOTCH1 and SF3B1 gene mutations in cases with low CD20 antigen expression was 6.96 (95% CI = 2.53-19.18; p = 0.0001). The revealed regularities were statistically significant for patients in whom the diagnosis was established in all Binet - Rai stages except A0-AI. Our data confirmed a reduced CD20 expression in CLL patients with NOTCH1 and SF3B1 mutations. In addition, an approach was proposed to identify high-risk CLL patients for prediction of such mutations: previously untreated CLL patients at advanced Binet - Rai stages (BII, CIII, CIV) with a reduced number of double-positive CD20+CD5+ cells in peripheral blood and/or low iMFI of CD20+ cells.

Study of immunophenotypic markers and clinico-hematological findings in chronic lymphocytic leukemia

Background and objective: Chronic lymphocytic leukemia (CLL) is a clonal, mature B-cell neoplasm, its clinical features, cell morphology, and immunophenotyping are used to establish the diagnosis. Immunophenotyping by flow cytometry is the most accurate procedure for diagnosing CLL, there is no single marker exclusively expressed in CLL, however, a complex of immunophenotypic markers that incorporates several B-cell markers and assists in differentiating CLL from other mature B-cell neoplasms, the expression of these immunophenotypic markers is considered in the specific CLL scoring system (Moreue scoring system).this study aimed to assess the clinico – hematological features and immunophenotypic characteristics of CLL patients and to assess the role of immunophenotyping in the differential diagnosis of CLL. Methods: an observational prospective and retrospective study was carried out at Nanakaly hospital for blood diseases and oncology in Erbil city, Iraq. That was conducted on 100 patients newly diagnosed with mature B cell neoplasm which included 68 cases of CLL and 32 cases with other mature B cell neoplasm (MBN), usinga convenience sampling method. The study period was from the1st of September 2021 to the end of April 2022. An interview questionnaire was used to collect the study data from the patients. Results: The mean of age ± standard deviation of the CLL patients (58.85 ± 10.69) years and (66.2%) was male, The most frequent clinical presentations for CLL cases were fatigue (50%), lymphadenopathy (41.2%), and splenomegaly (41.2%), (50%) of CLL patients had anemia, thrombocytopenia was seen in (32.4%) and leukocytosis was seen (98.5%), all patients had lymphocytosis and (97%) had an absolute B lymphocyte count of more than 5 x109 /L. all the studied CLL patients expressed both CD45 and CD19 markers, the expression of the immunophenotypic markers was as following: CD5 (98.5%), CD23 (97.1%) and CD200 (97.1%), Half of the patients (50%) showed expression of monoclonal lambda light chain, sIgM (4.4%), CD20 (88.2%) and CD43 (54.4%) and CD38 (26.5%). The expression of the following marker had a significant role in the differentiation between CLL and other MBN: CD5, CD23, CD79b, FMC7, sIgM, CD200, and CD43. Conclusion: Our results have shown that the clinical presentations and hematological profile of Iraqi CLL patients were not significantly different from that of previous local and global studies, the distinct immunophenotyping, as well as it has been found that immunophenotyping is a promising method for supporting the clinical and morphological characterization of CLL.

Intraocular sarcoid-like reaction in patients with chronic lymphocytic leukemia

ObjectiveTo investigate the frequency and clinical features of intraocular paraneoplastic sarcoid-like reaction (SLR) in patients with chronic lymphocytic leukemia (CLL). MethodsRetrospective 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. ResultsOf 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. ConclusionIntraocular 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.

[Research Progress in Treatment of Chronic Lymphocytic Leukemia --Review].

Chronic lymphocytic leukemia (CLL) is a low-grade lymphoproliferative tumor that occurs frequently in middle-aged and elderly people. Early and precise intervention can effectively improve the clinical prognosis of CLL patients. In the past, chemotherapy was the main treatment plan. With the development of molecular biology and the continuous advent of immune targeting drugs, targeted drugs targeting B cell receptor signaling pathway have shown high clinical application value in the diagnosis and treatment path of CLL. Cellular immunotherapies such as CAR-T also offer hope for patients with relapsed and refractory CLL. Allogeneic hematopoietic stem cell transplantation and multi-drug combination have also shown remarkable results in clinical practice. The purpose of this article is to review the latest research progress in the treatment of CLL.

A Snapshot of the Management of Chronic Lymphocytic Leukemia in Italy. Preliminary Analysis on over 3000 Patients Enrolled in the Gimema CLL2121 Trial

In recent years the management of patients (pts) with chronic lymphocytic leukemia (CLL) has benefited from a deeper knowledge of the mechanisms underlying the disease and from the development of novel therapeutic approaches. That notwithstanding, local and national accessibility to drugs and tests may lead to distinct “real-world” practices in terms of management of pts that are worth of being recorded and compared to understand the degree of reproducibility and applicability of international guidelines. This could also be relevant for the design of future clinical trials, more tailored to the true patient's needs. To this end, within the GIMEMA cooperative study group the observational retrospective and prospective CLL2121 study (NCT04867915) has been designed with the objective of evaluating the diagnosis and management of CLL in all hematological centers in Italy through the assessment of: 1) the methods and the actual diagnostic/prognostic work-up capacity; 2) the algorithms applied to define disease progression and treatment requirements with respect to national and international guidelines; 3) the clinical and biological variables not strictly associated with CLL, but capable of influencing the clinical course and overall survival; 4) the true incidence of some rarer complications associated with CLL. The study consists of a collection of clinico-biological data from all pts with newly diagnosed CLL, small lymphocytic lymphoma (SLL) or CLL-like monoclonal B-cell lymphocytosis (MBL), according to the iwCLL 2018 criteria in Italy. The retrospective part aims at including all cases followed at the participating centers with a diagnosis between January 2010 and September 2021, while the prospective part will include all pts with a documented diagnosis of CLL, SLL or MBL between September 2021 and September 2025. In this pilot analysis of the study, we examined pts' demographics, diagnosis, treatment line and type. Data were collected using the REDCap electronic data capture platform, analyzed using the SAS software v.9.4 and reported as numbers and frequencies. Between 2 November 2021 and 28 June 2023, 3294 eligible pts were enrolled in 75 hematology centers (out of the total of 110 centers who will be activated during the study) across the entire Italian territory. At the time of the present report, 3033 pts had clinical data available for our preliminary analysis. The vast majority of pts registered (N=2599, 85.7%) belonged to the retrospective cohort while only a minority (N=434, 14.3%) to the prospective cohort. Pts had a median age of 68 years ranging from 29 to 97; 60% of pts were males. 2630 pts (86.8%) had a diagnosis of CLL, 187 (6.2%) of SLL and 214 (7.0%) of MBL (2 missing information). Among those with available results 112 pts (12.6%) were TP53 mutated, 526 (45.6%) del(13q) positive, 174 (14.9%) del(11q) positive, 142 (11.9%) del(17p) positive and 226 (20.4%) presented a trisomy 12. The majority of pts (57.6%) were untreated, while 42.4% have been treated. Within the latter subset, 67.3% of pts have received one line of therapy, 21.4% 2 lines of therapy, 11.3% ≥3 lines of therapy. The most common therapeutic regimens were the combination of chemotherapy with an anti-CD20 antibody (39.3%), mainly rituximab, and those based on BTK inhibitors (33.3%), mainly ibrutinib. Chemotherapy alone was used in 12% of pts. Only 5% of pts was treated with the BCL2 inhibitor venetoclax. In the remaining 10% of pts, other approaches were used. This is the initial report of a nation-based real-world data collection aimed at describing the biological and clinical features of pts diagnosed with CLL in virtually all Italian hematology centers starting from 2010. The pattern of treatments highlighted in our preliminary analysis, with a wide use of the watch &amp; wait policy and of chemoimmunotherapy, will help understand how the introduction of novel therapies impacted treatment habits also in light of the timing of the local reimbursement policy. The different time of drug access in Italy, typically delayed after the EU approval, may also have affected the limited use of venetoclax-based treatment. The continuous accrual of pts in this study will allow to obtain a close-to-registry vision of CLL management in Italy over time, in terms of coverage of the entire country but enriched with the granularity of the data and flexibility of the collection typical of a real-world study.

Machine Learning in CLL

Introduction: Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are closely related diseases with similar characteristics, classified as mature B cell neoplasms. They involve the accumulation of monoclonal B lymphocytes and are considered as one disease with different manifestations. CLL is more prevalent and is usually detected through routine blood tests, while SLL is identified by primary lymph node involvement. Although many patients with CLL/SLL are asymptomatic, some may experience lymphoma-related symptoms. The diagnosis involves blood tests and immunophenotypic analysis. CLL prognosis varies, and staging systems help in determining the appropriate treatment regimen. Machine learning (ML) is being increasingly used in hematology to aid in diagnosis, treatment, and risk-stratification. This review explores the application of ML in the classification and diagnosis of CLL, discussing the performance and limitations of existing models, with the goal of encouraging further research and integration into clinical settings to improve patient care. Materials and Methods: A literature search was conducted using the PubMed/MEDLINE and EMBASE databases. EndNote and Rayyan software were used to eliminate duplicate entries and for screening the articles. In addition, the references of the identified articles were manually screened to identify additional relevant studies. Articles with primary data pertaining to the use of ML in CLL/SLL diagnosis and classification were included without language or time restrictions. Results: A total of 169 articles were identified and duplicates were removed using Endnote® and Rayyan® software, resulting in 149 articles eligible for screening. The included articles met specific criteria: they utilized ML methods, reported conclusions on the method's reliability or accuracy, and focused on CLL diagnosis and classification. Excluded articles were non-English, animal/in vitro studies, abstracts, and review articles. After screening, 14 studies met the inclusion criteria. Studies examining the potential of ML algorithms in enhancing the diagnosis of CLL used various data sources like blood smears, flow cytometry, genetic data, and histopathological images. The current evidence suggests that ML can effectively predict CLL diagnosis, aid in screening, identify potential biomarkers, and explore the underlying molecular mechanisms. Many of the ML models evaluated in this review demonstrate high accuracy, ranging from 83% to 100%. Implementing AI and ML in hematology can automate tasks involved in patient workup, risk assessment, and treatment, allowing hematologists to focus on critical aspects of patient care and research. Despite the promising potential, some important considerations should be acknowledged. First, many reviewed models had limited sample sizes from single centers, limiting their generalizability. It's crucial to develop models using larger, diverse datasets from multiple centers to improve generalizability. Second, there is a lack of prospective studies and research on the impact of ML models on patient outcomes. Future investigations should focus on prospectively assessing the effect of ML models on CLL diagnosis, prognosis, and patient outcomes. Third, the integration of ML applications into direct patient care raises ethical and medico-legal concerns, including liability, data privacy, and doctor-ML application interaction. An ethical framework specific to ML applications in healthcare is needed, and doctors should receive training on ML applications to understand their capabilities and limitations. Addressing these considerations can lead to successful implementation of ML applications in the care of CLL patients, improving diagnosis and patient outcomes. Conclusion: Our findings demonstrate the promising potential of ML algorithms in accurately predicting CLL diagnosis, conducting CLL screening, and identifying genetic biomarkers associated with CLL. Future research endeavors should prioritize the development of large, standardized datasets to effectively train ML models, conduct prospective evaluations to assess their performance, explore their impact on patient outcomes, and establish ethical frameworks to govern their utilization.

Clinical and Economic Burden Among Patients with Chronic Lymphocytic Leukemia Using a Novel Real-World Patient-Centered Database

Introduction Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults, with an estimated 18,740 new cases of CLL in 2023. This study describes current treatment patterns, healthcare resource use (HCRU) and patient voice in patients with CLL in the US using a novel patient-centered database. Methods A retrospective study using data from the Inspire Integrated Analytical Database (IIAD), which links Inspire patient voice with electronic health records (EHR) and medical and pharmacy claims through HIPAA-compliant tokenization. Patients worldwide with various conditions join Inspire's online health community and contribute their experience through online posts and survey participation (see Figure 1). Medical and pharmacy claims in IIAD range from 2013 to present, with EHR data ranging from 2010 to present. Inspire members were included in the study if they resided in the US and had at least two diagnoses for CLL (ICD-10 codes C91.10, C91.11 or C91.12) on at least two distinct dates that were between 30 and 60 days of each other. The first observed CLL diagnosis date was considered the index date. Patients with an index date on or before 6/30/2022 were included in the analysis. Baseline patient characteristics and HCRU were evaluated. CLL treatment was identified from medical and pharmacy claims. Online posts which CLL patients have viewed at least once were evaluated. Post topics are defined as named entities recognized by Inspire's Natural Language Processing (NLP) engine from all of the discussion posts written by any Inspire members. Descriptive statistics were reported. Results A total of 331 CLL patients were identified in the online community with linked claims and EHR data. Median follow-up time was 59 months from index date. The median age at diagnosis was 73 and 49% of patients were female. Patients were geographically represented across the US. 63% had ≥100 claims from a median of 25 care sites across 33 providers. During follow-up a median of 3 hospitalizations per patient were observed. 5% of patients experienced a Richter's transformation and 22% developed a secondary malignancy (lung, gastrointestinal or skin cancer) after their index CLL date. 104 patients (31%) of the cohort had available data for CLL treatment. Median time to first CLL treatment was 11.7 months (range: 1 day - 86.8 months). Ibrutinib was the most common medication (n = 43), followed by venetoclax (n = 30) and rituximab (n = 20). The 5 most common topics viewed by patients on the Inspire community website included: skin, side-effect, muscle, biopsy, and infection. Prior to starting therapy, searches on the Inspire platform included terms such as “imbruvica,” “calquence,” and “living with CLL.” Searches after CLL treatment revealed that patients broadened search terms to include other cancer types such as “pelvic cancer,” “liver metastasis” and “melanoma.” Conclusions This report utilized a unique dataset that integrates patient voice with EHR and claims data to describe clinical characteristics, and treatment patterns of CLL patients drawn from the patient-centered Inspire digital health community. The online population had a median age of 73 at diagnosis, consistent with the average age of CLL diagnosis (70 yrs.). Patients in our cohort initiated treatment approximately 1 year after CLL diagnosis. Online activities on the Inspire platform demonstrated that CLL patients are engaged in searching and reading discussion posts concerning the impact of side effects and treatments on quality of life, and emphasized emerging concerns about the potential impact of secondary malignancies. Future real-world studies need to integrate patient voice to fully understand the consequences of a cancer diagnosis.

Real-World Comparison of Healthcare Costs of Venetoclax-Obinutuzumab Vs. Btki Use Among Elderly U.S. Medicare Beneficiaries with Chronic Lymphocytic Leukemia in the Front-Line (1L) Setting

Background: Since the March 2016 FDA approval of ibrutinib as a front-line therapy in chronic lymphocytic leukemia (CLL), BTK inhibitors (BTKi) used as continuous therapy until progression or toxicity, are increasingly utilized early in the CLL treatment pathway. Conversely, the BCL-2 inhibitor venetoclax, approved for front-line (1L) CLL in May 2019, has been shown to generate durable responses. As a result, venetoclax has gained approval with a fixed treatment duration wherein a venetoclax plus obinutuzumab (VenO) regimen is to be completed after 12 months in the 1L setting. Fixed-duration therapy with a treatment-free remission has the potential advantage of lowering health care costs by avoiding continuous exposure to treatment. However, little real-world evidence has been generated to assess the potential economic benefits of a fixed-duration treatment such as VenO relative to treat-to-progression therapies like BTKis. The objective of this study was to examine healthcare costs before and after completion of the fixed-duration treatment period for VenO relative to that observed for BTKis in a national sample of elderly U.S. Medicare beneficiaries with CLL in the 1L setting. Methods: Our analysis used 2016-2021 100% Medicare Parts A, B, and D claims. Elderly fee-for-service Medicare beneficiaries initiating VenO (VenO group) or an available BTKi treatment (BTKi group) between 6/1/2019 and 6/30/2020 (index date = first prescription fill date) were included in the sample. Additional inclusion criteria for both groups were as follows: (a) ≥66 years old, (b) ≥1 diagnoses of CLL and no diagnoses for other indications of the index agent in the 12-month pre- and post-index period, (c) continuous medical and prescription coverage in the 36 months pre- and 12 months post-index period, (d) no prior CLL treatment in the 36-month pre-index period (i.e., to proxy 1L patients), and (e) continuous medical and prescription coverage from 13 to 18 months after the index date or until death if it occurs earlier (to capture costs after fixed-duration VenO treatment is completed). Healthcare cost measures included all-cause and CLL-related monthly total, prescription, and medical costs. Mean monthly cost measures were captured for both groups over two fixed time periods calculated from the index date: Month 0 to 12 (i.e. proxy for on-treatment period for VenO) and Month 13 to Month 18 (i.e. proxy for off-treatment period for VenO). Risk-adjusted monthly costs were estimated using generalized linear models controlling for differences in sociodemographic and clinical factors between the two groups. Difference-in-Difference method was used to assess reduction in costs across the two fixed time periods. Results: The final sample contained 193 patients (pts) in the VenO group (mean [SD] age 75.6 [5.5] years, 69.4% male, 90.2% White) and 1,577 pts in the BTKi group (mean [SD] age 77.6 [6.3] years, 55.8% male, 92.5% White). Between months 0 to 12, risk-adjusted all-cause monthly total costs were slightly lower for VenO pts ($13,887) than BTKi pts ($14,492) (Table 1). However, during months 13 to 18 the monthly all-cause total costs declined by 67% for VenO pts ($13,887 to $4,462) but only by 10% for BTKi pts ($14,492 to $13,051). Hence, the relative reduction in costs across the two periods was significantly larger for VenO (-$9,425) vs. BTKI (-$1,441) pts (i.e. Difference-in-Difference=-$7,984, p&amp;lt;0.001). Similar patterns were observed for CLL-related costs with the substantially larger reductions in CLL-related total monthly costs (-$9,880 VenO vs. -$1,753 BTKi, p&amp;lt;0.001) for the VenO group relative to BTKi group being primarily driven by the larger reduction in CLL-related monthly prescription costs (-$9,437 VenO vs. -$2,020 BTKi, p&amp;lt;0.001) (Table 1). Conclusions: This real-world study of elderly Medicare beneficiaries with CLL found a large reduction in monthly health care costs in the VenO group after the fixed-duration treatment period of 12 months. This drop was largely driven by the reduction in CLL-related prescription drug costs; however, similar declines were not observed in the BTKi group. Hence, the costs for pts on VenO after the fixed-duration treatment period were approximately $8000 per month lower than the BTKi group. Our study highlights the substantial economic benefits of VenO relative to treat-to-progression therapies like BTKis and carries implications for treatment decision-making CLL.

Not All Lymphocytosis Is Chronic Lymphocytic Leukemia (CLL): A Retrospective Review of Patients Referred to an Academic Hematology Oncology Center for CLL

Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults, especially in elderly patients. Most patients with CLL are asymptomatic at presentation and have routine blood work that prompts further investigation. In patients with CLL, their complete blood cell count with differential typically demonstrates lymphocytosis due to the increased number of malignant B-lymphocytes. Although lymphocytosis can be suggestive of CLL, diagnostic workup can sometimes reveal an alternative diagnosis. Here we describe a retrospective review of 36 patients referred to our hematology oncology clinic for the suspected diagnosis of CLL. Out of the 36 patients referred for CLL, 8 patients (22%) had diagnostic workup confirming an alternative diagnosis including non-Hodgkin lymphoma (NHL) (5 patients), hairy cell leukemia (1 patient), and monoclonal B-cell lymphocytosis (2 patients). Only 28/36 (78%) of total patients had flow cytometry confirming the diagnosis of CLL. Out of the 36 total patients, 34 patients had lab work revealing lymphocytosis (absolute lymphocyte count greater or equal to 5.0 10 3/mL) prompting referral. At presentation, total patients (34/36) with lymphocytosis had an absolute lymphocyte count range of 5-593.0 (10 3/mL), median of 17.6 (10 3/mL), and average of 50.8 (10 3/mL). 27/34 (79%) of patients with lymphocytosis were diagnosed with CLL, while 7/34 (21%) of patients with lymphocytosis initially suggestive of CLL were diagnosed with alternative diagnoses (follicular lymphoma (1), marginal zone lymphoma (2), mantle lymphoma (1), hairy cell leukemia (1), and monoclonal B-cell lymphocytosis (2)). The patients with lymphocytosis not diagnosed with CLL (7/34 patients) had an absolute lymphocyte count range of 5-105.6 (10 3/mL), median of 18.27 (10 3/mL), and average of 45.2 (10 3/mL). Their average age at presentation was 63 years old (range of 53-80). Most common symptoms at presentation were asymptomatic (3), B-symptoms plus lymphadenopathy (2), lymphadenopathy (1), and gastrointestinal symptoms (1). The asymptomatic patients were monoclonal B-cell lymphocytosis (2) and mantle lymphoma (1). Hairy cell leukemia, marginal zone lymphoma, and follicular lymphoma had significantly elevated absolute lymphocyte count (86.8, 105.6, 89.45 (10 3/mL) respectively) and associated anemia. Only one patient referred for CLL was diagnosed with follicular lymphoma had anemia and thrombocytopenia without lymphocytosis. The patients with lymphocytosis confirmed to have CLL (27/34 patients) had an absolute lymphocyte count range of 5-593 (10 3/mL), median of 17.6 (10 3/mL), and average of 50.8 (10 3/mL). Their average age at presentation was 70 years old (range 54-93). Most common symptoms at presentation were asymptomatic (16), B-symptoms plus lymphadenopathy (5), lymphadenopathy only (2), B-symptoms only (2), and neck/back pain (2). 59% of patients were asymptomatic with abnormal lab work including lymphocytosis only (14), anemia (1), and abnormal M-spike on serum protein electrophoresis (1). We wish to emphasize the role of flow cytometry and its value in confirming diagnosis of CLL. Even if clinical suspicion for CLL is high, it is important to not solely rely on complete blood cell count and peripheral lymphocyte count. NHL, hairy cell leukemia, and monoclonal B-cell lymphocytosis can have similar lab work and initial presenting symptoms to patients with CLL. A few patients in this review were receiving chemotherapy for CLL initially and were later found to have a different diagnosis. It is important to keep clinical suspicion high for alternative diagnoses for lymphocytosis to guide appropriate management.

Patient Preferences for Fixed Versus Treat-to-Progression Therapies in Chronic Lymphocytic Leukemia

The treatment landscape for chronic lymphocytic leukemia (CLL) has evolved in the last 8 years to include novel targeted therapies as alternatives to chemoimmunotherapy. These treatments vary in their benefit-risk profiles, mode and frequency of administration, and duration of treatment. Previous preference studies in CLL have evaluated preferences for treatment attributes such as efficacy, tolerability, and mode and frequency of administration. However, few have assessed preferences for treatment duration independently of mode of administration. This study sought to further understand the factors that influence patient preferences for treatment duration and to quantify the tradeoffs that patients were willing to accept to have a fixed duration therapy versus a treat-to-progression therapy. The study was conducted in 2 phases: (1) a qualitative phase of in-depth individual interviews with patients to identify the factors that influence patient preferences for treating until progression versus a fixed duration as well as the CLL treatment attributes that patients consider most important, and (2) a quantitative phase to estimate the tradeoffs that patients would accept among CLL treatment attributes. In the qualitative phase, the semistructured interview guide included open-ended questions and probes to understand perceptions of fixed-duration treatments compared with treat-to-progression regimens and to elicit a list of treatment attributes that influence CLL treatment preference. The results of the interviews informed the development of a web-based discrete-choice experiment (DCE) survey. Respondents to the online survey answered 12 DCE questions, each offering a choice between 2 hypothetical treatment profiles defined by 7 attributes with varying levels, including treatment duration, which included levels for treat to progression and fixed duration for either 6 or 12 months. Data were analyzed using a random-parameters logit model, and estimated preference weights were used to calculate the maximum acceptable risk (MAR) of treatment-related adverse events the average respondent would accept in exchange for a move from a treat-to-progression to a fixed-duration therapy. The MAR is estimated as the ratio of the relative importance of an improvement in an attribute to the relative importance of a unit change in the level of risk (i.e., tumor lysis syndrome (TLS), atrial fibrillation, or fatigue). Interviews were conducted with 20 adults with a self-reported diagnosis of CLL. The mean age was 59 years, and 55% of participants (n = 11) identified as female. The mean time since diagnosis of CLL was 3 years, and 70% of participants (n = 14) had received treatment for CLL. Overall, 93 treatment attributes were spontaneously reported, including treatment duration. When probed, treatment duration was reported by 50% of participants as “very important” in their treatment decision. Almost all participants (n = 17) preferred a treatment with a fixed duration compared with treat-to-progression, assuming each had the same efficacy. Table 1 reports patients' perceived benefits and drawbacks of fixed-duration versus treat-to-progression therapies. The DCE survey was completed by 229 adults with a self-reported diagnosis of CLL for at least 3 months. The mean age was 66 years, and nearly 60% of the sample identified as female (n = 136). About 60% of the sample (n = 138) was diagnosed 5 or more years ago, and 152 respondents (66%) had experience with treatment for CLL. The results of the preference analysis showed that respondents preferred a fixed duration of either 6 months or 12 months versus treat-to-progression and, based on the MAR estimates, were willing to accept the following levels of risks to have a fixed-duration treatment versus treat to progression: more than a 3% increased risk of TLS, 6%-7% increased risk of atrial fibrillation, and 21%-26% increased risk of fatigue (Table 2). Past research has shown efficacy as the most important factor, yet qualitative interview participants also identified treatment duration as an important factor in their decision when choosing a CLL therapy. This finding was confirmed by the quantitative preference study, which revealed a preference for fixed-duration therapies over treat-to-progression regardless of the timeframe (6 or 12 months). Results from this study can help inform shared decision-making when considering alternative therapies for CLL.

Clime: CLL Immune Micro-Environment and Risk of Infections Pre- and Post-Diagnosis: A Population-Based Study

Background: Immune dysfunction precedes a diagnosis of chronic lymphocytic leukemia (CLL) in some patients. More information is needed about which patients experience immune dysfunction and how it impacts disease progression, as well as the development of post-diagnosis infections and second malignancies. The objectives of this study were to 1) examine the rate of pre-diagnosis infection for individuals diagnosed with CLL compared to population controls, 2) evaluate the impact of pre-diagnosis infection on time to first treatment, 3) compare the rate of immune dysfunction before the start of treatment by stage, and 4) compare the rate of immune dysfunction before the start of treatment for each year post-treatment. Methods: We used a retrospective matched cohort study design that included all individuals in Manitoba diagnosed with CLL from 2006 to 2019. Individuals were identified from the Manitoba CLL database and the Manitoba Cancer Registry (MCR). Individuals with CLL were matched by age, sex, and area of residence (urban versus rural) to population controls identified from the Manitoba Health Population Registry. Provincial pharmacy, hospital admissions, medical claims, and MCR data were used to determine infection, second malignancies, and IgR therapy. Immune dysfunction was defined as two or more infections, a diagnosis with a secondary malignancy, or receipt of IgR therapy. The pre-diagnosis time period was defined as three to 15 months prior to diagnosis. The pre-treatment time period was defined as 12 months prior to treatment. The following analyses were used: conditional logistic regression for objective 1, competing risk for objective 2, logistic regression for objective 3, and logistic GEE models for objective 4. Results: A total of 1,776 CLL patients were matched to 17,760 non-CLL controls. Sixty-two percent were male, the mean age at diagnosis was 71 years, and 62% lived in an urban area. Fifty-one percent of CLL patients had a pre-diagnosis infection compared to 46% of controls. Compared to individuals with no prior infection, those who had a prior infection were more likely to be diagnosed with CLL (Odds Ratio (OR) 1.17, 95% confidence Interval (CI) 1.03, 1.33 for one infection, OR 1.29, 95% CI 1.15, 1.45 for two or more infections). After adjusting for the number of outpatient visits and comorbidity, individuals with two or more infections were 14% more likely to be diagnosed with CLL (OR 1.14, 95% CI 1.00-1.30). Conclusions: We found that infections that occurred in the three to 15 months before diagnosis increased the odds of being diagnosed with CLL. Work is ongoing examining time to treatment, immune dysfunction by stage, as well comparing immune dysfunction before and after treatment.

Epic: A Second Interim Analysis of the Non-Interventional, Observational Multi-Centre Cohort Study of Patients with Chronic Lymphocytic Leukaemia Treated with First-Line Acalabrutinib through the UK Early Access Programme

Background: Acalabrutinib, a second-generation Bruton Tyrosine Kinase inhibitor (BTKi), has shown an acceptable safety profile and high response rates in clinical trials of treatment naïve patients with chronic lymphocytic leukaemia (CLL). However, real-world data detailing the safety and effectiveness of first-line acalabrutinib treatment for CLL is limited. Here we present a second interim analysis (IA) of patients with CLL who were initiated on first-line acalabrutinib within the UK Early Access Programme (EAP). Methods: This is an ongoing observational multi-centre cohort study involving retrospective data collection from medical records (ClinicalTrials.gov: NCT05557695). Treatment-naïve patients with CLL from 9 UK clinical centres who initiated acalabrutinib as part of the UK EAP between 1 st April 2020 - 1 st April 2021 were eligible to participate. Patients will be followed for up to 60 months from the date of acalabrutinib initiation (index). Collected data for this IA (data cut-off 31 st May 2023) includes baseline demographics, clinical characteristics, and treatment patterns. Results: 101 patients were included in this IA. Median (interquartile range (IQR)) age at index was 73.8 (66.1-78.4) years; 56% (n=57/101) of patients were male; 89% (n=83/93) of patients were White British, 6% (n=6/93) were White other, 3% (n=3/93) were Asian and 1% (n=1/93) were of Mixed ethnicity (missing data n=8). Median (IQR) duration of follow-up was 32.4 (29.2-35.4) months; 89% (n=90/101) of patients had a follow-up duration of ≥1 year and 84% (n=85/101) ≥2 years. 88% (n=52/59) of patients had an Eastern Cooperative Oncology Group performance status (PS) of 0-1, 10% (n=6/59) had a PS of 2 and 2% (n=1/59) had a PS of 3 (missing n=42). 50% (n=40/80) of patients had a creatinine clearance &amp;lt;60 mL/min at index. 5% (n=5/101) of patients had a confirmed ATM mutation and no patients had a confirmed 17p13.1 deletion. 5% (n=5/101) had a confirmed TP53 mutation and of 10 patients with confirmed IgHV mutational status, 20% (2/10) had mutated IgHV (91 unknown). Median (IQR) time between CLL diagnosis and index was 2.8 (1.2-5.4) years. At index, 100 patients received 100 mg of acalabrutinib twice a day, 1 patient received 100 mg daily. The continuation rate (n=100) at 12 and 24 months was 81.0% (95% confidence interval [CI], 73.7%-89.1%) and 74.0% (95% CI, 65.9%-83.1%), respectively (1 patient not recorded). 68% (n=69/101) of patients remained on treatment at the time of data cut. Of those patients reporting reasons for treatment discontinuation, 48% (n=15/31) were due to adverse events (AEs; of the 14/15 patients reporting type of AEs resulting in discontinuation, 14% (2/14) was reported for each of the following AEs; cardiovascular, haematoma, headache and urinary tract infection), 6% (n=2/31) due to disease progression, 3% (n=1/31) due to patients' decision and 42% (n=13/31) other reasons (1 unknown). Of 39 patients with treatment interruptions, 72% (n=28/39) patients had interruptions due to AEs, 15% (n=6/39) due to a minor operation and/or procedure and 21% (n=8/39) other reasons. Of the 22/28 patients reporting type of AE resulting in treatment interruption, the most common AEs were upper respiratory tract infection (23%, n=5/22) and thrombocytopenia (18%, n=4/22). Of those with relevant medical records, 62% (n=40/65) had a recorded COVID-19 diagnosis; of these, 93% (n=37/40) diagnoses were confirmed via test. Sotrovimab was the most common treatment received for COVID-19 (20% of patients, n=8/40). COVID-19 vaccination and biannual boosters is offered to all patients with CLL as per UK guidelines, available data from 58 patients showed that 72% (n=42/58) of patients had received ≥4 COVID-19 vaccination doses and 28% (n=16/58) had received &amp;lt;4 doses at the time of datacut (missing n=43). Conclusion: This IA reports 12 and 24-month real-world acalabrutinib continuation rates of 81.0% (95% CI, 73.7%-89.1%, n=100) and 74.0% (95% CI, 65.9%-83.1%, n=100), respectively, in treatment naïve patients with CLL in UK. These findings provide clinical decision makers with valuable insights into acalabrutinib use in the real-world as well as highlighting the importance of BTKi AE management in a real-world clinical setting. Further IAs are planned.

Infection Outcomes and Hypogammaglobulinemia in Patients with Chronic Lymphocytic Leukemia Treated with Immunoglobulin Replacement Therapy

CONCLUSIONS Hypogammaglobulinemia (HGG), a secondary immunodeficiency (SID), can manifest in patients with chronic lymphocytic leukemia (CLL) due to the disease and its treatments. Up to half of all deaths from CLL are attributed to infection; however, use of immunoglobulin replacement therapy (IgRT) for the prevention of infections in selected patients varies. We aimed to assess real-world IgRT utilization and infection outcomes in patients with CLL. A retrospective, longitudinal study evaluating real-world IgRT use in adult patients with CLL diagnosed after 2010, with ≥ 3 visits/year and ≥ 12 months of clinical data, was conducted. De-identified clinical data came from the Massachusetts General Brigham Research Patient Data Registry. Immunoglobulin G (IgG) testing, infection outcomes, and antimicrobial use were compared before versus after IgRT initiation. Generalized estimating equation logistic regression models calculated odds ratios (ORs), 95% CIs, and P-values. Of 3960 patients with CLL assessed, 2652 (67.0%) patients had IgG testing (29.0% tested at CLL diagnosis); 917 (34.6%) had HGG (IgG level &amp;lt; 500mg/dL). Median (interquartile range [IQR]) age was 68.0 (60.0, 76.0) years, 61.2% were men, 67.8% were treatment-naïve, and median (IQR) follow-up duration was 4.8 (2.4, 7.4) years. Among recipients of IgRT (n = 259), 56.8% received ≥ 2 administrations and the median (IQR) number of IgRT administrations was 2.0 (1.0, 4.0). Median (IQR) time from CLL diagnosis to IgRT initiation was 38.0 (11.4, 64.7) months. Significantly fewer patients had HGG 3 months after IgRT versus 3 months before (33.8% vs 72.8%; P &amp;lt; 0.0001). Significantly lower odds of infections and antimicrobial use were observed after IgRT initiation in 3- and 6-month time periods for: all infections, sinopulmonary and skin or soft tissue infections, infections requiring antimicrobials, all severe infections, severe sinopulmonary and skin or soft tissue infections, and severe infections requiring antimicrobials ( Table). In this real-world study of patients with CLL, IgRT was associated with significant reductions in HGG, infection rates, and infections requiring antimicrobials. Guidelines are needed to optimize IgG testing, IgRT initiation, and SID management for patients with CLL.

Outcomes and Treatment Sequences of Therapies with BCL2- and BTK Inhibitors in Chronic Lymphocytic Leukemia (CLL): An Analysis of Patient Data within the German CLL Study Group (GCLLSG) Registry

Introduction: Targeted agents, in particular BCL2-inhibitors (BCL2i) and BTK-inhibitors (BTKi), have profoundly improved the outcome of patients (pts) with chronic lymphocytic leukemia (CLL) and are considered standard treatment. However, the transition from treatments evaluated within clinical trials into routine clinical practice can be complex. We here present real-world data from the German CLL Study Group (GCLLSG) registry and report outcomes and treatment sequences of pts treated with either BCL2i (venetoclax) or BTKi (acalabrutinib, ibrutinib, spebrutinib, tirabrutinib, or zanubrutinib) as first administered targeted agent. Methods: Pts from multiple German sites with confirmed diagnosis of CLL and with at least one documented first-line CLL treatment between July 1 st 2014 and January 30 th 2023 were included in this analysis. Pts participating in an active clinical trial were excluded. Treatments were categorized according to the backbone of therapy and pts were allocated to either the venetoclax (Ven) or the BTKi cohort depending on their first treatment with one of these substances. Time to next treatment (TTNT), event-free survival (EFS) and overall survival (OS) were analyzed using Kaplan-Meier methods. Results: A total of 274 pts were treated with a Ven-based regimen while 915 pts were treated with a BTKi as first therapy. Median observation time from the first documented treatment (irrespective if given as first-line or in a later therapy line) was 26 months (range 0 - 296) in the Ven cohort and 78 months (range 0-266) in the BTKi cohort. For the Ven cohort, median age at the time of first Ven treatment was 71 years (range 32 - 87) with 172 pts (62.8%) being male. Median CIRS score was 2 (range 0-13) and 12 pts (7.5%) had an ECOG performance status &amp;gt; 1. Among 57 pts with known molecular genetics, 32 pts (56.1%) had an unmutated IGHV status and 9 out of 51 evaluable pts (17.6%) had a deletion and/or mutation TP53. Applying the CLL-IPI, 11 out of 58 evaluable pts (19.0%) were in the very high-risk group. In the BTKi cohort, median age at time of first BTKi treatment was 72 (range 32 - 92), with 628 pts (68.6%) being male. Median CIRS score was 3 (range 0-17) and 45 pts (9.5%) had an ECOG performance status &amp;gt; 1. Among 162 pts with available data, 108 pts (66.7%) had an unmutated IGHV status and 59 out of 130 evaluable pts (45.4%) had a deletion and/or mutation TP53. Using the CLL-IPI, 46 out of 145 evaluable pts (31.7%) were in the very high-risk group. A total of 152 of 274 pts (55.5%) in the Ven cohort received Ven as first-line treatment (median number of prior treatments: 0, range 0-9) and 352 of 915 pts (38.5%) in the BTKi cohort received a BTKi as first-line treatment (median number of prior treatments: 1, range 0-12). Among all 222 administered treatments prior to first Ven and 1090 treatments administered prior to first BTKi, chemoimmunotherapy (70.3% and 68.3%, respectively) and chemotherapy (10.4% and 17.8%, respectively) were the most frequent. For subsequent therapy following the first documented Ven or BTKi treatment, most pts were treated with targeted agent regimens. In the Ven cohort, 37 subsequent treatments were documented in 26 pts, of which 10 (27.0%) were a Ven-containing regimen and 13 (35.1%) a BTKi-containing regimen. Within the BTKi cohort, 393 subsequent treatments were administered in 264 pts, of which 146 (37.2%) included Ven and 106 (27.0%) a BTKi Treatment sequences were visualized with a sankey-diagram ( Figure 1). Median EFS from the start of the first documented Ven treatment was 31.8 months, with an estimated 2-year EFS rate of 66.6%. Median TTNT was 63.7 months and median OS was 96.5 months with an estimated 2-year OS rate of 89.5%. When Ven was given as first-line treatment, the estimated 2-year OS rate was 93.6% versus 86.5% when given in a later therapy line for the first time. For the BTKi cohort, median EFS from start of first documented BTKi treatment was 23.2 months, with an estimated 2-year EFS rate of 48.6%. Median TTNT was 68.4 months and median OS was 85.9 months with an estimated 2-year OS rate of 84.9%. When BTKi were given as first-line treatment, the estimated 2-year OS rate was 92.3% versus 81.3% when given in a later therapy line for the first time. Conclusion: EFS, TTNT and OS were comparable following Ven versus BTKi-based therapy in pts documented in the GCLLSG registry between 2014 and 2023.

Coronado CLL: A Phase Ib/II Trial of Combination Rp-3500 and Olaparib in DNA Damage Repair Pathway Deficient Relapsed/Refract ory Chronic Lymphocytic Leukemia

Background: Genes within the DNA damage repair ( DDR) pathways are frequently mutated in relapsed/refractory ( R/R) chronic lymphocytic leukemia ( CLL) and clinically correlate with decreased response rates and shortened progression-free ( PFS) and overall survivals ( OS). The most commonly affected DDR genetic aberrations include deletion 17p13 [ del(17p)], deletion 11q22.3 [ del(11q)], and mutations in TP53, ATM, SF3B1, XPO1 and POT1. Due to their poor clinical outcomes, patients (pts) with DDR-deficient CLL remain an area of unmet need and the development of novel drugs and combinations will be critical to improving their prognosis. Mechanistically, CLL cells with DDR genetic alterations lack double-stranded DNA breakage repair and major cell cycle checkpoint pathways. Therefore, R/R CLL cells are dependent on single-stranded DNA breakage ( SSB) repair and alternative DNA replication arrest machinery to ensure DNA integrity, strand repair and cell survival. DNA damage at the replication fork is primarily recognized by ataxia telangiectasia and rad3 ( ATR) protein, which ensures mitotic arrest and recruitment of poly (ADP-ribose) polymerase ( PARP) based SSB repair mechanisms. In germline DDR-deficient breast and ovarian cancers with BRCA1/BRCA2 mutations, the use of both single agent PARP inhibitors ( PARPi) and ATR inhibitors ( ATRi) have led to significant disease response and improved OS. Furthermore, combination PARPi and ATRi have demonstrated synergistic activity in preclinical data producing increased apoptosis and cell death in BRCA2-mutated ovarian cell lines. In DDR-deficient CLL primary cell and murine models, single agent PARPi and ATRi have demonstrated significant cell death as compared to wildtype CLL and healthy donor lymphocytes. RP-3500 is a highly potent ATRi. In preclinical data generated in SUM149PT DDR-deficient breast cancer cell lines, combining RP-3500 with the PARPi, olaparib, substantially reduced tumor volume at lower doses than the previously determined maximum tolerated dose ( MTD) of each drug when used as monotherapy. Furthermore, intermittent dosing of both drugs (3 days per week) demonstrated equal cell apoptosis as continuous dosing. Therefore, we hypothesize that the combination of RP-3500 and olaparib will be a highly efficacious treatment for R/R DDR-deficient CLL pts and that the lower dosages and intermittent dosing schedule required of each drug when administered in combination will improve safety of the treatment. Study Design and Methods: This is a multi-site (University of Utah and the Ohio State University), phase Ib/II investigator-initiated clinical trial using combination RP-3500 and olaparib in R/R CLL pts with DDR pathway deficiencies to determine the safety and efficacy of the drug combination (NCT05405309). Primary objectives include determining the MTD in phase Ib leading to the recommended phase 2 dose ( RP2D), and overall response rate ( ORR) in phase II. Key secondary objectives include safety and tolerability, PFS, OS and duration of response of the combination. Eligibility: Key inclusion criteria include a diagnosis of CLL according to the 2018 iwCLL guidelines, age ≥18 years, ECOG performance status of ≤2, R/R after at least 2 prior lines of therapy. Primary CLL cells must exhibit any one of the following abnormalities: a) somatic mutation(s) in TP53, ATM, SF3B1, XPO1 or POT1, or b) positive FISH for either del(17p) or del(11q). Statistical Methods: Phase Ib: The phase Ib of the trial will utilizea keyboard design, which is a novel Bayesian method that typically underestimates the MTD. The target toxicity is 30% with an equivalence interval between 25-33% of pts. With an anticipated 3 dose levels ( DL) and an option for a DL-1, up to 18 pts may be required to determine the MTD and RP2D. Phase II: Any pt treated at the RP2D within phase Ib will be rolled into the phase II analysis for efficacy. With a planned 24 evaluable pts in phase II, the target ORR will be 60%, which was selected due to a recent phase I/II study of pirtobrutinib enrolling a similar CLL pt population demonstrating an ORR of the drug ~63%. ORR will be summarized by the observed proportion and an exact one-sided 95% confidence interval (Clopper-Pearson method). With 24 evaluable pts, the lower bound of the confidence interval will be approximately 17-20% below the observed proportion for observed ORR near 60%, which is an acceptable level of precision in a dose expansion cohort.