Project description:The concept of precision cell therapy targeting tumor-specific mutations is appealing but requires surface-exposed neoepitopes, which is a rarity in cancer. B cell receptors (BCR) of mature lymphoid malignancies are exceptional in that they harbor tumor-specific-stereotyped sequences in the form of point mutations that drive self-engagement of the BCR and autologous signaling. Here, we use a BCR light chain neoepitope defined by a characteristic point mutation (IGLV3-21R110) for selective targeting of a poor-risk subset of chronic lymphocytic leukemia (CLL) with chimeric antigen receptor (CAR) T cells. We develop murine and humanized CAR constructs expressed in T cells from healthy donors and CLL patients that eradicate IGLV3-21R110 expressing cell lines and primary CLL cells, but neither cells expressing the non-pathogenic IGLV3-21G110 light chain nor polyclonal healthy B cells. In vivo experiments confirm epitope-selective cytolysis in xenograft models in female mice using engrafted IGLV3-21R110 expressing cell lines or primary CLL cells. We further demonstrate in two humanized mouse models lack of cytotoxicity towards human B cells. These data provide the basis for advanced approaches of resistance-preventive and biomarker-guided cellular targeting of functionally relevant lymphoma driver mutations sparing normal B cells.

| S-EPMC10837166 | biostudies-literature

IGLV3-21R110 mutation has prognostic value in patients with treatment-naive chronic lymphocytic leukemia.

Project description: Not available

| S-EPMC10726246 | biostudies-literature

IGLV3-21R110 identifies an aggressive biological subtype of chronic lymphocytic leukemia with intermediate epigenetics.

Project description:B-cell receptor (BCR) signaling is crucial for chronic lymphocytic leukemia (CLL) biology. IGLV3-21-expressing B cells may acquire a single point mutation (R110) that triggers autonomous BCR signaling, conferring aggressive behavior. Epigenetic studies have defined 3 CLL subtypes based on methylation signatures reminiscent of naïve-like (n-CLL), intermediate (i-CLL), and memory-like (m-CLL) B cells with different biological features. i-CLL carries a borderline IGHV mutational load and significantly higher use of IGHV3-21/IGLV3-21. To determine the clinical and biological features of IGLV3-21R110 CLL and its relationship to these epigenetic subtypes, we characterized the immunoglobulin gene of 584 CLL cases using whole-genome/exome and RNA sequencing. IGLV3-21R110 was detected in 6.5% of cases: 30 (38%) of 79 i-CLLs, 5 (1.7%) of 291 m-CLLs, and 1 (0.5%) of 189 n-CLLs. All stereotype subset 2 cases carried IGLV3-21R110, whereas 62% of IGLV3-21R110 i-CLL cases had nonstereotyped BCR immunoglobulins. IGLV3-21R110 i-CLL had a significantly higher number of SF3B1 and ATM mutations and total number of driver alterations. However, the R110 mutation was the sole alteration in 1 i-CLL and was accompanied only by del(13q) in 3. Although IGHV mutational status varied, IGLV3-21R110 i-CLL transcriptomically resembled n-CLL/unmutated IGHV CLL with a specific signature including WNT5A/B overexpression. In contrast, i-CLL lacking IGLV3-21R110 mirrored m-CLL/mutated IGHV. Patients with IGLV3-21R110 i-CLL had a short time to first treatment and overall survival similar to those of n-CLL/unmutated IGHV patients, whereas patients with non-IGLV3-21R110 i-CLL had a good prognosis similar to that of patients with m-CLL/mutated IGHV. IGLV3-21R110 defines a CLL subgroup with specific biological features and an unfavorable prognosis independent of IGHV mutational status and epigenetic subtype.

| S-EPMC8191863 | biostudies-literature

Real-world comparative effectiveness of acalabrutinib and ibrutinib in patients with chronic lymphocytic leukemia.

Project description:Novel agents, including Bruton tyrosine kinase inhibitors (BTKis), have become the standard of care for patients with chronic lymphocytic leukemia (CLL). We conducted a real-world retrospective analysis of patients with CLL treated with acalabrutinib vs ibrutinib using the Flatiron Health database. Patients with CLL were included if they initiated acalabrutinib or ibrutinib between 1 January 2018 and 28 February 2021. The primary outcome of interest was time to treatment discontinuation (TTD). Kaplan-Meier analysis was used to estimate unweighted and weighted median TTD. A weighted Cox proportional hazards model was used to compare the TTD between cohorts. Of the 2509 patients included in the analysis, 89.6% received ibrutinib, and 14.1% received acalabrutinib. TTD was not significantly different between cohorts in the unweighted analysis. After weighting, the cohorts were balanced on all baseline characteristics except cardiovascular risk factors and baseline medications use. The median (95% confidence interval [CI]) TTD was not reached (NR; 95% CI, 25.1 to NR) for the acalabrutinib cohort and was 23.4 months (95% CI, 18.1-28.7) for the ibrutinib cohort. The discontinuation rate at 12 months was 22% for the weighted acalabrutinib cohort vs 31% for the weighted ibrutinib cohort (P = .005). After additional adjustment for prior BTKi use, the acalabrutinib cohort had a 41% lower risk of discontinuation vs ibrutinib (hazard ratio, 0.59; 95% CI, 0.43-0.81; P = .001). In the largest available study comparing BTKis, patients with CLL receiving acalabrutinib demonstrated lower rates of discontinuation and a prolonged time to discontinuation vs those receiving ibrutinib.

| S-EPMC10424141 | biostudies-literature

Real-World Effectiveness of Frontline Treatments Among Patients with Chronic Lymphocytic Leukemia: Results from ConcertAI.

Project description:Background: The long-term follow-up of clinical trials of novel first-line (1L) therapies for chronic lymphocytic leukemia (CLL) demonstrates 6-10-year progression-free survival. We describe the effectiveness of 1L CLL treatments in real-world settings, with an emphasis on the important real-world outcome of time to next treatment or death (TTNT-D). Methods: This retrospective, observational study utilized de-identified electronic health records from the ConcertAI RWD360™ database with linked administrative open claims. Adults with CLL who initiated an approved 1L CLL therapy (June 2019-March 2023) were included. Duration of therapy (DoT), TTNT-D, and overall survival were assessed. Results: At 1L, 39.8% of 1843 patients received first-generation covalent Bruton tyrosine kinase inhibitors (cBTKis), 23.0% second-generation cBTKis, 12.4% venetoclax-obinutuzumab (VenO), 7.4% chemotherapy/chemoimmunotherapy (CT/CIT), and 17.4% anti-CD20 monotherapy. Median (range) follow-up in months was 24.9 (13.1-36.6) for first-generation cBTKis, 13.4 (7.3-21.7) for second-generation cBTKis, 16.0 (8.4-27.8) for VenO, 21.8 (11.2-32.7) for CT/CIT, and 19.7 (10.0-33.4) for anti-CD20 monotherapy. Median (range) DoT was 11.5 (4.2-25.0) and 8.6 (3.0-16.1), 9.1 (5.9-12.2), 5.6 (3.2-5.8), and 1.6 (1.6-4.5) months for first- and second-generation cBTKis, VenO, CT/CIT, and anti-CD20 monotherapy, respectively. Regarding TTNT-D, at 2 years' follow-up, 69.1%, 82.5%, 86.3%, 79.1%, and 53.0% of patients treated with first- and second-generation cBTKis, VenO, CT/CIT, and anti-CD20 monotherapy, respectively, had not initiated subsequent treatment or experienced death. Conclusions: TTNT-D is an important real-world outcome in CLL. Our findings demonstrated the utility of time-limited VenO, with potentially more time off treatment, relative to continuous 1L cBTKi therapies.

| S-EPMC11899398 | biostudies-literature

Real-world incidence and prevention of tumor lysis syndrome in chronic lymphocytic leukemia treated with venetoclax.

Project description:AbstractVenetoclax is a B-cell lymphoma 2 inhibitor used in chronic lymphocytic leukemia (CLL), which can cause tumor lysis syndrome (TLS). We aimed to determine the incidence of, and risk factors for, TLS among patients with CLL/small lymphocytic lymphoma who received treatment with venetoclax at our institution from 1 January 2016 to 31 December 2020. We included 616 venetoclax escalations among 136 patients with CLL. Overall, 74 patients (54%) underwent escalation exclusively outpatient, 35 (26%) had at least 1 planned hospitalization, and 27 (20%) were escalated exclusively inpatient. During venetoclax initiation, 86% of patients received allopurinol, 71% intravenous hydration, 18% phosphate binders, and 10% prophylactic rasburicase. Among the entire cohort, 7 patients (5.1%) developed laboratory TLS by modified Cairo Bishop criteria and none developed clinical TLS. Incidence of laboratory TLS was 15% for those escalated exclusively inpatient, 2.9% for those with any prophylactic hospitalization, and 2.7% for those escalated exclusively outpatient. Those who developed TLS were more likely to have higher TLS risk, and no additional risk factors were identified. In this single institution retrospective cohort study, laboratory TLS was observed, although clinical TLS was not. Prophylactic measures, including use of IV hydration, may have contributed to low rates of observed TLS in the outpatient setting.

| S-EPMC11609363 | biostudies-literature

Real-world testing and treatment patterns in chronic lymphocytic leukemia: A SEER patterns of care analysis.

Project description:BackgroundLaboratory testing and treatments for chronic lymphocytic leukemia (CLL) have changed dramatically within the last decade. The authors evaluated changes in patterns of real-world testing and treatment over time by comparing 2 population-based cohorts.MethodsThe National Cancer Institute-sponsored Patterns of Care study was conducted among patients with CLL who were sampled from 14 Surveillance, Epidemiology, and End Results (SEER) program registries. Demographics, testing, and treatment data were abstracted from medical records within 24 months of diagnosis.ResultsA total of 1008 patients diagnosed in 2008 and 1367 patients diagnosed in 2014 were included. There was a significant increase in fluorescence in situ hybridization (FISH) testing, immunoglobulin heavy-chain variable region gene (IgVH ) mutation analyses, and lymph node biopsies between 2008 and 2014. FISH testing was performed in the majority of, but not all, treated patients (53% in 2008, which increased to 62% in 2014). Some differences in the receipt of FISH testing by age and insurance status were observed over time (older patients and Medicare patients without private insurance were less likely to be tested in 2014). There were contrasting testing patterns noted by practice type and year, with nonteaching hospitals more likely to perform bone marrow biopsies in 2008, and teaching hospitals more likely to perform FISH and IgVH testing in 2014. There also were differences in treatments over time, with the use of bendamustine and rituximab being more common in 2014, at the expense of fludarabine, cyclophosphamide, and rituximab.ConclusionsThere have been rapidly changing practices in the testing and treatment patterns of patients with CLL within the last decade.

| S-EPMC6309467 | biostudies-literature

Systematic Literature Review of Real-World Effectiveness Results Data for First-Line Ibrutinib in Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma.

Project description:Background and objectiveIbrutinib, an oral Bruton's tyrosine kinase inhibitor, has demonstrated efficacy as a first-line treatment for chronic lymphocytic leukemia in multiple, phase III, randomized clinical trials. This systematic literature review assessed the clinical effectiveness of ibrutinib in the first-line treatment of chronic lymphocytic leukemia in real-world clinical settings.MethodsMEDLINE, EMBASE, and relevant conference websites were searched for articles published in the USA from 1 January, 2014 to 30 June, 2020. Overall survival, progression-free survival, overall response rate, and time to next treatment were summarized.ResultsThis analysis included a total of 12 publications representing data from 112 to 2033 patients from community and academic centers, and the multicenter informCLL registry. Patients were predominantly male (60-99%) with a median age range from 62 to 77 years, and included those with high-risk genomic features (del[17p]: 21-33%; del[11q]: 33%; and unmutated immunoglobulin heavy chain variable gene: 59%). Real-world effectiveness with ibrutinib complemented the efficacy demonstrated in randomized clinical trials. Across various studies, the 12-month overall survival rates ranged from 95% to 96%; 18-month overall survival rates were similarly high (91%). Twelve-month progression-free survival rates ranged from 89% to 93%, and the overall response rate ranged from 71% to 90% across four studies. In the studies that reported time to next treatment, 91% and 87% of patients treated with first-line ibrutinib did not initiate new treatment at 12 months and 24 months, respectively.ConclusionsThis systematic literature review confirms the benefit of ibrutinib as a first-line treatment in patients with chronic lymphocytic leukemia in real-world clinical settings and is consistent with results from randomized clinical trials, including in patients with high-risk genomic features.

| S-EPMC9943824 | biostudies-literature

Real-world treatment and outcomes among older adults with chronic lymphocytic leukemia before the novel agents era.

Project description: Not available

| S-EPMC6165790 | biostudies-literature