Phase II Study of Acalabrutinib, Venetoclax, and Obinutuzumab in a Treatment-Naïve Chronic Lymphocytic Leukemia Population Enriched for High-Risk Disease.

Purpose: The AMPLIFY trial recently established fixed-duration acalabrutinib, venetoclax, and obinutuzumab (AVO) as a new standard-of-care option for patients with previously untreated chronic lymphocytic leukemia (CLL) with wild-type ; however, due to the chemoimmunotherapy control arm, AMPLIFY excluded patients with high-risk aberration, for whom current standards of care are continuous Bruton tyrosine kinase inhibitor therapy or alternatively fixed-duration venetoclax-based doublets. AVO has not previously been evaluated in patients with CLL with aberration.

Methods: This investigator-sponsored, multicenter, phase II study enrolled patients with treatment-naïve CLL enriched for high-risk CLL, defined by aberration (ClinicalTrials.

Investigating the influence of germline variants in chronic lymphocytic leukemia on cancer vulnerability.

Chronic lymphocytic leukemia (CLL) patients have an increased risk of secondary cancers, along with predisposition to CLL in their relatives. We have previously identified germline ATM variants as associated with CLL risk; here, we present their impact on predisposition to secondary neoplasms in CLL patients and their relatives. Patients enrolled in our tissue bank who had germline ATM status available were mailed a questionnaire between April 2022 and May 2023.

Assaying and classifying T cell function by cell morphology.

Immune cell function varies tremendously between individuals, posing a major challenge to emerging cellular immunotherapies. This report pursues the use of cell morphology as an indicator of high-level T cell function. Short-term spreading of T cells on planar, elastic surfaces was quantified by 11 morphological parameters and analyzed to identify effects of both intrinsic and extrinsic factors.

FoxO1/Rictor axis induces a nongenetic adaptation to ibrutinib via Akt activation in chronic lymphocytic leukemia.

Bruton tyrosine kinase (BTK) inhibitor therapy induces peripheral blood lymphocytosis in chronic lymphocytic leukemia (CLL), which lasts for several months. It remains unclear whether nongenetic adaptation mechanisms exist, allowing CLL cells' survival during BTK inhibitor-induced lymphocytosis and/or playing a role in therapy resistance. We show that in approximately 70% of CLL cases, ibrutinib treatment in vivo increases Akt activity above pretherapy levels within several weeks, leading to compensatory CLL cell survival and a more prominent lymphocytosis on therapy.

Myeloid clonal hematopoiesis of indeterminate potential in patients with chronic lymphocytic leukemia.

Clonal hematopoiesis of indeterminate potential (CHIP) in patients with chronic lymphocytic leukemia (CLL) has not been extensively characterized. The objective of this study was to describe the prevalence of myeloid CHIP (M-CHIP) in patients with CLL, and to determine its association with time to first treatment (TTFT) and overall survival (OS). We retrospectively analyzed data from patients participating in a prospective CLL database at the Dana-Farber Cancer Institute who had standard-of-care targeted 95-gene next-generation sequencing (NGS) performed.

The influence of sampling method and season on modeling of selenium into coldwater fish and implications on tissue-based water quality benchmarks.

Selenium (Se) contamination of aquatic ecosystems has led to the local extirpation of some Se-sensitive fish species. Although Se exposure occurs primarily via diet, considerable uncertainty lies in modeling Se transfer and bioaccumulation from sediment, detritus, and/or periphyton through benthic macroinvertebrates (BMI) to fish. Here we estimated Se concentrations in four coldwater fish species (northern pike, white sucker, lake whitefish, and ninespine stickleback) inhabiting boreal lakes downstream from a uranium mill in northern Canada.

Genetic events associated with venetoclax resistance in CLL identified by whole-exome sequencing of patient samples.

Although BCL2 mutations are reported as later occurring events leading to venetoclax resistance, many other mechanisms of progression have been reported though remain poorly understood. Here, we analyze longitudinal tumor samples from 11 patients with disease progression while receiving venetoclax to characterize the clonal evolution of resistance. All patients tested showed increased in vitro resistance to venetoclax at the posttreatment time point.

Circulating Th17 T cells at treatment onset predict autoimmune toxicity of PI3Kδ inhibitors.

PI3Kδ inhibitors are approved for the therapy of B cell malignancies, but their clinical use has been limited by unpredictable autoimmune toxicity, despite promising efficacy and evidence that toxicity is associated with improved clinical outcomes. Prior phenotypic evaluation by CyTOF has identified increases in activated CD8 T cells with activation of Th17 T cells, as well as decreases in Tregs, particularly in patients with toxicity. Here we sought to further understand the effects of idelalisib and duvelisib in vitro, and demonstrate that both idelalisib and duvelisib can inhibit T cell proliferation as well as Th1 and Treg differentiation in vitro, while promoting Th2 and Th17 differentiation.

A phase 1b study of ibrutinib in combination with obinutuzumab in patients with relapsed or refractory chronic lymphocytic leukemia.

This study investigated ibrutinib plus obinutuzumab in relapsed/refractory CLL, evaluating tolerability of 3 sequencing regimens as well as overall safety and efficacy. Fifty-two patients were initially randomized 1:1:1 to receive either obinutuzumab 1 month before ibrutinib initiation, ibrutinib 1 month prior to obinutuzumab initiation, or to start both drugs concomitantly. Higher rates of infusion-related reactions were observed with the first sequence, and only the latter 2 cohorts were expanded.

Evolutionary history of transformation from chronic lymphocytic leukemia to Richter syndrome.

Richter syndrome (RS) arising from chronic lymphocytic leukemia (CLL) exemplifies an aggressive malignancy that develops from an indolent neoplasm. To decipher the genetics underlying this transformation, we computationally deconvoluted admixtures of CLL and RS cells from 52 patients with RS, evaluating paired CLL-RS whole-exome sequencing data. We discovered RS-specific somatic driver mutations (including IRF2BP2, SRSF1, B2M, DNMT3A and CCND3), recurrent copy-number alterations beyond del(9p21)(CDKN2A/B), whole-genome duplication and chromothripsis, which were confirmed in 45 independent RS cases and in an external set of RS whole genomes.

Rare Germline Variants Influence the Development of Chronic Lymphocytic Leukemia.

Purpose: Germline missense variants of unknown significance in cancer-related genes are increasingly being identified with the expanding use of next-generation sequencing. The ataxia telangiectasia-mutated () gene on chromosome 11 has more than 1,000 germline missense variants of unknown significance and is a tumor suppressor. We aimed to determine if rare germline variants are more frequent in chronic lymphocytic leukemia (CLL) compared with other hematologic malignancies and if they influence the clinical characteristics of CLL.

Functional Testing to Characterize and Stratify PI3K Inhibitor Responses in Chronic Lymphocytic Leukemia.

Purpose: PI3K inhibitors (PI3Ki) are approved for relapsed chronic lymphocytic leukemia (CLL). Although patients may show an initial response to these therapies, development of treatment intolerance or resistance remain clinical challenges. To overcome these, prediction of individual treatment responses based on actionable biomarkers is needed.

Idelalisib activates AKT via increased recruitment of PI3Kδ/PI3Kβ to BCR signalosome while reducing PDK1 in post-therapy CLL cells.

Idelalisib targets PI3Kδ in the BCR pathway generating only a partial response in CLL patients, indicating that the leukemic cells may have evolved escape signals. Indeed, we detected increased activation of AKT accompanied by upregulation of MYC/BCL2 in post-therapy CLL cells from patients treated with idelalisib/ofatumumab. To unravel the mechanism of increased AKT-activation, we studied the impact of idelalisib on a CLL-derived cell line, MEC1, as a model.

Idelalisib reduces regulatory T cells and activates T helper 17 cell differentiation in relapsed refractory patients with chronic lymphocytic leukaemia.

Phosphatidylinositol 3 kinase (PI3K) inhibitors such as idelalisib have been associated with potentially severe autoimmune toxicity. In the present study, we demonstrate that relapsed refractory patients with chronic lymphocytic leukaemia treated with idelalisib rituximab on the phase III registration trial show uniform decrease in regulatory T cells (Tregs) and increase in CD8 T cells with treatment. Patients who do not develop toxicity show enrichment for T cells expressing multiple chemokine receptors, while those who do develop toxicity have an activated CD8 T cell population with T helper 17 cell differentiation at baseline, which then increases, leading to an increased CD8:Treg ratio that likely triggers autoimmune toxicity.

A T cell inflammatory phenotype is associated with autoimmune toxicity of the PI3K inhibitor duvelisib in chronic lymphocytic leukemia.

Several PI3Kδ inhibitors are approved for the therapy of B cell malignancies, but their clinical use has been limited by unpredictable autoimmune toxicity. We have recently reported promising efficacy results in treating chronic lymphocytic leukemia (CLL) patients with combination therapy with the PI3Kδγ inhibitor duvelisib and fludarabine cyclophosphamide rituximab (FCR) chemoimmunotherapy, but approximately one-third of patients develop autoimmune toxicity. We show here that duvelisib FCR treatment in an upfront setting modulates both CD4 and CD8 T cell subsets as well as pro-inflammatory cytokines.

Activation of and Signaling via B-cell-Restricted Depletion of Generates a Consistent Murine Model of Chronic Lymphocytic Leukemia.

Chronic lymphocytic leukemia (CLL) is characterized by disordered DNA methylation, suggesting these epigenetic changes might play a critical role in disease onset and progression. The methyltransferase is a key regulator of DNA methylation. Although somatic mutations in CLL are rare, we found that low expression is associated with more aggressive disease.

Post-Transformation IGHV-IGHD-IGHJ Mutations in Chronic Lymphocytic Leukemia B Cells: Implications for Mutational Mechanisms and Impact on Clinical Course.

Analyses of IGHV gene mutations in chronic lymphocytic leukemia (CLL) have had a major impact on the prognostication and treatment of this disease. A hallmark of IGHV-mutation status is that it very rarely changes clonally over time. Nevertheless, targeted and deep DNA sequencing of IGHV-IGHD-IGHJ regions has revealed intraclonal heterogeneity.

Multi-Factor Clustering Incorporating Cell Motility Predicts T Cell Expansion Potential.

Expansion of an initial population of T cells is essential for cellular immunotherapy. In Chronic Lymphocytic Leukemia (CLL), expansion is often complicated by lack of T cell proliferation, as these cells frequently show signs of exhaustion. This report seeks to identify specific biomarkers or measures of cell function that capture the proliferative potential of a starting population of cells.

Preneoplastic Alterations Define CLL DNA Methylome and Persist through Disease Progression and Therapy.

Most human cancers converge to a deregulated methylome with reduced global levels and elevated methylation at select CpG islands. To investigate the emergence and dynamics of the cancer methylome, we characterized genome-wide DNA methylation in pre-neoplastic monoclonal B cell lymphocytosis (MBL) and chronic lymphocytic leukemia (CLL), including serial samples collected across disease course. We detected the aberrant tumor-associated methylation landscape at CLL diagnosis and found no significantly differentially methylated regions in the high-count MBL-to-CLL transition.