Chronic Lymphocytic Leukemia

P3, N=600, Active, not recruiting, Loxo Oncology, Inc. | Recruiting --> Active, not recruiting

P1/2, N=23, Active, not recruiting, Joshua Brody | Recruiting --> Active, not recruiting | Trial completion date: Dec 2025 --> Nov 2026

P2, N=35, Recruiting, Fred Hutchinson Cancer Center | N=20 --> 35 | Trial completion date: Oct 2026 --> Mar 2027 | Trial primary completion date: Dec 2024 --> Mar 2025

In addition, we explore efficacy based on patient response and comparison between monotherapy and combination therapy. We also highlight the need for innovative strategies to overcome treatment resistance and enhance patient outcomes.

T-cell-dependent antibody responses require the activation of B cells by helper T cells. Reduced B cell numbers in immunocompromised patients infected with SARS-CoV-2 indicate the need for these patients to take additional precautions to prevent COVID-19 infection.

P1, N=316, Active, not recruiting, Eli Lilly and Company | Trial completion date: Dec 2024 --> Dec 2025

P1/2, N=54, Completed, Incyte Corporation | Active, not recruiting --> Completed

Despite a 60 % survival rate achieved with R-CHOP regiment for DLBCL, approximately 40 % of patients experience relapse or develop resistance to treatment...Furthermore, BCL11A protein expression levels demonstrated significant associations with P53 and C-MYC protein expression levels in the Germinal Center B-cell-like (GCB) subtype. These findings suggest that BCL11A may serve as a potential prognostic marker and therapeutic target for DLBCL.

Moreover, the TT genotype identifies CLL patients with a faster clinical progression even within subgroups of patients with low-risk biological and clinical hallmarks. In conclusion, our data show that the TT genotype identifies CLL patients with a shorter TTFT, pointing to this SNP as a possible prognostic factor, which can improve patients' risk stratification leading to better patient management and personalized therapeutic choices.

Interestingly, we found a higher CD4+HLA-G+ percentage in the group with unmutated immunoglobulin heavy chain variable region (IGHV) genes compared to the group with mutated IGHV gene after 48 h co-culture. In summary, increasing evidence has revealed that, in addition to HLA-G expressed on tumor cells, intercellular transfer of HLA-G among cancer cells and immune cells through trogocytosis plays important roles in mechanism of immune escape, disease progression and poor clinical outcome.

Here, we review FoxO1's roles across B cell and myeloid malignancies, namely acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Burkitt lymphoma (BL), Hodgkin lymphoma (HL), and multiple myeloma (MM). We also discuss preclinical evidence for FoxO1 targeting by currently available inhibitors (AS1708727, AS1842856, cpd10).

P2, N=15, Active, not recruiting, Bnai Zion Medical Center | Recruiting --> Active, not recruiting | Trial primary completion date: Mar 2024 --> Dec 2024

P1, N=154, Completed, Xencor, Inc. | Active, not recruiting --> Completed | N=270 --> 154 | Trial completion date: Jan 2025 --> Apr 2024 | Trial primary completion date: Oct 2024 --> Apr 2024

Based on our experience, SHM status can be achieved by routine NGS testing. Our first-year mutated-versus-unmutated test results are reasonably close to what is reported in the literature, supporting the effectiveness of this assay. The majority (66.6%) of QNS samples were due to lack of evidence of clonality in CLL samples.

Our NGS testing found tier 1 or 2 variants in the majority of cases, supporting its use in the clinical setting. Additionally, a subset of variants identified with the pan-Heme list likely represents mutations of clonal hematopoiesis of indeterminate potential, which could be removed with a more lymphoma-specific gene list. Given these findings, and a growing number of targets in indolent B cell lymphomas, future studies focusing on evaluation of a lymphoma-specific gene list is of interest for clinical validation and implementation.

P1, N=16, Active, not recruiting, Sana Biotechnology | Recruiting --> Active, not recruiting | N=57 --> 16 | Trial completion date: Dec 2027 --> Nov 2038 | Trial primary completion date: Dec 2026 --> Nov 2025

P1, N=20, Completed, Noah Merin | Active, not recruiting --> Completed | N=30 --> 20 | Trial completion date: Nov 2031 --> Nov 2024

P1/2, N=80, Recruiting, Beijing Tiantan Hospital, Capital Medical University; Hyperway Pharmaceutical Co.,Ltd.

P1, N=30, Not yet recruiting, National Heart, Lung, and Blood Institute (NHLBI)

Conclusions The presented liquid biopsy-based approach demonstrates the feasibility of identifying malignant cell fraction, BCR repertoires, clinically significant mutations, and immune and tissue specific processes from cfRNA. This study also suggests that the cfRNA platform may support longitudinal monitoring of CLL progression and relapse, as well the development of MRD tests with future validation.

VO is highly effective and feasible in both academic and community settings. The ability of obi to debulk patients prior to ven initiation allowed most patients to receive ven initiation in the outpatient setting. TLS is rare and was only seen secondary to obi.

Responses are durable, with 89%, 87%, and 77% 4-yr PFS in all-comer, uIGHV, and TP53 aberrant pts. Our data support further study of AVO for pts with TN high risk CLL in GCLLSG CLL16 and future trials.

Zanubrutinib is a second-generation BTKi with superior PFS and safety compared with ibrutinib (Brown NEJM 2023). Five-year follow up of the BOVen regimen demonstrates frequent uMRD4 in PB (96%) and BM (92%), and uMRD4 was durable with a median MRD4-free survival of 34 mo. Retreatment with zanubrutinib-venetoclax was also well-tolerated and effective. A phase 2 trial of BOVen with ΔMRD400-directed treatment duration is ongoing.

We selected 108 CLL patient samples with genetic annotation and exposed them ex-vivo to small-molecule inhibitors used clinically (ibrutinib/BTKi, duvelisib/PI3Ki, trametinib/MEKi, everolimus/mTORi, selinexor/XPO1i) or targeting key signaling pathways (compound 26/TLRi, MK2206/AKTi, nutlin-3a/MDM2i, IBET872/BETi) for 48h. In conclusion, the addition of targeted pathway perturbations to the GEP of primary CLL samples can greatly enhance the potential for molecular and functional classification of disease and subgroups. Our study provides a blueprint to use perturbed omics profiling and interaction testing to link disease drivers to pathway activation and function.

This study supports the use of MRD testing to guide duration of Ven / Obin therapy in the 1L setting. Early discontinuation of Ven/Obin for pts who are uMRD6 at C9 achieves similar PFS to pts who completed 12C of Ven/Obin and have uMRD5 status before entering TFO. In this study, concordance rate between PB and BM was relatively low (approximately two-thirds concordance) at 10-6 (C9) and 10-5 (C12) sensitivities.

Introduction: Combined treatment with covalent BTK-inhibitor (cBTKi), such as ibrutinib, acalabrutinib, or zanubrutinib with BCL2-inhibitor, venetoclax, +/- CD20 monoclonal antibody obinutuzumab showed high rates of undetectable MRD (U-MRD4, 10-4 sensitivity) remission in patients (pts) with CLL (Jain, NEJM 2019; Munir NEJM 2023; Wierda, JCO 2021; Kater, NEJM Evidence 2022). We report results of combined pirtobrutinib, venetoclax, and obinutuzumab in pts with previously untreated CLL. We observed a very high rate of BM U-MRD6 at 6-months and 12-months of combined treatment. Adverse event profile was similar to what was noted in previous studies with these agents.

P1/2, N=32, Active, not recruiting, Dana-Farber Cancer Institute | Phase classification: P1b/2 --> P1/2

P1/2, N=5, Terminated, University of Utah | N=39 --> 5 | Trial completion date: Aug 2027 --> Oct 2024 | Recruiting --> Terminated; This study was terminated due to sponsor de-activation of all programs associated with RP-3500 (camonsertib).

P=N/A, N=104, Completed, AstraZeneca | Active, not recruiting --> Completed

P1/2, N=24, Recruiting, Jonsson Comprehensive Cancer Center | Trial completion date: Oct 2025 --> Oct 2026 | Trial primary completion date: Oct 2024 --> Oct 2025

P1/2, N=40, Completed, Nanjing Zenshine Pharmaceuticals | Recruiting --> Completed | N=70 --> 40

Finally, all acute myeloid leukaemia (n = 52) and most T-cell non-Hodgkin lymphoma (n = 31/32) tested samples were negative for ROR1 via IHC. In conclusion, ROR1 shows a heterogeneous tumour cell expression profile across multiple leukaemias and lymphomas, making it a tumour target that would require different patient selection strategies to develop novel therapeutic modalities.

In addition, cold physical plasma and PTL treatment elevated ITGB3 mRNA expression in CLL patients' leukocytes compared to untreated and healthy controls. Collectively, our study suggests selective effects of direct cold physical plasma and PTL exposure on blood leukocytes from leukemia patients, but further and more detailed studies are needed to provide additional rationales for such treatment options as future therapy.

P2, N=100, Not yet recruiting, VA Office of Research and Development | Trial completion date: Dec 2029 --> Dec 2030 | Trial primary completion date: Jun 2029 --> Jun 2030

P2, N=60, Active, not recruiting, Jennifer R. Brown, MD, PhD | Trial primary completion date: Dec 2023 --> Dec 2026

P1, N=120, Active, not recruiting, Kymera Therapeutics, Inc. | Recruiting --> Active, not recruiting

P=N/A, N=200, Recruiting, Masonic Cancer Center, University of Minnesota | Trial completion date: Oct 2025 --> Oct 2026 | Trial primary completion date: Oct 2024 --> Oct 2025

We found that quercetin increased Bcl-2-associated X protein (Bax) expression in KG-1. Our study provides a novel function for quercetin and presents a promising strategy for AML treatment using venetoclax.

FOXO3a increases the expression of superoxide dismutase-2, catalase, glutathione peroxidase, peroxiredoxin-3 and -5, and the activity of natural killer cells, which promotes the survival of tumor cells. The development of new targeted pharmacological agents that are capable of accumulating reactive oxygen species and reducing antioxidant protection due to the degradation of erythroid nuclear factor-2 and activation of NADPH-quinone oxidoreductase-1 is underway, which modernizes the therapy of chronic lymphocytic leukemia.

P1, N=165, Recruiting, AbbVie

P1, N=25, Terminated, Novartis Pharmaceuticals | Active, not recruiting --> Terminated; Business, strategic, and development considerations and not due to any safety concerns

Together, this highlights CD38 as an important regulator of CD45 activity via CD43 and galectin-1, in turn acting as a positive modulator of CLL proliferation. Ultimately, the CD38/CD45 molecular hub could be an important therapeutic target in CLL.