Traditional Chemoimmunotherapy Research Articles

Recent Advances in the Molecular Biology of Chronic Lymphocytic Leukemia: How to Define Prognosis and Guide Treatment

Chronic Lymphocytic Leukemia (CLL) is the most frequent type of leukemia in Western countries. In recent years, there have been important advances in the knowledge of molecular alterations that underlie the disease’s pathogenesis. Very heterogeneous prognostic subgroups have been identified by the mutational status of immunoglobulin heavy variable genes (IGVH), FISH analysis and molecular evaluation of TP53 mutations. Next-generation sequencing (NGS) technologies have provided a deeper characterization of the genomic and epigenomic landscape of CLL. New therapeutic targets have led to a progressive reduction of traditional chemoimmunotherapy in favor of specific biological agents. Furthermore, in the latest clinical trials, the minimal residual disease (MRD) has emerged as a potent marker of outcome and a guide to treatment duration. This review focuses on recent insights into the understanding of CLL biology. We also consider the translation of these findings into the development of risk-adapted and targeted therapeutic approaches.

Current Approaches and Novel Agents in the Treatment of Chronic Lymphocytic Leukemia.

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

Chronic Lymphocytic Leukemia: Management of Adverse Events in the Era of Targeted Agents.

The treatment landscape for CLL has undergone a profound transformation with the advent of targeted agents (TAs) like Bruton's Tyrosine Kinase inhibitors (BTKis) and BCL-2 inhibitors (BCL-2is). These agents target crucial cellular pathways in CLL, offering superior efficacy over traditional chemo-immunotherapy, which has led to improved progression-free and overall survival rates. This advancement promises enhanced disease control and potentially normal life expectancy for many patients. However, the journey is not without challenges, as these TAs are associated with a range of adverse events (AEs) that can impact treatment efficacy and patient quality of life. This review focuses on detailing the various AEs related to TA management in CLL, evaluating their frequency and clinical impact. The aim is to present a comprehensive guide to the effective management of these AEs, ensuring optimal tolerability and efficacy of TAs. By reviewing the existing literature and consolidating findings, we provide insights into AE management, which is crucial for maximizing patient outcomes in CLL therapy.

Polatuzumab Vedotin (Polivy)


 CADTH recommends that Polivy in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) not be reimbursed by public drug plans for the treatment of adult patients with previously untreated large B-cell lymphoma (LBCL), including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOS), high-grade B-cell lymphoma, Epstein-Barr virus–positive DLBCL NOS, and T-cell/histiocyte-rich LBCL.
 Evidence from a clinical trial showed that 6.6% more patients with newly diagnosed moderate- to high-risk LBCL were alive without their disease progressing 2 years after treatment with Polivy in combination with R-CHP compared to those treated with traditional chemoimmunotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP]). However, there is uncertainty whether this difference observed in the clinical trial translates to a meaningful difference in the real world. The evidence from the trial did not show that Polivy combined with R-CHP prolonged survival compared to R-CHOP. It is also unknown if Polivy in combination with R-CHP would reduce disease symptoms or improve functioning compared to R-CHOP because there were no differences between the 2 groups.
 Patients identified a need for treatments that prolong disease remission, prolong survival, control disease symptoms, normalize blood counts, and improve quality of life. Based on the evidence submitted, it is not clear that Polivy in combination with R-CHP would provide a meaningful benefit in prolonging remission or meet the other important needs in LBCL.

Treatment of Richter's Transformation with Novel Therapies.

This review presents recently published clinical trial data and ongoing investigations regarding the treatment of Richter's transformation (RT). Recently, numerous approaches have been investigated for the treatment of RT including: traditional chemoimmunotherapy regimens combined with targeted agents such as BTKi and BCL2i; immunotherapy combined with targeted agents; non-covalent BTKis; bispecific T cell engagers; and CART therapy. In addition, various novel targeted agents are currently being studied for the treatment of RT in phase 1 and 2 clinical trials. Standard of care treatment with chemoimmunotherapy for RT has limited efficacy in achieving durable remissions. Here, we review recent data on the use of combination treatments and targeted agents in RT. Although some progress has been made in the investigation to optimize treatment of RT, further study is needed to evaluate long term outcomes of recently published trials and test efficacy of upcoming novel agents.

How I Manage Chronic Lymphocytic Leukemia.

Chronic lymphocytic leukemia (CLL), is a hematologic malignancy characterized by the uncontrolled proliferation of mature B lymphocytes. CLL is the most prevalent leukemia in Western countries. Its presentation can range from asymptomatic with the incidental finding of absolute lymphocytosis on a routine blood test, to symptomatic disease requiring immediate intervention. Prognosis of the disease is defined by the presence or absence of specific mutations such as TP53, chromosomal abnormalities such as del(17p), a type of IGHV mutational status, and elevation of B2M and LDH. Treatment of CLL in the United States and Europe has evolved over the recent years thanks to the development of targeted therapies. The standard of care has shifted from traditional chemoimmunotherapy approaches to targeted therapies including Bruton tyrosine kinase inhibitors (BTKis) and BCL2 inhibitors, administered either as monotherapy or in combination with CD20 monoclonal antibodies. Several clinical trials have also recently evaluated combinations of BTKi and venetoclax and showed the combination to be well tolerated and able to induce deep remissions. Targeted therapies have a good safety profile overall; however, they also have unique toxicities that are important to recognize. Diarrhea, fatigue, arthralgia, infections, cytopenias, bleeding, and cardiovascular toxicities (including atrial fibrillation, ventricular arrhythmias, and hypertension) are the adverse events (AEs) commonly associated with BTKis. Initiation of therapy with venetoclax requires close monitoring because of the risk for tumor lysis syndrome associated with this agent, particularly in patients with a high disease burden. Development of newer target therapies is ongoing and the therapeutic landscape in CLL is expanding rapidly.

Systematic literature review of quality-of-life questionnaires in Waldenström macroglobulinaemia-need for a disease-specific tool.

Systematic literature review of quality-of-life questionnaires in Waldenström macroglobulinaemia-need for a disease-specific tool.

A History of Targeted Therapy Development and Progress in Novel-Novel Combinations for Chronic Lymphocytic Leukemia (CLL).

Over the last 10 years, the traditional treatment paradigms for CLL have been upended as the use of traditional chemoimmunotherapy regimens has declined in favor of novel targeted therapies. Targeted therapies have become the new standard of care in CLL given their superior progression-free survival (and overall survival, in some cases) when compared with chemoimmunotherapy, as well as their improved toxicity profiles. Targeted agents are FDA approved for the treatment of CLL including ibrutinib, acalabrutinib, zanubrutinib, and venetoclax. Importantly, as opposed to traditional chemotherapy regimens, the benefits of these targeted therapies appear to be consistent regardless of high-risk mutational status. In this review, we discuss the pivotal CLL studies of the last decade and the data supporting doublet and triplet novel-novel combinations. We explore the use of new surrogate end points for PFS/OS in targeted therapies such as undetectable minimal residual disease (uMRD) and their potential role in minimizing toxicity by permitting earlier treatment discontinuation. We also highlight areas that warrant further exploration and future studies that may help address some of these key questions.

Real-world management of targeted therapies in chronic lymphocytic leukemia.

The advent of novel targeted therapies, including B-cell receptor (BCR) pathway and B-cell lymphoma 2 (BCL2) inhibitors, has substantially changed the treatment paradigm for chronic lymphocytic leukemia (CLL). Although targeted therapies have improved outcomes compared to traditional chemoimmunotherapy in the front-line and relapsed or refractory settings, they are associated with resistance mutations and suboptimal outcomes in certain high-risk patients. Additionally, targeted therapies are associated with drug interactions and unique adverse effect profiles which can be challenging for patients and clinicians to manage. Ongoing studies continue to address questions regarding optimal sequencing of therapies, the role of treatment combinations, and the efficacy of next-generation novel agents. This review provides a comprehensive overview regarding the clinical management of targeted therapies for CLL and applies current literature to clinical practice.

Sustained and Long-Term Release of Doxorubicin from PLGA Nanoparticles for Eliciting Anti-Tumor Immune Responses.

Immunogenic cell death (ICD) is a powerful trigger eliciting strong immune responses against tumors. However, traditional chemoimmunotherapy (CIT) does not last long enough to induce sufficient ICD, and also does not guarantee the safety of chemotherapeutics. To overcome the disadvantages of the conventional approach, we used doxorubicin (DOX) as an ICD inducer, and poly(lactic-co-glycolic acid) (PLGA)-based nanomedicine platform for controlled release of DOX. The diameter of 138.7 nm of DOX-loaded PLGA nanoparticles (DP-NPs) were stable for 14 days in phosphate-buffered saline (PBS, pH 7.4) at 37 °C. Furthermore, DOX was continuously released for 14 days, successfully inducing ICD and reducing cell viability in vitro. Directly injected DP-NPs enabled the remaining of DOX in the tumor site for 14 days. In addition, repeated local treatment of DP-NPs actually lasted long enough to maintain the enhanced antitumor immunity, leading to increased tumor growth inhibition with minimal toxicities. Notably, DP-NPs treated tumor tissues showed significantly increased maturated dendritic cells (DCs) and cytotoxic T lymphocytes (CTLs) population, showing enhanced antitumor immune responses. Finally, the therapeutic efficacy of DP-NPs was maximized in combination with an anti-programmed death-ligand 1 (PD-L1) antibody (Ab). Therefore, we expect therapeutic efficacies of cancer CIT can be maximized by the combination of DP-NPs with immune checkpoint blockade (ICB) by achieving proper therapeutic window and continuously inducing ICD, with minimal toxicities.

Majic: A Phase 3 Prospective, Multicenter, Randomized, Open-Label Trial of Acalabrutinib Plus Venetoclax Versus Venetoclax Plus Obinutuzumab in Previously Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

Majic: A Phase 3 Prospective, Multicenter, Randomized, Open-Label Trial of Acalabrutinib Plus Venetoclax Versus Venetoclax Plus Obinutuzumab in Previously Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

Real-World Testing Patterns for Risk Assessment and Implications on the Adoption of Novel Therapeutics in Chronic Lymphocytic Leukemia: IGHV Mutation Status, FISH Cytogenetic, and Immunophenotyping

Introduction: Prognostic testing, including immunoglobulin heavy-chain variable region gene (IgHV) mutation status, cytogenetic abnormalities by fluorescence in situ hybridization (FISH), and immunophenotyping has been recommended in all newly diagnosed patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) prior to treatment initiation, and even in previously treated patients in some settings. Recent data have shown that disease with high-risk genetic features is better managed with novel agents than traditional chemoimmunotherapy. As such, the need for testing has become more relevant for disease management. However, there is limited recent data on real-world patterns of testing for risk factor assessment and in-turn, patterns of evidence-based treatment selection. This study aimed to examine: (1) the frequency and results of testing, (2) timing of testing by line of therapy, and (3) factors associated with the receipt of testing.Methods: De-identified data from the Flatiron Health EHR-derived database was used to identify patients who were ≥18 years old with newly-diagnosed CLL/SLL, who had ≥6-month continuous enrollment, and no prior treatment from January 2014 to May 2021. Testing evaluated included IgHV mutation status, FISH cytogenetic (11q deletion [del(11q)], 13q deletion [del(13q)], 17p deletion [del(17p)], Trisomy 12 [+12]) and other biomarkers (including CD38 and ZAP-70) by immunophenotyping. Descriptive analyses were conducted to examine the frequency and results in the overall population, and compared by patient characteristics and across sociodemographic groups. Multivariable logistic regression was conducted to examine factors associated with the likelihood of receiving testing. Statistical significance was determined as a p-value of <0.05.Results: A total of 3,037 CLL patients were included (median age=73, 62.3% male, 74.6% white). The majority of patients (92%) received treatment in community practices, with 54.1% commercially-insured. We observed over half of CLL patients did not receive risk factor testing (Figure 1): IgHV mutation analyses (76.2%, n=2,315), FISH (61.5%, n=1,868) and immunophenotyping (72.1%, n=2,190). Of those who had testing, the majority (99%) had it done once prior to starting first-line therapy. Significant differences in the receipt of testing were observed between different age, gender, race/ethnicity, and regional subgroups (Table 1). Among patients who received testing, the presence of high-risk biomarkers was as follows: unmutated IgHV (56.1%), del(17p) present (14.4%), del(11q) present (16.9%), and CD38 present (30.8%). Compared to patients <65 years, testing results in elderly patients ≥65 years showed a lower presence of unmutated IgHV (53.8%) and del(11q) (15.7%) while higher del(17p) (14.7%) and +12 (28.1%). No significant disparity was observed in white vs. non-white patients except for a lower incidence of mutated IgHV and del(13q) presence. Compared to tested men, tested women had a lower presence of unmutated IgHV (53.9%), del(11q) (11.4%) and CD38+ (25.8%) while higher del(17p) (18.2%). We then investigated the impact of risk testing on therapy selection, and noted that patients with del(17p) had a higher likelihood than those who tested negative (73.6% vs. 48.4%) of being treated with novel agents (ibrutinib, acalabrutinib, or venetoclax). In contrast, 26.4% of those who tested del(17p) present and 39.8% among those who did not get tested received chemotherapy. Multivariable regression showed that patients who were older (≥65 years), female or those living in the west of U.S. were significantly less likely to receive testing.Conclusions: The NCCN guidelines recommend novel agents for patients with high-risk CLL/SLL. Thus, all patients are advised to complete risk-factor testing for both prognostication and selection of optimal, evidence-based therapy. Our real-world data highlights not only a significant gap in testing, but that this suboptimal testing is more common in vulnerable populations. We observed that despite identification of del(17), a quarter of CLL patients failed to receive novel agents in the frontline setting. Our analysis identified an unmet need for further education and refinement of clinical practice. This is necessary to achieve the best clinical outcome in CLL patients through robust risk-assessment testing and optimal therapeutic triaging. [Display omitted] DisclosuresChanan-Khan: BieGene, Jansen, Ascentage: Consultancy; Ascentage, Starton, Cellectar, NonoDev, Alpha2 Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Alpha2 Pharmaceuticals: Patents & Royalties: Tabi; Ascentage: Research Funding; Cellectar: Current equity holder in publicly-traded company; Alpha2 Pharmaceuticals, NonoDev, Starton: Current holder of stock options in a privately-held company; BeiGene, Jansen, Ascentage: Honoraria. Yang: BeiGene, Ltd.: Current Employment. Liu: BeiGene, Ltd.: Current Employment. Zimmerman: BeiGene, Ltd.: Current Employment. Tang: BeiGene, Ltd.: Current Employment. Ailawadhi: Ascentage: Research Funding; Medimmune: Research Funding; Pharmacyclics: Consultancy, Research Funding; GSK: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Genentech: Consultancy; Xencor: Research Funding; BMS: Consultancy, Research Funding; Karyopharm: Consultancy; Cellectar: Research Funding; Sanofi: Consultancy; Janssen: Consultancy, Research Funding; AbbVie: Consultancy; Beigene: Consultancy; Takeda: Consultancy.

Impact of Molecular Features of Diffuse Large B-Cell Lymphoma on Treatment Outcomes with Anti-CD19 Chimeric Antigen Receptor (CAR) T-Cell Therapy

Impact of Molecular Features of Diffuse Large B-Cell Lymphoma on Treatment Outcomes with Anti-CD19 Chimeric Antigen Receptor (CAR) T-Cell Therapy

Case Presentation – Frontline Treatment of Older Patient with CLL: Options and Consideration

AbstractThe advent of novel targeted therapies, specifically Bruton’s tyrosine kinase (BTK) inhibitors and the B-cell lymphoma 2 (BCL2) inhibitor, venetoclax, has revolutionized the treatment approach in the frontline setting for patients with chronic lymphocytic leukemia (CLL). By targeting BTK, a critical kinase in proximal B-cell receptor (BCR) signaling, this class of small molecule inhibitors impairs BCR-signaling and activation of NF-κB, and inhibits cell proliferation and migration.1,2 BCL2 is an antiapoptotic protein that is overexpressed in various B-cell cancers, including CLL.3 Venetoclax disrupts antiapoptotic signaling through BCL2, thereby inducing programmed cell death of CLL cells.4 Both of these options have significantly improved the efficacy of treatment in older patients in which efficacy of more traditional chemoimmunotherapy regimens was often hampered by increased toxicity limiting therapy. When embarking on initial therapy for patients with CLL and deciding between various options, it has become important to consider age, comorbidities, and functional condition as well as their disease specific features such as the results of their FISH and IGHV mutational status. Armed with this information, a provider can then review potential options of therapy with each patient focusing on both their disease specific features and comorbidities while taking into consideration their desire for continuous treatment versus time-limited therapy.

Reinforcing the Induction of Immunogenic Cell Death Via Artificial Engineered Cascade Bioreactor-Enhanced Chemo-Immunotherapy for Optimizing Cancer Immunotherapy.

Traditional chemo-immunotherapy can elicit T cell immune response by inducing immunogenic cell death (ICD), however, insufficient ICD limits the lasting antitumor immunotherapeutic efficacy. Herein, tadpole-ovoid manganese-doped hollow mesoporous silica coated gold nanoparticles (Au@HMnMSNs) as biodegradable catalytic cascade nanoreactors are constructed to generate intratumoral high-toxic hydroxyl radicals combined with DOX and Aspirin (ASA) for enhancing the induction of ICD and maturation of dendritic cells (DCs). The released Mn2+ can catalyze endogenous H2 O2 to hydroxyl radicals, while internal gold nanoparticles mimetic glucose oxidase (GOx) converted glucose into H2 O2 to accelerate the generation of hydroxyl radicals. On the other hand, tadpole oval-structured Au@HMnMSNs can avoid the inactivation of gold nanoparticles due to strong protein adsorption. The introduction of ASA is to recruit DCs and cytotoxic T lymphocytes (CTLs) to tumor sites and restrain the intratumoral infiltration of immunosuppressive cells by decreasing the expression of prostaglandin E2 (PGE2 ). Accordingly, this work presents a novel insight to introduce GOx-like catalytic cascade ICD nano-inducer into antitumor immunotherapy for synergistic tumor therapy.

Novel Treatments for Mantle Cell Lymphoma: From Targeted Therapies to CAR T Cells.

Mantle cell lymphoma is a rare B-cell non-Hodgkin's lymphoma that retains a sobering prognosis despite an extensive research effort. Mantle cell lymphoma remains incurable even with aggressive, and at times toxic, chemoimmunotherapy with early incorporation of autologous stem cell transplantation. Given this, attention has turned to the use of targeted therapies addressing dysregulation of B-cell signaling pathways. Drugs such as immunomodulatory agents, proteasome inhibitors, and Bruton's tyrosine kinase inhibitors have shown success in the relapsed/refractory population, and there is ongoing investigation into the utilization of novel Bruton's tyrosine kinase, B-cell leukemia/lymphoma-2, and spleen tyrosine kinase inhibitors alone or in combination in both the front-line and relapsed settings. Other areas of research in novel immunotherapies include investigations of bispecific T-cell engagers and antibody-drug conjugates. Most recently, chimeric antigen receptor T-cell therapy has been granted US Food and Drug Administration approval as a result of durable remissions even in high-risk patients who have classically done poorly with traditional chemoimmunotherapy. The intent of this article is to review the literature describing these selective therapies and discuss their current and future roles in the treatment of mantle cell lymphoma.

Zanubrutinib (BGB-3111), a Second-Generation Selective Covalent Inhibitor of Bruton's Tyrosine Kinase and Its Utility in Treating Chronic Lymphocytic Leukemia.

The understanding of the B cell receptor (BCR) pathway and its contribution to chronic lymphocytic leukemia (CLL) pathogenesis have led to the development of targeted BCR inhibitors which have transformed the treatment paradigm of CLL. Ibrutinib is a first-in-class oral Bruton’s tyrosine kinase (BTK) inhibitor which has demonstrated improvements in both progression free (PFS) and overall survival (OS) in both the treatment naïve and relapsed/refractory setting as compared to traditional chemoimmunotherapy. Despite its clinical efficacy, many patients discontinue treatment due to adverse events, which are thought to be mediated through off-target kinase inhibition. Zanubrutinib is a second-generation non-covalent BTK inhibitor with higher potency, allowing for inhibition of BTK with fewer off target effects. Early phase clinical trials have demonstrated excellent efficacy and a well-tolerated safety profile. Long-term follow-up is needed, but zanubrutinib holds promise to be an effective therapy for CLL with a manageable side effect profile and will be an exciting addition to our treatment paradigm.

High-Risk Mantle Cell Lymphoma in the Era of Novel Agents.

Mantle cell lymphoma (MCL) is a heterogenous disease with a variety of morphologic and genetic features, some of which are associated with high risk disease. Here we critically analyze the current state of the understanding of MCL's biology and its implications in therapy, with a focus on chemotherapy-free and targeted therapy regimens. Mantle cell lymphoma (MCL) is a rare subtype of non-Hodgkin's lymphoma, defined by a hallmark chromosomal translocation t(11;14) which leads to constitutive expression of cyclin D1. Recent discoveries in the biology of MCL have identified a number of factors, including TP53 mutations and complex karyotype, that lead to unresponsiveness to traditional chemoimmunotherapy and poor outcomes. Bruton tyrosine kinase inhibitors, BH3-mimetics and other novel agents thwart survival of the neoplastic B-cells in a manner independent of high-risk mutations and have shown promising activity in relapsed/refractory MCL. These therapies are being investigated in the frontline setting, while optimal responses to chemotherapy-free regimens, particularly in high-risk disease, might require combination approaches. High-risk MCL does not respond well to chemoimmunotherapy. Targeted agents are highly active in the relapsed refractory setting and show promise in high-risk disease. Novel approaches may soon replace the current standard of care in both relapsed and frontline settings.

Results of a Phase I Trial of Lenalidomide, Rituximab (R2) and Ixazomib for Frontline Treatment of High Risk Follicular and Indolent Non-Hodgkin Lymphoma

Results of a Phase I Trial of Lenalidomide, Rituximab (R2) and Ixazomib for Frontline Treatment of High Risk Follicular and Indolent Non-Hodgkin Lymphoma

Reaserch Advance on Inhibitor Targeting at the B-Cell Receptor Pathway in Chronic Lymphocytic Leukemia --Review

Abstract Disregulated BCR signaling pathway plays an important role in the occurence and progress of chronic lymphocytic leukemia (CLL). As key kinases of BCR pathway, the Bruton tyrosine kinase (BTK), phosphoinositide 3-kinase (PI3K) and spleen tyrosine kinase (SYK) have become the focus of CLL targeted therapy. Over the past decade, drugs targeting of BCR pathway for CLL treatment have been continuously developed, including BTK inhibitors, PI3K inhibitors and SYK inhibitors. To date, the BTK inhibitor Ibrutinib, PI3K inhibitors Idelalisib and Duvelisib have been approved for CLL treatment, and some novel inhibitors are still in clinical trials. These targeted drugs are much less toxic than chemoimmunotherapy and show better efficacy in certain high-risk patients such as del 17P. These inhibitors targeted BCR pathway are increasingly prominent in CLL treatment and gradually replace traditional chemoimmunotherapy.