Enhancement of complement-dependent cytotoxicity by linking factor-H derived short consensus repeats 19-20 to CD20 antibodies.

Antibody-mediated complement-dependent cytotoxicity (CDC) on malignant cells is regulated by several complement control proteins, including the inhibitory complement factor H (fH). fH consists of 20 short consensus repeat elements (SCRs) with specific functional domains. Previous research revealed that the fH-derived SCRs 19-20 (SCR1920) can displace full-length fH on the surface of chronic lymphocytic leukemia (CLL) cells, which sensitizes CLL cells for e.g. CD20-targeting therapeutic monoclonal antibody (mAb) induced CDC. Therefore, we constructed lentiviral vectors for the generation of cell lines that stably produce mAb-SCR-fusion variants starting from the clinically approved parental mAbs rituximab, obinutuzumab and ofatumumab, respectively. Flow-cytometry revealed that the modification of the mAbs by the SCRs does not impair the binding to CD20. Increased in vitro lysis potency compared to their parental mAbs was corroborated by showing specific and dose dependent target cell elimination by CDC when compared to their parental mAbs. Lysis of CLL cells was not affected by the depletion of NK cells, suggesting that antibody-dependent cellular cytotoxicity plays a minor role in this context. Overall, this study emphasizes the crucial role of CDC in the elimination of CLL cells by mAbs and introduces a novel approach for enhancing CDC by directly fusing fH SCR1920 with mAbs.

Complex evaluation of serum immunoglobulin levels in patients with chronic lymphocytic leukemia: Significant increase in IgA after first-line chemoimmunotherapy.

INTRODUCTION: The impact of chemoimmunotherapy (CIT) on immunoglobulin (Ig) quantities in patients with chronic lymphocytic leukemia (CLL) has not been extensively studied. METHODS: We analyzed Ig levels in 45 stable patients with indolent CLL (without indication for treatment) and 87 patients with progressive disease before first-line treatment. Fifty-five patients were evaluated again after the treatment with CIT. RESULTS: We observed significantly lower levels of all Ig classes and subclasses in patients with progressive disease compared to patients with indolent disease. After treatment, median IgA increased from 0.59 g/L to 0.74 g/L (p = 0.0031). In stable patients, lower IgA2 was associated with shorter time to first treatment, although it did not reach statistical significance (p = 0.056). Shorter overall survival was observed in patients with progressive disease and lower IgG2 (p = 0.043). Surprisingly, among the patients with progressive CLL, unmutated IGHV genes were associated with higher levels of IgG, IgG1 and IgM, while TP53 mutation and/or 17p deletion were associated with higher levels of IgA and IgA1. CONCLUSIONS: CIT may lead to increase in IgA levels. Hypogammaglobulinemia is more common in patients with progressive CLL and unmutated IGHV or TP53 dysfunction.

Contemporary Standard of Care Therapy for Richter's Transformation and Future Directions.

Richter's transformation (RT) is a life-threatening evolution of chronic lymphocytic leukemia (CLL) into a more aggressive lymphoma, typically diffuse large B-cell lymphoma (DLBCL), marking a challenging juncture in CLL management due to the associated poor prognosis and limited treatment options. This review delves into the current therapeutic landscape for RT. Despite the modest efficacy of traditional chemoimmunotherapy (CIT) regimens such as R-CHOP and its variations, this regimen remains the most commonly recommended standard of care. Multiple therapeutic strategies are under investigation, including targeted kinase inhibitors, checkpoint inhibitors, bispecific antibodies, and CAR T therapy. Given the complex nature of RT and the evolving therapeutic paradigms, ongoing research is imperative to refine treatment strategies and integrate novel therapeutic agents to enhance survival and quality of life for people with RT. Given the lack of a clear standard of approach in the management of RT, patients with RT should be prioritized to enroll on clinical trials where feasible.

Knowledge, skills, and confidence gaps impacting treatment decision making in relapsed/refractory chronic lymphocytic leukemia and mantle cell lymphoma: a quantitative survey study in France, Germany, and the United States.

BACKGROUND: With recent advancements in the treatment of chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), healthcare specialists may face challenges making treatment and management decisions based on latest evidence for the optimal care of patients with these conditions. This study aimed to identify specific knowledge, skills, and confidence gaps impacting the treatment of CLL and MCL, to inform future educational activities. METHODS: Hematologists and hemato-oncologists (HCPs, n = 224) from France (academic settings), Germany, and the United States (academic and community settings) responded to a 15-minute quantitative needs assessment survey that measured perceived knowledge, skills, and confidence levels regarding different aspects of treatment and management of CLL and MCL patients, as well as clinical case questions. Descriptive statistics (cross tabulations) and Chi-square tests were conducted. RESULTS: Four areas of educational need were identified: (1) sub-optimal knowledge of treatment guidelines; (2) sub-optimal knowledge of molecular testing to inform CLL/MCL treatment decisions; (3) sub-optimal skills when making treatment decisions according to patient profile (co-morbidities, molecular testing results); and (4) challenges balancing the risk of toxicities with benefits of treatment. Over one-third of the respondents reported skill gaps when selecting suitable treatment options and prescribing therapies and reported a lack in confidence to initiate and manage treatment. Larger gaps in knowledge of guidelines and skills in patient assessment were identified in MCL, compared to CLL. CONCLUSIONS: This study suggests the need for continuing medical education specifically to improve knowledge of treatment guidelines, and to assist clinicians in developing skills and confidence when faced with clinical decision-making scenarios of patients with specific comorbidities and/or molecular test results, for example, through case-based learning activities.

Adverse In-Hospital Outcomes after Radical Prostatectomy in Leukemia History Patients.

INTRODUCTION: Leukemia history affects some radical prostatectomy (RP) patients. Although its prevalence and effect as an adverse risk factor are well known in cardiac surgery, the number of RP patients with a leukemia history, as well as their rate of adverse in-hospital outcomes, are unknown. METHODS: We identified RP patients (National Inpatient Sample 2000-2019), stratified according to the presence or absence of a leukemia history. Descriptive analyses, propensity score matching (PSM, ratio 1:10), and multivariable logistic regression models were used. RESULTS: Of 259,939 RP patients, 416 (0.2%) had a leukemia history. Their proportion increased from 0.1 to 0.2% covering the study span (p < 0.01). Leukemia history patients were older (median age, 64 vs. 62 years, p < 0.001). After PSM for age, insurance status, ethnicity, pelvic lymph node dissection, and Charlson Comorbidity Index, leukemia history RP patients exhibited higher rates of acute kidney injury (<2.6 vs. 0.9%; Odds Ratio [OR] 2.0, p = 0.02), more frequently underwent dialysis (3.6 vs. 1.9%; OR 1.9, p = 0.03), and more frequently had a length of stay exceeding one week (4.8 vs. 2.5%; OR 2.0, p = 0.006). CONCLUSIONS: Although leukemia history RP patients are rare, their numbers have increased. Renal complications and extended hospital stays are more frequent in those individuals.

Utility of Targeted Sequencing Compared to FISH for Detection of Chronic Lymphocytic Leukemia Copy Number Alterations.

Chronic lymphocytic leukemia (CLL) is characterized by multiple copy number alterations (CNAs) and somatic mutations that are central to disease prognosis, risk stratification, and mechanisms of therapy resistance. Fluorescence in situ hybridization (FISH) panels are widely used in clinical applications as the gold standard for screening prognostic chromosomal abnormalities in CLL. DNA sequencing is an alternative approach to identifying CNAs but is not an established method for clinical CNA screening. We sequenced DNA from 509 individuals with CLL or monoclonal B-cell lymphocytosis (MBL), the precursor to CLL, using a targeted sequencing panel of 59 recurrently mutated genes in CLL and additional amplicons across regions affected by clinically relevant CNAs [i.e., del(17p), del(11q), del(13q), and trisomy 12]. We used the PatternCNV algorithm to call CNA and compared the concordance of calling clinically relevant CNAs by targeted sequencing to that of FISH. We found a high accuracy of calling CNAs via sequencing compared to FISH. With FISH as the gold standard, the specificity of targeted sequencing was >95%, sensitivity was >86%, positive predictive value was >90%, and negative predictive value was >84% across the clinically relevant CNAs. Using targeted sequencing, we were also able to identify other common CLL-associated CNAs, including del(6q), del(14q), and gain 8q, as well as complex karyotype, defined as the presence of 3 or more chromosomal abnormalities, in 26 patients. In a single and cost-effective assay that can be performed on stored DNA samples, targeted sequencing can simultaneously detect CNAs, somatic mutations, and complex karyotypes, which are all important prognostic features in CLL.

CAR-T cell therapy in AML: recent progress and future perspectives.

Despite several small-molecule drugs that have revolutionized the current treatment strategy for acute myeloid leukemia (AML), hematopoietic stem cell transplantation remains the only curative treatment in most cases to date. Chimeric antigen receptor (CAR)-T cell therapy is one of the most promising next-generation cancer therapies for hematological malignancies and is clinically available for treatment of AML. However, developing AML-targeted CAR-T therapy is challenging because of the heterogeneity of target antigen expression across leukemic cells and patients, the difficulty in excluding on-/off-target tumor effects, and the immunosuppressive tumor microenvironment. To date, various targets, including CD33, NKG2D, CD123, CLL-1, and CD7, have been actively studied for CAR-T cells. Although no CAR-T cell products are close to practical use, several clinical trials have shown promising results, particularly for CAR-T cells targeting CLL-1 or CD123. Meanwhile, research exploring the ideal target for AML-targeted CAR-T therapy continues. Furthermore, as collecting autologous lymphocytes from patients with AML is difficult, development of off-the-shelf CAR-T products is being actively pursued. This review discusses the challenges in AML-targeted CAR-T cell therapy development from the perspectives of target antigen characteristics and AML-specific on-target/off-tumor toxicity. Moreover, it discusses the clinical development and prospects of AML-targeting CAR-T cells.

PI3K/AKT confers intrinsic and acquired resistance to pirtobrutinib in chronic lymphocytic leukemia.

PURPOSE: Pirtobrutinib, a non-covalent Bruton's tyrosine kinase (BTK) inhibitor, has been approved as the first agent to overcome resistance to covalent BTK inhibitors (such as ibrutinib, acalabrutinib, and zanubrutinib). However, the mechanisms of pirtobrutinib resistance in chronic lymphocytic leukemia (CLL) remain poorly understood. METHODS: To investigate pirtobrutinib resistance, we established resistant cell models using BTK knock-out via CRISPR-Cas9 or chronic exposure to pirtobrutinib in MEC-1 cells. These models mimicked intrinsic or acquired resistance, respectively. We then analyzed differential protein expression between wild-type (WT) and resistant MEC-1 cells using Revers Phase Protein microArray (RPPA) and confirmed the findings through Western Blot. Additionally, we evaluated potential drugs to overcome pirtobrutinib resistance by conducting cell proliferation assays, apoptosis studies, and animal experiments using both sensitive and resistant cells. RESULTS: MEC-1 cells developed resistance to pirtobrutinib either through BTK knock-out or prolonged drug exposure over three months. RPPA analysis revealed significant activation of proteins related to the PI3K/AKT pathway, including AKT and S6, in the resistant cells. Western Blot confirmed increased phosphorylation of AKT and S6 in pirtobrutinib-resistant MEC-1 cells. Notably, both the PI3K inhibitor (CAL101) and the AKT inhibitor (MK2206) effectively reduced cell proliferation and induced apoptosis in the resistant cells. The anti-tumor efficacy of these drugs was mediated by inhibiting the PI3K/AKT pathway. In vivo animal studies further supported the potential of targeting PI3K/AKT to overcome both intrinsic and acquired resistance to pirtobrutinib. CONCLUSION: The PI3K/AKT pathway plays a crucial role in both intrinsic and acquired resistance to pirtobrutinib in CLL. Therapeutically targeting this pathway may offer a promising strategy to overcome pirtobrutinib resistance.

CD38/NAD+ glycohydrolase and associated antigens in chronic lymphocytic leukaemia: From interconnected signalling pathways to therapeutic strategies.

Chronic lymphocytic leukaemia (CLL) is a heterogenous disease characterized by the accumulation of neoplastic CD5+/CD19+ B lymphocytes. The spreading of the leukaemia relies on the CLL cell's ability to survive in the blood and migrate to and proliferate within the bone marrow and lymphoid tissues. Some patients with CLL are either refractory to the currently available therapies or relapse after treatment; this emphasizes the need for novel therapeutic strategies that improving clinical responses and overcome drug resistance. CD38 is a marker of a poor prognosis and governs a set of survival, proliferation and migration signals that contribute to the pathophysiology of CLL. The literature data evidence a spatiotemporal association between the cell surface expression of CD38 and that of other CLL antigens, such as the B-cell receptor (BCR), CD19, CD26, CD44, the integrin very late antigen 4 (VLA4), the chemokine receptor CXCR4, the vascular endothelial growth factor receptor-2 (VEGF-R2), and the neutrophil gelatinase-associated lipocalin receptor (NGAL-R). Most of these proteins contribute to CLL cell survival, proliferation and trafficking, and cooperate with CD38 in multilayered signal transduction processes. In general, these antigens have already been validated as therapeutic targets in cancer, and a broad repertoire of specific monoclonal antibodies and derivatives are available. Here, we review the state of the art in this field and examine the therapeutic opportunities for cotargeting CD38 and its partners in CLL, e.g. by designing novel bi-/trispecific antibodies.

How receptor tyrosine kinase-like orphan receptor 1 meets its partners in chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is the most common leukemia in western societies, recognized by clinical and molecular heterogeneity. Despite the success of targeted therapies, acquired resistance remains a challenge for relapsed and refractory CLL, as a consequence of mutations in the target or the upregulation of other survival pathways leading to the progression of the disease. Research on proteins that can trigger such pathways may define novel therapies for a successful outcome in CLL such as the receptor tyrosine kinase-like orphan receptor 1 (ROR1). ROR1 is a signaling receptor for Wnt5a, with an important role during embryogenesis. The aberrant expression on CLL cells and several types of tumors, is involved in cell proliferation, survival, migration as well as drug resistance. Antibody-based immunotherapies and small-molecule compounds emerged to target ROR1 in preclinical and clinical studies. Efforts have been made to identify new prognostic markers having predictive value to refine and increase the detection and management of CLL. ROR1 can be considered as an attractive target for CLL diagnosis, prognosis, and treatment. It can be clinically effective alone and/or in combination with current approved agents. In this review, we summarize the scientific achievements in targeting ROR1 for CLL diagnosis, prognosis, and treatment.

COLEC10 inhibits the stemness of hepatocellular carcinoma by suppressing the activity of ß-catenin signaling.

BACKGROUND: Liver cancer stem cells (CSCs) contribute to tumor initiation, progression, and recurrence in hepatocellular carcinoma (HCC). The Wnt/ß-catenin pathway plays a crucial role in liver cancer stemness, progression, metastasis, and drug resistance, but no clinically approved drugs have targeted this pathway efficiently so far. We aimed to elucidate the role of COLEC10 in HCC stemness. METHODS: The Cancer Genome Atlas (TCGA) and the Clinical Proteomic Tumor Analysis Consortium (CPTAC) databases were employed to search for the association between COLEC10 expression and HCC stemness. Colony formation, sphere formation, side population, and limiting dilution tumor initiation assays were used to identify the regulatory role of COLEC10 overexpression in the stemness of HCC cell lines. Wnt/ß-catenin reporter assay and immunoprecipitation were performed to explore the underlying mechanism. RESULTS: COLEC10 level was negatively correlated with HCC stemness. Elevated COLEC10 led to decreased expressions of EpCAM and AFP (alpha-fetoprotein), two common markers of liver CSCs. Overexpression of COLEC10 inhibited HCC cells from forming colonies and spheres, and reduced the side population numbers in vitro, as well as the tumorigenic capacity in vivo. Mechanically, we demonstrated that overexpression of COLEC10 suppressed the activity of Wnt/ß-catenin signaling by upregulating Wnt inhibitory factor WIF1 and reducing the level of cytoplasmic ß-catenin. COLEC10 overexpression promoted the interaction of ß-catenin with the component of destruction complex CK1α. In addition, KLHL22 (Kelch Like Family Member 22), a reported E3 ligase adaptor predicted to interact with CK1α, could facilitate COLEC10 monoubiquitination and degradation. CONCLUSION: COLEC10 inhibits HCC stemness by downregulating the Wnt/ß-catenin pathway, which is a promising target for liver CSC therapy.

BCL6B-dependent suppression of ETV2 hampers endothelial cell differentiation.

BACKGROUND: B-cell CLL/lymphoma 6 member B (BCL6B) operates as a sequence-specific transcriptional repressor within the nucleus, playing crucial roles in various biological functions, including tumor suppression, immune response, stem cell self-renew, and vascular angiogenesis. However, whether BCL6B is involved in endothelial cell (EC) development has remained largely unknown. ETS variant transcription factor 2 (ETV2) is well known to facilitate EC differentiation. This study aims to determine the important role of BCL6B in EC differentiation and its potential mechanisms. METHODS: Doxycycline-inducible human induced pluripotent stem cell (hiPSC) lines with BCL6B overexpression or BCL6B knockdown were established and subjected to differentiate into ECs and vessel organoids (VOs). RNA sequencing analysis was performed to identify potential signal pathways regulated by BCL6B during EC differentiation from hiPSCs. Quantitative real-time PCR (qRT-PCR) was used to detect the expression of pluripotency and vascular-specific marker genes expression. EC differentiation efficiency was determined by Flow cytometry analysis. The performance of EC was evaluated by in vitro Tube formation assay. The protein expression and the vessel-like structures were assessed using immunofluorescence analysis or western blot. Luciferase reporter gene assay and chromatin immunoprecipitation (ChIP)-PCR analysis were used to determine the regulatory relationship between BCL6B and ETV2. RESULTS: Functional ECs and VOs were successfully generated from hiPSCs. Notably, overexpression of BCL6B suppressed while knockdown of BCL6B improved EC differentiation from hiPSCs. Additionally, the overexpression of BCL6B attenuated the capacity of derived hiPSC-ECs to form a tubular structure. Furthermore, compared to the control VOs, BCL6B overexpression repressed the growth of VOs, whereas BCL6B knockdown had little effect on the size of VOs. RNA sequencing analysis confirmed that our differentiation protocol induced landscape changes for cell/tissue/system developmental process, particularly vascular development and tube morphogenesis, which were significantly modulated by BCL6B. Subsequent experiments confirmed the inhibitory effect of BCL6B is facilitated by the binding of BCL6B to the promoter region of ETV2, led to the suppression of ETV2's transcriptional activity. Importantly, the inhibitory effect of BCL6B overexpression on EC differentiation from hiPSCs could be rescued by ETV2 overexpression. CONCLUSIONS: BCL6B inhibits EC differentiation and hinders VO development by repressing the transcriptional activity of ETV2.

Chronic Lymphocytic Leukemia (CLL)-Derived Extracellular Vesicles Educate Endothelial Cells to Become IL-6-Producing, CLL-Supportive Cells.

We hypothesized that via extracellular vesicles (EVs), chronic lymphocytic leukemia (CLL) cells turn endothelial cells into CLL-supportive cells. To test this, we treated vein-derived (HUVECs) and artery-derived (HAOECs) endothelial cells with EVs isolated from the peripheral blood of 45 treatment-naïve patients. Endothelial cells took up CLL-EVs in a dose- and time-dependent manner. To test whether CLL-EVs turn endothelial cells into IL-6-producing cells, we exposed them to CLL-EVs and found a 50% increase in IL-6 levels. Subsequently, we filtered out the endothelial cells and added CLL cells to this IL-6-enriched medium. After 15 min, STAT3 became phosphorylated, and there was a 40% decrease in apoptosis rate, indicating that IL-6 activated the STAT3-dependent anti-apoptotic pathway. Phospho-proteomics analysis of CLL-EV-exposed endothelial cells revealed 23 phospho-proteins that were upregulated, and network analysis unraveled the central role of phospho-ß-catenin. We transfected HUVECs with a ß-catenin-containing plasmid and found by ELISA a 30% increase in the levels of IL-6 in the culture medium. By chromatin immunoprecipitation assay, we observed an increased binding of three transcription factors to the IL-6 promoter. Importantly, patients with CLL possess significantly higher levels of peripheral blood IL-6 compared to normal individuals, suggesting that the inducers of endothelial IL-6 are the neoplastic EVs derived from the CLL cells versus those of healthy people. Taken together, we found that CLL cells communicate with endothelial cells through EVs that they release. Once they are taken up by endothelial cells, they turn them into IL-6-producing cells.

RNA Sequencing Reveals Candidate Genes and Pathways Associated with Resistance to MDM2 Antagonist Idasanutlin in TP53 Wild-Type Chronic Lymphocytic Leukemia.

Chronic lymphocytic leukemia (CLL) is a genetically and clinically diverse hematological cancer affecting middle-aged and elderly individuals. Novel targeted therapy options are needed for patients who relapse following initial responses or who are intrinsically resistant to current treatments. There is a growing body of investigation currently underway on MDM2 inhibitors in clinical trials, reflecting the increasing interest in including these drugs in cancer treatment regimens. One of the developed compounds, idasanutlin (RG7388), has shown promise in early-stage clinical trials. It is a second-generation MDM2-p53-binding antagonist with enhanced potency, selectivity, and bioavailability. In addition to the TP53 status, which is an important determinant of the response, we have shown in our previous studies that the SF3B1 mutational status is also an independent predictive biomarker of the ex vivo CLL patient sample treatment response to RG7388. The objective of this study was to identify novel biomarkers associated with resistance to RG7388. Gene set enrichment analysis of differentially expressed genes (DEGs) between RG7388-sensitive and -resistant CLL samples showed that the increased p53 activity led to upregulation of pro-apoptosis pathway genes while DNA damage response pathway genes were additionally upregulated in resistant samples. Furthermore, differential expression of certain genes was detected, which could serve as the backbone for novel combination treatment approaches. This research provides preclinical data to guide the exploration of drug combination strategies with MDM2 inhibitors, leading to future clinical trials and associated biomarkers that may improve outcomes for CLL patients.

The Utility of CD43 and CD200 in Differentiating Chronic Lymphocytic Leukemia from Other Mature B-Cell Neoplasms: A Cross Sectional Study.

To evaluate the utility of CD43 and CD200 in differentiating chronic lymphocytic leukemia (CLL) from other mature B-cell neoplasms. This was a cross-sectional study on patients diagnosed with B-cell neoplasms on flowcytometry. The median fluorescence intensity (MFI) of CD43, CD200 expressing neoplastic B-cells were compared between the CLL and non-CLL B-cell neoplasms followed by receiver operating characreristic curve (ROC) analysis. In addition, the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of CD43 and CD200 in diagnosing CLL were analysed. A total of 137 patients were included. The CLL group consisted 87 patients and non-CLL group consisted 50 patients. The Mann-Whitney U test showed significant CD43 expression (U = 997.5, Z= - 5.265, p < 0.001) and CD200 expression (U = 932.0, Z = - 5.5, p < 0.01) in CLL patients compared to non-CLL patients. The area under the curve were 0.771 and 0.786 for MFI of CD43 and CD200 in differentiating CLL from non-CLL group respectively. The optimal cut-off of MFI for CD43 and CD200 were 1323 and 1775 respectively. The sensitivity, specificity, PPV and NPV of CD43 in diagnosing CLL cases were 97.7%, 66%, 83.3% and 94.2% respectively. The sensitivity, specificity, PPV and NPV of CD200 in diagnosing CLL cases were 100%, 32%, 71.9% and 100% respectively. CD43 and CD200 are useful markers in differentiating CLL from other mature B-cell neoplasms with higher MFI expression of both markers found in CLL.

Recent advances in CAR-T therapy for the treatment of acute myeloid leukemia.

Chimeric antigen receptor T-cell (CAR-T) therapy, which has demonstrated notable efficacy against B-cell malignancies and is approved by the US Food and Drug Administration for clinical use in this context, represents a significant milestone in cancer immunotherapy. However, the efficacy of CAR-T therapy for the treatment of acute myeloid leukemia (AML) is poor. The challenges associated with the application of CAR-T therapy for the clinical treatment of AML include, but are not limited to, nonspecific distribution of AML therapeutic targets, difficulties in the production of CAR-T cells, AML blast cell heterogeneity, the immunosuppressive microenvironment in AML, and treatment-related adverse events. In this review, we summarize the recent findings regarding various therapeutic targets for AML (CD33, CD123, CLL1, CD7, etc.) and the results of the latest clinical studies on these targets. Thereafter, we also discuss the challenges related to CAR-T therapy for AML and some promising strategies for overcoming these challenges, including novel approaches such as gene editing and advances in CAR design.

Recent advances in CAR-T therapy for acute myeloid leukemia Acute myeloid leukemia (AML) remains a clinical challenge despite the advent of chimeric receptor T-cell (CAR-T) therapy, as there are obstacles hindering the application of CAR-T cells in AML. In this review, we discuss the results of current relevant clinical trials, existing treatment strategies for AML and recent advances in preclinical research to provide insight for overcoming the inefficacy of CAR-T therapy for AML.

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.

Treatment Sequencing in Chronic Lymphocytic Leukemia in 2024: Where We Are and Where We Are Headed.

As treatments with BTK inhibitors and BCL2 inhibitors have replaced the use of chemoimmunotherapy in CLL in both first-line and relapsed patients, it becomes critical to rationalize their use and exploit the full potential of each drug. Despite their proven, robust, and manifest efficacy, BTKis and BCL2is fail to provide long-term disease control in some categories of patients, and to date this is an unmet clinical need that is critical to recognize and address. Ongoing clinical trials are evaluating new treatment algorithms and new molecules to progressively thin this population. In this review for each category of patients we explicate the different possible patterns of treatment sequencing based on currently available evidence, starting from the frontline to currently ongoing trials, in order to optimize therapies as much as possible.

Covalent Bruton's Tyrosine Kinase Inhibitors in Chronic Lymphocytic Leukemia.

Inhibitors of Bruton's tyrosine kinase (BTK) are among the most widely used therapies for chronic lymphocytic leukemia (CLL) and established a new expectation for efficacy and safety in the treatment of this disease. Currently there are 3 covalent inhibitors of BTK approved for the treatment of CLL: ibrutinib, acalabrutinib, and zanubrutinib. The first-in-class covalent BTK inhibitor is ibrutinib, which as monotherapy has excellent efficacy in the front-line setting with a 7-year progression free survival (PFS) of 59%. Ibrutinib-based therapies have also demonstrated superiority over standard chemoimmunotherapy in the front-line and the relapsed/refractory setting. Acalabrutinib is a second-generation BTK inhibitor that has higher selectivity to BTK. Acalabrutinib has efficacy in both frontline and relapsed CLL and is associated with a decreased incidence of atrial fibrillation and hypertension when compared to ibrutinib. Like acalabrutinib, zanubrutinib was designed to be more selective for BTK than ibrutinib and to maximize BTK inhibition in tissues. Zanubrutinib has demonstrated clinical efficacy in first line and relapsed/refractory setting. These agents are indicated as monotherapy, with dosing until disease progression or intolerable toxicity, and are mainly differentiated by safety profile, although efficacy differences may exist as well. Combination with CD20 monoclonal antibodies and/or BCL2 inhibitors are alternative options for use. Here we will review efficacy and safety considerations with these agents.