B-cell Chronic Lymphocytic Leukemia Research Articles

A Novel Triple-Action Inhibitor Targeting B-Cell Receptor Signaling and BRD4 Demonstrates Preclinical Activity in Chronic Lymphocytic Leukemia.

B-cell chronic lymphocytic leukemia (CLL) results from intrinsic genetic defects and complex microenvironment stimuli that fuel CLL cell growth through an array of survival signaling pathways. Novel small-molecule agents targeting the B-cell receptor pathway and anti-apoptotic proteins alone or in combination have revolutionized the management of CLL, yet combination therapy carries significant toxicity and CLL remains incurable due to residual disease and relapse. Single-molecule inhibitors that can target multiple disease-driving factors are thus an attractive approach to combat both drug resistance and combination-therapy-related toxicities. We demonstrate that SRX3305, a novel small-molecule BTK/PI3K/BRD4 inhibitor that targets three distinctive facets of CLL biology, attenuates CLL cell proliferation and promotes apoptosis in a dose-dependent fashion. SRX3305 also inhibits the activation-induced proliferation of primary CLL cells in vitro and effectively blocks microenvironment-mediated survival signals, including stromal cell contact. Furthermore, SRX3305 blocks CLL cell migration toward CXCL-12 and CXCL-13, which are major chemokines involved in CLL cell homing and retention in microenvironment niches. Importantly, SRX3305 maintains its anti-tumor effects in ibrutinib-resistant CLL cells. Collectively, this study establishes the preclinical efficacy of SRX3305 in CLL, providing significant rationale for its development as a therapeutic agent for CLL and related disorders.

Abstract 2749: iPSC-derived natural killer cells as the front-runner program of the EVOcells Oncology platform: From inception to translational validation using patient samples

Abstract Cancer immunotherapy has transformed the oncology landscape and shown promising therapeutic results in the clinic but it is also clearly facing multiple limitations. So far, the focus of immunotherapies has mainly been on the modulation of T-cells. Natural killer (NK) cells offer promising perspectives for immunotherapies as they directly kill tumor cells and produce pro-inflammatory cytokines to activate and recruit T-cells and other immune cells. Thus, NK cells are considered key players in the anti-tumor immune response that can make a “cold” tumor “hot”. However, in the tumor microenvironment (TME) of cancer patients, the low numbers of NK cells present and their exhaustion due to local immunosuppression often limit tumor cell killing. The development of NK based cell therapy products can overcome these limitations, either as single therapy or in combination with biologics such as e.g. NK cell engagers or monoclonal antibodies for boosting ADCC (antibody dependent cell cytotoxicity). To overcome the main hurdle of current autologous cell therapies, the EVOcells Oncology platform aims at developing a streamlined manufacturing process for iPSC-derived immune effector cells. The goal is to develop “off-the-shelf” cell therapy products for clinical use in large patient populations. We are currently establishing a multi-asset portfolio combining multiple immune effector cell types with different genetic editing strategies that serve to optimize this approach further. iPSC-derived NK cells (iNK cells) offer an attractive option for improving both therapeutic efficacy and safety of CAR cell therapies. Our robust, feeder-free production protocol produces iNK cells that can be reliably frozen with good recovery rates. We have generated multiple genetically modified iNK cells and have validated that the genetic modifications boost iNK function. At the end of the production process, iNK cells show phenotypic properties and single cell RNA sequencing profiles comparable to blood-derived NK cells. Importantly, iNK cells are fully functional with the ability to produce key pro-inflammatory cytokines and to form lytic immunological synapses leading to efficient killing of cancer cell lines. In addition to the killing of established tumor cell lines, we also evaluated the ability of iNK cells to kill primary leukemia cells ex vivo by using blood samples from B-cell chronic lymphocytic leukemia patients. In combination with a standard of care anti-CD20 antibody, iNK cells demonstrated the ability to kill primary leukemia cells via ADCC. Taken together, these promising results obtained with iNK cells show the potential of the EVOcells Oncology platform to deliver the next generation of cell therapies in oncology paving the way to develop a portfolio of iPSC-derived immune effector cells. Citation Format: Michael Esquerré, Audrey Holtzinger, Mélanie Pichery, Stefanie Pfaender, Saniye Yumlu, Mandy Richter, Delphine Betous, Oriane Bombarde, Mylène Gador, Nadja Sailer, Michael Paillasse, Loïc Ysebaert, Fabien Despas, Matthias Austen, Andreas Scheel, Markus Dangl. iPSC-derived natural killer cells as the front-runner program of the EVOcells Oncology platform: From inception to translational validation using patient samples [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2749.

Plasma cell myeloma – therapeutic opportunities

Introduction: Plasmocytic myeloma (PCM) is a neoplastic disease with a multistage course. Monoclonal plasmocytes undergo uncontrolled, multifocal growth in the bone marrow, which results in the production of monoclonal immunoglobulin or its fragments that damage the bone marrow.
 Aim: The aim of this study is to present selected therapeutic possibilities of multiple myeloma.
 Materials and methods: The work uses the method of non-systematic review and analysis of the available scientific literature. Databases such as PubMed, Google Scholar, Arianta, Scopus, Web of Science were searched. The years 2005-2022 were assumed as the review period.
 Discussion: Multiple myeloma accounts for 1-2% of all cancer cases, and 10-15% of all hematological cancers. It is the third most common lymphoid neoplasm after chronic lymphocytic leukemia and large B-cell lymphoma. The diagnosis of PCM requires the presence of a minimum of 10% clonal plasmocytes in the bone marrow or biopsy confirmed plasmocytoma. Moreover, the CRAB and SLiM CRAB criteria are also important. Treatment should be initiated in all symptomatic patients meeting the SLiM CRAB criteria. The first stage of treatment is to induce remission of the disease. 
 Conclusions: Thanks to the progress of medicine, an increasing percentage of patients achieve permanent remissions. The success of the therapy is a component of the earliest possible detection of the disease and the use of appropriate, individually selected drugs.

Redirecting T-cell Activity with Anti-BCMA/Anti-CD3 Bispecific Antibodies in Chronic Lymphocytic Leukemia and Other B-cell Lymphomas.

Besides reported BCMA expression on multiple myeloma, we demonstrate BCMA can be detected and enhanced using γ-secretase inhibition on cell lines and primary material of various B-cell malignancies. Furthermore, using CLL we demonstrate that low BCMA-expressing tumors can be targeted efficiently using the BCMAxCD3 DuoBody teclistamab.

Multiple vertebral fractures following ibrutinib therapy in a patient with B-cell chronic lymphocytic leukemia

Multiple vertebral fractures following ibrutinib therapy in a patient with B-cell chronic lymphocytic leukemia

CD200 as a Valuable Marker for Differentiating between CLL and Other B-cell Lymph Proliferative Disorders

Chronic lymphocytic leukaemia (CLL) being the commonest subtype of mature B-cell lymphoid neoplasms need to be differentiated correctly from other B-chronic lymphoproliferative disorders (BCLPD). CD200 is being an essential marker for prognosis and diagnosis of CLL. Sixty patients diagnosed with BCLPD were evaluated for CD200 expression with eight-colour flow cytometry. An integration of modified Matutes score and CD200 were applied for CLL diagnosis. The overall immunophenotype of CLL patients in this study showed significant, frequent expression of CD5, CD22, CD23, CD43 and CD200. Atypical versus typical CLL patients’ phenotype comparison revealed significant lower expression of CD5 and CD43 with higher expression of CD79b in atypical CLL patients. CD200 was expressed significantly higher in CLL patients (typical and atypical) than in MCL patients who showed dim CD200 expression in only twenty-five percent of patients. The inclusion of CD200 within the diagnostic markers can empower the modified Matutes score accuracy for CLL.

No increased risk of mature B-cell non-Hodgkin lymphoma after Q fever detected: results from a 16-year ecological analysis of the Dutch population incorporating the 2007-2010 Q fever outbreak.

BackgroundA causative role of Coxiella burnetii (the causative agent of Q fever) in the pathogenesis of B-cell non-Hodgkin lymphoma (NHL) has been suggested, although supporting studies show conflicting evidence. We assessed whether this association is present by performing a detailed analysis on the risk of mature B-cell NHL after Q fever during and after the largest Q fever outbreak reported worldwide in the entire Dutch population over a 16-year period.MethodsWe performed an ecological analysis. The incidence of mature B-cell NHL in the entire Dutch population from 2002 until 2017 was studied and modelled with reported acute Q fever cases as the determinant. The adjusted relative risk of NHL after acute Q fever as the primary outcome measure was calculated using a Poisson regression.ResultsBetween January 2002 and December 2017, 266 050 745 person-years were observed, with 61 424 diagnosed with mature B-cell NHL. In total, 4310 persons were diagnosed with acute Q fever, with the highest incidence in 2009. The adjusted relative risk of NHL after acute Q fever was 1.02 (95% CI 0.97–1.06, P = 0.49) and 0.98 (95% CI 0.89–1.07, P = 0.60), 0.99 (95% CI 0.87–1.12, P = 0.85) and 0.98 (95% 0.88–1.08, P = 0.67) for subgroups of diffuse large B-cell lymphoma, follicular lymphoma or B-cell chronic lymphocytic leukaemia, respectively. Modelling with lag times (1–4 years) did not change interpretation.ConclusionWe found no evidence for an association between C. burnetii and NHL after studying the risk of mature B-cell NHL after a large Q fever outbreak in Netherlands.

Comparative Clinical Value of Pharmacologic Therapies for B-Cell Chronic Lymphocytic Leukemia: An Umbrella Analysis.

Several new drugs are progressively improving the life span of patients with B-cell chronic lymphocytic leukemia (CLL). However, the rapidly evolving standard of care precludes robust assessments of the incremental clinical value of further innovative drugs. Therefore, we systematically reviewed comparative evidence on newly authorized CLL drugs, as reported by standard and network meta-analyses (MA) published since 2016. Overall, 17 MAs addressed the relative survival or safety of naïve and/or refractory/relapsed (R/R) CLL patients. In R/R patients, therapies including BTK- and BCL2-inhibitors reported progression free survival (PFS) hazard ratios ranging from 0.08 to 0.24 (versus chemotherapy) and a significant advantage in overall survival (OS). In naïve patients, the PFS hazard ratios associated with four recent chemo-free therapies (obinutuzumab- and/or acalabrutinib-based) ranged from 0.11 to 0.61 versus current standard treatments (STs), without a significant OS advantage. Ten MAs addressed the risk of cardiovascular, bleeding, and infective events associated with BTK inhibitors, with some reporting a different relative safety in naïve and R/R patients. In conclusion, last-generation therapies for CLL consistently increase PFS, but not OS, and minimally decrease safety, as compared with STs. Based on available evidence, the patient-customized adoption of new therapies, rather than universal recommendations, seems desirable in CLL patients.

BTK Inhibitors Impair Platelet-Mediated Antifungal Activity.

In recent years, the introduction of new drugs targeting Bruton’s tyrosine kinase (BTK) has allowed dramatic improvement in the prognosis of patients with chronic lymphocytic leukemia (CLL) and other B-cell neoplasms. Although these small molecules were initially considered less immunosuppressive than chemoimmunotherapy, an increasing number of reports have described the occurrence of unexpected opportunistic fungal infections, in particular invasive aspergillosis (IA). BTK represents a crucial molecule in several signaling pathways depending on different immune receptors. Based on a variety of specific off-target effects on innate immunity, namely on neutrophils, monocytes, pulmonary macrophages, and nurse-like cells, ibrutinib has been proposed as a new host factor for the definition of probable invasive pulmonary mold disease. The role of platelets in the control of fungal growth, through granule-dependent mechanisms, was described in vitro almost two decades ago and is, so far, neglected by experts in the field of clinical management of IA. In the present study, we confirm the antifungal role of platelets, and we show, for the first time, that the exposure to BTK inhibitors impairs several immune functions of platelets in response to Aspergillus fumigatus, i.e., the ability to adhere to conidia, activation (as indicated by reduced expression of P-selectin), and direct killing activity. In conclusion, our experimental data suggest that antiplatelet effects of BTK inhibitors may contribute to an increased risk for IA in CLL patients.

Immunoproteasome Activity in Chronic Lymphocytic Leukemia as a Target of the Immunoproteasome-Selective Inhibitors.

Targeting proteasome with proteasome inhibitors (PIs) is an approved treatment strategy in multiple myeloma that has also been explored pre-clinically and clinically in other hematological malignancies. The approved PIs target both the constitutive and the immunoproteasome, the latter being present predominantly in cells of lymphoid origin. Therapeutic targeting of the immunoproteasome in cells with sole immunoproteasome activity may be selectively cytotoxic in malignant cells, while sparing the non-lymphoid tissues from the on-target PIs toxicity. Using activity-based probes to assess the proteasome activity profile and correlating it with the cytotoxicity assays, we identified B-cell chronic lymphocytic leukemia (B-CLL) to express predominantly immunoproteasome activity, which is associated with high sensitivity to approved proteasome inhibitors and, more importantly, to the immunoproteasome selective inhibitors LU005i and LU035i, targeting all immunoproteasome active subunits or only the immunoproteasome β5i, respectively. At the same time, LU102, a proteasome β2 inhibitor, sensitized B-CLL or immunoproteasome inhibitor-inherently resistant primary cells of acute myeloid leukemia, B-cell acute lymphoblastic leukemia, multiple myeloma and plasma cell leukemia to low doses of LU035i. The immunoproteasome thus represents a novel therapeutic target, which warrants further testing with clinical stage immunoproteasome inhibitors in monotherapy or in combinations.

Circulating Endocannabinoids in Canine Multicentric Lymphoma Patients.

The endocannabinoid system is increasingly being implicated in the pathogenesis and progression of various human cancers. Specifically, increased levels of 2-arachidonoylglycerol (2-AG) and oleoythanolamide (OEA) have been demonstrated in human diffuse large B-cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL) patients, respectively. The objectives of this paper were to compare 2-AG, OEA, N-arachidonoylethanolamine (AEA), and palmitoylethanolamide (PEA) levels between dogs with multicentric lymphoma and healthy control dogs. In addition, evaluate 2-AG, OEA, AEA, and PEA levels as biomarkers for progression free interval (PFI) and overall survival time (OST) in the dogs with lymphoma. The study consisted of 26 dogs with multicentric B cell lymphoma, 14 dogs with multicentric T cell lymphoma, and 12 healthy control dogs. Serum 2-AG, OEA, AEA, and PEA levels were measured using liquid chromatography combined with tandem mass spectrometry (LC—MS/MS) in dogs with lymphoma and in healthy dogs. OEA, AEA, and PEA levels were significantly elevated in dogs with lymphoma compared to healthy controls (p < 0.05). Total AG was significantly higher in healthy control dogs (p = 0.049). There was no significant difference between dogs with B cell and T cell lymphoma for any of the measured endocannabinoids. Elevated PEA was significantly associated with decreased PFI (p = 0.04) in dogs with lymphoma with a hazards ratio of 1.816 [95% Confidence Interval (CI): 1.020–3.232]. Overall, dogs with lymphoma have elevated levels of OEA, AEA, and PEA. PEA levels have the potential to be a prognostic biomarker.

Chronic lymphocytic leukemia diagnosed during pregnancy - case report and review of literature

Introduction. B-cell chronic lymphocytic leukemia (CLL) can be easily overlooked in pregnancy, particularly in cases with inadequate antenatal care. We report a case of pregnant woman diagnosed with CLL and evaluate this patient with cases in literature. Case report. An asymptomatic 35-year-old woman presented with slightly elevated absolute lymphocyte count at antenatal monitoring in her second pregnancy. Further hematological investigations disclosed CLL with monoallelic deletion of chromosome 13q14. She was monitored during throughout the pregnancy, being asymptomatic and without treatment, and delivered a healthy child at term with no complications. After almost four years of follow up patient is without any signs of disease progression and her absolute lymphocyte counts remained on predelivery levels. This is the first published case of CLL diagnosed during pregnancy in Serbia. Rare similar cases published so far have been discussed, especially in terms of disease course, long-term prognosis and available therapeutic modalities. Conclusion. Due to the fact that nowadays many women are delaying childbearing in middle age it can be expected that cancer diagnose could be more often found in pregnant women in the future. In a view of the complex nature of such condition, a multidisciplinary approach for diagnosing and treating of pregnant women is highly recommended.

CYTOGENETIC STUDY OF MANIFESTATIONS OF THE UNIVERSAL PHENOMENON OF THE BYSTANDER RESPONSE.

to establish the level of chromosomal instability in peripheral blood lymphocytes (PBL) from healthyindividuals and cells from patients with B-cell chronic lymphocytic leukemia (CLL) under co-cultivation conditions and to determine the possibility of inducing manifestations of the universal phenomenon of bystander response in them. Cytogenetic analysis of uniformly stained chromosomes from human PBL, which differed by cytogenetic markers of sex; the presence of oncological transformation and in vitro irradiation of 137Cs in a dose of 0.50 Gy under the conditions of their joint cultivation was performed. The frequency of chromosome aberrations in PBL from healthy individuals when co-cultured with the blood from CLL patients was 3.35 per 100 cells, exceeded the control (1.48 per 100 cells, р < 0.01), did not significantly differ from the rate in non-irradiated blood T-lymphocytes from patients with B-cell CLL (3.18 per 100 cells, р > 0.05) and was lower than when co-cultivated with irradiated blood from CLL patients (5.00 per 100 cells, р < 0.01). In irradiated in vitro blood lymphocytes from CLL patients, the mean group level of chromosome aberrations under separate cultivation was 12.36 per 100 cells and exceeded the indicator during their co-cultivation with lymphocytes from healthy individuals (8.35 per 100 cells, р < 0.05). A tumor-induced bystander effect (TIBE) develops in PBL from healthy individuals when co-cultured with the blood from CLL patients and in T lymphocytes of B-cell CLL patients, the cytogenetic manifestation of which is an increase in the frequency of single chromatid fragments. The interaction of irradiated blood cells from CLL patients with lymphocytes from healthy individuals causes an increase in chromosomal instability in the latter due to the development of a radiation-induced bystander effect (RIBE) and leads to a decrease in the level of chromosomal instability in irradiated lymphocytes from CLL patients (rescue effect). An increase in the level of chromatid-type aberrations in T-lymphocytes of CLL patients during in vitro irradiation is a consequence of the development of RIBE against the background of TIBE.

Zanubrutinib in lymphoproliferative disorders: a comprehensive review.

The availability of Bruton tyrosine kinase (BTK) inhibitors has brought about a paradigm shift in the treatment of patients with B-cell lymphomas and chronic lymphocytic leukemia. BTK was clinically validated as a target by the efficacy of the first-in-class inhibitor ibrutinib. The extended survival conferred by BTK inhibitors has brought long-term tolerability to the foreground. To minimize toxicities thought to be attributable to off-target kinase inhibition, a next generation of BTK inhibitors with greater selectivity was developed. In the United States, zanubrutinib, a next-generation BTK inhibitor, has been approved for treating adults with mantle cell lymphoma who have received at least one prior therapy, for adults with Waldenström macroglobulinemia, and for adults with relapsed or refractory marginal zone lymphoma who have received at least one anti-CD20–based therapy. Because few head-to-head comparative trials of BTK inhibitors have so far been reported, no BTK ‘inhibitor of choice’ can be identified. Zanubrutinib has promising efficacy in its approved indications and appears to have reduced cardiac toxicities, particularly atrial fibrillation, which may influence the choice of BTK inhibitor treatment by prescribers. Further studies are needed to inform on optimal treatment sequencing of zanubrutinib and its combination with other agents. Here, we summarize existing clinical evidence for its efficacy and safety in mantle cell lymphoma, Waldenström macroglobulinemia, marginal zone lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, and other B-lymphoproliferative indications.Plain Language Summary Zanubrutinib is a drug that was shown to effectively treat cancer of B cells without causing excessive serious side effects Patients with certain B-cell malignancies (cancers of white blood cells) benefit from treatment with Bruton tyrosine kinase (BTK) inhibitors, drugs that block the BTK protein and keep cancer from growing and spreading. Patients experience extended survival with ibrutinib, the first-generation BTK inhibitor approved by US Food and Drug Administration (FDA); however, one in five patients quit treatment because of harmful side effects. Ibrutinib-related side effects such as increased risk of bleeding, atrial fibrillation (abnormal heart rhythm), and high blood pressure are thought to be caused by ibrutinib blocking other proteins besides the intended target protein BTK. To reduce these side effects, zanubrutinib, a next-generation BTK inhibitor, was designed to block BTK more specifically than ibrutinib. Results of clinical studies on zanubrutinib treatment appear promising in patients with several types of B-cell malignancies, including mantle cell lymphoma (MCL), Waldenström macroglobulinemia (WM), marginal zone lymphoma (MZL), chronic lymphocytic leukemia, and small lymphocytic lymphoma. There are not yet enough clinical data to determine which BTK inhibitor is most effective in treating B-cell malignancies without causing harmful side effects. Early data from the phase 3 ALPINE clinical study suggest that zanubrutinib works better than ibrutinib, and fewer patients experience side effects and quit treatment. Zanubrutinib is currently approved for use for treatment of adult patients with MCL who have received at least one prior therapy, for adults with WM, and for adults with MZL who have received at least one anti-CD20–based therapy.

POSC209 Cost of Treatment with Biosimilars - Case with Rituximab in Oncohematology

Rituximab is a chimeric monoclonal antibody targeted against CD20 which is a surface antigen present on B cells. In last 20 years Rituximab becomes a standard of care for treatment of several rare diseases like Chronic lymphocytic leukemia, Folicular limphoma and Diffuse large B-cell lymphoma. It is expected that the entry of biosimilars on the market will lead to a reduction in the cost of drug therapy.

Зміни гліканових детермінант мембран лімфоцитів периферійної крові хворих на B–клітинний хронічний лімфолейкоз за умов протипухлинної терапії

The purpose of the study was to study the nature of changes in the exposure of surface glycans of peripheral blood lymphocytes in patients with B-cell chronic lymphocytic leukemia under conditions of antitumor therapy. Materials and methods. We studied the features of exposure of surface glycotopes of peripheral blood lymphocytes in patients with B-cell chronic lymphocytic leukemia under conditions of antitumor therapy using a set of seven lectins labeled with FITC and monoclonal antibodies to Tn-antigen- FITC for the detection of Tn antigen and CD43 exposure on blood lymphocytes. Cytostatic therapy included cyclophosphamide, vincristine (oncovin), prednisolone. Data were recorded on a Beckman Coulter EPICS flow cytometer. The results were processed using FCS3 Express. Results and discussion. The number of lymphocytes of healthy donors with a positive reaction to ConA, PHA-L, SNA, MAA-II and α1-acid glycoprotein amounted to 16.0±3.0%, 23.0±2.3%, 15.0±1.5%, 25.0±1.8% and 15.0±1.3%, respectively. The number of LABA-, UEA I-positive lymphocytes was 0.90±0.03% and 2.9±0.2%, respectively, and there was no binding to antibodies to Tn- and CD43-antigens. In the blood of patients with chronic lymphocytic leukemia, the level of ConA-, SNA- and MAA-II-positive lymphocytes increased relative to control by 2.2, 3.7 and 2.6 times, respectively. The number of LABA- and UEA I-positive lymphocytes in patients with chronic lymphocytic leukemia increased by 11 (p &lt;0.01) and 23 (p &lt;0.001) times and amounted to 10.5±0.5% and 67.5±5.5% respectively. The number of lymphocytes with CD43 antigen on their surface increased by 72 times, and the Tn antigen increased by 80 times. Cytostatic therapy reduced the level of LABA- and UEA I-positive lymphocytes by almost half, and MAA II-positive cells and lymphocytes interacting with antibodies to CD43 and Tn antigen by a third. The level of PHA-L-positive lymphocytes in the blood of chronic lymphocytic leukemia patients after undergoing alkylating therapy increased by 18.0±2.0% and almost did not differ from those obtained in the control group. Conclusion. 1. In chronic lymphocytic leukemia patients, the structure of glycoconjugates in peripheral blood lymphocytes changes, manifested in increased exposure of L-fucose, α-mannose and N-acetylneuraminic acid, which is confirmed by a significant increase in relation to the control of the number of ConA-, SNA-, MAA-II-, LABA I-positive cells. 2. Patients with chronic lymphocytic leukemia showed a significant increase in the number of lymphocytes, in which the markers of carcinogenesis CD43 and Tn antigens were found. 3. Cytostatic therapy significantly reduced the level of LABA-, UEA I- and MAA II-positive cells, as well as partially Tn- and CD43-antigen-positive lymphocytes, which indicates its positive effect on the treatment of chronic lymphocytic leukemia

Дослідження глікобіому поверхні лімфоцитів хворих на В-клітинний хронічний лімфолейкоз

The purpose of the study was to investigate the intensity of exposure of peripheral blood lymphocyte surface glycans in patients with B-cell chronic lymphocytic leukemia by measuring the density of lectin- or antigen-positive epitopes under antitumor therapy in order to evaluate it for a more reasonable selection of qualitative and quantitative composition of therapy. Materials and methods. The objects of the study were blood lymphocytes of patients with chronic lymphocytic leukemia (n=15) aged 58-66 years before and after a course of standard chemotherapy according to the COP scheme. The control group consisted of healthy volunteers (n=15) aged 55 to 65 years. Isolation of lymphocytes was performed by a modified method of A. Boyum. Polyclonal antibodies to α1-acid glycoprotein and fibronectin were used. Exposure to Tn antigen and CD43 on blood lymphocytes was determined with secondary antibodies to mouse immunoglobulins conjugated to FITC (Millipore, USA). To study the exposure of glycans on the surface of lymphocytes, we used a set of seven lectins labeled with FITC. Data recording was performed on a Beckman Flower EPICS flow cytometer. Processing of the results was done using the program FCS3 Express. Results and discussion. Compared with the group of hematologically healthy donors on the surface of lymphocytes in patients with chronic lymphocytic leukemia, a 20-fold increase in the density of exposure to ConA epitopes, 10 times – UEAI- and SNA-positive epitopes were shown; MAA II epitope, Tn, and CD43 antigen densities were increased 100-fold (p &lt;0.01). Exposure densities of MAA II-, Tn-, and CD43-positive epitopes on the plasma membrane of lymphocytes in patients with chronic lymphocytic leukemia receiving alkylation therapy decreased 10-fold relative to treatment data, but remained 10-fold higher than in the group of healthy hematologists. Conclusion. On the plasma membranes of lymphocytes in patients with chronic lymphocytic leukemia, the density of exposure of mannose and neuraminic acid residues was significantly increased. COP therapy reduced the density of these epitopes to control values. A significant increase in the density of carcinogenesis markers – Tn- and CD43-antigens on the plasma membranes of lymphocytes in patients with chronic lymphocytic leukemia has been shown. COP therapy provided only a partial decrease in their density, which indicates the insufficient effectiveness of COP therapy, its inability to completely stop the oncological process in patients with chronic lymphocytic leukemia

Co-Morbidities and Treatment Decisions in Newly Diagnosed CLL Patients Cross All Disease Stages in Kurdistan Region-Iraq

Co-Morbidities and Treatment Decisions in Newly Diagnosed CLL Patients Cross All Disease Stages in Kurdistan Region-Iraq

Bone Marrow Lymphoid Niche Adaptation to Mature B Cell Neoplasms.

B-cell non-Hodgkin lymphoma (B-NHL) evolution and treatment are complicated by a high prevalence of relapses primarily due to the ability of malignant B cells to interact with tumor-supportive lymph node (LN) and bone marrow (BM) microenvironments. In particular, progressive alterations of BM stromal cells sustain the survival, proliferation, and drug resistance of tumor B cells during diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and chronic lymphocytic leukemia (CLL). The current review describes how the crosstalk between BM stromal cells and lymphoma tumor cells triggers the establishment of the tumor supportive niche. DLBCL, FL, and CLL display distinct patterns of BM involvement, but in each case tumor-infiltrating stromal cells, corresponding to cancer-associated fibroblasts, exhibit specific phenotypic and functional features promoting the recruitment, adhesion, and survival of tumor cells. Tumor cell-derived extracellular vesicles have been recently proposed as playing a central role in triggering initial induction of tumor-supportive niches, notably within the BM. Finally, the disruption of the BM stroma reprogramming emerges as a promising therapeutic option in B-cell lymphomas. Targeting the crosstalk between BM stromal cells and malignant B cells, either through the inhibition of stroma-derived B-cell growth factors or through the mobilization of clonal B cells outside their supportive BM niche, should in particular be further evaluated as a way to avoid relapses by abrogating resistance niches.

Real-World Assessment of Patient Care and Practice Efficiency With the Introduction of Subcutaneous Rituximab.

INTRODUCTION: A subcutaneous (SC) formulation of the anti-CD20 monoclonal antibody, rituximab (Rituxan), is approved in diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and chronic lymphocytic leukemia (CLL). Rituximab-SC (R-SC) has been associated with time and clinic resource savings vs the original intravenous formulation (R-IV). Insight into the resource implications of widening R-SC adoption in a US oncology setting is needed. METHODS: A single-institution, retrospective observational analysis was conducted in adult patients with DLBCL, FL, or CLL. The primary outcome measure was chair occupancy time (difference between patient room-in and room-out times). Prescribing patterns were a secondary outcome. RESULTS: Overall, 1190 patients were analyzed (treatment time frame: pre-R-SC adoption: n = 490 [41%], pre- and post R-SC adoption: n = 189 [16%], post R-SC adoption: n = 511 [43%]). Of the patients in the post-R-SC period, 374 (73%) received R-IV, 52 (10%) received R-IV and R-SC, and 85 (17%) received R-SC. When administered, R-SC reduced combination therapy chair time vs R-IV by a mean 37% (93.2 minutes; P < .001). Monotherapy (any route) reduced chair time vs combination by a mean 35.2 minutes (P < .001), with a further 40.2-minute reduction with R-SC (P < .001), a 62% (133.4-minute) total chair time savings vs R-IV. Doctors were more likely to prescribe R-SC to patients with FL than DLBCL. CONCLUSIONS: R-SC is associated with significantly reduced chair time vs R-IV in a US oncology setting. Widespread adoption would be expected to improve practice efficiency and patient access to care, and to reduce health care resource burden.