Lymphoproliferative Neoplasms Research Articles

Different phenotypes with different endings-Telomere biology disorders and cancer predisposition with long telomeres.

Rare germline pathogenic variants (GPVs) in genes essential in telomere length maintenance and function have been implicated in two broad classes of human disease. The telomere biology disorders (TBDs) are a spectrum of life-threatening conditions, including bone marrow failure, liver and lung disease, cancer and other complications caused by GPVs in telomere maintenance genes that result in short and/or dysfunctional telomeres and reduced cellular replicative capacity. In contrast, cancer predisposition with long telomeres (CPLT) is a disorder associated with elevated risk of a variety of cancers, primarily melanoma, thyroid cancer, sarcoma, glioma and lymphoproliferative neoplasms caused by GPVs in shelterin complex genes that lead to excessive telomere elongation and increased cellular replicative capacity. While telomeres are at the root of both disorders, the term TBD is used to convey the clinical phenotypes driven by critically short or otherwise dysfunctional telomeres and their biological consequences.

High-Accuracy and Lightweight Image Classification Network for Optimizing Lymphoblastic Leukemia Diagnosisy.

Leukemia is a hematological malignancy that significantly impacts the human immune system. Early detection helps to effectively manage and treat cancer. Although deep learning techniques hold promise for early detection of blood disorders, their effectiveness is often limited by the physical constraints of available datasets and deployed devices. For this investigation, we collect an excellent-quality dataset of 17,826 morphological bone marrow cell images from 85 patients with lymphoproliferative neoplasms. We employ a progressive shrinking approach, which integrates a comprehensive pruning technique across multiple dimensions, including width, depth, resolution, and kernel size, to train our lightweight model. The proposed model achieves rapid identification of acute lymphoblastic leukemia, chronic lymphocytic leukemia, and other bone marrow cell types with an accuracy of 92.51% and a throughput of 111 slides per second, while comprising only 6.4 million parameters. This model significantly contributes to leukemia diagnosis, particularly in the rapid and accurate identification of lymphatic system diseases, and provides potential opportunities to enhance the efficiency and accuracy of medical experts in the diagnosis and treatment of lymphocytic leukemia.

Carfilzomib, lenalidomide, dexamethasone (KRD) in BTKi relapsed or refractory mantle cell lymphoma: A phase II study fromFondazione Italiana Linfomi.

Mantle cell lymphoma (MCL) is a rare lymphoproliferative neoplasm considered incurable, with a median survival of 3-5 years. In recent years, Bruton's tyrosine kinase inhibitors (BTKi) have been introduced, demonstrating high therapeutic activity. However, the prognosis for MCL patients failing ibrutinib therapy is particularly poor, with a survival expectation of a few months. In this phase II trial, we assessed the efficacy and safety of the carfilzomib-lenalidomide-dexamethasone (KRD) combination in MCL patients who were relapsed/refractory (R/R) or intolerant to BTKi and in need of treatment. The primary objective of the study was to evaluate the antitumor efficacy of the KRD combination in terms of 12-month overall survival (12-month OS). From September 2019 to December 2020, 16 patients were enrolled from 11 Italian centers. After a median follow-up of 2.37 months (95% CI 0.92-6.47), the 12-month OS was 13%. The rate of grade 3-4 adverse events (AEs) was 35%, and the overall response rate (ORR) was 19%. These results led to the premature termination of enrollment, as defined in the protocol stopping rules. The efficacy of the KRD combination in advanced-stage MCL patients who are R/R to BTKi is unsatisfactory and too toxic.

Systemic deficits in lipid homeostasis promote aging-associated impairments in B cell progenitor development.

Organismal aging has been associated with diverse metabolic and functional changes across tissues. Within the immune system, key features of physiological hematopoietic cell aging include increased fat deposition in the bone marrow, impaired hematopoietic stem and progenitor cell (HSPC) function, and a propensity towards myeloid differentiation. This shift in lineage bias can lead to pre-malignant bone marrow conditions such as clonal hematopoiesis of indeterminate potential (CHIP) or clonal cytopenias of undetermined significance (CCUS), frequently setting the stage for subsequent development of age-related cancers in myeloid or lymphoid lineages. At the systemic as well as sub-cellular level, human aging has also been associated with diverse lipid alterations, such as decreased phospholipid membrane fluidity that arises as a result of increased saturated fatty acid (FA) accumulation and a decay in n-3 polyunsaturated fatty acid (PUFA) species by the age of 80 years, however the extent to which impaired FA metabolism contributes to hematopoietic aging is less clear. Here, we performed comprehensive multi-omics analyses and uncovered a role for a key PUFA biosynthesis gene, ELOVL2 , in mouse and human immune cell aging. Whole transcriptome RNA-sequencing studies of bone marrow from aged Elovl2 mutant (enzyme-deficient) mice compared with age-matched controls revealed global down-regulation in lymphoid cell markers and expression of genes involved specifically in B cell development. Flow cytometric analyses of immune cell markers confirmed an aging-associated loss of B cell markers that was exacerbated in the bone marrow of Elovl2 mutant mice and unveiled CD79B, a vital molecular regulator of lymphoid progenitor development from the pro-B to pre-B cell stage, as a putative surface biomarker of accelerated immune aging. Complementary lipidomic studies extended these findings to reveal select alterations in lipid species in aged and Elovl2 mutant mouse bone marrow samples, suggesting significant changes in the biophysical properties of cellular membranes. Furthermore, single cell RNA-seq analysis of human HSPCs across the spectrum of human development and aging uncovered a rare subpopulation (<7%) of CD34 + HSPCs that expresses ELOVL2 in healthy adult bone marrow. This HSPC subset, along with CD79B -expressing lymphoid-committed cells, were almost completely absent in CD34 + cells isolated from elderly (>60 years old) bone marrow samples. Together, these findings uncover new roles for lipid metabolism enzymes in the molecular regulation of cellular aging and immune cell function in mouse and human hematopoiesis. In addition, because systemic loss of ELOVL2 enzymatic activity resulted in down-regulation of B cell genes that are also associated with lymphoproliferative neoplasms, this study sheds light on an intriguing metabolic pathway that could be leveraged in future studies as a novel therapeutic modality to target blood cancers or other age-related conditions involving the B cell lineage.

20. FIP1L1::KIT fusion in a case of peripheral T-cell lymphoproliferative neoplasm responsive to tyrosine kinase inhibitor

20. FIP1L1::KIT fusion in a case of peripheral T-cell lymphoproliferative neoplasm responsive to tyrosine kinase inhibitor

Hemangiosarcoma Cells Promote Conserved Host-Derived Hematopoietic Expansion.

Hemangiosarcoma and angiosarcoma are soft-tissue sarcomas of blood vessel-forming cells in dogs and humans, respectively. These vasoformative sarcomas are aggressive and highly metastatic, with disorganized, irregular blood-filled vascular spaces. Our objective was to define molecular programs which support the niche that enables progression of canine hemangiosarcoma and human angiosarcoma. Dog-in-mouse hemangiosarcoma xenografts recapitulated the vasoformative and highly angiogenic morphology and molecular characteristics of primary tumors. Blood vessels in the tumors were complex and disorganized, and they were lined by both donor and host cells. In a series of xenografts, we observed that the transplanted hemangiosarcoma cells created exuberant myeloid hyperplasia and gave rise to lymphoproliferative tumors of mouse origin. Our functional analyses indicate that hemangiosarcoma cells generate a microenvironment that supports expansion and differentiation of hematopoietic progenitor populations. Furthermore, gene expression profiling data revealed hemangiosarcoma cells expressed a repertoire of hematopoietic cytokines capable of regulating the surrounding stromal cells. We conclude that canine hemangiosarcomas, and possibly human angiosarcomas, maintain molecular properties that provide hematopoietic support and facilitate stromal reactions, suggesting their potential involvement in promoting the growth of hematopoietic tumors.

Factors influencing the mortality risk of heart failure in patients receiving antineoplastic immunotherapy: A national inpatient database study 2016-2020.

e24011 Background: Immunotherapy is increasingly being used for management of solid and lymphoproliferative tumors due to their more desirable side effect profile as compared to traditional cancer therapies. However, these medications are associated with cardiac complications and little is known about the factors influencing the prognosis in these patients. Methods: This is a retrospective analysis of the National Inpatient Database from 2016 to 2020 using the International Classification of Diseases (ICD) 10 codes performed with STATA BE 18.0. Chi square test was used for crude analysis and multivariate logistic regression was performed to assess the risk of inpatient death among cancer patients with heart failure receiving immunotherapy. Results were adjusted for potential confounders like age, gender, race, hypertension, diabetes, coronary artery disease, smoking, and alcohol consumption. Multicollinearity of the model was assessed using Variance Inflation Factor (VIF) post-estimation test. Results: Out of 5166 cancer patients receiving immunotherapy with a mean age of 43.63 土 26.33 years and 41% females, 45 patients had heart failure. Logistic regression showed that heart failure was significantly associated with mortality (LR 𝜒² 38.74, p value &lt; 0.001) on adjusting for potential confounders. Although the effect size was small, increased age (OR 1.025, CI 1.01-1.04) had a significantly higher risk of mortality. Patients belonging to the female gender and white, hispanic, and asian races had a lower risk of mortality while those belonging to the african american race and those with coronary artery disease had a higher mortality risk, although not statistically significant. Diabetes and alcohol consumption had a fourfold and sixfold increased risk of mortality respectively. Hypertension and smoking that are known to increase mortality risk in heart failure patients showed a paradoxically protective effect in this cohort. Conclusions: This study highlights the importance of risk stratification and prognostication among patients with heart failure receiving antineoplastic immunotherapy. Increased age, african american race, diabetes, alcohol consumption, and coronary artery disease have shown an increased mortality risk in these patients. [Table: see text]

Does Double Mean Trouble? Coexistence of Myeloproliferative and Lymphoproliferative Neoplasms.

Background: The occurrence of myeloproliferative neoplasms (MPNs) that evolve into each other is well-described, as is this occurrence of lymphoproliferative neoplasms (LPNs). However, less is known about rare MPN/LPN coexistence, and the aim of our study was to analyze charachteristics of these patients after long term follow-up. Methods: Fourteen patients with MPN/LPN coexistence were diagnosed and treated according to guidelines at a single university center across two decades. Results: The overall median age was 53 years (22-69). MPNs patients with subsequent LPNs had a shorter period of second malignancy development and a more aggressive course of LPN, which can cause fatal outcomes. Polycythemia vera and chronic lymphocytic leukemia were most commonly associated (36%). The JAK2V617F mutation had 2/3 and cytogenetic abnormalities occurred in 1/3 of patients. MPN/LPN coexistence cases had significantly higher thrombotic potential (42.8%) and a higher third malignancy accruement frequency (21.4%) versus those without such malignancies. Conclusions: Considering the younger ages at MPN diagnosis, it is recommended to check regularly for blood lymphocytosis or lymphadenopathy occurrences and organomegaly progression faster than expected for MPN, with the aim of timely LPN diagnoses. The presence of molecular-cytogenetic abnormalities in a majority of patients indicate possible genetic instability and increased risk of development of multiple neoplasms, thus elevating thrombotic risk.

Characterization of T-/natural killer cell lymphoproliferative neoplasms associated with systemic, chronic, active Epstein-Barr virus in adults: A report of 5 cases in a Western population.

Because of its low frequency in adult populations and clinical and laboratory overlap with hemophagocytic lymphohistiocytosis and other T-cell lymphomas, T-cell/natural killer (NK) cell systemic, chronic, active Epstein-Barr virus (EBV) (T/NK sCAEBV) infection remains underdiagnosed, preventing critical, prompt therapeutic interventions. We report a 5-case series that included 2 adult patients with T/NK sCAEBV and 3 additional adult patients with T/NK lymphomas with concomitant systemic EBV infection to review these entities' overlapping diagnostic and clinical features. Approximately 95% of the world population has been infected with EBV during their lifetime, and infection is usually asymptomatic, with symptomatic cases eventually resolving spontaneously. A small subset of immunocompetent patients develops CAEBV, a life-threatening complication resulting from EBV-infected T-cell or NK cell neoplastic lymphocytes. The sites of end-organ damage in T/NK sCAEBV demonstrate pathologic findings such as reactive lymphoid proliferations, making the diagnosis difficult to establish, with the only curative option being an allogeneic hematopoietic stem cell transplant. This diagnosis is most prevalent in Asia, with few cases reported in Western countries. Adult age is an independent risk factor for poor outcomes, and most cases are diagnosed in pediatric populations.

Primary Cutaneous Follicle Center Lymphoma in an Adult African American Male

Primary cutaneous B-Cell Lymphomas (PCBCL) is a form of a lymphoproliferative neoplasm consisting of proliferation localized to the skin. Cutaneous lymphomas originate from mature T-lymphocytes, B-lymphocytes, or NK cells. The incidence of PCBCL is significantly lower in patients with Skin of Color (SoC) and is quite rare among African American (AA) individuals, compared to their Caucasian counterparts. The clinical course of PCFCL in SoC is not widely studied or reported in literature due to the low incidence in the AA population. We present a case of PCBCL in an AA individual along with a brief review of the clinical presentation, pathology, and treatment options of the condition. According to the U.S. Census Bureau, approximately half of the U.S population will have SoC by 2050; by adding our case of PCFCL to the body of literature, we hope to promote awareness of the presentation and course of this cutaneous disorder in SoC patients.

CAD204520 Targets NOTCH1 PEST Domain Mutations in Lymphoproliferative Disorders.

NOTCH1 PEST domain mutations are often seen in hematopoietic malignancies, including T-cell acute lymphoblastic leukemia (T-ALL), chronic lymphocytic leukemia (CLL), splenic marginal zone lymphoma (SMZL), mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL). These mutations play a key role in the development and progression of lymphoproliferative tumors by increasing the Notch signaling and, consequently, promoting cell proliferation, survival, migration, and suppressing apoptosis. There is currently no specific treatment available for cancers caused by NOTCH1 PEST domain mutations. However, several NOTCH1 inhibitors are in development. Among these, inhibition of the Sarco-endoplasmic Ca2+-ATPase (SERCA) showed a greater effect in NOTCH1-mutated tumors compared to the wild-type ones. One example is CAD204520, a benzimidazole derivative active in T-ALL cells harboring NOTCH1 mutations. In this study, we preclinically assessed the effect of CAD204520 in CLL and MCL models and showed that NOTCH1 PEST domain mutations sensitize cells to the anti-leukemic activity mediated by CAD204520. Additionally, we tested the potential of CAD204520 in combination with the current first-line treatment of CLL, venetoclax, and ibrutinib. CAD204520 enhanced the synergistic effect of this treatment regimen only in samples harboring the NOTCH1 PEST domain mutations, thus supporting a role for Notch inhibition in these tumors. In summary, our work provides strong support for the development of CAD204520 as a novel therapeutic approach also in chronic lymphoproliferative disorders carrying NOTCH1 PEST domain mutations, emerging as a promising molecule for combination treatment in this aggressive subset of patients.

GATA-3-dependent Gene Transcription is Impaired upon HDAC Inhibition.

Many peripheral and cutaneous T-cell lymphoma (CTCL) subtypes are poorly responsive to conventional chemotherapeutic agents and associated with dismal outcomes. The zinc finger transcription factor GATA-3 and the transcriptional program it instigates are oncogenic and highly expressed in various T-cell neoplasms. Posttranslational acetylation regulates GATA-3 DNA binding and target gene expression. Given the widespread use of histone deacetylase inhibitors (HDACi) in relapsed/refractory CTCL, we sought to examine the extent to which these agents attenuate the transcriptional landscape in these lymphomas. Integrated GATA-3 chromatin immunoprecipitation sequencing and RNA sequencing analyses were performed in complementary cell line models and primary CTCL specimens treated with clinically available HDACi. We observed that exposure to clinically available HDACi led to significant transcriptional reprogramming and increased GATA-3 acetylation. HDACi-dependent GATA-3 acetylation significantly impaired both its ability to bind DNA and transcriptionally regulate its target genes, thus leading to significant transcriptional reprogramming in HDACi-treated CTCL. Beyond shedding new light on the mechanism of action associated with HDACi in CTCL, these findings have significant implications for their use, both as single agents and in combination with other novel agents, in GATA-3-driven lymphoproliferative neoplasms.

Fine Needle Aspiration Cytology of Lymph Nodes in Metastatic Cancer and Lymphoma: Our Single-institution Experience.

Lymphadenopathy is a common finding in clinical practice. The cause of enlarged nodes on clinical examination alone is challenging and there may be multiple reasons for this enlargement. It may become enlarged due to stimulation by infectious agents or the involvement of metastasis or malignant diseases, such as lymphoma. The aim of the study was to investigate the diagnostic role of fine needle aspiration cytology of lymph nodes in metastatic cancer and lymphoma. A total of 48 FNAC lymph nodes suspicious for malignancy were sampled with follow-up biopsy in Clinical Center of University of Sarajevo from 2017 to 2023. Lymph nodes were aspirated using 20-22 G needle with minimally 2 passes, spread on slides, air-dried, stained with May-Grünwald-Giemsa or Papanikolaou and residual material sent for cytoblock. Out of 48 cytological samples, 30 (62.5%) revealed metastatic epithelial cells and 12 (25%) lymphoproliferative neoplasm. Three samples were suspected for malignancies, one sample was unrepresentative, one inconclusive and one falsely negative. Histopathological confirmation had 35 patients, while others were confirmed based on clinical presentation and radiological techniques. Compared to histopathological diagnosis, cytology had a sensitivity of 89.47%, specificity of 93.33%, positive predictive value (PPV) 95.04% and negative predictive values (NPV) 86.13% for epithelial metastatic cancer. The overall diagnostic test accuracy was 91.06%. For lymphoproliferative neoplasms cytology in comparison to histopathology had sensitivity 85.71%, specificity 91.18%, PPV 76.4% and NPV 95.04%. The overall diagnostic test accuracy was 89.81%. In both ways cytology is showing significant possibility to be used as a primary tool in detecting cancers. FNAC is a fast, reliable, and efficient method for diagnosing malignant lymphadenopathy. The cytological diagnosis can sometimes be accepted as the definitive diagnosis without further correlation with histopathology, especially in advanced malignancies and known primary malignancies.

Exploring the applicability of a lesion segmentation method on [18F]fluorothymidine PET/CT images in diffuse large B-cell lymphoma

Background and purposeThe determination of the total metabolic tumour volume based on [18F]fluorothymidine ([18F]FLT) PET/CT images in diffuse large B-cell lymphoma has a potential clinical value for detecting early relapse in this type of heterogeneous lymphoproliferative tumours. Tumour segmentation is a key step in this process. For this purpose, our objective was to determine a segmentation threshold of [18F]FLT PET/CT images, based on a reference tissue uptake, on a cohort of patients with diffuse large B-cell lymphoma (DLBCL) that have been scanned at different stages of the treatment.MethodsWe enrolled 23 adult patients with DLBCL confirmed in II-IV stages without nervous system compromise. All patients were scanned using [18F]FLT PET/CT at the time of diagnosis (baseline PET), interim PET (iPET), and at the end of treatment (fPET). The administered activity was 1.8–2.6 MBq/kg body weight, performed 60–70 min after injection and without use of contrast-enhanced CT. First, we assessed the [18F]FLT uptake stability in liver and bone marrow along the patient follow-up. For the lesion segmentation, three threshold values were assessed.ResultsBoth, liver, and bone marrow can be indistinctly taken as reference tissue. The SUV threshold for a voxel to be considered as belonging to a lesion is expressed in terms of a percentage relative to the patient’s uptake in the reference tissue. Found thresholds were: for liver, 62%, 33%, 27%; and for bone marrow, 35%, 21% and 22%, for baseline, iPET and fPET stages, respectively. The relative threshold throughout the treatment has a decreasing tendency along the stages.ConclusionBased on the results obtained with [18F]FLT PET/CT during staging and follow-up in patients with DLBCL, reference values were obtained for each stage referring to liver and bone marrow uptake that could be used in clinical practice oncology.

Frequency of Geriatric Evaluation and Results in the Treatment of the Patient with Hematological Malignancy

Introduction: Hematologic malignancies (HM) are a diverse group of blood cancers with diverse etiologies, incidence, prognosis, and survival. HM represents the fourth most common malignancy; approximately 1.29 million people are living with HM. Half of the cases are diagnosed in people over 65 years of age, and 70% of cancer deaths occur in this same population. This group of patients is more vulnerable, which complicates their care. Cognitive impairment, functional dependence, and frailty are frequent factors; they are associated with greater toxicity to treatment. The management of these patients is a challenge due to comorbidities and physiological changes associated with age, which are relationed to the risk of treatment complications. There is little evidence of clinical management guidelines for decision-making in this population. The American Society of Clinical Oncology (ASCO) recommends that all older adults with cancer receiving chemotherapy have a geriatric evaluation. There are recommended evaluation scales, such as the G8 and the geriatric evaluation in hematology (GEH), of which the latter is considered the gold standard. Recent clinical trials suggest that geriatric assessment-guided interventions reduce treatment toxicity, improve quality of life, and improve communication with patients and caregivers. Unfortunately, these trials were conducted on patients with solid tumors. Aim Describe the frequency of geriatric evaluation and its value in decision-making regarding chemotherapy treatment in geriatric patients with HM. Methods: We retrospectively reviewed the data from clinical records of patients with a diagnosis of hematological malignancy aged 65 years or older who have received treatment at the National Institute of Cancerology from 2018 to 2022. An overall survival analysis was performed using the methodology described in the Kaplan - Meier method, looking for differences between groups using the log rank test. Results: We analyzed 405 patients with a hematological diagnosis in the elderly; 52 % were women, and the median age at diagnosis was 72 years (range 65-92 years). The diagnoses were non-Hodgkin lymphoma in 71 %, multiple myeloma in 14 %, Hodgkin lymphoma in 6 %, acute leukemia in 4 %, myeloprolipherative neoplasm in 2 %, lymphoproliferative neoplasm in 2.2%, and myelodysplasia neoplasm in 1.5 %. The most prevalent lymphoma corresponds to diffuse large B-cell lymphoma at 66.7 %. All patients (62.4%) with at least one comorbidity. The stratification and risk of hematological diagnosis correspond to advanced and high risk in 74.6 % and 65.4%, respectively. The frequency of geriatric evaluation was 10.6 % at diagnosis. Considered 15.6 % with fragility for geriatricians, 39 % with fragility for hematologists, and 45.4 % non-fragility. Received intensive chemotherapy in 59 %, adjusted in 34%, and palliative in 4 %. The frequency of treatment modification was 14.8 %, according to the recommendations issued in the geriatric evaluation prior to the start of treatment, which were 4.9%, and modification for the hematologist was 60 %. The frequency of treatment modifications according to the recommendations issued in the geriatric evaluation during treatment is 40 %. The response was complete in 58%, with 31 % relapse or progression and 10 % partial response. The complications that occurred more frequently were sepsis in 64 % and SARS COV-2 infection in 13 %. Of all patients, 52.5% are alive (follow-up was 60 months), median overall survival (OS) was 27.4 months, and treatment-related mortality (TRM) was 9.4%. Overall survival at 1 year is 82%, at 2 years, 58%, and at 3 years, 27%. Conclusions: Assessment geriatric in patients with hematological malignancy is 10.6 %. Intensive chemotherapy is more frequently administered in patients younger than 75 years, but there is no difference in OS with respect to clinical stage, presence of comorbidities, type of chemotherapy (intensive or adjusted), or presence of complications (p ≥ 0,05). OS is better when evaluated by a geriatrician (p = 0,000), for which reason a comprehensive geriatric assessment is considered important for the management of geriatric patients. We recommend that all older adults with cancer receiving chemotherapy have a geriatric evaluation.

Immunophenotypic Profile of Chronic Lymphoproliferative Diseases in the State of Rio Grande Do Norte, Northeast, Brazil

INTRODUCTION: Chronic lymphoproliferative diseases (CLPD) are considered as a heterogeneous group of diseases characterized by monoclonal expansion and accumulation of apparently mature lymphocytes, which have a proliferative and/or survival advantage over normal lymphocytes in different organs such as bone marrow, peripheral blood and lymph nodes. This translates into the progressive accumulation of clonal cells and their products, causing peripheral blood and bone marrow lymphocytosis, in addition to lymphadenopathy, splenomegaly or other organomegaly. According to the World Health Organization, which reflects the international consensus and is based on pathological, genetic and clinical factors, lymphoproliferative neoplasms are classified according to the stage of maturation and the lineage where the neoplastic transformation occurs through flow cytometry (FC). OBJECTIVES: The aim of this study was to demonstrate the immunophenotypic diagnostic profiles of patients with CLPD in Rio Grande do Norte, Brazil by FC. METHODOLOGY: Were investigated 884 patients with CLPD of both sexes through CF with a panel of monoclonal antibodies directed to CLPD. In addition, other patient information, such as age, gender, and clinical and hematological data were also collected. RESULTS: The results showed that 89.7% of the cases were B Cell CLPD (B-CLPD) and 10.3% T and natural killer cells (T/NK-CLPD). The distribution of B-CLPD cases were as follows: 487 Chronic lymphocytic leukemia; 18 B-Cell Pro-lymphocytic leukemia; 25 Hairy cell leukemia; 6 variant Hairy cell leukemia; 6 Follicular lymphoma leukemized; 4 Splenic lymphoma with villous lymphocytes; 33 Mantle cell lymphoma; 4 Waldenstrom's macroglobulinemia; 69 Multiple myeloma; 14 Plasma cell leukemia; 11 Burkitt's lymphoma and 117 Leukemic Non-Hodgkin lymphoma (Table 1). The distribution of CLPD-T/NK was as follows: 12 Large granular lymphocytic leukemia; 14 T-Cell prolymphocytic leukemia; 18 Adult T-cell leukemia; 20 Sézary syndrome; and 24 Peripheral T-Cell lymphoma and 2 DLPC-NK (Table 1). DISCUSSION: The B-CLPD are the most commonly observed corresponding to more than 85% of all cases and are characterized by the presence of clonal B lymphocytes with expression of a single type of immunoglobulin light chain (kappa or lambda) in a proportion greater than 1/10, associated the strong positivity of Pam-B antigens such as CD19, CD22 and CD20 and the absence or low expression of Pam-T antigens. However, other antigens such as CD200, CD5, FMC7, CD79b and CD103, among others, may be present or absent, specifically characterizing these entities as Chronic lymphocytic leukemia (weak CD22+; CD200+, CD5+, FMC7-, CD79b-), Hairy cells leukemia (strong CD22+; FMC7+; CD79b+; CD5-; CD200-; CD103+; CD123+; CD11c+ and Follicular lymphoma (strongCD22+/CD20+, CD10+, CD200-, CD79B+, FMC7+). T/NK-CLPD are less frequent and are characterized by the expression of Pan-T antigens CD2, CD3, CD5, CD7, CD28 and TCL-1, with clonality evidenced by strong positivity of TCRα/β in most cases and increase of TCD4+ or TCD8+ lymphocytes in a ratio above 1:10 in most cases. In this group, large granular lymphocyte leukemia (LGLG) is a rare type of T/NK cell CLPD characterized by peripheral and medullary infiltration of large hypergranular lymphocytic cells, comprising about 2-5% of all cases, the most commonly seen being CD8+ T cells. CONCLUSION: The results presented demonstrate that immunophenotyping is a defining technique for clarifying the diagnosis of patients with CPLD, clonality was also successfully characterized in the investigated cases of CPLP of B ,T and NK lineages.

Rituximab Is Associated with an Increased Risk of Malaria Infection in a Malaria-Endemic Region

Rituximab has become a standard of care for the treatment of lymphoproliferative B-cell neoplasms, such as diffuse large B cell lymphoma (DLBCL). As an anti-CD20 monoclonal antibody, rituximab depletes the B lymphocyte compartment and is associated with downstream impairment in humoral immunity and increased risk of infections. While such infections are often bacterial, non-bacterial infections also do occur. Malaria is a vector-borne protozoal infection caused by plasmodium species and is endemic in most parts of sub-Saharan Africa (SSA) where HIV infection is also endemic and an independent risk factor for malaria. Most studies evaluating the safety and efficacy of rituximab were in non-endemic malaria areas with a low prevalence of HIV in the US and Europe. Therefore, the effect of rituximab-induced immunodeficiency on malaria-specific immunity and the risk of malaria among DLBCL in malaria-endemic regions is not well established. The incidence of DLBCL in SSA is increasing due to the growth and aging of the population as well as epidemic levels of HIV infection. The objective of this retrospective study is to evaluate the risk for malaria infection among DLBCL patients treated with standard chemotherapy in Malawi, a malaria-endemic country with high HIV prevalence. We performed a retrospective analysis of 96 patients, aged ≥18 with DLBCL from the Kamuzu Central Hospital (Lilongwe, Malawi) Lymphoma Study, a prospective observational cohort treated with CHOP or R-CHOP 2013-2019. Symptomatic malaria cases were determined by retrospective chart review and defined as individuals with documented positive malaria rapid diagnostic test (MRDT) or peripheral blood film (PBF) during treatment or up to one year of follow-up. Laboratory malaria cases were individuals with positive P. falciparum histidine-rich protein 2 (HRP2) antigenemia using quantitative ELISA at mid-treatment (2 months), completion (4 months), or post-treatment (12 months). HRP2 antigenemia is suggestive of current or very recent P. falciparum malaria infection. Unadjusted odds ratios were calculated for risk factors for malaria using logistic regression. Treatment regimens varied slightly with 59 patients (62%) receiving CHOP, and 37 (38%) receiving R-CHOP. Fourteen of the 96 DLBCL (14.6%) patients developed symptomatic malaria during the treatment period and the remainder remained free of malaria-associated symptoms. Symptomatic malaria was not significantly associated with age, gender, DLBCL stage, number of treatment cycles received, prior history of TB, performance status, HIV infection, or HIV RNA viral load &amp;gt; 1,000 copies. However, among the symptomatic malaria cases, five (36%) received CHOP, and nine (64%) received R-CHOP. Patients treated with R-CHOP were more likely to develop symptomatic malaria than CHOP patients (OR 3.38, 95% CI 1.05-12.26; p=0.03). Thirty-two (24 CHOP, 8 R-CHOP) patients were positive for malaria based on the HRP-2 antigen test and there was no correlation with rituximab treatment. However, HRP-2 antigen concentrations were significantly higher in R-CHOP patients compared to CHOP patients (2.3 OD vs 0.58 OD; p=0.01). To our knowledge, this is the first study to evaluate the effect of rituximab on malaria risk among DLBCL patients treated with chemotherapy in a malaria-endemic region. This study suggests that rituximab increases the risk of symptomatic malaria in adult DLBCL patients. Data investigating the effect of rituximab on malaria-specific antibody production is currently being analyzed. Further studies are needed to determine whether antimalarial chemoprophylaxis should be implemented to improve the comprehensive care of cancer patients residing in malaria-endemic areas.

Outcomes of Newly Diagnosed Hodgkin Lymphoma Patients in 4 Academic Centers in Paraguay. the Impact to Access to PET-CT Scanning in Survival

Background: Hodgkin's lymphoma (HL) is a highly curable lymphoproliferative neoplasm. Assessment of HL at baseline (pre-therapy), intermediate (iPET) and end-of-therapy (EOT) by positron emission tomography/computed tomography (PET/CT) is considered a “gold standard” procedure and has become the main tool for clinical decision making in the management of HL. However, inequity in access to diagnostic medical technology in Paraguay has not allowed clinicians to manage these patients as recommended by international guidelines. We describe here the clinical characteristics, access to PET/CT study and outcomes of patients with HL treated in Paraguay. Methods: We conducted a retrospective cohort study of patients aged ≥17 years with newly diagnosed HL in 4 academic centers in Paraguay between 2015 and 2022, with follow-up until July 2023. Medical records were manually reviewed and data were abstracted in a standardized form. A historical analysis was performed to evaluate the utilization of PET/CT in all stages of HL treatment (baseline, intermediate and EOT). Survival probabilities were estimated using the Kaplan-Meier method. Results: A total of 145 patients were identified; 101 had sufficient data for analysis (Table 1). Patients were young, with a median age of 29 years (16-79) and a slight male vs. female predominance (56.4% vs. 43.6%). Nodular sclerosis (76.6%) and mixed cellularity (20.2%) were the most frequent HL subtypes. More than half of the patients (58%) had ECOG 0, 50% advanced stage and 55.9% B symptoms. The majority of patients (97%) received an ABVD regimen as induction therapy. Sixty-nine percent of patients did not undergo PET/CT at baseline, most of them (97%) due to lack of insurance coverage, 16.5% underwent iPET and 58.4% underwent PET/CT at EOT. With a median follow-up of 44 months, overall survival (OS) at 4 years was 77% and progression-free survival (PFS) was 46%. In a subgroup analysis to investigate the short 4-year PFS observed in our cohort, the PFS of patients who underwent PET/CT at EOT versus those who did not was 84 versus 36, respectively (Figure 1). Conclusions: To our knowledge, this is the first study to characterize the clinical characteristics and outcomes of patients with HL in Paraguay. It is striking to see that lack of access to PET/CT had a significant impact on PFS in our patient population. HL is a highly curable disease affecting young people, therefore, minimizing late side effects in this patient population (e.g., secondary comorbidities and malignancies) remains a high priority. The authors' conclusion is to raise awareness of the importance of improving access to diagnostic tools such as PET/CT to provide optimal care for our patients, especially those who do not have access to PET/CT.

Pre-Clinical Activity of Navitoclax in TCR-Driven and Non-ALCL Mature T-Cell Lymphomas

Background: In contrast to many B-cell lymphomas that highly express BCL-2, BCL-2 expression is observed in &amp;lt;50% of most mature T-cell lymphoma (MTCL) subtypes, although a clinical trial investigating venetoclax in BCL-2 positive relapsed/refractory PTCL is ongoing (NCT03552692). In contrast, BCL-xL and/or MCL-1 are expressed in the majority of MTCL. Consistent with these findings, MCL-1 expressing anaplastic large cell lymphomas (ALCL) and typical (non-ETP) T-ALL, which highly express BCL-xL, have been shown by BH3 profiling to be dependent upon MCL-1 or BCL-xL, respectively. Among the more common MTCL subtypes, including cutaneous T-cell lymphomas (CTCL), the extent to which BCL-2 family members are a therapeutic vulnerability is uncertain. However, we have previously demonstrated that antigen- and costimulatory receptor signaling promote the growth and survival of these lymphomas and confers resistance to chemotherapy, and in conventional (non-malignant) T cells, these same signals upregulate BCL-xL, which is required for their clonal expansion and escape from cell death following T-cell activation. Therefore, given the increasing availability of selective BH3 mimetics and the need for improved therapeutic strategies, we were motivated to examine BCL-2 family member dependencies in these lymphomas. Methods: Peptides generated from BH3-only proteins and selective BH3 mimetics were utilized to perform “BH3 profilng” in MTCL. Cell viability upon exposure to BH3 mimetics was determined using standard approaches. Results: To pre-clinically assess BCL-2 family member dependencies and the mitochondrial apoptotic pathway in T-cell lymphoproliferative neoplasms, we performed BH3 profiling in 17 cell lines. Peptides derived from BIM and PUMA, which are promiscuous, were utilized to assess the extent to which cells are “primed” for apoptosis. Differences in apoptotic priming were not observed across subtypes, and most cell lines examined were highly primed. We next examined the dependence on specific antiapoptotic proteins by BH3 profiling using BAD (antagonizes BCL-2, BCL-xL, and BCL-w), HRK (antagonizes BCL-xL), MS1 (antagonizes MCL-1), and FS1 (antagonizes A1/BFL-1) peptides. BCL-2 dependence was not observed in the T-cell lymphoma cell lines we examined. However, and in stark contrast, most non-ALCL cell lines were BCL-xL dependent, whereas ALCL cell lines were largely MCL-1 dependent. In an effort to further confirm these results, and examine the extent to which peptide-based BH3 profiling predicts sensitivity to selective BH3 mimetics in MTCL, cell lines were treated with venetoclax, A1155463 (a BCL-xL selective antagonist), navitoclax (a BCL-2/BCL-xL antagonist), or S63845 (MCL-1 antagonist), and cell viability determined. Consistent with peptide-based BH3 profiling, all cell lines examined were resistant to venetoclax. ALCL cell lines were largely MCL-1 dependent, whereas the non-ALCL cell lines examined were largely BCL-xL dependent. Therefore, we examined BCL-xL and MCL-1 expression in these cells and observed a strong association between BCL-xL expression and both cytochrome c release in response to HRK peptide and cell viability in the presence of A1155463. A similar association was observed between MCL-1 expression and sensitivity to MS1 and S63845. Transcriptionally profiled MTCL specimens were stratified by MTCL classification (ALCL vs. non-ALCL) and in keeping with the data obtained using cell lines increased BCL-xL expression was observed in non-ALCL MTCL subtypes. Given the observed association between BCL-xL expression and vulnerability to BCL-xL antagonists, we sought to examined mechanisms that promote its expression. Both TCR signaling and CD28 costimulation are exploited by non-ALCL subtypes. We examined the extent to which TCR/CD28 stimulation regulates BCL-xL transcription. In MTCL specimens, a significant increase in BCL-xL transcription and sensitization to Bcl-xL antagonism were observed upon TCR/CD28 stimulation. A TCR-dependent GEM model was utilized, demonstrating that these MTCL are Bcl-xL dependent and sensitive to navitoclax. Conclusions: These findings suggest that BCL-xL is a therapeutic vulnerability for MTCL subsets, particularly non-ALCL subtypes that are TCR dependent, and provide a robust pre-clinical rationale for future studies investigating navitoclax in these lymphomas.

Lymphomatoid granulomatosis with infrequent manifestations: case report

Introduction: lymphomatoid granulomatosis is a very rare disease with few reports in the medical literature. Objective: to present the case of a lymphomatoid granulomatosis that constitutes a variety of primary lymphoproliferative neoplasms of the lung and constitutes the first case reported in our hospital. Case presentation: 44-year-old male, veterinarian with a history of health without toxic habits that began with respiratory symptoms, dermatological lesions, constitutional syndrome and flaccid paraplegia. After performing the essential complementary tests which showed pancytopenia; an image suggestive of pulmonary metastasis was found in the chest X-ray, which was corroborated in the pulmonary tomography; also performing magnetic resonance imaging that showed lesion compression at the dorsal level. Pathology studies of the skin and lungs revealed lymphomatoid granulomatosis with spinal cord invasion. The patient received chemotherapy treatment and died abruptly a month after it began. Conclusions: lymphomatoid granulomatosis is a rare disease currently considered as a lymphoid neoplasm associated with Epstein-Barr virus and large B-cell lymphoma. We present the case of a patient with said pathology, accompanied by neurological injury and whose diagnosis was only possible by pathological studies; making it impossible to carry out a necropsy due to family refusal.