Lymphocytic Leukemia Research Articles

Leveraging interdisciplinary management in people with HIV and lymphoid neoplasms.

Drug-drug interactions between antiretroviral treatment (ART) and cytostatics may have a negative impact in the prognosis of people with HIV (PWH) and cancer. The objective of this study is to evaluate the impact of the implementation of interdisciplinary management and the type of ART in PWH diagnosed with lymphoid neoplasms. This is a multicentric, retrospective observational cohort study including PWH diagnosed with lymphoid neoplasm who started first-line chemotherapy between 2008 and 2020. Demographic, clinical and therapeutic variables were obtained from the electronic medical records and associated with 5-year progression-free survival (PFS) and overall survival (OS) using Cox proportional hazard models. A total of 118 individuals were included. Boosted ART was being used in 55 (46.6%) cases at the time of neoplasm diagnosis. The Infectious Diseases or the Pharmacy Department was consulted before starting chemotherapy in 79/118 (66.9%) cases. Interdisciplinary management resulted in fewer subjects taking boosted ART (17.7% versus 71.8%, P < 0.001) and more subjects using unboosted integrase strand transfer inhibitor-based ART (74.7% versus 7.7%, P < 0.001). The use of boosted ART with chemotherapy was associated with worse 5-year PFS (P = 0.003) and 5-year OS (P = 0.016). There was a trend towards better 5-year PFS and OS when interdisciplinary management was implemented, with significant differences for individuals receiving boosted ART at neoplasm diagnosis (P = 0.0246 and P = 0.0329, respectively). Our findings underscore the significant impact of the type of ART on the prognosis of PWH undergoing chemotherapy. Encouraging collaborative management between oncologists, pharmacists and HIV teams for these patients enhances PFS and OS rates.

Immunophenotypic features of early haematopoietic and leukaemia stem cells.

Many tumours are organised in a hierarchical structure with at its apex a cell that can maintain, establish, and repopulate the tumour-the cancer stem cell. The haematopoietic stem cell (HSC) is the founder cell for all functional blood cells. Like HSCs, the leukaemia stem cells (LSC) are hypothesised to be the leukaemia-initiating cells, which have features of stemness such as self-renewal, quiescence, and resistance to cytotoxic drugs. Immunophenotypically, CD34+CD38- defines HSCs by adding lineage negativity and CD90+CD45RA-. At which stage of maturation the further differentiation is blocked, determines the type of leukaemia, and determines the immunophenotype of the LSC specific to the leukaemia type. No apparent LSC phenotype has been described in lymphoid leukaemia, and it is debated if a specific acute lymphocytic leukaemia-initiating cell is present, as all cells are capable of engraftment in a secondary mouse model. In chronic lymphocytic leukaemia, a B-cell clone is responsible for uncontrolled proliferation, not a specific LSC. In chronic and acute myeloid leukaemia, LSC is described as CD34+CD38- with the expression of a marker that is aberrantly expressed (LSC marker), such as CD45RA, CD123 or in the case of chronic myeloid leukaemia CD26. In acute myeloid leukaemia, the LSC load had prognostic relevance and might be a biomarker that can be used for monitoring and as an addition to measurable residual disease. However, challenges such as the CD34-negative immunophenotype need to be explored.

Identification of Gene Regulatory Networks in B-Cell Progenitor Differentiation and Leukemia.

Pro-B- and pre-B-cells are consecutive entities in early B-cell development, representing cells of origin for B-cell precursor acute lymphoid leukemia (BCP-ALL). Normal B-cell differentiation is critically regulated by specific transcription factors (TFs). Accordingly, TF-encoding genes are frequently deregulated or mutated in BCP-ALL. Recently, we described TF-codes which delineate physiological activities of selected groups of TF-encoding genes in hematopoiesis including B-cell development. Here, we exploited these codes to uncover regulatory connections between particular TFs in pro-B- and pre-B-cells via an analysis of developmental TFs encoded by NKL and TALE homeobox genes and by ETS and T-box genes. Comprehensive expression analyses in BCP-ALL cell lines helped identify validated models to study their mutual regulation in vitro. Knockdown and overexpression experiments and subsequent RNA quantification of TF-encoding genes in selected model cell lines revealed activating, inhibitory or absent connections between nine TFs operating in early B-cell development, including HLX, MSX1, IRX1, MEIS1, ETS2, ERG, SPIB, EOMES, and TBX21. In addition, genomic profiling revealed BCP-ALL subtype-specific copy number alterations of ERG at 21q22, while a deletion of the TGFbeta-receptor gene TGFBR2 at 3p24 resulted in an upregulation of EOMES. Finally, we combined the data to uncover gene regulatory networks which control normal differentiation of early B-cells, collectively endorsing more detailed evaluation of BCP-ALL subtypes.

Microbial and Metabolic Gut Profiling across Seven Malignancies Identifies Fecal Faecalibacillus intestinalis and Formic Acid as Commonly Altered in Cancer Patients.

The key association between gut dysbiosis and cancer is already known. Here, we used whole-genome shotgun sequencing (WGS) and gas chromatography/mass spectrometry (GC/MS) to conduct metagenomic and metabolomic analyses to identify common and distinct taxonomic configurations among 40, 45, 71, 34, 50, 60, and 40 patients with colorectal cancer, stomach cancer, breast cancer, lung cancer, melanoma, lymphoid neoplasms and acute myeloid leukemia (AML), respectively, and compared the data with those from sex- and age-matched healthy controls (HC). α-diversity differed only between the lymphoid neoplasm and AML groups and their respective HC, while β-diversity differed between all groups and their HC. Of 203 unique species, 179 and 24 were under- and over-represented, respectively, in the case groups compared with HC. Of these, Faecalibacillus intestinalis was under-represented in each of the seven groups studied, Anaerostipes hadrus was under-represented in all but the stomach cancer group, and 22 species were under-represented in the remaining five case groups. There was a marked reduction in the gut microbiome cancer index in all case groups except the AML group. Of the short-chain fatty acids and amino acids tested, the relative concentration of formic acid was significantly higher in each of the case groups than in HC, and the abundance of seven species of Faecalibacterium correlated negatively with most amino acids and formic acid, and positively with the levels of acetic, propanoic, and butanoic acid. We found more differences than similarities between the studied malignancy groups, with large variations in diversity, taxonomic/metabolomic profiles, and functional assignments. While the results obtained may demonstrate trends rather than objective differences that correlate with different types of malignancy, the newly developed gut microbiota cancer index did distinguish most of the cancer cases from HC. We believe that these data are a promising step forward in the search for new diagnostic and predictive tests to assess intestinal dysbiosis among cancer patients.

The genomic and molecular landscape of splenic marginal zone lymphoma, biological and clinical implications.

Splenic marginal zone lymphoma (SMZL) is a rare, predominantly indolent B-cell lymphoma constituting fewer than 2% of lymphoid neoplasms. However, around 30% of patients have a shorter survival despite currently available treatments and the prognosis is especially poor for the 5-15% of cases that transform to a large cell lymphoma. Mounting evidence suggests that the molecular pathogenesis of SMZL is critically shaped by microenvironmental triggering and cell-intrinsic aberrations. Immunogenetic investigations have revealed biases in the immunoglobulin gene repertoire, indicating a role of antigen selection. Furthermore, cytogenetic studies have identified recurrent chromosomal abnormalities such as deletion of the long arm of chromosome 7, though specific disease-associated genes remain elusive. Our knowledge of SMZL's mutational landscape, based on a limited number of cases, has identified recurring mutations in KLF2, NOTCH2, and TP53, as well as genes clustering within vital B-cell differentiation pathways. These mutations can be clustered within patient subgroups with different patterns of chromosomal lesions, immunogenetic features, transcriptional signatures, immune microenvironments, and clinical outcomes. Regarding SMZL epigenetics, initial DNA methylation profiling has unveiled epigenetically distinct patient subgroups, including one characterized by elevated expression of Polycomb repressor complex 2 (PRC2) components. Furthermore, it has also demonstrated that patients with evidence of high historical cell division, inferred from methylation data, exhibit inferior treatment-free survival. This review provides an overview of our current understanding of SMZL's molecular basis and its implications for patient outcomes. Additionally, it addresses existing knowledge gaps, proposes future research directions, and discusses how a comprehensive molecular understanding of the disease will lead to improved management and treatment choices for patients.

Posterior Reversible Encephalopathy Syndrome Associated with L-Asparaginase Treatment in Children: Literature Review and Six Case Reports.

L-asparaginase (L-ASNase) is an enzyme that shows targeted activity against Acute Lymphoblastic Leukemia (ALL) and similar lymphoid neoplasms by facilitating the breakdown of asparagine into L-aspartic acid, thereby reducing L-asparagine levels in leukemic cells. However, its therapeutic potential is hindered by its associated toxicity, leading to complications, such as thrombosis, hemorrhage, thrombocytopenia, fibrinolysis, hypersensitivity reactions, and the development of Posterior Reversible Encephalopathy Syndrome (PRES). This review compiles documented cases of PRES linked to treating B and T cell acute lymphoblastic leukemia in children using L-ASNase. Although this pathology is rare, understanding its management is crucial within ASNase-based chemotherapy protocols. As PRES lacks a specific treatment, focusing on symptomatic management becomes pivotal. Therefore, comprehending the underlying causes during L-ASNase treatment for acute lymphoblastic leukemia is essential. Understanding the etiology and clinical symptoms of this illness is critical for early diagnosis and treatment. The cases of PRES described in this review include instances in which this syndrome has appeared after the administration of L-ASNase in children. In some cases, PRES developed during induction therapy, while in others, it occurred during the reinduction phase. These cases resolved days after discontinuation of L-ASNase. The findings suggest a close relationship between drug administration and the appearance of brain lesions, as evidenced by the disappearance or decrease of these lesions when the drug was eliminated from the bloodstream.

Impact of Race and Ethnicity on Outcomes After Umbilical Cord Blood Transplantation

BackgroundUmbilical cord blood transplant (UCBT) improves access to transplant for patients lacking a fully matched donor. Previous Center for International Blood and Marrow Transplant Research (CIBMTR) showed that Black patients had a lower overall survival (OS) than White patients following single UCBT. The current study draws on a larger modern cohort and compares outcomes among White, Latinx, Black, and Asian patients. ObjectiveTo compare outcomes by social determinants of health. Study DesignWe designed a retrospective study using CIBMTR data. US patients were between ages 1 and 80; 983 received single and 1529 double UCBT as reported to CIBMTR, following either a myeloablative (N = 1752) or reduced intensity conditioning (N = 759) for acute myeloid leukemia, acute lymphoid leukemia, or myelodysplasia. The primary outcome was 2-year OS. Secondary outcomes included disease free survival, transplant related mortality (TRM), acute and chronic graft vs host disease (GVHD), and GVHD free, relapse free survival (GRFS). ResultsFor 1705 adults, in univariate analysis, 2-year OS was 41.5% (99% CI, 37.6 to 45.3) for Whites, 36.1% (99% CI, 28.2 to 44.5) for Latinx, 45.8% (99% CI, 36.7 to 55.1) for Blacks, and 44.5% (99% CI, 33.6 to 55.6) for Asians. In multivariate analysis of adults, Latinx patients had inferior OS compared to black patients (p = .0005, HR 1.45, 99% CI 1.18 to 1.79). OS improved over time for all racial/ethnic groups. GVHD rates were comparable among the different racial/ethnic groups. In the 807 children, the 2-year OS in univariate analysis was 66.1% (99% CI, 59.7 to 72.2) for Whites, 57.1% (99%CI, 49 to 64.9) for Latinx, 46.8% (99%CI, 35.3 to 58.4) for Blacks, and 53.8% (99%CI, 32.7 to 74.2) for Asians. In multivariate analysis, no difference in OS was observed among racial/ethnic groups (p = .051). Grade III/IV acute GVHD was higher in Blacks compared with Whites (p = .0016, HR 2.25, 99% CI 1.36 to 3.74) and Latinx (p = .0016, HR 2.17, 99% CI 1.43 to 3.30). There was no survival advantage to receiving a UCB unit from a donor of similar race and ethnicity, for any racial/ethnic groups, for both children and adults.Black and Latinx adult patients were more likely to live in areas defined as high poverty. Patients from high poverty level areas had worse OS (p = .03), due to a higher rate of TRM (p=0.04). Educational level, and type of insurance did not impact overall survival, GVHD, TRM or other transplant outcomes. Children from areas with a higher poverty level had higher TRM, regardless of race and ethnicity (p = .02). Public health insurance, such as Medicaid, was also associated with a higher TRM (p = .02). However, poverty did not impact pediatric OS, DFS, or other post-transplant outcomes. ConclusionsOS for UCBT has improved over time. In adults, OS is comparable among Whites, Blacks, and Asians and lower for Latinx patients. In children, OS is comparable among Whites, Blacks, Latinx, and Asians, but Grade III/IV acute GVHD was higher in Black patients. There was no survival benefit to matching UCB unit and patient by race and ethnicity for adults and children.

Precursor B Cell Acute Lymphoblastic Leukemia Presenting with Repeated Episodes of Hemophagocytic Lymphohistiocytosis

AbstractHemophagocytic lymphohistiocytosis (HLH) is a rare disorder characterized by dysregulated activation of cytotoxic T-lymphocytes and macrophages, resulting in excessive cytokine release and tissue damage. Although hematological malignancies and the chemotherapies used to treat them are frequently identified as triggering factors for HLH, B lymphoid leukemias are rarely implicated. In this report, we present an interesting case of a patient who presented with symptoms of HLH and was subsequently diagnosed with B-cell acute lymphoblastic leukemia. The further course of chemotherapy was complicated by another episode of HLH. This case highlights the complexity and the diverse triggers of HLH in the context of B lymphoid leukemia. Recognizing this atypical presentation is important to institute timely management strategies.

Incidence and Risk Factors for Arterial Thrombosis in Patients with Acute Leukemia and Lymphoid Malignancies: A Retrospective Single-Center Study.

The treatment of patients with hematological malignancies and acute arterial thrombosis (ATE) is challenging due to the risk of bleeding complications during treatment. Data on the incidence and risk factors for ATE in this group are very limited. We aimed to evaluate the incidence and risk factors for ATE in patients with acute leukemia (AL) and lymphoid malignancies. Patients with acute leukemia (AL), lymphoid malignancies, and ATE diagnosed following cancer diagnosis, who were treated and followed at the Department of Hematology, Karolinska University Hospital, 2005-2020, were candidates for inclusion in this study. Retrospective data on malignancy, ATE, and risk factors were collected. No differences in either the 15-year incidence of ATE (1.4%) nor in the risk factors for cardiovascular disease (CVD) between patients with AL and lymphoid malignancies and ATE were found. ATE at diagnosis was more frequent in patients with AL and lymphoid malignancies (excluding chronic lymphatic leukemia, CLL). Patients with AL and lymphoid malignancies have a similar risk of ATE when compared to each other and the general population, regardless of platelet levels. No difference could be found in the presence of CVD risk factors between patients with AL and lymphoid malignancies presenting with ATE.

P-364 Impact on fertility outcomes in survivors after hematopoietic stem cell transplantation for benign and malignant hematologic disorders: a systematic review and meta-analysis

Abstract Study question What is the prevalence of infertility after hematopoietic stem cell transplantation (HSCT) in females and males up to the age of 1 year? Summary answer The overall prevalence of infertility (95% CI) in women treated with HSTC is 64% (0.58-0.70) and in men 39% (0.31-0.47). What is known already HSCT is a well-established treatment that has significantly increased survival in haematological malignancies and also benign diseases since its introduction in the 1980s. The use of high-dose chemotherapy and radiotherapy, myeloablative conditioning, combined with HSCT exposes serious long-term complications, including gonadal dysfunction and infertility. The risk of ovarian and testicular damage seems to be very high. Therefore, the European Society for Blood and Marrow Transplantation (EBMT) had recommended in 2015 to consider fertility preservation measures in children and adolescents requiring HSCT. However, the data on which this recommendation was based was limited and heterogeneous. Study design, size, duration The systematic review and meta-analysis is part of the FertiTOX project (www.fertitox.com) which aims to close the gap of data regarding gonadotoxicity of cancer therapies to enable more accurate counselling regarding fertility preservation. A systematic literature search was conducted in Medline, Embase and Cochrane in November 2023, considering papers published since 2000. Participants/materials, setting, methods A total of 1632 records were identified for abstract screening. Only females and males without recurrent disease and follow up of more than one year were considered. For the systematic review, 68 studies fulfilled the criteria. For the meta-analysis, studies with &amp;lt; 10 patients were excluded. Infertility was defined in females as very low AMH, hypergonadotropic hypogonadism, amenorrhoea and/or need for hormone replacement therapy and in males as low inhibin B and/or azoospermia. Main results and the role of chance In total, 68 out of 1632 studies were included in the final analysis. Malignant diseases were mainly acute myeloid / lymphoblastic leukemia, chronic myeloid leukemia/ lymphocytic leukemia and non-hodgkin’s and hodgkin’s lymphoma. Benign diseases were sickle cell disease, Fanconi anaemia, and β-thalassemia major. In the meta-analysis, 56 studies were included, comprising 1853 female malignant cases, 241 female benign cases, 1871 male malignant cases, and 226 male benign cases. The analysis, employing a random-effects model for estimating prevalence and its 95% confidence interval, revealed that the overall pooled prevalence of infertility exceeded 30% in all groups. The prevalence of infertility was highest in female malignant cases (65%, 95% CI: 0.58-0.71). In women with benign diseases it was 61% (95% CI: 0.48-0.73). In males with malignant diseases it reached 41% (95% CI: 0.32 to 0.51) and with benign diseases 31% (95% CI: 0.19 to 0.46). Heterogeneity of data was high as shown by female as shown by the malignant cases of 83% and benign cases of 65% in women and the malignant cases of 91% and benign cases of 74% in males. Limitations, reasons for caution The heterogeneity of the included studies due to treatment variations and diverse characteristics of the study populations with large age ranges, did not allow further subgroup analyses. Thus, an individual and reliable fertility prognosis is still difficult to give. Wider implications of the findings The results of this meta-analysis support the clinical necessity of fertility preservation counselling in females and males undergoing HSCT treatment. Further prospective studies addressing the individual impact of the HSCT treatment on gonadal function are needed Trial registration number The study protocol was registered at the international Prospective Register of Systematic Reviews, PROSPERO (Registry number CRD42023486928).

EBV-positive diffuse large B-cell lymphoma, not otherwise specified: 2024 update on the diagnosis, risk-stratification, and management.

Epstein Barr virus-positive (EBV+) diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS) is an aggressive B-cell lymphoma associated with EBV infection included in the WHO classification of lymphoid neoplasms since 2016. Although historically associated to poor prognosis, outcomes seem to have improved in the era of chemoimmunotherapy. The diagnosis is established through meticulous pathological evaluation. Detection of EBV-encoded RNA (EBER) is the standard diagnostic method. The ICC 2022 specifies EBV+ DLBCL, NOS as occurring when >80% of malignant cells express EBER, whereas the WHO-HAEM5 emphasizes that the majority of tumor cells should be EBER positive without setting a defined threshold. The differential diagnosis includes plasmablastic lymphoma, DLBCL associated with chronic inflammation, primary effusion lymphoma, among others. The International Prognostic Index (IPI) and the Oyama score can be used for risk-stratification. The Oyama score includes age >70 years and presence of B symptoms. The expression of CD30 and PD-1/PD-L1 are emerging as potential adverse but targetable biomarkers. Patients with EBV+ DLBCL, NOS, should be staged and managed following similar guidelines than patients with EBV-negative DLBCL. EBV+ DLBCL, NOS, however, might have a worse prognosis than EBV-negative DLBCL in the era of chemoimmunotherapy. Therefore, inclusion of patients in clinical trials when available is recommended. There is an opportunity to study and develop targeted therapy in the management of patients with EBV+ DLBCL, NOS.

Immunohistochemical factors of prognosis of immunotherapy for metastatic melanoma: А prospective and retrospective study

Introduction. Anti-PD-1 immunotherapy (IT) is becoming the standard treatment for patients with metastatic melanoma. However, immune checkpoint inhibitors are only effective in a fraction of patients, and studies examining biological markers and their correlation with clinical efficacy are insufficient to draw unambiguous conclusions. Aim. To improve the outcomes of the first-line therapy for disseminated melanoma based on identifying clinical and immunohistochemical predictors of IT efficacy. Materials and methods. Data from 130 patients who were treated with immune checkpoint inhibitors (nivolumab or prolgolimab) in the first-line therapy for disseminated melanoma between 2017 and 2024 were analyzed. Results. Improvement was observed in 24 patients (18.4%): complete response in 18 patients (13.8%), partial response in 6 (4.6%), and stabilization in 71 (54.6%) patients. Progression was reported in 31 (24%) patients. Death occurred in 4 (3%) cases during IT with prolgolimab due to disease progression. The two-year disease-free survival (DFS) during IT was 53% (95% confidence interval [CI] 42–67), p=0.63; the median 2-year overall survival was not reached. In the immunohistochemical study, 47 (63.5%) patients had a predominance of tumor infiltration with CD8 lymphocytes over CD4, regardless of the IT type: 2-year DFS 82% (95% CI 70–96) vs 13% (95% CI 2.7–64) in the absence of CD8 predominance over CD4, p=0.0001; the median DFS was not reached in patients with the predominance of CD8 lymphocytes tumor infiltration over CD4 compared to the other group – 7.6 months in the absence of this feature (95% CI 5.8–0), p=0.001. The peritumoral location of the immune lymphoid infiltrate was observed in all 74 (100%) patients, and the intratumoral location was less common (52 patients, 70%). In the presence of both periand intratumoral location of the immune infiltrate, the 2-year DFS was 83% (95% CI 70–98) compared to the group of patients in whom no intratumoral location was detected – 5.5% (95% CI 0.8–36), p0.0001. The expression of programmed cell death ligand 1 (PD-L1) level 10% was observed in 47 (63.5%) patients. With this level of PD-L1 expression, the one-year DFS was 91% (95% CI 83–100) compared to 29% (95% CI 15–57) with a lower level of PD-L1 expression, p0.0001; the median DFS is reached, and in the group 2, DFS was only 6.6 months. In the case of PD-L110%, the 2-year DFS was high at 78% (95% CI 63–100), p0.0001. Conclusion. Based on the study's results, it can be assumed that immunohistochemical characteristics such as a PD-L1 expression level 10%, the simultaneous presence of periand intratumoral lymphoid tumor infiltration, and the predominance of CD8 over CD4 can be considered predictors of IT efficacy with nivolumab and prolgolimab.

Immunohistochemical study of non-Hodgkin lymphoma patients in Basrah (Single center experience)

Background. Non-Hodgkin lymphoma (NHL) represents a diverse group of lymphoid tissue cancers, predominantly arising from B-cells, T-cells, or natural killer cells. The accurate diagnosis of NHL subtypes is crucial, given their varying clinical behavior and treatment responses. This study focuses on the application of immunohistochemistry (IHC) in diagnosing and classifying NHL, comparing its efficacy to traditional hematoxylin and eosin (H&amp;E) staining methods. Methods. Conducted at Al-Sadr Teaching Hospital, Basrah, this cross-sectional study involved 48 newly diagnosed NHL cases in 2015. Patients were initially examined using H&amp;E-stained sections from lymph nodes and extranodal tissue biopsies. IHC staining, employing a range of primary antibodies, was then used to confirm diagnoses and subtype NHL cases. Results. The study revealed a predominance of diffuse large B-cell lymphoma (DLBCL) at 50%. Other subtypes that were identified included mantle cell lymphoma, Burkitt lymphoma, lymphoblastic lymphoma, MALToma, peripheral T-cell lymphoma, and follicular lymphoma. The IHC method proved critical in identifying specific NHL subtypes, which were not detectable by H&amp;E staining alone, such as mantle cell lymphomas and peripheral T-cell lymphomas. The study highlighted discrepancies with regional studies, emphasizing variations due to sample size and regional factors. Conclusion. Immunohistochemical staining is an indispensable tool for accurately diagnosing and classifying NHL, complementing H&amp;E staining. This study underscores the need for a comprehensive diagnostic approach, including a panel of antibodies, to optimize the diagnostic process and ensure accurate treatment planning.

Challenges in addressing Chronic Lymphoid Leukemia: when to treat or not to treat?

A leucemia linfoide crônica (LLC) é uma neoplasia maligna caracterizada pela proliferação clonal de linfócitos morfologicamente maduros, mas imuno-incompetentes, que se acumulam em medula óssea, sangue periférico, baço e linfonodos, onde ocorrepredominantemente a expansão clonal de células B CD5+ e CD23+. A mutação cromossômica mais comum é del (13q), estando as mutações de TP53 associadas a um pior prognóstico. A LLC acomete pacientes de meia-idade e idosos, sendo frequentemente encontrada nos países ocidentais, eos pacientes do sexo masculino são mais acometidos do que os de sexo feminino. A maioria dos indivíduos são diagnosticados incidentalmente durante um hemograma de rotina, uma vez que a doença apresenta grande heterogeneidade nas manifestações clínicas. Os critérios para iniciar o tratamento baseiam-se nos sistemas de estadiamento Rai e Binet e na presença de sintomas relacionados à doença.Este estudo objetiva apresentar uma análise abrangente sobre a leucemia linfoide crônica e o desafio de quando iniciar ou não o tratamento. Para tal, foi realizada uma revisão bibliográfica com busca por artigos científicos e meios eletrônicos publicados entre 2015 e 2022.

Post-transplant cyclophosphamide compared to sirolimus/tacrolimus in reduced intensity conditioning transplants for patients with lymphoid malignancies.

Despite novel cellular and immunomodulatory therapies, allogeneic hematopoietic stem cell transplantation (HSCT) remains a treatment option for lymphoid malignancies. Post-transplant cyclophosphamide (PTCY) is increasingly employed for graft vs. host disease (GVHD) prophylaxis. This study aims to evaluate the safety and efficacy of PTCY in reduce intensity (RIC) HSCT for patients with lymphoid neoplasms compared to sirolimus with tacrolimus (SIR/TAC). The primary endpoint was to compare grade III-IV acute GVHD, severe chronic GVHD, and relapse-free survival (GRFS) between the two GVHD prophylaxis strategies. This study, conducted from January 2012 to December 2020, included 171 consecutive patients (82 in the PTCY and 89 in the SIR/TAC group). Results revealed a significantly decreased incidence of moderate and severe forms of chronic GVHD in PTCY cohort (5.8% [95% CI, 1.8 to 13.1]) versus the SIR/TAC cohort (39.6% [95% CI, 29.3 to 49.7] (p < 0.001)). Other outcomes, including GRFS (PTCY [45.9% (95% CI, 35.8-58.7)] and SIR/TAC groups [36.8% (95% CI, 28-48.4)], (p = 0.72)), non-relapse mortality (NRM), relapse and overall survival (OS) were similar in both groups. Interestingly, the failure to achieve GRFS was mainly attributed to GVHD in the SIR/TAC group, while disease relapse was the primary reason in the PTCY cohort.

Cutaneous Lymphoma in a Tertiary Skin Hospital and Referral Centre in Nepal.

Primary cutaneous lymphomas are a distinct group of rare lymphoid neoplasms with absence of extracutaneous lymphomas at the time of presentation. They are rare in Nepal and no data on cutaneous lymphoma have been published from this country till date. This retrospective study included 15 cases of cutaneous lymphomas retrieved from the records of department of Dermatopathology, DI Skin Hospital and Referral Centre, Bansbari, Kathmandu, Nepal. Patients were diagnosed according to the current WHO classification for cutaneous lymphoma. A total of 15 cases were studied with median age of 45 years (range: 22 to 81 years) and male to female ratio of 1.5:1. Primary cutaneous lymphomas constituted 13 cases out of 15 and the most common type of cutaneous lymphoma was mycosis fungoides and variants 5 (33%), followed by CD30 positive primary cutaneous anaplastic large cell lymphoma constituting 2 (13%). T-cell cutaneous lymphoma constituted 13 (87%) and B-cell cutaneous lymphoma 2 (13%). Cutaneous T-cell lymphomas were more frequent than cutaneous B-cell lymphomas in Nepalese patients. Mycosis fungoides and variants are commonest type of primary cutaneous lymphomas.

The role of serum interleukins in Cancer: A Multi-center Mendelian Randomization study

The occurrence of cancer is often accompanied by immune evasion and tumor-promoting inflammation, with interleukins (IL) playing a pivotal role in the immune-inflammatory mechanism. However, the precise contribution of serum interleukins in cancer remains elusive. We obtained GWAS summary data for 35 interleukins from eight independent large-scale serum proteome studies of European ancestry populations and for 23 common cancers from the FinnGen Consortium. We then conducted a multicenter Mendelian Randomization (MR) study to explore the relationship between systemic inflammatory status and cancers. 24 causal associations between interleukins and cancers were supported by multicenter data, 18 of which were reported for the first time. Our results indicated that IL-1α (Hodgkin lymphoma), IL-5 (bladder cancer), IL-7 (prostate cancer), IL-11 (bone malignant tumor), IL-16 (lung cancer), IL-17A (pancreatic cancer), IL-20 (bladder cancer), IL-22 (lymphocytic leukemia), IL-34 (breast cancer), IL-36β (prostate cancer), and IL-36γ (liver cancer) were risk factors for related cancers. Conversely, IL-9 (malignant neoplasms of the corpus uteri), IL-17C (liver cancer), and IL-31 (colorectal cancer, bladder cancer, pancreatic cancer, and cutaneous melanoma) exhibited protective effects against related cancers. Notably, the dual effects of serum interleukins were also observed. IL-18 acted as a risk factor for prostate cancer, however, was a protective factor against laryngeal cancer. Similarly, IL-19 promoted the development of lung cancer and myeloid leukemia, while conferring protection against Breast, cervical, and thyroid cancers. Our study confirmed the genetic association between multiple serum interleukins and cancers. Immune and anti-inflammatory strategies targeting these associations provide opportunities for prevention and treatment.

Knocking Out CD70 Rescues CD70-Specific NanoCAR T Cells from Antigen-Induced Exhaustion.

CD70 is an attractive target for chimeric antigen receptor (CAR) T-cell therapy for the treatment of both solid and liquid malignancies. However, the functionality of CD70-specific CAR T cells is modest. We optimized a CD70-specific VHH-based CAR (nanoCAR). We evaluated the nanoCARs in clinically relevant models in vitro, using co-cultures of CD70-specific nanoCAR T cells with malignant rhabdoid tumor organoids, and in vivo, using a diffuse large B-cell lymphoma patient-derived xenograft (PDX) model. Although the nanoCAR T cells were highly efficient in organoid co-cultures, they showed only modest efficacy in the PDX model. We determined that fratricide was not causing this loss in efficacy but rather CD70 interaction in cis with the nanoCAR-induced exhaustion. Knocking out CD70 in nanoCAR T cells using CRISPR/Cas9 resulted in dramatically enhanced functionality in the diffuse large B-cell lymphoma PDX model. Through single-cell transcriptomics, we obtained evidence that CD70 knockout CD70-specific nanoCAR T cells were protected from antigen-induced exhaustion. In addition, we demonstrated that wild-type CD70-specific nanoCAR T cells already exhibited signs of exhaustion shortly after production. Their gene signature strongly overlapped with gene signatures of exhausted CAR T cells. Conversely, the gene signature of knockout CD70-specific nanoCAR T cells overlapped with the gene signature of CAR T-cell infusion products leading to complete responses in chronic lymphatic leukemia patients. Our data show that CARs targeting endogenous T-cell antigens negatively affect CAR T-cell functionality by inducing an exhausted state, which can be overcome by knocking out the specific target.

The use of low doses of gabapentin in patients with neuropathic pain and with thrombocytopenia

Introduction. Approximately 21–27% of patients with blood system diseases receive opioid analgesics, with neuropathic pain being one of the most common reasons for prescription. Gabapentin is used as a first-line drug for neuropathic pain (NP), but has been poorly studied in patients with blood system diseases.The objective was to study the effectiveness and safety of gabapentin in patients with blood system diseases with chronic pain.Materials and methods. A single-center, prospective observational study included 24 patients with thrombocytopenia and pain between October 2017 and October 2022. The patients’ age ranged from 18 to 71 years (median 40 years). All patients with blood system diseases: non-tumor blood system diseases (aplastic anemia) in 8% (n = 2), myeloid tumor blood system diseases (acute myeloid leukemia) in 34% (n = 8), lymphoid tumor blood system diseases (acute lymphoblastic leukemia, follicular lymphoma, diffuse B – large cell lymphoma, T-cell lymphomas, multiple myeloma) in 58% (n = 14). All patients had thrombocytopenia less than 150∙109/l, 66% (n = 16) had less than 90∙109/l. All patients were diagnosed with neuropathic pain (NP), localized according to the neuroanatomical distribution and accompanied by sensory disturbances typical of NP. The localization of pain was different, pain predominated in the lower extremities (63% (n = 15), 95% CI: 43 – 79%), caused by peripheral polyneuropathy of predominantly toxic origin (vincristine, bortezomib), and pain was also caused by the course of the underlying disease: cephalalgia and neck pain, this pain was caused by compression of the nerve structures by the lymph nodes, postherpetic neuralgia, trigeminal neuralgia caused by tumor growth. All patients had intractable, high-intensity pain requiring trimeperidine at a dose of 20–40 mg/day. All patients were prescribed gabapentin therapy at a dose of 900–1200 mg/day.Results. When taking gabapentin in the study group of patients (n = 24), already on the 3rd day, there was a clinically and statistically significant decrease in pain intensity: 1) by median: from the initial 6 to 4 points, p = 0.01 (and up to 3 points by 7th day of therapy) and 2) on average: from initial 6.5 to 3.9 points, p = 0.01 (and up to 3.2 points by the 7th day). Stratification of the dynamics of pain intensity reduction by type of blood system disease (BSD) shows that the decrease by day 3 (sustained and further by day 7) was clinically and statistically significant (p = 0.01) for groups of patients with lymphoid and myeloid BSD, and clinically and approximately statistically significant in patients (n = 2) with non-tumor BSD. Analgesic therapy using small doses of gabapentin gave a pronounced, stable positive effect (pain intensity statistically significantly decreased by an average of 50%). After 7 days of gabapentin therapy, a decrease in the opioid dose was noted in 52% of patients. Side effects were dominated by drowsiness 67% (n = 16), dizziness 32% (n = 8).Conclusion. The results of this study indicate that gabapentin is effective in the treatment of chronic neuropathic pain in patients with BSD and is safe when used in minimal/average therapeutic doses within the daily dosing ranges established by the official instructions for use.

Genetic drivers and cellular selection of female mosaic X chromosome loss.

Mosaic loss of the X chromosome (mLOX) is the most common clonal somatic alteration in leukocytes of femaleindividuals1,2, but little is known about its genetic determinants or phenotypic consequences. Here, to address this, we used data from 883,574 female participants across 8 biobanks; 12% of participants exhibited detectable mLOX in approximately 2% of leukocytes. Female participants with mLOX had an increased risk of myeloid and lymphoid leukaemias. Genetic analyses identified 56 common variants associated with mLOX, implicating genes with roles in chromosomal missegregation, cancer predisposition and autoimmune diseases. Exome-sequence analyses identified rare missense variants in FBXO10 that confer a twofold increased risk of mLOX. Only a small fraction of associations was shared with mosaic Y chromosome loss, suggesting that distinct biological processes drive formation and clonal expansion of sex chromosome missegregation. Allelic shift analyses identified X chromosome alleles that are preferentially retained in mLOX, demonstrating variation at many loci under cellular selection. A polygenic score including 44 allelic shift loci correctly inferred the retained X chromosomes in 80.7% of mLOX cases in the top decile. Our results support a model in which germline variants predispose femaleindividuals to acquiring mLOX, with the allelic content of the X chromosome possibly shaping the magnitude of clonal expansion.