Rare Case of Cryptococcal Meningitis in Non-HIV Patient with Mantle Cell Lymphoma Associated with Acalabrutinib (Tyrosine Kinase Inhibitor)

Cryptococcus neoformans infections are more common among immunosuppressed individuals, causing the most widespread opportunistic CNS infection among HIV-positive patients [1]. Specifically, those with cellular immunosuppression, such as patients with HIV positive CD4 counts less than 100. When a patient presents with atypical symptoms, it can be difficult to diagnose due to its infrequent presentation in HIV negative patients. Due to the rarity of encounters in HIV-negative patients, when atypical symptoms are present, it poses a diagnostic challenge. Mantle cell lymphoma (MCL) is a rare subtype of non-Hodgkin B-cell lymphoma that is known to be associated with cellular immunosuppression [2]. This demonstrates the need for early diagnosis and recognition of cryptococcal infections and as a physician should be vigilant to diagnose cryptococcal who is on Acalabrutinib with MCL [3]. CLL patients receiving ibrutinib should be evaluated for cryptococcal infection, which is potentially life threatening if overlooked [4]. Meningitis caused by Cryptococcus mainly presents with fever and altered mental status but in this case, our patient 78-year-old male with mantle cell lymphoma, undergoing a regimen of Rituximab-Bendamustine (BR) in combination with acalabrutinib (TKI), presented with hypotension to ED in June 2021. Cryptococcal infection in patient receiving ibrutinib were mostly reported in patients with Chronic lymphocytic leukemia, who have poor immune reconstitution. Here we are reporting case of cryptococcal meningoencephalitis in patient with MCL on acalabrutinib which is never reported before.

Osteoarthritis Linked to Diabetes Characterized Sharp decreasing in Ser /Proline /PLCγ2 with Increasing PLCγ1, Where Inhibiting S6K/BTK / PLCγ2 Affect TXA2 Synthesis Cause C-lymphocytic Leukemia

proper S6K /BTK and PLCγ2 are main regulations for thromboxane-A synthesis, and necessary for B-cell maturations and T-cells modulations and functions. The main factors that cause the Osteoarthritis “OA” and diabetes and linked between them are the deficiency of Ser amino acids and decreasing or down regulations of Ser phosphorylation signalling pathway which necessary for proper S6K productions, where normally the Ser phosphorylation signalling pathway is the basis of Ser /Thr phosphorylation signalling which normally necessary for proper Akt, S6K1 synthesis and necessary for RORs and IFNs synthesis and also necessary for running proper BTK and proper PLCγ2 productions , where S6K is main regulator for ATPase and for proper PLCγ1 and for PLCγ2 synthesis which necessary for bone growth and for increasing and modulating immune efficiency

Cytogenetic abnormalities in patients with hematological malignancies in Lahore city, Pakistan

Hematological and hematopoietic cells malignancies of the genes and hematopoietic cells are associated with the genetic mutation, often at the chromosomal level. The standard cytogenetic study is widely accepted as one of the main diagnostics and prognostic determinants in patients. Therefore, the current descriptive and cross-sectional study sought to determine the cytogenetic analysis of frequent hematological malignancies in Pakistan. A total of 202 peripheral bone marrow or blood samples from patients with benign and malignant hematological malignancy were taken using a conventional G-banding technique. Among enrolled patients, the mean age was 21.5 years ± 23.4, and gender-wise distribution showed a marked predominance of the male 147 (73%) population compared to the female 55 (27%). Patients in the age group (2-10 years) had the highest frequency, 48 (24%), of hematological neoplasms, followed by age (11-20 years) with 40 (20%). Normal karyotypes (46, XX/46, XY) was found in 51% (n=103) patients. Furthermore, the frequency of complex karyotype was 30 (15%), while normal was seen in 171 (85%) patients. Pre-B Acute Lymphoblastic Leukemia (Pre-B ALL) was the most prevalent malignancy of 66 (33%), followed by Chronic Myelogenous Leukemia (CML) of 41 (20%) and Acute Lymphocytic Leukemia of 29 (14%). Translocation was the most prevalent 50 (25%), followed by hypotriploidy 14 (7%) and monosomy 8 (4%) on chromosome aberration analysis. In addition, t(9:22) translocation was found to be 20 (10%) in CML, with the majority in the age group (31-40 years). This study recommends that karyotyping should be tested frequently in hematological conditions because it may provide insight into the relative chromosomal changes associated with particular malignancies.

Case Report: Long-Term Survival of a Dog With Chronic Lymphocytic Leukemia Treated With Chlorambucil, Prednisolone, and Imatinib

A 7-year-old castrated male Poodle dog presented with chronic progressive lymphocytosis. Hematologic and peripheral blood smear findings included remarkable lymphocytosis with well-differentiated small lymphocytes. Cytology of bone marrow aspirate showed hypercellular integrity with infiltration of small mature lymphocytes, accounting for 45% of all nucleated cells. Flow cytometry of blood and marrow samples revealed neoplastic lymphocytes predominantly expressing the CD21 molecule. B-cell chronic lymphocytic leukemia (CLL) was diagnosed on an immunophenotypic analysis. Administrations of prednisolone and chlorambucil were initiated and the response was unremarkable. Therefore, additional treatment with imatinib was provided, which resolved the hematologic abnormalities associated with CLL. Flow cytometry after ~1 year of treatment showed normalization of the count of lymphocytes positive for CD21 and resolved hematologic lymphocytosis. The dog was followed-up for 2 years, and there were no severe adverse effects. This case indicates that imatinib may be a good option as an adjunctive therapy with prednisolone and chlorambucil treatment for CLL in dogs without treatment response.

High-Sensitive TRBC1-Based Flow Cytometric Assessment of T-Cell Clonality in Tαβ-Large Granular Lymphocytic Leukemia

Flow cytometric (FCM) analysis of the constant region 1 of the T-cell receptor β chain (TRBC1) expression for assessing Tαβ-cell clonality has been recently validated. However, its utility for the diagnosis of clonality of T-large granular lymphocytic leukemia (T-LGLL) needs to be confirmed, since more mature Tαβ cells (i.e., T-LGL normal-counterpart) show broader TRBC1+/TRBC1− ratios vs. total Tαβ cells. We compared the distribution and absolute counts of TRBC1+ and TRBC1− Tαβ-LGL in blood containing polyclonal (n = 25) vs. clonal (n = 29) LGL. Overall, polyclonal TRBC1+ or TRBC1− Tαβ-LGL ranged between 0.36 and 571 cells/μL (3.2–91% TRBC1+ cells), whereas the clonal LGL cases showed between 51 and 11,678 cells/μL (<0.9% or >96% TRBC1+ cells). Among the distinct TCRVβ families, the CD28− effector-memory and terminal-effector polyclonal Tαβ cells ranged between 0 and 25 TRBC1+ or TRBC1− cells/μL and between 0 and 100% TRBC1+ cells, while clonal LGL ranged between 32 and 5515 TRBC1+ or TRBC1− cells/μL, representing <1.6% or >98% TRBC1+ cells. Our data support the utility of the TRBC1-FCM assay for detecting T-cell clonality in expansions of Tαβ-LGL suspected of T-LGLL based on altered percentages of TRBC1+ Tαβ cells. However, in the absence of lymphocytosis or in the case of TαβCD4-LGL expansion, the detection of increased absolute cell counts by the TRBC1-FCM assay for more accurately defined subpopulations of Tαβ-LGL-expressing individual TCRVβ families, allows the detection of T-cell clonality, even in the absence of phenotypic aberrations.

InterTADs: integration of multi-omics data on topologically associated domains, application to chronic lymphocytic leukemia

ABSTRACT The integration of multi-omics data can greatly facilitate the advancement of research in Life Sciences by highlighting new interactions. However, there is currently no widespread procedure for meaningful multi-omics data integration. Here, we present a robust framework, called InterTADs, for integrating multi-omics data derived from the same sample, and considering the chromatin configuration of the genome, i.e. the topologically associating domains (TADs). Following the integration process, statistical analysis highlights the differences between the groups of interest (normal versus cancer cells) relating to (i) independent and (ii) integrated events through TADs. Finally, enrichment analysis using KEGG database, Gene Ontology and transcription factor binding sites and visualization approaches are available. We applied InterTADs to multi-omics datasets from 135 patients with chronic lymphocytic leukemia (CLL) and found that the integration through TADs resulted in a dramatic reduction of heterogeneity compared to individual events. Significant differences for individual events and on TADs level were identified between patients differing in the somatic hypermutation status of the clonotypic immunoglobulin genes, the core biological stratifier in CLL, attesting to the biomedical relevance of InterTADs. In conclusion, our approach suggests a new perspective towards analyzing multi-omics data, by offering reasonable execution time, biological benchmarking and potentially contributing to pattern discovery through TADs.

B cell receptor antigen receptor expression and phosphatidylinositol 3-kinase signaling regulate genesis and maintenance of mouse chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is a frequent lymphoproliferative disorder of B cells. Although inhibitors targeting signal proteins involved in B cell antigen receptor (BCR) signaling constitute an important part of the current therapeutic protocols for CLL patients, the exact role of BCR signaling, as compared to genetic aberration, in the development and progression of CLL is controversial. To investigate whether BCR expression per se is pivotal for the development and maintenance of CLL B cells, we used the TCL1 mouse model. By ablating the BCR in CLL cells from TCL1 transgenic mice, we show that CLL cells cannot survive without BCR signaling and are lost within eight weeks in diseased mice. Furthermore, we tested whether mutations augmenting B cell signaling influence the course of CLL development and its severity. The Phosphatidylinositol-3-kinase (PI3K) signaling pathway is an integral part of the BCR signaling machinery and its activity is indispensable for B cell survival. It is negatively regulated by the lipid phosphatase PTEN, whose loss mimics PI3K pathway activation. Herein, we show that PTEN has a key regulatory function in the development of CLL, as deletion of the Pten gene resulted in greatly accelerated onset of the disease. By contrast, deletion of the gene TP53, which encodes the tumor suppressor p53 and is highly mutated in CLL, did not accelerate disease development, confirming that development of CLL was specifically triggered by augmented PI3K activity through loss of PTEN and suggesting that CLL driver consequences most likely affect BCR signaling. Moreover, we could show that in human CLL patient samples, 64% and 81% of CLL patients with a mutated and unmutated IgH VH, respectively, show downregulated PTEN protein expression in CLL B cells if compared to healthy donor B cells. Importantly, we found that B cells derived from CLL patients had higher expression levels of the miRNA-21 and miRNA-29, which suppresses PTEN translation, compared to healthy donors. The high levels of miRNA-29 might be induced by increased PAX5 expression of the B-CLL cells. We hypothesize that downregulation of PTEN by increased expression levels of miR-21, PAX5 and miR-29 could be a novel mechanism of CLL tumorigenesis that is not established yet. Together, our study demonstrates the pivotal role for BCR signaling in CLL development and deepens our understanding of the molecular mechanisms underlying the genesis of CLL and for the development of new treatment strategies.

First-line treatment of chronic lymphocytic leukemia with ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab: final analysis of the randomized, phase 3 iLLUMINATE trial

iLLUMINATE is a randomized, open-label phase 3 study of ibrutinib plus obinutuzumab (n=113) versus chlorambucil plus obinutuzumab (n=116) as first-line therapy for patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma. Eligible patients were aged ≥65 years, or