Large Granular Lymphocytes Research Articles

Severe cytopenia after chimeric antigen receptor-T cell driven by large granular lymphocytes and responsive to steroids.

Immune effector cell-associated hematotoxicity (ICAHT) is a common toxicity associated with an important morbidity after chimeric antigen receptor (CAR)-T-cell therapy. Multiple factors seem to be involved in the development of severe ICAHT, making its management difficult. Here, we report three cases of severe ICAHT after axicabtagene-ciloleucel (axi-cel) for diffuse large B-cell lymphoma showing an expansion of large granular lymphocyte in the bone marrow with a CD3/CD57-positive non-CAR-T immunophenotype. We show that it is possible to treat them with low-dose steroids, obtaining a striking resolution of cytopenias with no deleterious impact on the underlying malignancy.

T-cell clones of uncertain significance. When is the rogue clone dangerous?

T cell large granular lymphocyte clones that persist over time and that exhibit molecular and immunophenotypic features closely resembling those of T-cell Large Granular Lymphocyte Leukemia (T-LGLL) may be detectable in individuals who lack any clinical or laboratory features supporting a diagnosis of T-cell malignancy. This condition represents a potential precursor state termed T cell clones of uncertain significance (T-CUS). T-CUS represents the even more benign extreme of the wide spectrum of clonal T- large granular lymphocyte proliferations, emphasizing the need for an appropriate multiparametric diagnostic assessment that avoids misdiagnosis of T-cell neoplasia. This approach should overcome the numerical cut-offs as the sole criteria to differentiate the benign condition from the related malignancies. In particular, genomic aberrancies might prospectively identify individuals who are at risk of progression to full blown T-cell malignancy. We herein discuss the significance of these T cell clones in both healthy and disease states suggesting molecular assays for tracking early steps of disease.

Natural history of chronic idiopathic neutropenia of the adult

Chronic idiopathic neutropenia (CIN) is a rare benign condition caused by an immune attack against neutrophils, either primary or in the context of other autoimmune conditions, lymphoproliferative syndromes, and inborn errors of immunity. In this single-center prospective study, 131 adult CIN patients were enrolled (median age 55 years, range: 20–93). At baseline, 56% had anti-neutrophil autoantibodies and 31% had autoimmune comorbidities. Over a median 3-year follow-up, the rate of grade ≥ 2 infections was 42%, with 10% grade ≥ 3, irrespective of neutrophil counts, demographics, and anti-neutrophil antibodies positivity, and G-CSF was used in 6 patients only. No malignant evolution nor deaths were observed. Bone marrow evaluation showed a large granular lymphocyte (LGL) infiltrate in 52%, mostly polyclonal, and hypocellularity in 31% of cases. Immune-histochemistry highlighted deposits of IgG, IgM, and complement fractions C3 and C4d in most cases. Interestingly, 19% of tested patients displayed somatic mutations of myeloid genes with an association with age. In conclusion, adult CIN appears to be a benign condition without life-threatening infections, yet deserving an extensive hematologic evaluation including bone marrow assessment to inform the differential diagnosis.

Kikuchi-Fujimoto lymphadenitis in a patient with human immunodeficiency virus infection: The importance of precision pathology.

Kikuchi-Fujimoto lymphadenitis (or histiocytic necrotising lymphadenitis) is a rare disease that is usually benign and self-limiting. A higher prevalence is reported amongst East Asian populations. No clear etiology has been identified although it has been associated with some viruses, rarely the Human Immunodeficiency Virus (HIV) and autoimmune pathologies. To date, there has only been a handful of cases reported globally in association with HIV, and this association is even rarer in the Asian context. A 20-year-old Asian ethnic Malay male, with no past medical history, presented with daily fevers and chills for 2weeks associated with constitutional symptoms and bilateral non-tender cervical, axillary and inguinal lymphadenopathy. Full blood count showed lymphocytosis with large granular lymphocytes. HIV viral load returned positive at >10million copies/mL. His absolute CD4 T helper cell count was 375cells/uL (7%). The rest of the infective and autoimmune workup were negative. Excision biopsy of an enlarged left cervical lymph node revealed Kikuchi lymphadenitis in the proliferative phase, with no evidence of lymphoproliferative disease. He was started on anti-retroviral therapy with resolution of the lymphadenopathy in 3months. We present a case of Kikuchi lymphadenitis associated with HIV. This highlights that Kikuchi lymphadenitis may mimic sinister pathologies (such as tuberculosis and lymphoma) and that it needs to be considered in the differential diagnosis before empirical treatment for tuberculosis or invasive investigations for lymphoma are done.

Analysis of Cytotoxic Granules and Constitutively Produced Extracellular Vesicles from Large Granular Lymphocytic Leukemia Cell Lines.

Large granular lymphocyte leukemias (LGLLs) are rare lymphoproliferative malignancies caused by clonal expansion of granular lymphocytes. T-cell LGLL and natural killer (NK) cell LGLL are defined based on their cellular origin. Their clinical manifestation and pathophysiology vary depending on the subtype and include, e.g., neutropenia, anemia, recurrent infections, and autoimmunity. A limited number of available patient-derived cell lines are considered valuable tools to study the biology of these malignancies. They differ in the expression of lineage-specific surface markers, but generally contain cytotoxic effector molecules in characteristic granules. We investigated the presence and release of lysosome-associated effector proteins in patient-derived LGLL cell lines by flow and imaging cytometry, by Western blotting and by bottom-up proteomics profiling. The tested cell lines did not express FasL (CD178), but did express CD26/DPP4+. Intracellularly, we detected major differences in the abundance and subcellular distribution of granzymes, perforin, and granulysin. Similar differences were seen in enriched lysosome-related effector vesicles (LREVs). The proteomics profiling of enriched EVs from an NK-LGLL line (NKL) and a T-LGLL line (MOTN-1), confirmed individual profiles of effector molecules. Our analyses underscore the individual distribution of effector proteins but also open new routes to define the role of intra- and extracellular granules in the disease manifestation or pathology of LGLLs.

Gamma-delta T-cell large granular lymphocytic leukemia in the setting of rheumatologic diseases.

T-cell leukemia originating from large granular lymphocytes (T-LGL leukemia) is a rare lymphoid neoplasia characterized by clonal proliferation of large granular T lymphocytes expressing αβ or γδ T-cell receptor (TCR) on the cell membrane. γδT-LGL leukemia, accounting for approximately 17% of all T-LGL leukemia cases, is associated with autoimmune diseases. However, the features of γδT-LGL leukemia in patients with rheumatologic diseases are still insufficiently characterized. In this retrospective study, 15 patients with rheumatologic disease-associated γδT-LGL leukemia were included. The patients were obtained from a single center from 2008 to 2023. Data related to clinical characteristics and rheumatologic diagnoses were collected. Immunophenotype evaluations as well as T-lymphocyte clonality (based on TCR-γ, TCR-β, and TCR-δ gene rearrangements), and signal transducer and activator of transcription (STAT) three and STAT5B mutation analyses (by next-generation sequencing) were performed on blood, bone marrow, and spleen samples. All but one patient had rheumatoid arthritis (RA). In 36% of patients, manifestations of γδT-LGL leukemia were present before or concurrently with clinical manifestations of RA. Splenomegaly was observed in 60% of patients and neutropenia (<1.5 × 109/L) was detected in 93% of cases. CD4-/CD8- and CD4-/CD8+ subtypes were detected in seven cases each. Mutations in STAT3 were detected in 80% of patients; however, STAT5B mutations were not detected. Evaluations of T-cell clonality and variant allele frequencies at STAT3 in the blood, bone marrow, and spleen tissue revealed an unusual variant of CD4-/CD8- γδT-LGL leukemia with predominant involvement of the spleen, involvement of the bone marrow to a less extent, and no tumor cells in peripheral blood. The mechanism by which γδT-LGL leukemia may induce the development of RA in some patients requires further investigation. Cases of RA-associated γδT-LGL leukemia with neutropenia and splenomegaly but no detectable tumor-associated lymphocytes in peripheral blood (the so-called splenic variant of T-LGL leukemia) are difficult to diagnose and may be misdiagnosed as Felty syndrome or hepatosplenic T-cell lymphoma.

Preclinical Development of a Romidepsin Nanoparticle Demonstrates Superior Tolerability and Efficacy in Models of Human T-Cell Lymphoma and Large Granular Lymphocyte Leukemia.

Histone deacetylase (HDAC) inhibitors are a widely recognized and valued treatment option for patients with relapsed or refractory peripheral T cell lymphomas (PTCL). Romidepsin is a relatively selective Class I HDAC inhibitor originally approved for patients with relapsed or refractory (R/R) cutaneous T cell lymphoma (CTCL) and subsequently R/R PTCL. Unfortunately, the FDA approval of romidepsin for R/R PTCL was withdrawn due to a negative Phase 4 post-marketing requirement (PMR), diminishing further the treatment options for patients with PTCL. Herein we describe the development of a first-in-class polymer nanoparticle of romidepsin (Nanoromidepsin) using an innovative amphiphilic di-block copolymer-based nanochemistry platform. Nanoromidepsin exhibited superior pharmacologic disposition, with improved tolerability and safety in murine models of T-cell lymphoma. Nanoromidepsin also exhibited superior anti-tumor efficacy in multiple models including in vitro T cell lymphoma (TCL) cell lines, ex vivo LGL leukemia primary patient samples, and murine TCL xenografts. Nanoromidepsin demonstrated greater accumulation in tumors and a statistically significant improvement in overall survival (OS) compared to romidepsin in murine xenograft models. These findings collectively justify the clinical development of Nanoromidepsin in patients with T-cell malignancies.

Characteristics of large granular lymphocyte leukemia associated with variable common immunodeficiency disorders: A study of 12 cases.

Common Variable Immunodeficiency Disorders (CVID) and Large Granular Lymphocytes leukemia (LGLL) exhibit diverse clinical manifestations including infections, dysimmunity, and lymphoproliferation. Recent decades have seen the discovery of new genes in the lymphopoiesis pathway, such as JAK-STAT. This case series supplemented by a literature review aims to describe clinical and biological characteristics of patients with both CIVD and LGLL. Patients were included through a call for comments to French and Belgian centers and through a literature review via PubMed. Clinical characteristics were compared to two large French cohort involving CVID and LGLL patients. Twelve patients were included. In all cases, CVID precedes LLGL (median diagnosis delay for LLGL was 7 years). Most cases presented with splenomegaly and autoimmune cytopenia. Ten out of 12 patients underwent splenectomy during follow up. Patients with LGLL and CVID differ from patients without immune deficiency in term of clinical presentation and prognosis. We suggest CVID may act as a trigger of LGL lymphocytosis, due to endogenous and exogenous antigenic pressure leading to the selection of a dominant LGL clone and stimulation of the JAK-STAT pathway. The role of splenomegaly and splenectomy in LGLL onset warrant further investigation in future studies.

Efficacy of ruxolitinib in the treatment of relapsed/refractory large granular lymphocytic leukaemia.

Large granular lymphocytic (LGL) leukaemia is a rare chronic lymphoproliferative disorder characterized by an expansion of cytotoxic T or NK cells. Despite a usually indolent evolution, most patients will require a treatment over the course of the disease because of cytopenia or symptomatic associated autoimmune disorders. First-line treatment is based on immunosuppressive agents, namely cyclophosphamide, methotrexate and ciclosporin. However, relapses are frequent, and there is no consensus on the management of relapsed/refractory patients. The implication of the JAK/STAT pathway in the pathogenesis of this disease has prompted our group to propose treatment with ruxolitinib. A series of 21 patients who received this regimen is reported here. Ten patients (47.6%) were refractory to the three main immunosuppressive drugs at the time of ruxolitinib initiation. Ruxolitinib yielded an overall response rate of 86% (n = 18/21), including 3 complete responses and 15 partial responses. With a median follow-up of 9 months, the median response duration was 4 months. One-year event-free survival and 1-year overall survival were 57% and 83% respectively. Mild side effects were observed. Biological parameters, notably neutropenia and anaemia, improved significantly, and complete molecular responses were evidenced. This study supports ruxolitinib as a valid option for the treatment of relapsed/refractory LGL leukaemia.

Clinical characteristics of myeloid tumors combined with the proliferation of large granular lymphocytes

Myeloid neoplasms (MNs) belong to a group of hematological malignancies characterized by the abnormal biological functions of hematopoietic stem progenitor cells. The abnormal immune and hematopoietic microenvironment of patients with MN interact with malignant clonal hematopoietic stem cells, promoting the occurrence and development of their diseases. MN large granular lymphocyte proliferation (MN-LGLP) is a special and rare clinical phenomenon in this type of disease. Currently, research on this disease in domestic and international cohorts is limited. This study analyzes the clinical and laboratory characteristics of this type of patient and explores the impact of LGLP on the clinical characteristics and survival of patients with MN. Patients with MN-LGLP are prone to neutropenia and splenomegaly. The presence of LGLP is not a risk factor affecting the survival of patients with MN-LGLP. STAG, ASXL1, and TET2 are the most common accompanying gene mutations in MN-LGLP, and patients with MN-LGLP and STAG2 mutations have poor prognoses.

РЕВМАТОИДНЫЙ АРТРИТ И ЛЕЙКОЗ ИЗ БОЛЬШИХ ГРАНУЛЯРНЫХ Т-ЛИМФОЦИТОВ: ОПИСАНИЕ КЛИНИЧЕСКОГО СЛУЧАЯ

Rheumatoid arthritis (RA) is a chronic autoimmune disease affecting the musculoskeletal system. Neutropenia often develops in RA, the pathogenesis of which is currently insufficiently studied. One of the causes of severe neutropenia may be a hematological disease, namely T-cell large granular lymphocyte leukemia (LGL). A third of patients with RA are also diagnosed with LGL, which is due to a similar pathogenetic mechanism. The clinical picture is very diverse and insufficiently specific, which causes difficulties in making a diagnosis. The purpose of this work was to analyze the features of the management of a patient with rheumatoid arthritis combined with T-cell leukemia from large granular cells. A patient born in 1953 with a long history of RA without special treatment was hospitalized in the hematology department with complaints of severe weakness, manifestations of hemorrhagic syndrome. The general blood test revealed severe anemia, leukopenia with agranulocytosis and thrombocytopenia. The patient underwent additional instrumental examinations. Substitution therapy was performed with a positive effect. In this case, peripheral blood immunophenotyping was not performed and the diagnosis was based on trepanobiopsy. According to the immunohistochemical study, leukemia from large granular T-lymphocytes was diagnosed, and therefore the patient receives treatment according to national clinical guidelines. Diagnosis of T-LGL is an urgent issue due to the frequent combination with RA, which indicates the need for a thorough differential diagnosis of neutropenia in this category of patients.

Large Granular Lymphocytic Leukemia: Clinical Features, Molecular Pathogenesis, Diagnosis and Treatment.

Large granular lymphocytic (LGL) leukemia is a lymphoproliferative disorder characterized by persistent clonal expansion of mature T- or natural killer cells in the blood via chronic antigenic stimulation. LGL leukemia is associated with specific immunophenotypic and molecular features, particularly STAT3 and STAT5 mutations and activation of the JAK-STAT3, Fas/Fas-L and NF-κB signaling pathways. Disease-related deaths are mainly due to recurrent infections linked to severe neutropenia. The current treatment is based on immunosuppressive therapies, which frequently produce unsatisfactory long-term responses, and for this reason, personalized approaches and targeted therapies are needed. Here, we discuss molecular pathogenesis, clinical presentation, associated autoimmune disorders, and the available treatment options, including emerging therapies.

Abstract 3245: Use of hypomethylating agents to reprogram the epigenome in large granular lymphocyte leukemia

Abstract Large granular lymphocyte (LGL) leukemia is a rare heterogeneous blood cancer that is characterized by the clonal lymphoproliferation of CD8+ T cells (T-LGL leukemia) or, less frequently, natural killer cells (NK-LGL leukemia). These cells evade activation induced cell death, allowing them to accumulate as highly cytotoxic lymphocytes that contribute to autoimmune attacks, neutropenia, and anemia. Frontline treatments are limited to repurposed, nonspecific immunosuppressive agents with limited efficacy and incomplete response rates. As there are no FDA-approved antineoplastic agents for LGL leukemia, our research explores novel therapeutic avenues for this orphan disease. Somatic activating mutations in the transcription factor STAT3 are the most common molecular alteration found in &amp;gt;50% of patients, and STAT3 signaling is dysregulated in almost all LGL leukemia patients. In the largest molecularly profiled LGL leukemia patient cohort to date, we found that STAT3 mutations frequently co-occur with mutations in chromatin and epigenetic modifying genes, suggesting crosstalk and cooperativity between STAT3 activation and epigenetic dysregulation. Moreover, TET2, which promotes DNA demethylation, is frequently inactivated in LGL leukemia via loss-of-function mutations and promoter hypermethylation. As DNA hypermethylation is an emerging hallmark of LGL leukemia, we evaluated the therapeutic potential of two epigenetic agents, azacitidine (AZA) and cladribine (CLAD), that directly and indirectly inhibit DNA hypermethylation, respectively. We hypothesize that AZA and CLAD will 1) exhibit cell intrinsic efficacy, 2) reprogram the epigenome of LGL leukemia through DNA hypomethylation to normalize aberrant gene expression, and 3) induce cytokine-mediated immune responses. AZA and CLAD cytotoxicity was assessed by the Cell Titer Glo viability assay in human LGL leukemia cell lines. Each exhibited potent anti-leukemic effects with IC50 values in the low micromolar and nanomolar ranges. Western blotting analysis demonstrated the decrease in protein expression of DNA methyltransferases and phosphorylated STAT3 levels with treatment in a time- and dose-dependent manner. We also explored the immunomodulatory effects of these hypomethylating agents since LGL leukemia is a pro-inflammatory malignancy with cytotoxic lymphocytes. Preliminary findings using the Isoplexis platform suggest that AZA and CLAD induce production of anti-inflammatory cytokines in LGL leukemia cells. Ongoing studies will identify differential methylation, chromatin accessibility, and gene expression using RRBS, ATAC-seq, and RNA-seq of AZA or CLAD treated samples to define the mechanisms and consequences of DNA demethylation. Uncovering the reprogramming capabilities of AZA and CLAD could allow for the potential repurposing of these inhibitors for treatment of LGL leukemia patients. Citation Format: Ariana Sabzevari, Ipsita Pal, Tess Deddens, Todd Fox, Aakrosh Ratan, David J. Feith, Thomas P. Loughran. Use of hypomethylating agents to reprogram the epigenome in large granular lymphocyte leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3245.

Abstract 3201: Preclinical development of a novel Romidepsin nanoparticle for the treatment of T-Cell lymphoid malignancies

Abstract The histone deacetylase inhibitors (HDACi) have long been regarded as an important class of drugs for treating T-cell lymphoid malignancies (TCL). Romidepsin (Romi), a bicyclic peptide, was approved for patients with relapsed or refractory cutaneous (CTCL) and peripheral T-cell lymphomas (PTCL). Unfortunately, the approval of Romi for relapsed/refractory PTCL was withdrawn due to a negative Phase 4 post-marketing requirement. Given its potent activity against Class I HDACs, Romi is considered one of the most effective HDAC inhibitors studied and used in patients with TCL. Herein, we report on a first-in-class nanoparticle of Romi (NanoRomi) with a superior safety and efficacy profile compared to the free drug in preclinical models of PTCL and large granular lymphocyte leukemia (LGLL). We developed a first-in-class NanoRomi using our proprietary amphiphilic di-block copolymer-based nanochemistry platform. NanoRomi was characterized in cell viability, flow cytometry, and western blotting (WB) assays to determine the concentration-effect relationships with regard to the induction of apoptosis and histone acetylation in cell lines representative of TCL and LGLL, as well as primary LGLL patient PBMC samples. In addition, we performed extensive in vivo modeling using murine xenografts of CTCL, including repeated dose toxicity, biodistribution, efficacy, and survival studies. Cytotoxicity assays demonstrated superior/comparable activity of NanoRomi (IC50: 1.1-2.3 nM) compared to free Romi (IC50: 4.8-10.6 nM) across all PTCL and LGLL cell lines studied, while in primary LGLL samples, NanoRomi exhibited superior cytotoxicity (2-fold) compared to Romi. WB analysis showed that NanoRomi induced apoptosis and increased acetylation of histone H3 and H4 in a time and concentration-dependent manner in cell lines representing CTCL, ALK+-ALCL, and LGLL. Repeat dose toxicity studies in CTCL xenografts confirmed that the overall tolerability of NanoRomi was substantially better than Romi. Tracking studies with a fluorescent dye (DiO) in the NanoRomi demonstrated preferential localization of NanoRomi in tumors of mice compared to the normal organs after 6 hours of drug administration. NanoRomi exhibited superior efficacy in the murine CTCL xenograft models, including a significant improvement in overall survival compared to Romi. Collectively, these data show that NanoRomi exhibits markedly superior pharmacokinetics, tolerability, and efficacy in models of TCL. We anticipate that the improved activity and tolerability of NanoRomi relate to the altered pharmacologic profile and superior bioavailability of the drug, which optimizes the effects of the drug for its influence on epigenetic biology. This unique platform offers the prospect of improving the tolerability and efficacy of epigenetic treatment strategies in these challenging diseases. Citation Format: Ipsita Pal, Anuradha Illendula, Andrea Joyner, Tess M. Deddens, Deepthi P. Damera, Todd E. Fox, Marya E. Dunlap-Brown, Kallesh D. Jayappa, Thomas P. Loughran, David J. Feith, Owen A. O'Connor. Preclinical development of a novel Romidepsin nanoparticle for the treatment of T-Cell lymphoid malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3201.

In vitro chemosensitivity testing of the feline large granular lymphocyte cell line (S87).

Feline large granular lymphocyte (LGL) lymphoma is an aggressive neoplasia characterised by short survival and poor response to chemotherapy. In this study, the effect of different chemotherapeutic agents on the growth kinetics of the feline cell line S87, a non-MHC-restricted feline LGL cell line, was investigated. Where possible, IC50 (inhibitory concentration 50) values were determined. The IC50 values of the cell line as lymphoma models can provide clues to the situation in vivo and serve as a basis for studying resistance mechanisms. Cells were incubated with various concentrations of vincristine, doxorubicin, 4-hydroperoxycyclophosphamide, prednisolone, methotrexate and L-asparaginase for 24 and 48h, respectively. The IC50 values could be determined as 14.57 (7.49-28.32) μg/mL at 24h incubation and 5.72 (4.05-8.07) μg/mL at 48h incubation for doxorubicin and 9.12 (7.72-10.76) μg/mL at 24h incubation and 4.53 (3.74-5.47) μg/mL at 48h incubation for 4-hydroperpoxycyclophosphamide. Treatment with vincristine and methotrexate resulted in relatively high cell resistance whereas L-asparaginase and prednisolone treatment led to a reduction in cell number compared to control while cell viability was not affected (cytostatic effect). Overall, the feline LGL cell line S87 proves to be relatively sensitive to doxorubicin and 4-hydroperoxycyclophosphamide and relatively resistant to treatment with vincristine, prednisolone, methotrexate and L-asparaginase. The results of this study can be used for further investigations on resistance mechanisms in feline LGL lymphoma. Doxorubicin and cyclophosphamide can be interpreted as promising candidates for the therapy of feline LGL lymphomas.

Long-Term Remission After Chemotherapy with Bendamustine in a Patient with Refractory Large Granular Lymphocyte Leukemia.

Long-Term Remission After Chemotherapy with Bendamustine in a Patient with Refractory Large Granular Lymphocyte Leukemia.

Feline high-grade and large granular lymphocyte alimentary lymphomas treated with COP- or CHOP-based chemotherapy: A multi-centric retrospective study of 57 cases.

Specific data regarding outcome of cats with high-grade and large granular lymphocyte alimentary lymphoma (HGAL and LGL, respectively) treated with multi-agent chemotherapy are scarce. The aims of this multi-centric, retrospective study were to describe the outcome of cats with HGAL and LGL treated with COP- or CHOP-based chemotherapy and to identify potential prognostic factors. Cats with a cytological or histological diagnosis of HGAL or LGL lymphoma treated with COP- or CHOP-based protocol as first-line chemotherapy were included. Data regarding diagnosis, staging, treatment and follow-up were collected. Fifty-seven cats treated with CHOP (n = 37) or COP (n = 20) protocols were included. Complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) were observed in 20%, 22%, 36% and 22% of cats, respectively, for an overall response rate of 42%. Median progression-free interval (PFI) was 148 days and overall median survival time (OST) was 131 days. Cats achieving CR, PR or SD showed significantly longer PFI (p < .01) and OST (p < .015) compared with cats with PD. Other positive prognostic factors in multi-variate analysis were rescue treatment (p < .001) and absence of lymph node involvement (p < .03). Negative prognostic factors were diffuse infiltration of the gastrointestinal tract (p = .035) and infiltration of a non-haematopoietic organ (p < .01).

T-Cell Large Granular Lymphocyte Population Involving Chimeric Antigen Receptor-Modified T (CAR T) Cells in Patients with Cytopenia after CD19-Targeted CAR T-Cell Therapy: Case Series

T-Cell Large Granular Lymphocyte Population Involving Chimeric Antigen Receptor-Modified T (CAR T) Cells in Patients with Cytopenia after CD19-Targeted CAR T-Cell Therapy: Case Series

A Case of Plasmablastic Lymphoma Complicated with Pure Red Cell Aplasia Caused by T-cell Large Granular Lymphocytic Leukemia.

Plasmablastic lymphoma (PBL) is an aggressive subtype of large B-cell lymphoma associated with immunodeficient states, such as HIV and EBV infections, and aging. PBL frequently harbor STAT3 mutations, which are crucial for their development. We herein report a rare case of PBL complicated by T-cell large granular lymphocytic leukemia (T-LGLL) and pure red cell aplasia (PRCA). The patient was treated with six cycles of chemotherapy and developed transfusion-dependent anemia. Large granular lymphocytes and T-cell receptor rearrangement were detected, thus leading to the diagnosis of T-LGLL and PRCA. This is the first documented case of PBL with T-LGLL and PRCA, offering insight into PBL's pathophysiology and the complications of PBL.

Kernel-Based Particle Filtering for Scalable Inference in Partially Observed Boolean Dynamical Systems

This paper addresses the inference challenges associated with a class of hidden Markov models with binary state variables, known as partially observed Boolean dynamical systems (POBDS). POBDS have demonstrated remarkable success in modeling the ON and OFF dynamics of genes, microbes, and bacteria in systems biology, as well as in network security to represent the propagation of attacks among interconnected elements. Despite existing optimal and approximate inference solutions for POBDS, scalability remains a significant issue due to the computational cost associated with likelihood evaluations and the exploration of extensive parameter spaces. To overcome these challenges, this paper proposes a kernel-based particle filtering approach for large-scale inference of POBDS. Our method employs a Gaussian process (GP) to efficiently represent the expensive-to-evaluate likelihood function across the parameter space. The likelihood evaluation is approximated using a particle filtering technique, enabling the GP to account for various sources of uncertainty, including limited likelihood evaluations. Leveraging the GP’s predictive behavior, a Bayesian optimization strategy is derived for effectively seeking parameters yielding the highest likelihood, minimizing the overall computational burden while balancing exploration and exploitation. The proposed method’s performance is demonstrated using two biological networks: the mammalian cell-cycle network and the T-cell large granular lymphocyte leukemia network.