Aggressive natural killer cell leukemia: diagnosis, treatment recommendations, and emerging therapies.

INTRODUCTION: Aggressive natural killer cell leukemia (ANKL) is a rare hematologic malignancy characterized by the EBV-driven proliferation of mature natural killer cells. It mostly frequently affects younger adults and has a fulminant course with a median overall survival of 2 months. Challenges in managing this disease include an aggressive clinical course, hematologic complications, limited clinical evidence, and a lack of consensus on therapeutic strategies. AREAS COVERED: Here, authors reviewed the key aspects of the epidemiology and current understandings of the molecular pathogenesis of ANKL. The available clinical evidence and proposed diagnostic and therapeutic algorithms in treating ANKL are discussed. Currently, the only potential cure is induction therapy with L-asparaginase-based combined chemotherapy regimens, followed by allogeneic hematologic stem transplant. However, options are extremely limited in the relapsed/refractory setting. Recently, international efforts have been made to understand the aberrant molecular pathways of ANKL and identify potential drug targets for this disease; PD-1 inhibitors, EBV-specific cytotoxic lymphocyte therapy, BCL-2 inhibitors, and JAK2 inhibitors in combination with other agents have been shown to have promising potential in treating this aggressive disease. EXPERT OPINION: When clinical trials are not available, a personalized approach using next-generation sequencing results should be encouraged in the relapse/refractory setting.

Case Report: Endocapillary Glomerulopathy Associated With Large Granular T Lymphocyte Leukemia.

Large granular T lymphocyte leukemia (T-LGLL) is a rare indolent lymphocyte leukemia. The clonal proliferation of T cells, which is related to STAT3 gene mutation and abnormal Fas-mediated apoptosis pathway after cell activation, plays a major role in disease progression. Some studies have found that the exogenous and continuous stimulation of endogenous antigens, such as virus infection, is related to the pathogenesis of T-LGLL. The renal pathological manifestations of T-LGLL have rarely been described. In this study, we report a case of T-LGLL with kidney involvement as proteinuria, acute kidney injury, with the appearance of circulating T-LGL infiltrating intra-glomerular capillaries, and endocapillary glomerulopathy. We also summarize reported cases of renal injury associated with LGLL.

Hemolytic Anemia as Presentation of T-Cell Large Granular Lymphocytic Leukemia After Kidney Transplantation: A Case Report.

T-cell large granular lymphocytic (T-LGL) leukemia is a rare clonal proliferation presenting with cytopenia, splenomegaly, and autoimmune manifestations. It has rarely been described in recipients of solid organ transplants. We report the clinical case of a young kidney transplant recipient that developed T-LGL leukemia 3 years after kidney transplantation. The disorder manifested with a severe form of autoimmune hemolytic anemia in the absence of other laboratory abnormalities. The anemia was successfully treated with an intense course of corticosteroids ands witch of immunosuppressive therapy from a calcineurin inhibitor to sirolimus, a mammalian target of rapamycin inhibitor. Our case shows that autoimmune hemolytic anemia can be a life-threatening manifestation of T-LGL disease. The antiproliferative effects of sirolimus may be useful in the treatment of symptoms of T-LGL leukemia in kidney transplantation.

Clinical features and treatment outcomes in patients with T-cell large granular lymphocytic leukemia: A single-institution experience.

AIM: Large granular lymphocyte leukemia (LGLL) is a rare lymphoproliferative disorder associated with failure of hematopoiesis and autoimmune diseases. This study describes the clinical features and treatment responses of 108 patients with T-cell large granular lymphocyte leukemia (T-LGLL). METHODS: Clinical data were collected from T-LGLL patients treated at an anemia treatment center within the hematology and blood diseases unit of a single hospital from January 2009 to April 2019. RESULTS: The majority of patients (78 %) were symptomatic at the time of presentation. Splenomegaly was observed in 41 % of cases, while hepatomegaly and lymphadenopathy were rare (6 % and 7 %, respectively). Cyclosporine (CsA) monotherapy was used as first-line therapy for 16 patients, with an overall response rate (ORR) of 56 %. CsA in combination with steroids was administered in 83 patients, with an ORR of 48 %. Among patients experiencing relapse or resistance to first-line therapy, 10 received antithymocyte globulin (ATG) therapy, with an ORR of 50 %; an additional 9 patients received a modified regimen of high-dose cyclophosphamide (CTX) therapy, yielding an ORR of 78 %. CONCLUSIONS: This study provides new information regarding the clinical features and therapeutic strategies for T-LGLL, which can be used to improve clinical decision making for T-LGLL patients. The data presented here indicate the CsA is an effective option for the treatment of T-LGLL, while modified regimens of high-dose CTX or ATG are safe and effective choices for patients with CsA refractory disease.

Large granular lymphocytic leukaemia after solid organ and haematopoietic stem cell transplantation.

T-cell large granular lymphocytic leukaemia (T-LGLL) is a chronic clonal lymphoproliferative disorder of cytotoxic T lymphocytes which commonly occurs in older patients and is often associated with autoimmune diseases. Among 246 patients with T-LGLL seen at our institution over the last 10 years, we encountered 15 cases following solid organ or haematopoietic stem cell transplantation. Here, we studied the clinical characterization of these cases and compared them to de novo T-LGLL. This experience represented a clear picture of the intricate nature of the disease manifestation and the complexities of several immune mechanisms triggering the clonal expansion.

T-cell large granular lymphocyte leukemia in solid organ transplant recipients: case series and review of the literature.

T-cell large granular lymphocyte (T-LGL) leukemia is a rare clonal proliferation of cytotoxic lymphocytes rarely described in solid organ transplant (SOT). We reviewed records from 656 kidney transplant recipients in follow-up at our Center from January 1998 to July 2017. In addition, we researched, through PubMed, further reports of T-LGL leukemia in SOT from March 1981 to December 2017. We identified six cases of T-LGL leukemia in our cohort of patients and 10 in the literature. This lymphoproliferative disorder was detected in one combined liver-kidney, one liver and 14-kidney transplant recipients. Median age at presentation was 46.5 years (IQR 39.2-56.9). The disease developed after a median age of 10 years (IQR 4.9-12) from transplantation. Anemia was the most common presentation (62.5%) followed by lymphocytosis (43.7%) and thrombocytopenia (31.2%). Splenomegaly was reported in 43.7% of the patients. Eight patients (50%) who experienced severe symptoms were treated with non-specific immunosuppressive agents. Six of them (75%) had a good outcome, whereas two (25%) remained red blood cell transfusion dependent. No cases progressed to aggressive T-LGL leukemia or died of cancer at the end of follow-up. These results suggest that T-LGL leukemia is a rare but potentially disruptive hematological disorder in the post-transplant period.

Distinctive clinical characteristics and favorable outcomes in patients with large granular lymphocytosis after allo-HCT: 12-year follow-up data.

An increase in large granular lymphocytes (LGL) is frequently seen in patients following allogeneic hematopoietic cell transplantation (allo-HCT) and it has been associated with better outcomes in some reports. We assessed 826 consecutive patients at our institution with over 12 years of follow-up for the occurrence of LGL lymphocytosis after allo-HCT. The 3-year cumulative incidence of LGL lymphocytosis was 14.5% with a median duration of over 3.5 years. The development of LGL lymphocytosis was strongly correlated with CMV viremia and GVHD. The clinical course of patients with LGL lymphocytosis after allo-HCT was indolent, with the majority of these patients not displaying any clinical signs or symptoms related to the LGL proliferation. LGL lymphocytosis was associated with better outcomes, including higher overall survival (OS 86.6% vs 44.7% at 3 years), lower non-relapse mortality (NRM 5.5% vs 30.4% at 3 years), and lower risk of relapse (8.9% vs 22.9% at 3 years). A time-dependent multivariable analysis confirmed the favorable impact of LGL lymphocytosis on OS and NRM, but not on the risk of relapse. In multivariable analysis, a longer duration of LGL lymphocytosis was associated with better OS and NRM. Improved immunomodulatory properties of these cells, regulating GVHD and infections, may explain the observed favorable outcomes of patients who developed LGL lymphocytosis following allo-HCT.

Large granular lymphocytic leukemia. Current diagnostic and therapeutic approaches and novel treatment options.

INTRODUCTION: Large granular lymphocytic leukemia (LGLL) is a low grade lymphoproliferative disorder characterized by the clonal proliferation of large granular lymphocytes (LGL) and recognised by the WHO. The diagnosis and management of these patients is challenging due to the limited information from prospective studies. Guidelines for front-line therapy have not been established. The prognosis is favourable with median overall survivals greater than 10 years. Areas covered: This manuscript is a review of the clinical features, diagnosis, pathogenesis and, in particular, the various available therapeutic options for this rare lymphoid leukemia. A systematic literature search using electronic PubMed database has been carried out. Expert commentary: A watch and wait strategy without therapeutic intervention is recommended in asymptomatic patients. The immunomodulators methotrexate, cyclophosphamide and cyclosporin are the most commonly used drugs in the routine practice with responses ranging from 50 to 65% and without evidence of cross-resistance among them. Purine analogs such as 2´deoxycoformycin and fludarabine alone or in combination may be indicated in patients with bulky and/or widespread disease. Trials using monoclonal antibodies such as Alemtuzumab and agents targeting the disrupted JAK/STAT pathway in LGLL such as JAK-3 inhibitors are promising particularly in a relapse setting.

Donor-Derived T-Cell Large Granular Lymphocytic Leukemia in a Patient With Peripheral T-Cell Lymphoma.

T-cell large granular lymphocytic (T-LGL) leukemia after hematopoietic stem cell transplantation (SCT) is rare and its natural history and clinical outcome have not been well described. We report the clinical, morphologic, immunophenotypic, and molecular features of a case of donor-derived T-LGL leukemia in a 16-year-old man who received allogeneic SCT for peripheral T-cell lymphoma not otherwise specified (PTCL-NOS). The patient presented with persistent neutropenia and splenomegaly 9 months after SCT when the chimerism study showed a 100% donor pattern. A splenectomy revealed T-LGL leukemia. Flow cytometric analysis showed an aberrant T-cell population positive for CD3, CD5 (dim, subset), CD7, CD8, CD16 (subset), CD57, CD94 (dim, partial), and T-cell receptor (TCR) αß, and negative for CD4, CD26, CD56, and TCRγδ. Molecular studies showed monoclonal TCRß and TCRγ gene rearrangements. Both the immunophenotype and molecular profile of the T-LGL leukemia were different from the pre-SCT PTCL. Sequencing analysis for STAT3 exon 21 did not reveal any mutation in both pre-SCT and post-SCT specimens. The patient did not receive any treatment for T-LGL leukemia; however, his count progressively increased after splenectomy, despite the presence of persistent T-LGL leukemia in the bone marrow. There was no evidence of recurrent PTCL. We propose an algorithm to diagnose this rare post-SCT neoplasm.

Atypical combined immunodeficiency due to Artemis defect: a case presenting as hyperimmunoglobulin M syndrome and with LGLL.

SCID can be caused by various genetic mutations leading to distinctive phenotypes according to the presence of T, B and NK cells. Artemis is a gene encoded on chromosome 10p. The deficiency of this molecule causes an inability to repair DNA double strand breaks and is one of the causes of radiosensitive T-B-NK+ SCID. The syndrome usually presents with opportunistic infections in the first years of life that leads to death if not treated with stem cell transplantation. The spectrum of the disease can be wide because of the heterogeneity of the mutations. Herein we present an atypical SCID (CID) patient with Artemis defect mimicking hyper IgM syndrome. Our patient had high serum IgM with low IgG and IgA levels, lymphocytosis and recurrent infections, intractable diarrhea, growth retardation, systemic CMV infection and sclerosing cholangitis. He also developed large granular lymphocytic leukemia and survived until the age of 6.5 years.