Concomitant presentation of acute myeloid leukemia with T-cell large granular lymphocytic leukemia

T-cell large granular lymphocyte leukemia (T-LGL) also known as T-cell chronic lymphocytic leukemia is rare and comprises a small minority of all small lymphocytic leukemias. The concomitant presentation of T-LGL with acute myeloid leukemia (AML) has not been previously reported. We present an elderly gentleman with concomitant T-LGL and AML (non-M3) diagnosed by a combination of morphologic evaluation, immunophenotyping by flow cytometry, and T-cell gene rearrangement studies. The patient was managed with combination AML chemotherapy. He remains alive and well seven months after initial diagnosis. A brief review of literature is also presented.     

Recurrent alterations of TNFAIP3 (A20) in T‐cell large granular lymphocytic leukemia

The pathogenesis of T‐cell large granular lymphocytic leukemia (T‐LGL) is poorly understood, as STAT3 mutations are the only known frequent genetic lesions. Here, we identified non‐synonymous alterations in the TNFAIP3 tumor suppressor gene in 3 of 39 T‐LGL. In two cases these were somatic mutations, in one case the somatic origin was likely. A further case harbored a SNP that is a known risk allele for autoimmune diseases and B cell lymphomas. Thus, TNFAIP3 mutations represent recurrent genetic lesions in T‐LGL that affect about 8% of cases, likely contributing to deregulated NF‐κB activity in this leukemia.     

T-cell large granular lymphocytic (T-LGL) leukemia: a single institution experience

Background T-cell large granular lymphocytic (T-LGL) leukemia is a rare lymphoproliferative disease which usually affects elderly people. The clinical course of T-LGL leukemia is generally indolent, with lymphocytosis and splenomegaly in 20–50% patients, hepatomegaly in 5–20% of patients, and less commonly, lymphadenopathy. T-LGL leukemia is associated with immunological abnormalities: rheumatoid factor with or without rheumatoid arthritis (RA), Coombs positive hemolytic anemia, idiopathic thrombocytopenic purpura (ITP), pure red cell aplasia (PRCA), positive anti-nuclear antibodies (ANA), anti-neutrophil cytoplasmic antibodies (ANCA), hypogammaglobulinemia, and polyclonal hypergammaglobulinemia. Aim To compare clinical and laboratory features of T-LGL leukemia patients and their responses to different chemotherapy regimens. Methods Six patients (3 males and 3 females) with T-LGL leukemia were analyzed. The diagnosis was based on accepted morphologic criteria, immunophenotype, and polymerase chain reaction (PCR) detection of T-cell receptor (TCR) gene rearrangements. Results All patients exhibited lymphocytosis, mainly with unusual morphologies, splenomegaly, and elevated serum lactate dehydrogenase (LDH). Three patients were treated with a Fludarabine–Cyclophosphamide (FC) combination as initial therapy while three patients received CHOP. Two patients received more than one treatment regimen. One patient died due to T-LGL leukemia in first year after diagnosis, one patient died 4 years after diagnosis, two patients interrupted their treatment, and two patients are still alive. Conclusions Further prospective studies are needed for establishing a gold standard therapy for T-LGL leukemia.     

21例T细胞大颗粒淋巴细胞白血病的临床分析及文献回顾

目的:分析T细胞大颗粒淋巴细胞白血病(T-cell large granular lymphocytic leukemia,T-LGLL)患者的临床特征、治疗方案及生存情况。方法:回顾性分析2009年2月至2019年12月山东大学齐鲁医院收治的21例T-LGLL患者的临床及实验室检查资料,总结其临床特征、治疗方案及预后情况。结果:T-LGLL患者多为中老年男性,主要临床表现为乏力(61.9%)、感染(28.6%)、脾肿大(61.9%),6例患者合并自身免疫性疾病。T-LGLL患者血常规通常表现为白细胞减少(42.9%)和(或)贫血(71.4%),骨髓涂片可见大颗粒淋巴细胞增多,骨髓活检可见粒红系增生受抑,典型的T-LGLL免疫表型为CD3⁺CD4^-CD8⁺CD57⁺CD16⁺,88.9%患者TCR基因重排阳性。T-LGLL通常疾病进展缓慢,免疫抑制治疗总有效率为60%,血液学完全缓解率为20%,部分缓解率为40%。结论:T-LGLL为一种以血细胞减少、骨髓及外周血中大颗粒淋巴细...     

T-cell large granular lymphocyte leukemia and related disorders

T-cell large granular lymphocyte (LGL) leukemia is a clonal proliferation of cytotoxic T cells, which causes neutropenia, anemia, and/or thrombocytopenia. This condition is often associated with autoimmune disorders, especially rheumatoid arthritis, and other lymphoproliferative disorders. The diagnosis is suggested by flow cytometry demonstrating an expansion of CD8(+)CD57(+) T cells and is confirmed by T-cell receptor gene rearrangement studies. Mounting evidence suggests that LGL leukemia is a disorder of dysregulation of apoptosis through abnormalities in the Fas/Fas ligand pathway. In most patients, this is an indolent disorder, and significant improvement of cytopenias can be achieved with immunosuppressive agents such as steroids, methotrexate, cyclophosphamide, and cyclosporin A. This review provides a concise, up-to-date summary of LGL leukemia and the related, more aggressive, malignancies of cytotoxic T cells and natural killer cells.     

T-cell large granular lymphocytic (T-LGL) leukemia: experience in a single institution over 8 years

T-cell large granular lymphocytic (T-LGL) leukemia is characterized by cytopenia and clonal proliferation of large granular lymphocytes. We identified 26 patients with T-LGL leukemia seen at our institution over a period of 8 years. The majority of the patients were asymptomatic at diagnosis. Nine patients were treated with cyclosporine; one achieved a complete remission, and four had a hematological response. Other treatment modalities included single agent alemtuzumab, alemtuzumab combined with pentostatin, fludarabine, and combination of fludarabine and cyclophosphamide. Significant responses were not seen with any of these treatment regimens. We conclude that cyclosporine therapy may be beneficial for T-LGL leukemia patients. New treatment modalities are needed for these patients.     

X连锁高IgM综合征合并T细胞大颗粒淋巴细胞白血病一例并文献复习

目的探讨X连锁高IgM综合征(XHIGM)的临床特征、诊断要点、治疗方法等。方法回顾性分析中国医学科学院血液病医院2020年3月收治的1例23岁XHIGM合并T细胞大颗粒淋巴细胞白血病(T-LGLL)患者的临床特征及实验室资料,并进行文献复习。结果患者,男性,17岁开始出现反复感染症状,就诊后发现中性粒细胞减少、贫血伴有明显脾大,IgG、IgA水平减低。虽然IgM低于正常水平(典型XHIGM表现为IgM正常或升高),但通过二代测序证实该患者为CD40L基因纯合突变(染色体:chrX;位置:135730438;氨基酸变异情况:NM_000074:exon1:c.31C>T:p.R11X;突变类型:无义突变);其母亲检测到该基因突变位点为杂合突变,其父亲未检测到该基因突变。患者明确诊断为XHIGM。患者脾切除术后贫血和中性粒细胞减少得以缓解,因白细胞升高,依据流式细胞术检测、TCR基因重排呈阳性和骨髓病理免疫组织化学染色结果表明T细胞大颗粒淋巴细胞增高且为克隆性增殖。患者最终诊断为XHIGM合并T-LGLL。结论少数XHIGM患者可在成年后发病,且可表现为IgG、IgA和IgM水平均明显减低的非典型临床特征,CD40L基因突变是XHIGM最终的确诊标准。对于反复感染、IgG定量低于正常水平、合并中性粒细胞减少的男性患者,需进行XHIGM基因筛查。少数XHIGM患者可合并T-LGLL。     

Regulatory T-cell number is increased in chronic lymphocytic leukemia patients and correlates with progressive disease

Regulatory T-cells (Treg) actively maintain immunological self-tolerance and play a significant role in the progression of cancer. Treg cell numbers have been evaluated in 80 patients with previously untreated chronic lymphocytic leukemia (CLL) and in 40 normal healthy volunteers. Treg cells are higher in CLL patients than in controls and correlate with disease status (more advanced clinical stage, peripheral blood B-cell lymphocytosis, absolute CD38+ B-cell number, and more elevated LDH levels). No correlation was found with ZAP-70 expression, IgVH mutational status and cytogenetic abnormalities. This data shows that Treg cell number is abnormal in CLL patients.     

大颗粒T淋巴细胞白血病误诊1例报告

大颗粒淋巴细胞(LGL)占外周血有核细胞的10%~15%,其中T淋巴细胞占85%,自然杀伤细胞(NK)占15%.而大颗粒淋巴细胞白血病1985年首次被描述,是一种涉及血液、骨髓、脾脏的克隆性疾病[1].1993年Lubomir Sokolet根据其免疫表型将其分为T、NK细胞型[2].尽管大颗粒T细胞淋巴细胞白血病(T-cell large granular lymphocytic leukemia,T-LGLL)有粒细胞缺乏及贫血等症状,但无临床特异性,且疾病发展较慢,呈潜隐过程,常致漏诊和误诊.现将我科收治的1例以初诊时误诊为粒细胞缺乏症的大颗粒T淋巴细胞白血病的诊疗过程报道如下.     

Isolated anemia in patients with large granular lymphocytic leukemia (LGLL)

Patients with large granular lymphocytic leukemia (LGLL) frequently present with neutropenia. When present, anemia is usually accompanied by neutropenia and/or thrombocytopenia and isolated anemia is uncommon. We evaluated a cohort of 244 LGLL patients spanning 15 years and herein report the clinicopathologic features of 34 (14%) with isolated anemia. The patients with isolated anemia showed a significantly male predominance (p = 0.001), a lower level of hemoglobulin (p < 0.0001) and higher MCV (p = 0.017) and were less likely to have rheumatoid arthritis (p = 0.023) compared to the remaining 210 patients. Of the 34 LGLL patients with isolated anemia, 13 (38%) presented with pure red cell aplasia (PRCA), markedly decreased reticulocyte count and erythroid precursors, and more transfusion-dependence when compared to non-PRCA patients. There was no other significant clinicopathologic difference between PRCA and non-PRCA patients. 32 patients were followed for a median duration of 51 months (6–199). 24 patients were treated (11/11 PRCA and 13/21 non-PRCA patients, p < 0.02). The overall response rate to first-line therapy was 83% [8/11 (72.7%) for PRCA, 12/13 (92.3%) for non-PRCA], including 14 showing complete response and 6 showing partial response with a median response duration of 48 months (12–129). Half of non-PRCA patients who were observed experienced progressive anemia. During follow-up, no patients developed neutropenia; however, 5/27 (18.5%) patients developed thrombocytopenia. No significant difference in overall survival was noted between PRCA and non-PRCA patients. In summary, this study demonstrates the unique features of LGLL with isolated anemia and underscores the importance of recognizing LGLL as a potential cause of isolated anemia, which may benefit from disease-specific treatment. LGLL patients with PRCA were more likely to require treatment but demonstrated similar clinicopathologic features, therapeutic responses, and overall survival compared to isolated anemia without PRCA, suggesting PRCA and non-PRCA of T-LGLL belong to a common disease spectrum.Subject terms: Leukaemia, Leukaemia     

Establishment of the T-cell large granular lymphocyte leukemia cell line MOTN-1 carrying natural killer-cell antigens

A novel interleukin-2 (IL-2) dependent leukemia cell line MOTN-1 was established from the peripheral blood of a 63-year-old woman with T-cell large granular lymphocyte (LGL) leukemia in chronic phase. Primary peripheral blood leukemia cells were CD3+, CD5+, CD7+, CD56+, CD94+, CD161+, TcRalphabeta+, and HLA-DR+. The immunoprofile of the established cell line MOTN-1, however, showed CD3-, CD5-, CD7+, CD56+, CD94+, CD159+, CD161+, TcRalphabeta- and HLA-DR+; the MOTN-1 cells were cytoplasmatically positive for CD3varepsilon and the products of the T-cell receptor (TcR) genes beta and gamma. While the TcRbeta and TcRgamma genes were rearranged, the TcRdelta gene was found to be deleted. DNA fingerprinting and chromosome analysis identifying the t(2;6)(q?23;q?21) and t(12;18)(q13;q?22) alterations demonstrated the authenticity and the malignant nature of the cell line. The scientific significance of MOTN-1 lies in (1) the rarity of this type of leukemia cell lines, (2) the co-expression of various T- and natural killer (NK)-cell-associated markers, and (3) its unique chromosomal aberrations.     

Extracorporeal photopheresis as a curative treatment strategy in non epidermotropic T-cell lymphoma and large granular lymphocyte leukemia

Background To evaluate the efficacy of extracorporeal photopheresis (ECP) in noncutaneous T-cell lymphoma and large granular lymphocytes leukemia (LGL). Patients and methods We have treated 12 refractory/relapsed patients. Six peripheral T-cell lymphoma (PTCL), one T-lymphoblastic lymphoma and five LGL with blood involvement received six biweekly leukapheresis as induction phase, followed by one course a week for 4 weeks as consolidation and one course of maintenance per month for responders until progression/relapse or disappearance of the peripheral clone. Results Six patients responded to phototherapy. Two PTCL and two LGL achieved a complete response (CR) and two other PTCL a partial response. The median duration of CR was 117 months (45-150 months) for these four patients. The peripheral clone followed by flow cytometry decreased in all six responders. Two patients with a complete disappearance of the peripheral clone have not relapsed. Conclusions As for cutaneous T-cell lymphoma, ECP therefore to be efficient for PTCL and LGL. Early decrease and disappearance of the peripheral clone were the indicators of clinical response and nonrelapse, respectively.     

Identification of novel STAT5B mutations and characterization of TCRβ signatures in CD4+ T-cell large granular lymphocyte leukemia

CD4+ T-cell large granular lymphocyte leukemia (T-LGLL) is a rare subtype of T-LGLL with unknown etiology. In this study, we molecularly characterized a cohort of patients (n = 35) by studying their T-cell receptor (TCR) repertoire and the presence of somatic STAT5B mutations. In addition to the previously described gain-of-function mutations (N642H, Y665F, Q706L, S715F), we discovered six novel STAT5B mutations (Q220H, E433K, T628S, P658R, P702A, and V712E). Multiple STAT5B mutations were present in 22% (5/23) of STAT5B mutated CD4+ T-LGLL cases, either coexisting in one clone or in distinct clones. Patients with STAT5B mutations had increased lymphocyte and LGL counts when compared to STAT5B wild-type patients. TCRβ sequencing showed that, in addition to large LGL expansions, non-leukemic T cell repertoires were more clonal in CD4+ T-LGLL compared to healthy. Interestingly, 25% (15/59) of CD4+ T-LGLL clonotypes were found, albeit in much lower frequencies, in the non-leukemic CD4+ T cell repertoires of the CD4+ T-LGLL patients. Additionally, we further confirmed the previously reported clonal dominance of TRBV6-expressing clones in CD4+ T-LGLL. In conclusion, CD4+ T-LGLL patients have a typical TCR and mutation profile suggestive of aberrant antigen response underlying the disease.Subject terms: Chronic lymphocytic leukaemia, Cancer genetics, T-cell receptor