Chronic Lymphocytic Leukemia, T-Cell Large Granular Lymphocytic Leukemia in a Pediatric Patient without Underlying Condition

Abstract Background Large granular lymphocytic (LGL) leukemia is a rare hematological malignancy in children. The two types of LGL leukemia that have been described are T-cell and Natural Killer cell leukemia. It is most commonly diagnosed in older adults, average age of 60-year-old. About 20 cases of LGL leukemia have been reported in children and young adults. All the patients in the reported cases had immune dysregulation conditions, such as chronic graft versus host disease, common variable immunodeficiency disorder, Crohn's disease and autoimmune hemolytic anemia. Here we report a case of T-cell LGL leukemia in a 11-year-old boy without underlying condition who presented with chronic neutropenia associated with gingival hypertrophy, recurrent skin abscesses, aphthous ulcers, clubbing of nails and low bone density. Methods Multi-institution collaboration and literature review. Case Description 11-year-old male with two years history of episodic gum bleeding with gingival hypertrophy, skin abscesses, aphthous ulcers, chronic neutropenia and lymphocytosis presented to our clinic for further evaluation. Initial workup demonstrated moderate to severe neutropenia (absolute neutrophil count between 400/ul to 800/ul) with low segmented neutrophils of 2-4% and high lymphocytes of more than 80%, but normal white blood cell count, hemoglobin for age and platelet count. Peripheral blood smear showed several variant lymphocytes with cytoplasmic blebs and no immature cells present. Expansion of T-cell large granular lymphocytes were detected in peripheral blood by flow cytometry. Due to new symptom of lower back pain, a lumbar Magnetic Resonance Imaging was performed. Results showed low bone density with mild compression deformity of L1 and abnormal heterogeneous marrow signal with heterogeneous contrast enhancement. The abnormal bone marrow signal promoted the investigation of bone marrow aspiration and biopsy. Flow cytometry detected forty-five percent of lymphocytes with immuno-phenotype of CD3+, CD8+, CD57+, CD16+, CD7+ and CD5-. The morphology of minimal cytoplasm and mature chromatin along with immunophenotype were consistent with clonal T-cell large granular lymphocytic proliferation/leukemia. Further cytogenetic tests showed TCR gamma and beta genes rearrangement, STAT3 N647I mutation with normal male karyotype. A peripheral blood congenital neutropenia panel, which included a total of 18 genes, found a heterozygous mutation c 279 G>A in the Gata2 gene; a variant of uncertain significance. Next generation sequencing showed somatic mutations of TRGV10, TRGV8 TRGJ1, TNFAIP3 and STAT3. However, there was no germline mutations detected in sample from skin biopsy. Comprehensive evaluation by immunology, rheumatology and gastroenterology failed to detect any underlying conditions. Conclusion Due to rarity of LGL leukemia in pediatrics, standard of care guidelines are currently unavailable. Extrapolated from limited literature, two management options are considered: watch and wait approach versus early initiation of immunosuppressant chemotherapy. Improved diagnostics can aide management strategies in this patient population. Disclosures No relevant conflicts of interest to declare.

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CD8 Expression on B Cells in Chronic Lymphocytic Leukemia

Archives of Pathology & Laboratory Medicine ◽

10.5858/2000-124-1361-ceobci ◽

2000 ◽

Vol 124 (9) ◽

pp. 1361-1363

Author(s):

Anwarul Islam ◽

Adrian O. Vladutiu ◽

Theresa Donahue ◽

Selina Akhter ◽

Amy M. Sands ◽

...

Keyword(s):

Bone Marrow ◽

T Cell ◽

B Cells ◽

Chronic Lymphocytic Leukemia ◽

Tract Infection ◽

Respiratory Tract ◽

Respiratory Tract Infection ◽

Peripheral Blood ◽

Lymphocytic Leukemia ◽

Cell Antigen

Abstract The expression of CD8, a restricted T-cell antigen, on B cells in B chronic lymphocytic leukemia is rare, and its significance, if any, remains unknown. We report herein a patient with B chronic lymphocytic leukemia in whom CD8 was strongly expressed on all B cells, both in the bone marrow and peripheral blood. The patient required no therapy for 6 years after being diagnosed as having B chronic lymphocytic leukemia. Then, when the disease progressed, he was treated with conventional doses of fludarabine phosphate (25 mg/m2 daily for 5 days), but unlike other patients with B chronic lymphocytic leukemia he tolerated this therapy poorly. He received a total of only 4 series of fludarabine therapy, and following each course of treatment, he developed considerable myelosuppression. After the fourth course of therapy, his bone marrow failed to show any evidence of regeneration, and he died as a result of intercurrent respiratory tract infection 1 month after his last dose of fludarabine was given.

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T cell chronic lymphocytic leukemia: presence in bone marrow and peripheral blood of cells that suppress erythropoiesis in vitro

Blood ◽

10.1182/blood.v52.1.255.255 ◽

1978 ◽

Vol 52 (1) ◽

pp. 255-260 ◽

Cited By ~ 86

Author(s):

R Hoffman ◽

S Kopel ◽

SD Hsu ◽

N Dainiak ◽

ED Zanjani

Keyword(s):

Bone Marrow ◽

T Cell ◽

Chronic Lymphocytic Leukemia ◽

T Lymphocytes ◽

Peripheral Blood ◽

Lymphocytic Leukemia ◽

Transfusion Therapy ◽

Cell Chronic Lymphocytic Leukemia ◽

Marrow Cells

Abstract The pathogenesis of the anemia associated with malignancy was investigated in a patient with T cell chronic lymphocytic leukemia. The plasma clot culture system was used as a measure in vitro of erythropoiesis. The patient's peripheral blood and marrow T lymphocytes obtained both before and after transfusion therapy suppressed erythroid colony formation by normal human bone marrow cells. Pretreatment of the patient's bone marrow T cells by antithymocyte globulin (ATG) and complement reversed this suppression. In addition, pretreatment of the patient's marrow cells with ATG and complement markedly augmented erythropoiesis in vitro. The expression of erythroid activity caused by the selective destruction of the suppressor T lymphocytes in the patient's bone marrow with ATG and the suppression of normal erythropoiesis by the patient's bone marrow and peripheral blood lymphocytes suggest that interaction between the malignant T cell and the erythropoietin-responsive stem cell is important in production of anemia in this patient.

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Lymphocyte Surface Receptors in Childhood Acute Lymphocytic Leukemia

PEDIATRICS ◽

10.1542/peds.56.5.788 ◽

1975 ◽

Vol 56 (5) ◽

pp. 788-792

Author(s):

Elaine Esber ◽

William DiNicola ◽

Nasser Movassaghi ◽

Sanford Leikin

Keyword(s):

Bone Marrow ◽

T Cell ◽

Cell Surface ◽

Peripheral Blood ◽

Acute Lymphocytic Leukemia ◽

Lymphocytic Leukemia ◽

The Other ◽

Cell Surface Receptors ◽

Surface Receptors ◽

Lymphocyte Surface

B and T cell lymphocyte surface receptors were studied in the bone marrow and peripheral blood of 16 patients with childhood acute lymphocytic leukemia. T cell surface receptors were identified on the blasts of one patient. Increased percentages of T or B cell surface receptors were not found in the bone marrow of the other 15 patients. There was a negative correlation between the percentage of pathologic cells in the peripheral blood and the percentage of cells with T and B surface receptors. The results of this study indicate that childhood acute lymphocytic leukemia is a heterogeneous disease in terms of lymphcyte surface receptors and that the pathologic cells of the majority of patients with this disease cannot be identified as being of thymic or non-thymic origin.

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A Single-Centre Series of 40 Patients with Bone-Marrow Biopsy-Defined Large Granular Lymphocyte Leukemia; High Rates of Sustained Response to Oral Methotrexate

Blood ◽

10.1182/blood.v120.21.3937.3937 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3937-3937

Author(s):

Christopher Fox ◽

Talha Munir ◽

Ian Carter ◽

Sturch Elaine ◽

Faith Richardson ◽

...

Keyword(s):

Bone Marrow ◽

T Cells ◽

T Cell ◽

Peripheral Blood ◽

Lymphocyte Count ◽

Gene Rearrangements ◽

Single Centre ◽

Oral Methotrexate ◽

Lgl Leukemia

Abstract Abstract 3937 Large granular lymphocyte (LGL) leukaemia is a rare lymphoproliferation originating in activated cytotoxic CD8+ T cells or occasionally NK cells. Published series incorporating 40 or more patients are few in number with some differences in diagnostic definitions, making comparisons between studies challenging. Investigators have chiefly relied on peripheral blood for diagnosis; typically defined as a persistent excess (>0.5×109/l) of LGLs, associated with monoclonal T-cell receptor (TCR) gene rearrangements by PCR. However, benign monoclonal CD8+T-cell expansions, phenotypically indistinguishable from T-LGL, are well recognised in both healthy elderly individuals and those with autoimmune disease. To-date, reported response rates to oral Methotrexate (MTX) have been in the order of 40–60%, with MTX-failure reportedly occurring in two-thirds of patients after 1 year of follow-up. We studied 40 patients diagnosed with LGL leukemia at Nottingham University Hospitals NHS Trust, UK, between 1990 and 2011. All patients had a persistent (>6 months) large granular lymphocytosis and, importantly, 97.5% (39/40) patients had undergone a bone marrow (BM) biopsy. In all cases an interstitial infiltrate of cytotoxic T cells and/or NK cells, typically demonstrating characteristic linear arrays, established the diagnosis. A majority of patients had correlative peripheral blood PCR studies confirming clonal TCR gene rearrangements in 80%. Although 5 patients had a polyclonal TCR gene, for all such patients the BM findings (>20% LGLs in some cases) together with clinical context (neutropenia, lymphocytosis and 2 cases of pure red cell aplasia (PRCA)) established the diagnosis of LGL leukemia. The median age at diagnosis was 66 years (21–90 years), with an equal sex distribution. The median total lymphocyte count at clinical presentation was 2.7×109/l (0.7–9.4 x109/l) and a lymphocyte count of ≥2×109/l was seen in 27 patients (68%). Thirty patients (75%) were neutropenic at diagnosis (median neutrophil count 0.9 x109/l (range 0.0–6.5 x109/l). In 13 cases neutropenia was accompanied by anemia, thrombocytopenia or both. Rheumatoid factor was positive in 11 of 27 assessable cases (41%), whilst 11 of 40 (28%) had associated autoimmune clinical disorders, including Rheumatoid arthritis (n=6). With a median follow-up for living patients of 3.2 years (range 1.0–15.1 years), 15 patients (38%) have never required treatment. One further patient was already established on MTX at LGL diagnosis. Treatment was not required in any patients who presented with an isolated, asymptomatic lymphocytosis (n=8, 20%). The median time from diagnosis to treatment was 2.1 months; all treatment-requiring patients needed therapy within 6 months of presentation. Treatment was indicated in 24 patients: neutropenia and recurrent infections (n=8); severe neutropenia (n=6); cytopenias associated with other symptoms (mouth ulcers, skin lesions, organomegaly) (n=8); and PRCA (n=2). MTX (10mg/m2, weekly) was employed as first-line therapy (n=9) and after failure of Prednisolone (0.5–1mg/kg) monotherapy (n=7). Amongst 16 MTX-treated patients, 14 (87.5%) achieved a haematological PR (n=6) or CR (n=8) after a median of 2.5 months (1–9 months). (Improvements in quality of response) Continuing responses (haem-PR to CR) were seen up to 2yrs after starting MTX (of MTX). Notably, for the 14 MTX-responders the median duration of response was 6.5 years (0.3–16), censoring for death and drug-cessation due to patient choice. Neither of the 2 patients with PRCA responded to MTX, but Ciclosporin and Fludarabine were effective salvage therapies for MTX-failures. This is one of the largest single-centre series of LGL leukemia reported to-date. The strengths of our study include robust diagnostic evidence of LGL leukemia including BM biopsy and a long follow-up duration. By contrast to the published data, we describe high rates of response to MTX in both steroid-exposed and naive patients. Time to response exceeded 4 months in some cases and responses were sustained for >5 years in a majority of patients. The role of MTX in LGL leukemia warrants further study. Disclosures: No relevant conflicts of interest to declare.

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Insulin binding of acute lymphocytic leukemia cells

Blood ◽

10.1182/blood.v48.1.33.bloodjournal48133 ◽

1976 ◽

Vol 48 (1) ◽

pp. 33-39

Author(s):

EC Esber ◽

DN Buell ◽

SL Leikin

Keyword(s):

Bone Marrow ◽

T Cell ◽

Peripheral Blood ◽

Insulin Binding ◽

Lymphocytic Leukemia ◽

Cell Surface Receptor ◽

Cell Disease ◽

Binding Studies ◽

Null Cell ◽

The Mean

Because of differences in insulin binding of cultured lymphoic cell lines, T- and B-cell surface receptor and 125I-insulin binding studies were performed on the bone marrow and peripheral blood leukocytes of 13 children with active acute lymphocytec leukemia. Based on surface receptors, nine patients had null-cell disease and four had T-cell disease. The mean per cent insulin binding of the bone marrow cells from the null-cell patients was 10.0% +/- 8.1 and from the T-cell patients was 0.18% +/- 0.13. The mean insulin binding of the cell suspensions of the peripheral blood from the null-cell patients was 7.3% +/- 7.5 and 0.07% +/- 0.06 from the T-cell patients. Displacement studies with nonradioactive insulin indicated that null leukemic cells bore specific binding sites. These results indicated that there may be metabolic as well as surface membrane heterogeneity among the acute lymphocytic leukemias of childhood.

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T cell chronic lymphocytic leukemia: presence in bone marrow and peripheral blood of cells that suppress erythropoiesis in vitro

Blood ◽

10.1182/blood.v52.1.255.bloodjournal521255 ◽

1978 ◽

Vol 52 (1) ◽

pp. 255-260 ◽

Cited By ~ 1

Author(s):

R Hoffman ◽

S Kopel ◽

SD Hsu ◽

N Dainiak ◽

ED Zanjani

Keyword(s):

Bone Marrow ◽

T Cell ◽

Chronic Lymphocytic Leukemia ◽

T Lymphocytes ◽

Peripheral Blood ◽

Lymphocytic Leukemia ◽

Transfusion Therapy ◽

Cell Chronic Lymphocytic Leukemia ◽

Marrow Cells

The pathogenesis of the anemia associated with malignancy was investigated in a patient with T cell chronic lymphocytic leukemia. The plasma clot culture system was used as a measure in vitro of erythropoiesis. The patient's peripheral blood and marrow T lymphocytes obtained both before and after transfusion therapy suppressed erythroid colony formation by normal human bone marrow cells. Pretreatment of the patient's bone marrow T cells by antithymocyte globulin (ATG) and complement reversed this suppression. In addition, pretreatment of the patient's marrow cells with ATG and complement markedly augmented erythropoiesis in vitro. The expression of erythroid activity caused by the selective destruction of the suppressor T lymphocytes in the patient's bone marrow with ATG and the suppression of normal erythropoiesis by the patient's bone marrow and peripheral blood lymphocytes suggest that interaction between the malignant T cell and the erythropoietin-responsive stem cell is important in production of anemia in this patient.

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Insulin binding of acute lymphocytic leukemia cells

Blood ◽

10.1182/blood.v48.1.33.33 ◽

1976 ◽

Vol 48 (1) ◽

pp. 33-39 ◽

Cited By ~ 11

Author(s):

EC Esber ◽

DN Buell ◽

SL Leikin

Keyword(s):

Bone Marrow ◽

T Cell ◽

Peripheral Blood ◽

Insulin Binding ◽

Lymphocytic Leukemia ◽

Cell Surface Receptor ◽

Cell Disease ◽

Binding Studies ◽

Null Cell ◽

The Mean

Abstract Because of differences in insulin binding of cultured lymphoic cell lines, T- and B-cell surface receptor and 125I-insulin binding studies were performed on the bone marrow and peripheral blood leukocytes of 13 children with active acute lymphocytec leukemia. Based on surface receptors, nine patients had null-cell disease and four had T-cell disease. The mean per cent insulin binding of the bone marrow cells from the null-cell patients was 10.0% +/- 8.1 and from the T-cell patients was 0.18% +/- 0.13. The mean insulin binding of the cell suspensions of the peripheral blood from the null-cell patients was 7.3% +/- 7.5 and 0.07% +/- 0.06 from the T-cell patients. Displacement studies with nonradioactive insulin indicated that null leukemic cells bore specific binding sites. These results indicated that there may be metabolic as well as surface membrane heterogeneity among the acute lymphocytic leukemias of childhood.

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Prognostic value of T-cell receptor γ rearrangement in peripheral blood or bone marrow of patients with peripheral T-cell lymphomas

Leukemia & Lymphoma ◽

10.1080/10428190701784409 ◽

2008 ◽

Vol 49 (2) ◽

pp. 237-246 ◽

Cited By ~ 4

Author(s):

Christian SchüTzinger ◽

Harald Esterbauer ◽

Gregor Hron ◽

Cathrin Skrabs ◽

Martin Uffmann ◽

...

Keyword(s):

Bone Marrow ◽

T Cell ◽

T Cell Receptor ◽

Peripheral Blood ◽

Prognostic Value ◽

Cell Receptor ◽

T Cell Lymphomas ◽

Peripheral T Cell Lymphomas

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Bone marrow failure due to T-cell large granular lymphocytic leukemia in a patient with essential thrombocythemia

Leukemia Research ◽

10.1016/j.leukres.2010.09.004 ◽

2011 ◽

Vol 35 (2) ◽

pp. 278-282 ◽

Cited By ~ 3

Author(s):

Senthamil R. Selvan ◽

Patrick F. Sheehy ◽

F. Scott Heinemann ◽

Selvagambeer Anbuganapathi

Keyword(s):

Bone Marrow ◽

T Cell ◽

Essential Thrombocythemia ◽

Bone Marrow Failure ◽

Lymphocytic Leukemia ◽

Large Granular Lymphocytic Leukemia

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Anti-CD19 Chimeric Antigen Receptor T Cell Treatment of Relapsed /Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Resistant to Bruton's Tyrosine Kinase (BTK) Inhibitor

Blood ◽

10.1182/blood-2020-143099 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 36-36

Author(s):

Weihong Chen ◽

Xin Du ◽

Wenyujing Zhou ◽

Changru Luo ◽

Xiaoqing LI

Keyword(s):

Bone Marrow ◽

T Cells ◽

T Cell ◽

Cell Therapy ◽

Lymph Nodes ◽

Peripheral Blood ◽

Serum Levels ◽

Car T Cell ◽

Car T ◽

Btk Inhibitor

CASE PRESENTATION: A 68-year-old male was diagnosed with CLL/SLL in November 2007. Bone marrow asp/bx: 36.5% lymphocytes, 78% CD19, 65% ATM (11q22 deleted) positive cells, 13.5% D13S25 (13q14.3 deleted). On December 10, 2009, the patient took FCR scheme for five cycles, followed by FR scheme for one cycle, and then a month of Chlorambucil. On September 5, 2013, the patient took BR scheme for four cycles with no effect. From March 2015 to Feb 2016, 420 mg of Ibrutinib was administered daily. On January 15, 2016, the patient developed swollen lymph nodes in his right neck with intermittent lumps, fever and nausea. He was admitted into the hospital at Feb 2, 2016. Test results: multiple swollen superficial lymph nodes over the body, with the biggest measuring 60×30mm on the right neck, with no tenderness. Supplementary tests: peripheral white blood cells (WBC) 11.94×10E9/L, lymphocyte 7.5×10E9/L, CD19 cells 6.73×10E9/L, bone marrow lymphocyte 62%, peripheral blood lymphocyte 52%. Immunophenotype: CD5, CD19, CD20dim, CD23, CD11b dim, HLA-DR expression, visible CD5+CD19+ cell clusters, and visible immunoglobulin cKappa with restricted expression. On March 10, 2016, peripheral blood platelet 60 × 10E9/L, CD19 cells 1.94×10E9/L, lactate dehydrogenase 460U/L, FER 115.6ng/ml, hepatitis B virus carrier. Diagnosis: CLL/SLL IV stage, ATM (11q22) deletion, D13S25 (13q14. 3) positive, CD19 positive. Relapse of CLL/SLL occurred again after four months and at this stage the patient was considered for therapy in a clinical trial of CD19-specific chimeric antigen receptor (CAR-) T cell therapy. Ethical approval and informed consent were obtained for anti-CD19 CAR T Cell treatment of ibrutinib resistance in relapsed/refractory CLL/SLL. We infused autologous T cells transduced with a CAR T 19 retroviral vector with CLL/SLL at doses of 3.3 × 10E8 CART19 cells on Mar. 16 2016. Patients were monitored for responses, toxic effects, and the expansion and persistence of circulating CART19 cells. After CART19 cells were infused, the patient experienced chills, fever, headache, weak, anorexia, nausea, shortness of breath, chest tightness, heart palpitation, hypotension and shock for 9 days. The serum levels of IFN-Υ were at their highest at day 7 after CAR T cells infusion. Serum interleukin 6 (IL-6) was at 680pg/ml and CD3+ cells were 97.5%, CD8+ cells 72.8% (18.7-32.8%), FER was 1529.5ng/ml (Normal No. 22-322ng/ml) 14 days after CAR-T cell infusion. The serum levels of IL-6 were at their highest at day14. The patient was diagnosed as having cytokine release syndrome. After the patient took the anti-IL-6R antibody and anti-TNF antibody, he began to recover gradually. Enlarge lymph nodes shrunk after being infused with CART19 cells for 7 days. The peripheral blood CD19 B lymphocytes were 0 on day 14 after infused with CAR T19 cells. Q-PCR was used to detect the amount of the peripheral blood CART19 cells, which stood at 5485 copies/μl, 924 copies/μl, 191 copies/μl respectively 2 weeks, 6 weeks and 3 months after infusing with CART19 cells. The peripheral blood CART 19 cells were not detectable 4 months after infusing with CART19 cells until present. The lymphadenopathy was decreased gradually after 14 days of infusion. The MRI test showed that lymphadenopathy reduced markedly or disappeared after 6 months of infusion. ATM (11q22 deleted) negative, D13S25 (13q14.3 deleted) negative. After treatment with CAR T 19 cell therapy for 53 months, the patient remained disease-free, the patient's lymph nodes, lymphocytes and I mmunoglobulins were normal. CONCLUSIONS : Cancer immunotherapy as a method of cancer treatment is the most effective after conventional treatments such as radiotherapy, chemotherapy, and surgery. For BTK Inhibitor resistance in relapsed and refractory CD19+ CLL/SLL, CD19 is a favorable target, because the expression of CD19 is limited to B cells and not present in other tissues or cells. Currently, the efficacy of this treatment in treating CLL/SLL remains to be seen. The effects of chemotherapy on the patient's B cell lymphoma are negligible, due to the fact that his CLL/SLL have become relapsed and refractory. As a result we chose the CAR T19 cell therapy genetic engineering technique as a method of treatment, to which the patient has responded well. Therefor, CAR T cell technology overcome the limitations of existing cancer therapies and has great potential for development and application. Disclosures No relevant conflicts of interest to declare.

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