This category includes following disorders:

• T-prolymphocytic leukaemia
• T-large granular lymphocytic leukaemia
• NK-large granular lymphocytic leukaemia
• Adult T-cell leukaemia/lymphoma
• Aggressive NK-cell leukaemia 
• Sezary syndrome (Discussed under Mycosis fungoides)

T-Prolymphocytic Leukaemia

Introduction:

• Clonal proliferation of prolymphocytes with a mature post-thymic T-cell phenotype
• Associated with juxtaposition of TCL1A or MTCP1 gene next to a TCR locus.

Epidemiology: 

• Account for 2% cases of mature lymphoid leukemias 
• Median age 65 years 
• Common in males 

Etiopathogenesis:

inv(14)(q11q32) or t(14;14)(q11;q32) 

↓

Juxtapositioning of TCL1A to the TCR gene enhancer loci of TRA/TRD

↓

Constitutive expressions of these TCL1 oncogene

↓

Enhanced AKT signaling

↓

Increased cell proliferation and survival.

Clinical Features: 

• Skin lesions seen in 1/3 rd patients- Localised erythema in face and ear, nodules and erythroderma producing non-scaling, papular and non-pruritic rash. 
• Fatigue, weakness, weight loss 
• Hepatosplenomegaly 
• Lymphadenopathy 
• Effusions in 15% 

Investigations: 

• Hemogram:
  • Anemia
  • Thrombocytopenia 
  • Lymphocytosis with abnormal lymphoid cells (Usually >1lac/cmm)- Small to medium sized cells with round / Oval / markedly irregular nuclei. Condensed chromatin with visible nucleoli present. Cytoplasm is non granular and basophilic. Cytoplasmic protrusions / blebs are seen 
• BM aspiration and biopsy– Diffuse infiltration of same type of cells, interstitial infiltrate 
• Lymph node biopsy- 
  • Diffuse infiltration of tumor cells with predominant paracortical involvement
  • Prominent, numerous high endothelial venules which are infiltrated by tumor cells 
• Immunophenotyping 
  • Positive - CD2, 3, 7, CD52, CD5, TCP alpha-beta 
  • Negative- TdT, CD1a, B cell markers, HLA-DR, CD34, TCR-gamma-delta, CD10, CD11c, CD25, CD56, CD117  
  • CD4/CD8 expression varies 
• Serology for HTLV I/II negative 
• LFT- Impaired 
• Uric acid, LDH- increased 
• Molecular studies- 
  • T-cell antigen receptor chains are clonally arranged 
  • Deletions/ mutations of ATM genes may be present. 
• Cytogenetics 
  • Abnormalities involving chromosome 14
    • 80% have inv (14) with break points of q11 & q32 
    • 10% have  t (14:14) (q11: q32) 
    • These translocations juxtapose TCR  locus with the oncogene TCL1 on 14q32
  • Other abnormalities-   idic (8p11), t (8:8), trisomy 8q, del 12p13, t(x: 14) 

Criteria for diagnosis:

Essential (Major) criteria:

• Peripheral blood lymphocytosis >5000/cmm or bone marrow infiltrate with T-PLL immunophenotype
• T-cell monoclonality
• TCL1A or MTCP1 rearrangement, alternatively TCL1A protein expression

Minor diagnostic criteria (At least 1 required)

• Abnormalities involving chromosome 11 (11q22.3, ATM)
• Abnormalities in chromosome 8: idic(8)(p11), t(8;8), trisomy 8q
• Abnormalities in chromosome 5, 12, 13, or 22, or complex karyotype
• Involvement of specific sites (e.g. splenomegaly, effusions)

Prognosis: 

• Median survival <2 years 
• Poor prognosis with 
  • Over-expression of TCL1 and MTCP1 
  • Age above 65 years
  • Presence of serous effusions
  • Hepatic or CNS involvement
  • Bulky lymphadenopathy
  • Very high absolute lymphocyte counts
  • Complex karyotype
  • Bone marrow suppression
  • Organ dysfunction.

Differential Diagnosis: 

• Polyclonal T lymphocytosis 
• Large granular lymphocytic leukemia 
• Adult T cell leukemia/ lymphoma 
• Sezary syndrome 

Pretreatment Work-up: 

• History 
  • B-Symptoms 
• Examination 
  • LN: 
  • Spleen: 
• WHO P. S. 
• BSA 
• IHC/Flow cytometry 
• BMA and Bx 
• CT (CAP) or PET/CT scan
• Stage 
• Hemoglobin 
• TLC, DLC 
• Platelet count 
• LFT- Bili- T/D    SGPT:     SGOT: Albumin:      Globulin: 
• Creatinine 
• Electrolytes: Na:      K:       Ca: Mg:      PO4:    
• Uric acid: 
• LDH 
• HIV: 
• HBsAg:  
• HCV: 
• HTLV 1 Serology (Do western blot if ELISA is +ve) 
• CMV Serology (If Alemtuzumab planned) 
• UPT 
• Cytogenetics 
• FISH for inv (14), t(14:14), trisomy 8 
• ECHO (If anthracyclines planned)- LVEF-               % 
• Chemotherapy consent after informing about disease, prognosis, cost of therapy, side effects, hygiene, food and contraception
• Fertility preservation
• PICC line insertion and Chest X ray after line insertion
• Tumor board meeting and decision
• Attach supportive care drug sheet
• Inform primary care physician

Treatment Plan:

T-Large Granular Lymphocytic Leukaemia

Introduction: 

• It is a heterogeneous disorder characterized by persistent (>6 months) increase in the number of peripheral large granular lymphocytes, usually between 2,000-20,000/cmm, without a clearly identifiable cause. 

Epidemiology: 

• Represent 2-3% of cases of SLL 
• Median age- 55 years 
• M:F= 1:1 

Etiology: 

• Seen in patients with auto immune disorders (RA, SLE, Sjogren, Feltry’s syndrome) 
• Has HLA DR4 association 
• Sometimes associated with PNH, MDS and AML. 
• Somatic mutation of STAT3 is seen in 1/3rd of patients. 

Pathogenesis: 

Sustained immune stimulation

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Activation of prosurvival pathways and hence cells fail to undergo apoptosis

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Increased IL15, which leads to increased survival of NK and T cells

↓

Release of soluble agents such as FasL and perforin by tumor cells

↓

Cytopenia.

Clinical Features: 

• Usually asymptomatic 
• Cytopenias
  • Usually neutropenia- Due to antineutrophil antibody dependent cytotoxicity, maturation arrest mediated by neoplastic cells, enhanced FAS dependent apoptosis 
  • Thrombocytopenia- Due to inhibition of megakaryocytes, immune destruction of platelets and splenic sequestration. 
  • Autoimmune haemolytic anemia
• Auto immune disease 
• B Symptoms 
• Pure red cell aplasia- Seen in 15% patients 
• Splenomegaly 
• Lymphadenopathy 
• Hepatomegaly 
• Skin rash (rarely) 
• Pulmonary hypertension- Due to lysis of endothelial cells resulting from activation of NK receptors via signaling partners DAP 10 and DAP12) 

Investigations: 

• Hemogram
  • Lymphocyte- count is normal/ increased but majority of cells are large granular lymphocytes 
  • Large Granular Lymphocytes are large cells. Cytoplasm is abundant with fine / coarse azurophillic granules. Nucleus is eccentric with mature chromatin. No visible nucleolus 
  • LGL Count: 2-20 x 10⁹ /L (usually > 5 x 10⁹ /L) 
  • Neutropenia 
  • Sometimes anemia and thrombocytopenia 
• BM aspiration and biopsy
  • Normocellular or hypocellular in 50% patients, in rest of patients- hypercellular. 
  • Mild lymphoid infiltration in interstitial pattern 
  • Some times erythroid and myeloid hyperplasia with maturation arrest is seen
  • Granulocytes show shift to left 
• ANA, ANCA- may be positive 
• S. protein electrophoresis: Hyper / Hypo gammaglobulinaemia 
• Immunophenotyping 
  • Positive – CD2, CD3,  CD8, TIA – 1, CD16, CD5, CD7, CD16, CD57, Cytotoxic proteins (TIA1, Granzyme B) 
  • Negative –CD56, CD4, CD7, TCP gamma-delta 
  • Variable – CD11b, CD56, CD57 
• Molecular studies: T-cell receptor  gene rearrangements. (Note: Clonal TCR rearrangement without cytologic or immunophenotypic evidence of abnormal T cell population does not constitute a diagnosis of T cell malignancy) 
• Cytogenetic – Nothing specific 

Criteria for Diagnosis: (All 3 essential criteria or 2 essential criteria+1 desirable citeria must be present for diagnosis)

Essential

• An increase in circulating cytotoxic T-cells, often greater than 2000/cmm but may be less
• Presence of a T-cell population (usually CD8 positive) with down-regulation of CD5 and/or CD7 and/or abnormal expression of CD16 and NK-cell associated receptors
• Evidence of T-cell monoclonality 

Desirable:

• Bone marrow immunohistochemistry revealing intra-sinusoidal cytotoxic lymphocyte infiltrates
• Demonstration of STAT3 or STAT5B mutation

Prognosis: 

• Indolent course 
• 80% survive at 4 years, 
• Median survival > 10 years 

Differential Diagnosis: 

• Clonal reactive lymphocytosis  
  • Count is usually < 5 x 10⁹ / L 
  • TCR gene rearrangements in germ line configuration 
  • Seen following allogeneic stem cell transplantation, B-NHL, CML patients on Imatinib 
• Chronic neutropenia 
• PRCA 
• Rhematoid arthritis 
• HIV infection 

Indications for Treatment: 

• Severe cytopenias (ANC <500/cmm or Hemoglobin <10gm/dL, or Platelet count <50,000/cmm) 
• Autoimmune diseases with T-LGL requiring therapy 
• Severe B symptoms 
• Pulmonary artery hypertension secondary to LGL 
• Recurrent infections 
• Progressive lymphocytosis / organomegaly 

Pretreatment Work-up:  

• History 
  • B-Symptoms 
  • Autoimmune diseases especially rheumatoid arthritis
• Examination 
  • LN: 
  • Spleen: 
• WHO P. S. 
• BSA 
• Flow cytometry 
• CT (CAP) 
• Hemoglobin 
• TLC, DLC
• Platelet count 
• LFT- Bili- T/D  SGPT:      SGOT: Albumin:    Globulin: 
• Creatinine 
• Electrolytes: Na:    K:     Ca: Mg:     PO4:   
• Uric acid: 
• LDH 
• HIV:
• HBsAg: 
• HCV: 
• Serology for HTLV- 1, 2 
• PCR for viral DNA- CMV(If alemtuzumab is planned)
• Screen for autoimmune diseases
  • RA Factor:                         ANA:                            ESR: 
• UPT 
• STAT 3 and STAT5B Mutation tests 
• ECHO (If anthracyclines planned/RHF)- LVEF-               %
• Chemotherapy consent after informing about disease, prognosis, cost of therapy, side effects, hygiene, food and contraception
• Fertility preservation
• PICC line insertion and Chest X ray after line insertion
• Tumor board meeting and decision
• Attach supportive care drug sheet
• Inform primary care physician

Treatment plan: 

Response Criteria: Response assessment should be done after 4 months of treatment 

• Complete response: 
  • Recovery of counts with Hemoglobin >12gm/dL, ANC >1500/cmm, Platelet count >1.5lac/cmm 
  • Resolution of lymphocytosis (<4000/cmm) 
  • Circulating LGL- <500/cmm 
• Partial response: 
  • Recovery of counts, Hb>8gm/dL, ANC >500/cmm, Platelet count- >50,000/cmm 

About Each Modality of Treatment: 

• Cyclosporin A
  • 5-10mg/kg/day in 2 divided doses. 
  • Must be titrated to achieve response. 
  • Enhanced response with use of G-CSF or EPO. 
  • 3-4 months treatment is required to achieve response. 
  • Responders need long term maintenance therapy. 
  • Goal of treatment is correction of cytopenia. 
• Methotrexate
  • 10 mg/m² – weekly pulse- Tapered after 1 month of therapy 
• Cyclophosphamide
  • 200 – 300 mg / week. 
  • Limit use of cyclophosphamide to 4 months if no response and to less than 12 months, if PR is observed at 4 months, due to increased risk of leukemogenesis. 
• Corticosteroids 
  • Prednisolone- 1mg/Kg

Other Treatment Options: Newer treatment options: 

• Tipifarnib- Farnesyltransferase inhibitor 
• STAT3 inhibitors 
• Bortezomib 
• PI3K inhibitors 
• Anti CD2- Siplizumab 
• Anti CD112 Antibodies
• Anti- IL15 
• Monoclonal antibody against FAS ligand 
• Imatinib 

NK-Large Granular Lymphocytic Leukaemia

• Neoplasm characterized by a persistent increase in peripheral blood NK cells (usually greater than 2000/cmm) in the absence of a clearly identifiable cause
• Mutations of STAT3, CCL22 and TET2 are seen 
• Immunophenotyping- Positive for CD2, CD7, CD16, CD56, CD57, cytotoxic granule proteins (TIA-1, Granzyme B, Granzyme M) and negative for CD3, CD4, CD8 and CD5 
• Compared to T-LGL 
  • Seen in younger patients 
  • High incidence of B symptoms 
  • More massive hepatosplenomegaly 
  • Lymphadenopathy 
  • GI involvement is common 
• Criteria for diagnosis:
  • Essential:
    1. An increase in circulating NK-cells, typically greater than 2000/cmm, persisting greater than 6 months
    2. Flow cytometric evidence of peripheral blood or bone marrow aspirate involvement by a uniform population of surface CD3 negative, CD16 positive NK-cell population.
    3. A KIRs restricted pattern of expression, demonstrated by flow cytometry analysis (either a dominant expression of a relevant KIR or lack of them), is accepted as a surrogate marker of clonal expansion

• Desirable:
  • Bone marrow involved by intra-sinusoidal cytotoxic CD8 positive NK-cells
  • Demonstration of STAT3 and/or TET2 mutations with NK-cell lineage confirmed by flow cytometry
  • If both 2 and 3 essential criteria are present, a diagnosis of NK-LGLL can be made in the absence of documented persistence of an absolute peripheral blood NK-cell count of greater than 2000/cmm.
• Prognosis: Indolent course
• Treatment: Similar to T-LGL leukemia

Adult T-cell Leukaemia/Lymphoma

Epidemiology: 

• Common in Japan, Caribbean, Africa, and South America. 
• Median age- 62 years 

Etiopathogenesis: 

• HTLV 1-  P⁴⁰ tax viral protein causes transcriptional activation of many genes in infected lymphocytes 
• HTLV1-Basic leucine zipper factor causes T cell proliferation and oncogenesis 
• Lifetime risk of developing leukemia in infected patients is 1-5%. 

Clinical Features: There are 4 variants of this disease

• Acute variant (Leukemia variant) 
  • Increased WBC count 
  • Skin rash 
  • Generalized lymphadenopathy 
  • Hypercalcemia with / without lytic bone lesions 
  • Hepatosplenomegaly 
  • CNS involvement- Seen in 10% patients 
  • B Symptoms 
  • Opportunistic infections- PCP, Aspergillus, Candida, strongyloidiasis, CMV
• Lymphomatous variant
  • Prominent lymphadenopathy without peripheral blood involvement 
• Chronic variant
  • Skin lesions – exfoliative rash
  • Absolute lymphocytosis (>4000/cmm) with T lymphocytes (>3500/cmm)
• Smoldering variant
  • Normal WBC count without <5% circulating neoplastic cells. 

Investigations: 

• Peripheral smear:
  • Neoplastic lymphoid cells are medium to large sized and contain pleomorphic nuclei. Chromatin is coarsely clumped and there is distinct nucleoli. 
  • Some cells contain polylobated/ convoluted/ cerebriform nuclei (hence called flower cells/ cloverleaf cells) 
  • Cytoplasm is deeply basophilic
  • Small proportion of blast like cells are present 
  • Eosinophilia may be present 
  • Anemia and thrombocytopenia 
• Bone marrow aspiration and biopsy: Patchy infiltrate of tumor cells
• Skin biopsy- Poutrier like micro abscesses
• Lymph node biopsy
  • Leukemia pattern of infiltration
  • Dilation of LN sinuses
• Immunophenotyping 
  • Positive- Mature T-cell associated antigens (CD-2, 3, 5), CD4, CD30, CD25, TCR Alfa-beta, CCR4, FOXP3, CD29, HLA-DR 
  • Negative – CD7, 8, NK cell markers, CD11b, CD11c, TIA-1, Granzyme  
  • Any CD4 and CD8 combinations are possible. 
• Molecular studies:
  • Clonally integrated HTLV-1 is found
  • TCR genes clonally rearranged 
• LDH – Increased
• LFT – Abnormal 
• Serum calcium level- Elevated  (Due to release of cytokines like parathyroid like hormone, IL-1&  TNF- beta)
• Serology for HTLV antibodies-  Positive 

Criteria for Diagnosis: 

Essential:

• Neoplastic lymphoid cell proliferation with mature T-cell phenotype
• Proven HTLV-1 carriership

Desirable:

• Lymphoid cells with prominent convolutions and lobulation
• Identification of monoclonal integration of HTLV-1

Prognosis: 

• Average survival – 5 months- 13 months (Poor with acute and lymphoma variants) 
• Poor prognostic markers: 
  • Increased LDH 
  • Leucocytosis 
  • Hypercalcemia 
  • Age >40 years 
  • >3 involved lesions 
  • Poor performance score 
  • Thrombocytopenia 
  • Eosinophilia 
  • Bone marrow involvement 
  • CCR4 expression 
  • TP53 mutation. 

Pretreatment Work-up:  

• History 
  • B-Symptoms 
• Examination 
  • LN: 
  • Spleen: 
• WHO P. S. 
• BSA 
• IHC/Flow cytometry 
• CT (CAP) or PET-CT 
• Hemoglobin 
• TLC, DLC 
• Absolute number of atypical cells 
• Platelet count 
• LFT: Bili- T/D  SGPT:     SGOT: Albumin:      Globulin: 
• Creatinine 
• Electrolytes: Na:     K:         Ca: Mg:    PO4: 
• Uric acid: 
• LDH 
• HIV:
• HBsAg:
• HCV: 
• HTLV 1 (Do Western blot/PCR if serology is +ve) 
• UPT 
• Stool for Strongyloides 
• CT/ MRI Brain (If symptomatic) 
• CSF (in acute/ lymphoma subtypes and CNS symptoms) 
• ECHO (If anthracyclines planned) LVEF-               % 
• Chemotherapy consent after informing about disease, prognosis, cost of therapy, side effects, hygiene, food and contraception
• Fertility preservation
• PICC line insertion and Chest X ray after line insertion
• Tumor board meeting and decision
• Attach supportive care drug sheet
• Inform primary care physician

Treatment Plan: 

Exclude co-infection with Strongyloidiasis prior to therapy, as chemotherapy can lead to aggravation of infection. 

CNS prophylaxis with triple IT should be given. 

Response Criteria: 

• Complete response- All of the following 
  • Normal lymph nodes 
  • No extranodal masses 
  • No organomegaly 
  • Normal skin 
  • Normal peripheral blood 
  • Normal bone marrow 

About Each Modality of Treatment: 

• Interferon- 3 million units- OD + Zidovudine- 250mg- BD
  • Both should be continued for 5 years if patient tolerates 

Aggressive NK-cell Leukaemia

Introduction:

• It is a rare leukemic form of an NK cell neoplasm with aggressive clinical course.
• Generally skin and nose are not involved.

Epidemiology:

• Median age 40 years
• Rare tumor
• Common in Asia
• Median age- 39 years

Etiology:

• EBV infection

Clinical Features:Acute onset of 

• Cytopenia
• B symptoms- Particularly fever
• Jaundice
• Lymphadenopathy
• Hepatosplenomegaly
• Sometimes
  • DIC
  • Hemophagocytic syndrome
  • Liver dysfunction
  • Multi-organ failure

Investigations:

• Peripheral smear
  • Leukemic cells are slightly larger than normal large granular lymphocytes. Nucleus is normal looking or enlarged, with irregular folding and open chromatin. Nucleoli are inconspicuous / distinct. Cytoplasm is abundant and lightly basophilic
• Bone marrow aspiration and biopsy
  • Massive/ subtle/ focal infiltrate of tumor cells
  • Reactive histiocytes with hemophagocytosis
  • Necrosis is common
• Immunophenotyping
  • Positive – CD2, CD3E, CD7,CD56, CD16, Cytotoxic molecules
  • Negative – CD3, CD5, CD8, CD57
• Molecular studies- TCR genes are in germ line configuration
• Cytogenetics- del(6) (q21 q25), del 11q, del 17p, i(7)
• S. LDH- Elevated

Criteria for diagnosis:

Essential

• Presentation with fever, constitutional symptoms and a leukemic blood picture
• Systemic (multi-organ) proliferation of neoplastic lymphoid cells with an NK-cell immunophenotype
• Lack of TCR protein expression and/or lack of clonal rearrangement of TR genes

Desirable:

• EBER positivity (positive in ~90% of cases)
• Haemophagocytic lymphohistiocytosis

Prognosis:

• Fatal outcome within 1 year
• Overall survival- 2 months
  
   

Treatment Plan:

• Asparginase based intensive chemotherapy (Intensive ALL type therapy) with CNS prophylaxis
• Consolidation with Allo SCT or HDT with ASCR in CR1.

Recent advances:

Effective treatment with the selective cytokine inhibitor BNZ-1 reveals the cytokine dependency of T-LGL leukemia 

A phase 1/2 clinical trial of BNZ-1, a pegylated peptide that selectively inhibits the binding of interleukin-15 (IL-15) and other γc cytokines to their cellular receptor complex, was conducted in patients with T-cell large granular lymphocytic leukemia (T-LGLL) who had hematocytopenias. Clinical responses were assessed based on hematologic parameters, and BNZ-1 demonstrated clinical partial responses in 20% of T-LGLL patients with minimal toxicity. The study provides first-in-human proof that T-LGL leukemic cells are dependent on IL-15, and intervention with BNZ-1 shows therapeutic effects, shedding light on the pathogenesis of this disease. 

https://doi.org/10.1182/blood.2022017643 

Valemetostat for relapsed or refractory adult T-cell leukemia/lymphoma 

Valemetostat is  a potent enhancer of zeste homolog 2 (EZH2) and EZH1 inhibitor. Patients received valemetostat 200 mg/day orally until progressive disease or unacceptable toxicity. Valemetostat demonstrated promising efficacy and tolerability in heavily pretreated patients, warranting further investigation in treating R/R ATL. 

https://doi.org/10.1182/blood.2022016862 

First-line mogamulizumab-containing chemotherapy in adult T-cell leukaemia-lymphoma 

Mogamulizumab is a humanized monoclonal antibody directed against C-C chemokine receptor 4. Present study retrospectively analysed clinical outcomes in 39 transplant-ineligible patients with untreated aggressive ATL at Kumamoto University Hospital between 2010 and 2021. The probability of four-year overall survival was 46.3% in the first-line Mog-containing treatment group compared to 20.6% in the chemotherapy-alone group. 

https://doi.org/10.1111/bjh.18281 

Ruxolitinib in the treatment of relapsed/refractory large granular lymphocytic leukaemia

Large granular lymphocytic (LGL) leukemia is a rare disorder characterized by cytotoxic T or NK cell expansion. For patients with relapsed or refractory disease, ruxolitinib—a JAK/STAT pathway inhibitor—was evaluated in 21 patients, showing an 86% overall response rate, with 3 complete and 15 partial responses. 1-year event-free and overall survival rates were 57% and 83%, respectively. Ruxolitinib improved cytopenias with mild side effects, supporting its potential as a treatment for challenging cases of LGL leukemia.

https://doi.org/10.1111/bjh.19476