NON HODGKIN’S LYMPHOMA Sec C Group D

NHL is a heterogenous group of lymphoproliferative malignancies with differing patterns of behavior and responses to treatment. It usually originates in the lymphoid tissues and can spread to other organs. Separated from Hodgkin’s disease by the recognition of the Reed-Sternberg cells. However, unlike Hodgkin disease, NHL is much less predictable and has a far greater predilection to disseminate to extranodal sites. Non-Hodgkin’s Lymphoma

Non-Hodgkin ‘s Lymphoma It can occur at any age and are often marked by lymph nodes that are larger than normal, fever, and weight loss. There are many different types of non-Hodgkin lymphoma. These types can be divided into: – Aggressive (fast-growing) types – Indolent (slow-growing) types They can be formed from either B-cells or T-cells. Most NHLs are of B-cell origin. The prognosis depends on the histologic type, stage, and treatment.

Indolent lymphomas Relatively good prognosis, with median survival time as long as 10 years, but they are not usually curable in advanced stages. Early-stage (I and II) indolent NHL can be treated effectively with radiation therapy alone. Most of the indolent types are nodular (or follicular) in morphology. Aggressive Lymphomas It has a shorter natural history, but a significant number of these patients can be cured with combination chemotherapy regimens.

B-cell non-Hodgkin lymphomas Burkitt lymphoma Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) Diffuse large B-cell lymphoma Follicular lymphoma Immunoblastic large cell lymphoma Precursor B-lymphoblastic lymphoma Mantle cell lymphoma T-cell non-Hodgkin lymphomas Mycosis fungoides Anaplastic large cell lymphoma Precursor T-lymphoblastic lymphoma

General Aspects of Lymphoid Malignancies Chronic Lymphoid LeukemiaAcute Lymphoid Leukemia EpidemiologyOlder adults; men>women; Whites>blacks Children and young adults; among higher socioeconomic groups Etiology/ Predisposition Unknown EBV (L3/Burkitt’s) Trisomy 21, high energy radiation; industrial/agricultural chemicals exposure; smoking Fauci, et al., Harrison’s Principles of Internal Medicine, 17 th ed. US:Mcgraw Hill, p. 687

General Aspects of Lymphoid Malignancies Hodgkin’s LymphomaNon-Hodgkin’s Lymphoma EpidemiologyBimodal age distribution (20’s & 80s); males>females; whites>blacks Elderly; men>women Etiology/ Predisposition HIV EBV Primary & secondary immunodeficiency states; HIV; Organ transplant patients; inherited immune deficiency; Sicca syndrome; Rheumatoid arthritis Fauci, et al., Harrison’s Principles of Internal Medicine, 17 th ed. US:Mcgraw Hill, p. 687

Non-Hodgkin’s Lymphoma Incidence and patterns of expression of subtypes differ geographically – Asia – T cell lymphoma – Western countries – B cell (follicular) lymphoma – Southern Asia & Latin America – Angiocentric nasal T/NK lymphoma – Southern Japan & Carribean – Adult T cell Lymphoma (HTLV – 1) Fauci, et al., Harrison’s Principles of Internal Medicine, 17 th ed. US:Mcgraw Hill, p. 688

Non-Hodgkin’s Lymphoma Environmental Factors: – Infectious agents – Chemical exposures – Medical treatments Fauci, et al., Harrison’s Principles of Internal Medicine, 17 th ed. US:Mcgraw Hill, p. 688

Non-Hodgkin’s Lymphoma Infectious agents associated with the development of Lymphoid Malignancies Infectious agentLymphoid malignancy Epstein-Barr virus Burkitt’s lymphoma Primary CNS diffuse large B cell lymphoma Extranodal T cell/NK lymphoma HTLV-1 Adult T cell leukemia/lymphoma HIV Diffuse large B cell lymphoma Burkitt’s lymphoma Hepatitis C virus Lymphoplasmacytic lymphoma Helicobacter pylori Gastric MALT lymphoma Human herpesvirus 8 Primary effusion lymphoma Multicentric Castleman’s disease Fauci, et al., Harrison’s Principles of Internal Medicine, 17 th ed. US:Mcgraw Hill, p. 688

Non-Hodgkin’s Lymphoma Diseases or exposures associated with increased risk of development of malignant lymphoma Inherited immunodeficiency states Klinefelter’s syndrome Chediak-Higashi syndrome Ataxia telangiectasia syndrome Wiscott-Aldrich syndrome Common variable immunodeficiency states Acquired immunodeficiency states Iatrogenic immunosuppression HIV-1 infection Acquired hypogammaglobulinemia Autoimmune diseaseSjogren’s syndrome Celiac sprue Rheumatoid arthritis and SLE Chemical and drug exposuresPhenytoin Dioxin, phenoxyherbicides Radiation Prior chemotherapy and radiation therapy Fauci, et al., Harrison’s Principles of Internal Medicine, 17 th ed. US:Mcgraw Hill, p. 688

Immunology All lymphoid cells are derived from a common hematopoietic progenitor Sequential activation of a series of TF’s, cells becomes committed to the lymphoid lineage  T and B cells

B cells development A cell becomes committed to the B cell development  arrangement of immunoglobulin genes

T cell development A cell becomes committed to T cell differentiation – upon migration to the thymus – Reaarangement of T cell antigen genes

Malignancies Associated with recurring genetic abnormalities At a variety of chromosomal changes  – Gross (translocations, additions or deletions) – Rearrangement of specific genes – Underexpression – Mutation of specific oncogenes

Chromosomal translocations Antigen receptor genes Immunoglobulin genes on Chr. 2, 14, and 22 on B cells T cell antigen genes on chr. 7 and 14 in T cells. Rearrangement to generate mature antigen receptors  create a site vulnerability to abnormal recombination

Non-Hodgkins Lymphoma Clinical features

Non-Hodgkins Lymphoma -heterogenous group of lymphoproliferative malignancies with differing patterns of behavior and responses to treatment -originates in the lymphoid tissues and can spread to other organs -More common in elderly and males Harrison’s Principle of Internal Medicine 17 th edition

Lymphadenopathy the most common manifestation of lymphoma Waldeyer ring &mesenteric Lymph nodes are commonly involved Spreads in noncontiguous fashion Robbins & Cotran Pathologic Basis of Diseases, 7 th edition p. 686

Lymphadenopathy 2/3 of NHL (and virtually all cases of HL) present with NONTEDER nodal enlargement often >2cm size that can be localized or generalized The remaining 1/3 of NHL’s arise at extranodal sites ( e.g. skin, stomach and brain) Robbins & Cotran Pathologic Basis of Diseases, 7 th edition p. 668

Other Signs And Symptoms fevers, night sweats, weight loss, and fatigue pruritus shortness of breath, chest pain, cough, abdominal pain and distension, or bone pain pallor (suggesting anemia) purpura, petechiae, or ecchymoses (suggesting thrombocytopenia) Harrison’s Principle of Internal Medicine 17 th edition

TYPESALIENT CLINICAL FEATURES Precursor B-cell acute lymphoblastic/leukemia/lymphoma Predominantly children with Sx relating to pancytopenia secondary to marrow involvement; aggressive Precursor T-cell acute lymphoblastic/leukemia/lymphoma Predominantly adolescent males w/ thymic masses, variable splenic, hepatic and bone marrow involvement; aggressive Burkitt lymphomaAdolescents/young adults w/ jaw or extranodal abdominal masses, uncommonly presents as “leukemia”; aggressive Diffuse large B-cell lymphomaAll ages but most common in adults; often appear as a single rapidly growing mass; 30% extranodal; aggressive Robbins & Cotran Pathologic Basis of Diseases, 7 th edition p. 671

TYPESALIENT CLINICAL FEATURES Extranodal marginal zone lymphomaIn adults w/ chronic inflammatory diseases; may remain localized; indolent Follicular LymphomaOlder adults w/ generalized lymphadenopathy and marrow involvement; indolent Mantle cell lymphomaOlder males with disseminated disease; moderately aggressive Small lymphocytic lymphoma/ chronic lymphocytic leukemia Older adults with bone marrow, lynph nodes, spleen and liver disease; most have peripheral blood involvement; autoimmune involvement and thrombocytopenia in a minority; indolent Robbins & Cotran Pathologic Basis of Diseases, 7 th edition p. 671

TYPESALIENT CLINICAL FEATURES Anaplastic large cell lymphoma children and young adults, usually with lymph node and soft tissue disease; aggressive Hairy cell leukemiaOlder males with pancytopenia and splenomegaly; indolent Mycosis fungioides/ sezary syndromeAdult patients with cutaneous patches, plaques, nodules or generalized erythema; indolent Robbins & Cotran Pathologic Basis of Diseases, 7 th edition p. 671

Lymphoid neoplasia can be suspected from all the clinical features but histological examination of lymph nodes or other involved tissues is required for the diagnosis Robbins & Cotran Pathologic Basis of Diseases, 7 th edition p. 668

Staging evaluation for NHL Ann Arbor Staging system is applicable to both Hodgkin’s disease and NHL

Ann Arbor Staging System StageDefinition IInvolvement of a single LN region or lymphoid structure (eg. Spleen, thymus, Waldeyer’s ring) IIInvolvement of ≥2 LN regions on the same side of the diaphragm (the mediastinum is a single site; hilar LN should be considered as “lateralized” and, when involved on both sides, constitute stage II disease) IIIInvolvement of LN regions or lymphoid structures on both sides of the diaphragm III1Subdiaphragmatic involvement limited to spleen, splenic hilar nodes, celiac nodes, or portal nodes III2Subdiaphragmatic involvement includes paraaortic, iliac, or mesenteric nodes plus structures in III1 IVInvolvement of extranodal site(s) beyond that designated as “E” >1 extranodal deposit at any location Any involvement of liver or bone marrow Source: p. 691

Ann Arbor Staging System StageDefinition ANo symptoms B- Unexplained weight loss of >10% of the body weight during the 6 months before staging investigation - Unexplained, persistent, or recurrent fever with temperatures >38°C during previous month - Recurrent drenching night sweats during the previous month ELocalized, solitary involvement of extralymphatic tissue, excluding liver and bone marrow Source: p. 691 Staging for our patient: Stage III1B

Ancillary procedures for Primary staging CBC ESR LDH ß2- microglobulin Serum protein electrophoresis Chemistry studies reflecting major organ function CT scans (chest, abdomen, pelvis) Bone marrow biopsy Source: p. 692

International Prognostic Index (IPI) for NHL A powerful predictor of outcome in all subtypes of NHL Scoring: based on presence or absence of – 5 adverse prognostic factors – may have none or all 5 of these Source: p. 692

ECOG PERFORMANCE STATUS*

KARNOFSKY PERFORMANCE STATUS SCALE DEFINITIONS RATING (%) CRITERIA

International Prognostic Index (IPI) for NHL Five clinical Risk Factors Age ≥ 60 years Serum lactate DH levels elevated Performance status ≥ 2 (ECOG) or ≤ 70 (Karnofsky) Ann Arbor stage III or IV > 1 site of extranodal involvement Patients are assigned a number for each risk factor they have Patients are grouped differently based upon the type of lymphoma For diffuse large B cell lymphoma 0, 1 factor 2 factors 3 factors 4, 5 factors Low risk Low-intermediate risk High-intermediate risk High risk 35% of cases; 5-yr survival 73% 27% 51% 22% 43% 16% 26% For diffuse large B cell lymphoma treated with R-CHOP 0 factor 1, 2 factors 3, 4, 5 factors Very good Good Poor 10% of cases; 5-yr survival 94% 45% 79% 45% 55% Source: p. 692

IPI for Patient (Pre treatment) Age ≥ 60 years Stage III1B Age ≥ 60 years Stage III1B Serum LDH levels elevated 2 factors Low-intermediate risk 27% of cases; 5-yr survival 51% 3 factors High-intermediate risk 22% of cases; 5-yr survival 43%

Treatment of Non- Hodgkin’s Lymphoma

Precursor B cell Lymphoblastic Leukemia Remission induction with combination therapy Consolidation phase: – High dose systemic therapy – Treatment to eliminate CNS disease Continuing therapy: prevent relapse and effect cure

Precursor B cell Lymphoblastic Leukemia Combination therapy used: – Rituximab- fludarabine- cyclophosphamide Associated with grade III or IV neutropenia – Cyclophophamide- vincristine- prednisone – Cyclophosphamide- doxorubicin- vincristine- prednisone

B Cell Chronic Lymphoid Leukemia/ Small Lymphocytic Leukemia Most common: – Chlorambucil: orally; few immediate side effects Chosen in elderly patients who require therapy – Fludarabine: IV; with significant immune suppression more active agent; with significant incidence of complete remission Regimens inclusive of this drug is chosen for young patients presenting with leukemiarequiring therapy Second line agent for patients with tumors unresponsive to chlorambucin

B Cell Chronic Lymphoid Leukemia/ Small Lymphocytic Leukemia Rai stage O and Binet stage A ( no manifestations of disease other than BM involvement and lymphocytosis – Followed without a specific therapy With adequate number of circulating normal blood cells, asymptomatic – Require treatment for the first few years of follow up

B Cell Chronic Lymphoid Leukemia/ Small Lymphocytic Leukemia Rai stage III or IV or Binet stage C (Bone Marrow failure) – Require initial therapy – Immune manifestations should be managed independently of antileukemic therapy

MALT Lymphoma Radiation and Surgery – Because it is often localized Eradication of H. pylori infection With more extensive diseases: Chlorambucil

Mantle Cell Lymphoma With disseminated disease: aggressive combination chemotherapy regimens+ autologous/ allogeneic BM transplantation Localized diseases: combination chemotherapy + radiotherapy Asymptomatic, elderly patient: observation + single- agent chemotherapy

Follicular Lymphoma Asymptomatic patient, older patient: watchful waiting For those who require treatment: single- agent chlorambucil or cyclophosphamide or combination therapy with CVP or CHOP For patients with localized follicular lymphoma: radiotherapy

Follicular Lymphoma Most responsive to chemotherapy and radiotherapy Active therapies: – Fludarabine – Interferon α: prolong survival in patients on doxorubicin- containing combination therapies – Monoclonal antibodies with or without radionuclides – Lymphoma vaccines

Diffuse Large B Cell Lymphoma Initial Treatmant: combination chemotherapy regimen= CHOP + Rituximab – Stage I or non bulky stage II: 3-4 cycles + field radiotherapy – Bulky stage II, stage III, stage IV: 6-8 cycles or 4 cycles then reevaluate -> complete remission -> 2 more cycles, then therapy discontinued

Diffuse Large B Cell Lymphoma IPI : predict favorable responses – Score 0-1: 5 year survival >70 % – Score 4-5: 5 year survival ~20% For refractory cases or relapse – Salvage therapy – Alternative combination therapy – Autologous bone marrow transplantation

Burkitt’s Lymphoma Treatment should begin 48 hrs after diagnosis High doses of cyclophosphamide Prophylactic therapy to CNS mandatory

Hairy cell leukemia: Cladribine Splenic marginal zone lymphoma: splenectomy, chlorambucil Lymphoplasmacytic lymphoma: Chlorambucil, fludarabine and cladribine Nodal marginal zone lymphoma: treatment same as follicular lymphoma

Precursor T Cell Lymphoblastic Leukemia Very intensive remission induction and consolidation regimens Leukemia- like regimens: for older children and young adults With high levels of LDH or BM, CNS involvement: BM transplantation

Anaplastic Large T/ Null Cell Lymphoma Treatment regimens same as for other aggressive lymphomas (diffuse large B cell lymphoma) Rituximab is omitted

Mycoises Fungoides – Localized early stage: radiotherapy- total skin electron beam irradiation – More advanced disease: topical glucocorticoids, topical nitrogen mustard, phototherapy, psoralen with PUVA, electron beam radiation, IFN, Antibodies, fusion toxins and systemic cytotoxic therapy Adult T Cell Lymphoma/ Leukemia – Combination chemotherapy regimens