Lymphoma Presentation and Diagnosis Mark B. Juckett MD Division of Hematology University of Wisconsin June 19, 2003

Approach to Lymphadenopathy Palpable LAD in children – “the rule” LAD in adults –< 1cm considered “normal” (< 2cm in groin) LAD is normal response to foreign antigens –May include infections, allergens, autoimmune targets Pathologic LAD due to proliferation or infiltration

Normal B cell Development Travel Lymph Node Follicles Bone Marrow Pre B cell IgM B cell

B cell finds “meaning” B cell activation Germinal Center Formation “meaning”

Germinal Center Proliferation Signals Survival Signals “Never die” Signals Mutation Signals Germinal Center Activity

Plasma Cells travel back to bone marrow Memory B cell “Activated B cell” Plasmacytoid Cell IgM

Causes of LAD Infections –Bacterial – pyogenic, cat-scratch, syphilis, tularemia, plague –Mycobacterial – tuberculosis, leprosy, MAI –Fungal – histoplasmosis, coccidioidiomycosis –Chlamydial – lymphogranuloma venereum –Parasitic – toxo, trypanosomiasis, filariasis –Viral – EBV, CMV, rubella, HIV, hepatitis C

Causes of LAD (cont) Inflammatory disorders –Autoimmune - Rheumatoid arthritis, SLE –Drugs – serum sickness, phenytoin –Castleman’s disease –Histiocytic diseases (SHML, LH) –Kawasaki syndrome –Kimura’s disease –Sarcoidosis

Causes of LAD (cont) Storage diseases –Gaucher’s, Neimann-Pick disease –Amyloidosis Endocrinopathies –Hyperthyroidism, adrenal insufficiency Cancer –“Immune system” cancers –Metastatic carcinoma

Most Frequent Causes Unexplained (?) Infection Immune system disorders Immune system malignancies (Lymphoma) Metastatic carcinoma Other

Approach to patient with LAD Does the patient have a known illness that causes LAD? Treat and monitor Is there infection? Treat and monitor. Is the LAD large (> 3cm) or have unusual characteristic (i.e. hard)? Biopsy. If none are true, monitor 2 to 6 weeks, if persistent or large, biopsy.

Mortality Rate by Cancer Males Age

Mortality Rate by State NHL Males Age

Mortality Rate by Year NHL All ages

Incidence Rate by Year NHL All ages

Incidence Rate by Age NHL M/F

Classification of Lymphoma Past schemes: Rappaport, Kiel, Working formulation, “R.E.A.L.”, others World Health Organization involved to develop uniform classification Focus on defining distinct disease entities Classification defined 23 separate NHL and 5 Hodgkins lymphoma diagnoses.

General Comments on Diagnosis Initial diagnosis depends on tissue biopsy –FNA rarely useful Fresh tissue important for path studies –Flow cytometry and cytogenetics helpful Best imaging techniques: CT, PET scan Important labs: LDH, CBC –Also LFT’s, Alb, Cr, uric acid, lytes

WHO Lymphoma Types Precursor B-lymphoblastic leukemia/lymphoma CLL / SLL Prolymphocytic leukemia Lymphoplasmacytic lymphoma Marginal zone B-cell lymphoma Hairy cell leuekmia Follicle center lymphoma Mantle cell lymphoma Diffuse large cell B-cell lymphoma Burkitt's lymphoma/Burkitt's cell leukemia Precursor T-lymphoblastic leukemia/lymphoma T cell prolymphocytic leukemia T-cell granular lymphocytic leukemia Aggressive NK-Cell leukemia Adult T cell lymphoma/leukemia Extranodal NK/T-cell nasal type Enteropathy-type T-cell lymphoma Hepatosplenic T-cell lymphoma Subcutaneous panniculitis-like T-cell Mycosis fungoides/Sézary's syndrome Anaplastic large cell lymphoma Peripheral T cell lymphoma Angioimmunoblastic T cell lymphoma

General Comments on Prognosis Many lymphomas are curable –Even after relapse –The incurable NHL can be indolent International Prognostic Index –Most important for most NHL Age over 60 Stage 3 or 4 disease More than one extranodal site Elevated LDH Poor general health

Most Common NHL Diagnoses Diffuse Large B-cell Lymphoma Follicular Lymphoma Small Lymphocytic Lymphoma Mantle Cell Lymphoma Peripheral T-cell Lymphoma Armitage JCO 16:2780, 1998

Diffuse Large B-cell Lymphoma Present with symptoms from focal disease Most common lymphoma (30 – 40%) Aggressive behavior Median Age: 64 yo IPI predictive of response and survival Standard treatment: CHOP ± rituximab Curable with chemotherapy

Prognosis of DLCL by IPI RiskIPI ScoreCR rate5y DFS5y OS Low0 – 187%70%73% Low/ Intermediate 267%50%51% High/ Intermediate 355%49%43% High4 – 544%40%26% NEJM 329:987, 1993

Follicular Lymphoma Asymptomatic LAD Median age: 59 yo Indolent behavior –Median survival 10 years Stage III – IV disease 67% IPI predictive, few high risk Incurable with chemo –Stage I curable with XRT Treatment based on symptoms –No need to treat at diagnosis Characteristic t(14:18)

Small Lymphocytic Lymphoma Asymptomatic LAD Median Age 65 “Solid” counterpart to CLL Indolent behavior –Median survival 4 – 5 years Stage III – IV disease 91% Incurable with chemo Treatment based on symptoms –No need to treat at diagnosis Treatment as for CLL

Mantle Cell Lymphoma Few symptoms at diagnosis Indolent behavior at diagnosis –Relentless progression –Median survival 2 yrs Male predominance 3:1 Stage III – IV 80% GI/blood involvement common Poor overall response & survival Aggressive regimens may help Characteristic t(11:14)

Peripheral T-cell Lymphoma Present with symptoms from focal disease Aggressive behavior Median Age: 61 yo IPI not predictive of response and survival Survival short: median 1 year Standard treatment (?) CHOP Few are cured with chemotherapy Novel approaches needed

Treatment of NHL Most aggressive lymphomas –CHOP – cyclophosphamide, vincristine, doxorubicin, and prednisone Most indolent lymphomas –Many need no treatment – only for symptoms –Oral alkylators, CVP, CHOP, fludarabine, rituximab (antibiotics for MALT) Relapse – many patients will benefit from high dose chemotherapy (transplant)

High-dose Chemotherapy with Stem Cell Rescue Philip et al NEJM 333:1540, 1995

Rituximab (Rituxan®) FDA Approved Indication –“RITUXAN is indicated for the treatment of patients with relapsed or refractory low-grade or follicular, CD20 positive B-cell non- Hodgkin’s lymphoma” IgG1 kappa chimeric murine/human monoclonal antibody against CD20 Application in B-cell malignancy and autoimmunity

Making Chimeric Antibody Murine Anti-CD20 Ig gene Human IgG1 gene MouseHuman Chimeric Gene Clone Variable Region gene Clone Constant Region gene Cellular Producer

Mechanisms of Activity for IgG1 Antibodies Complement Dendritic Cell NK Cell

New Agents/Approaches Rituximab –Most commonly prescribed cancer drug Ibritumomab Tiuxetan (Zevalin®) –Yittrium 90 labeled rituximab Iodine 131 Tositumomab (Bexxar ® ) Alemtuzumab (Campath 1H ®) Pentostatin, Fludarabine, Cladribine

Conclusion Persistent LAD in older pts needs biopsy Many with aggressive lymphoma will be cured Many with indolent lymphoma will live many years with disease Our ability to define NHL has outpaced our knowledge of how to best treat Many new agents available (how to use?)