Lymphomas: The Basics Brad Kahl, MD Assistant Professor of Medicine Director, UW Lymphoma Service

Lymphomas: NHL vs Hodgkin’s EPIDEMIOLOGY Biology Classification Approach to the Patient

Hodgkin’s Disease Epidemiology 14% of malignant lymphomas 0.5% of all malignancies approximately 8000 new cases/yr in US approximately 1500 deaths/yr over past 30 years age adjusted incidence rates declined appreciably mortality rates declined substantially

Hodgkin’s Disease Epidemiology men > women whites > blacks > Asians no clear risk factors, several implicated EBV (pathogen or passenger) HIV woodworking, farming rare familial aggregations

NHL: Epidemiology Most common hematologic malignancy 60,000 new cases annually 6th leading cause of cancer death incidence rising overall incidence up by 73% since 1973 “epidemic” 2nd most rapidly rising malignancy

NHL: Epidemiology Why the increase? Other environmental factors? Increase noted mostly in farming states MN #1, WI #7 NHL incidence possible role of herbicides, insecticides, etc. Other environmental factors?

NHL: Epidemiology Other risk factors immunodeficiency states AIDS, post-transplant, genetic autoimmune diseases Sjogrens Sprue infections H. pylori, EBV, HHV-8

Epidemiology SEER 5 year survival data NHL Hodgkin’s 1974-76: 47.2 71.1% 1977-79: 48.1 73.0% 1980-82: 51.1 74.3% 1983-90 52.0 78.9%

Hodgkin’s Disease Epidemiology BIOLOGY Classification Approach to the Patient

Hodgkin’s Disease Background first described in 1832 by Dr. Thomas Hodgkin characterized by the presence of Reed-Sternberg cells multinucleated giant cells described by Sternberg in 1898 and Reed in 1902 classified as an infectious disease until 1950’s

Reed-Sternberg Cell

Hodgkin Biology RS is a “crippled” germinal center B cell does not have normal B cell surface antigens micromanipulation of single RS followed by PCR demonstrates clonally rearranged, but non functional immunoglobulin genes somatic mutations result in stop codon (no sIg) no apoptotic death malignant transformation unclear how this occurs; ? EBV unclear how cells end up with RS phenotype

Hodgkin’s Disease Epidemiology Biology CLASSIFICATION APPROACH TO THE PATIENT

Hodgkin Lymphoma Classification “Classic” Hodgkin’s Disease nodular sclerosis mixed cellularity lymphocyte depleted (very rare) classical lymphocyte rich HRS cells CD30 and CD15 positive nodular lymphocyte predominant HRS cells (L&H cells) have B cell markers CD 20 and surface Immunoglobulin

Classic Hodgkin Lymphoma

Nodular Sclerosing Hodgkin Lymphoma

Approach to the Patient Hodgkin’s Disease approach dictated mainly by where the disease is located rather (results of staging) than the exact histologic subtype NHL approach is dictated mainly by the histologic subtype rather than the results of staging

Hodgkin’s Disease Approach to the Patient staging evaluation H & P CBC, diff, plts ESR, LDH, albumin, LFT’s, Cr CT scans chest/abd/pelvis bone marrow evaluation **PET or gallium scan** **lymphangiogram or laparotomy**

Ann Arbor Staging System Stage I: single lymph node region (I) or single extralymphatic organ or site (IE) Stage II: > 2 lymph node regions on same side of diaphragm (II) or with limited, contiguous extra lymphatic tissue involvement (IIE) Stage III: both sides of diaphragm involved, may include spleen (IIIS) or local tissue involvement (IIIE) Stage IV: multiple/disseminated foci involved with > 1 extralymphatic organs (i.e. bone marrow) (A) or (B) designates absence/presence of “B” symptoms

Ann Arbor Staging System for Hodgkin's Disease and Non-Hodgkin's Lymphoma Historically, this staging methodology was designed for Hodgkin’s disease but has been adapted to NHL. Staging defines the extent of a cancer along three axes: tumor (T); node (N); and metastasis (M). The rationale behind a staging system is to accomplish the following: Plan treatment strategies Help evaluate the treatment results Standardize information to facilitate exchanges between health-care professionals and treatment centers Formulate a more accurate prognosis Promote the continuity of cancer investigation The Ann Arbor Staging System is the most commonly used in NHL. It is divided into four stages (I to IV), according to nodal and extralymphatic involvement, and subclassified into A and B categories. A designates the absence of the so-called B symptoms. B signals their presence. The B symptoms are as follows: Unexplained loss of more than 10% of body weight in the 6 months before diagnosis Unexplained fever with temperatures above 38o Celsius Drenching night sweats Skarin AT, ed. Dana-Farber Cancer Institute Atlas of Diagnostic Oncology. Philadelphia: Lippincott; New York: Gower Medical Pub; 1991. Available at http://www.acs.ohio-state.edu/units/cancer/handbook/staging.pdf. Accessed 6/25/02. Stage I Stage II Stage III Stage IV Reprinted with permission. Adapted from Skarin. Dana-Farber Cancer Institute Atlas of Diagnostic Oncology. 1991.

Modified Ann Arbor Staging “E” designation for extranodal disease B symptoms recurrent drenching night sweats during previous month unexplained, persistent, or recurrent fever with temps above 38 C during the previous month unexplained weight loss of more than 10% of the body weight during the previous 6 months Criteria for bulk 10 cm nodal mass mediastinal mass > 1/3 thorax diameter

Hodgkin Lymphoma Treatment approach depends upon stage, prognostic factors, and co-morbidities Stage I-II consider XRT, chemotherapy, or combined therapy Bulky stage I-II combined modality therapy Stage III-IV ABVD x 6-8 cycles gold standard

Hodgkin Lymphoma Adverse prognostic features for stage I & II (EORTC data) more than 3 nodal sites bulky adenopathy ESR > 50 B symptoms invasion into critical organs male age > 40 MC or LD subtype should probably not receive XRT alone if any of the above present (excessive relapse rate)

Hodgkin Lymphoma Independent adverse prognostic factors advanced stage (III-IV) male sex age > 45 albumin < 4 gm/dl HgB < 10.5 mg/dl stage IV disease WBC count > 15,000/mm3 lymphocyte count < 600/mm3 (Hasenclever et al, NEJM 339,1506-1514;1998)

Hodgkin’s Disease Role for Stem Cell Transplantation clinical trials show benefit for patients who receive high dose chemotherapy followed by SCT for patients who have relapsed after initial therapy or for patients are primary refractory

Hodgkin’s Disease Results of Treatment stage 5 year overall survival II 90% III 80% IV 65%

Hodgkin Lymphoma Late Complications depends upon treatment modality utilized XRT vs. MOPP vs. ABVD vs. CMT issues depends upon the age of patient relative risks higher in younger patients absolute risks higher in older patients major focus of current clinical trials to to maintain high cure rate while minimizing late complication shorter courses of chemotherapy with lower radiation doses in smaller fields elimination of radiotherapy

Hodgkin’s: future directions Limited stage and good prognosis advanced stage cure rate high current goal is to minimize late complications trials looking at CMT with less chemotherapy and less radiation Advanced stage cure rate around 50-70% trial comparing ABVD to Stanford V Clinical Trials

NHL Epidemiology BIOLOGY Classification Approach to the Patient

Lymphoma Biology Indolent vs. Aggressive NHL key principle in understanding biology, and approach to the patient Indolent = incurable Aggressive = curable WHY? Chromosomal Abnormalities in NHL frequent chromosomal translocations into Ig gene loci t(8;14), t(2;8), t(8;22) Burkitt’s t(14;18) follicular NHL

Lymphoma Biology Aggressive NHL Indolent NHL short natural history (patients die within months if untreated) disease of rapid cellular proliferation Indolent NHL long natural history (patients can live for many years untreated) disease of slow cellular accumulation

NHL Epidemiology Biology CLASSIFICATION Approach to the Patient

NHL: Classification Historically- a mess 1940s Gail and Mallory 1950s Rappaport 1970s Lukes-Collins 1970s Kiel 1982 Working 1994 REAL 1999 WHO

NHL: Classification Key Points Principle cell size: small cell vs. large cell nodal architecture: follicular vs. diffuse Principle More aggressive: diffuse, large cell More indolent: follicular, small cell

NHL: Classification Terminology (refers to natural history) Principle low grade = indolent intermediate grade = aggressive high grade = aggressive Principle indolent: slow growing, incurable aggressive: rapidly growing, curable

NHL Epidemiology Biology Classification APPROACH TO THE PATIENT

NHL: Approach to the Patient Approach dictated mainly by histology reliable hematopathology crucial Approach also influenced by: stage prognostic factors co-morbidities

NHL: Approach to the Patient Staging evaluation History and PE Routine blood work CBC, diff, plts, electrolytes, BUN, Cr, LFT’s, uric acid, LDH, B2M CT scans chest/abd/pelvis Bone marrow evaluation Other studies as indicated (lumbar puncture, gallium, etc…)

NHL: Approach to the Patient Indolent NHL: typical scenario patient presents with painless adenopathy otherwise asymptomatic follicular small cell histology average age 59 usually stage III-IV at diagnosis

NHL: Approach to the Patient Indolent NHL: guiding treatment principle early treatment does not prolong overall survival When to treat? constitutional symptoms compromise of a vital organ by compression or infiltration, particularly the bone marrow bulky adenopathy rapid progression evidence of transformation

NHL: Approach to the Patient Indolent NHL: typical scenario watchful waiting: 2-4 years first remission length: 3-4 years second remission: 2-3 years third remission: 1-2 years each subsequent remission shorter than prior median survival 8-12 years for FLSC

NHL: Approach to the Patient Indolent NHL: treatment options watchful waiting radiation to involved fields single agent chemotherapy chlorambucil + prednisone, fludarabine combination chemotherapy CVP, CF, FND, CHOP chemotherapy + interferon chemotherapy + monoclonal antibodies monoclonal antibodies radiolabeled monoclonal antibodies stem cell transplantation

NHL: Approach to the Patient Aggressive NHL: typical scenario patients notes B symptoms of several weeks duration work-up reveals pathologic adenopathy histology: diffuse large cell lymphoma about 50% patients stage I-II, 50% stage III-IV average age 64 IPI score

NHL: Approach to the Patient Aggressive NHL: treatment approach Stage I-II: combined modality therapy CHOP chemotherapy x 3 + IF radiotherapy cure rate around 70% Stage III-IV (also bulky stage II) (R)CHOP chemotherapy x 6-8 cycles cure rate around 40% (R)CHOP is the standard

NHL: Approach to the Patient International Prognostic Index Risk Factors (0-5) age > 60 two or more extranodal sites performance status > 2 elevated LDH stage III-IV Age adjusted IPI (0-3)

CR and OS stratified by IPI

NHL: Approach to the Patient Is CHOP the best we can do? R-CHOP may be better National Trials opening looking at alternative strategies in poor prognosis DLCL age adjusted IPI > 2 CHOP vs. CHOP + SCT Risk stratification is the current trend in NHL Sorting out role for stem cell transplantation Sorting out role for innovative combinations

NHL: Approach to the Patient Role for Autologous Stem Cell Transplantation Aggressive NHL clear benefit when used for aggressive NHL in first relapse in appropriately selected patients 1/3 of these patients can be cured by SCT Indolent NHL no indication that patients are cured no indication that OS is prolonged

NHL: future directions Indolent monoclonal antibodies (Rituximab) radiolabeled monoclonal antibodies chemotherapy combined with antibodies antibodies combined with immunomodulators Aggressive risk stratification CHOP vs. CHOP plus SCT chemotherapy plus antibodies Clinical Trials

Summary NHL incidence increasing, Hodgkin’s decreasing Hodgkin’s cure rate quite high approach is dictated mainly by disease stage NHL cure rate mediocre approach is dictated mainly by histologic subtype indolent vs. aggressive indolent: watchful waiting perfectly acceptable for asymptomatic patients aggressive: require aggressive treatment ASAP to achieve cure

Lymphoma Clinic Multidisciplinary Emphasis on clinical trials radiotherapy-Dr. Scott Tannehill hematopathology-Dr. Catherine Leith Emphasis on clinical trials formal testing of promising new therapies Every Wednesday Clinic phone #: 608-263-7022