* EPIDEMIOLOGY * Biology * Classification * Approach to the Patient

* 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

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

* 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

* Epidemiology * BIOLOGY * Classification * Approach to the Patient

* 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 deathmalignant transformation * unclear how this occurs; ? EBV * unclear how cells end up with RS phenotype

* Epidemiology * Biology * CLASSIFICATION * APPROACH TO THE PATIENT

* “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

* 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

* 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**

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

Stage I Stage II Stage III Stage IV Reprinted with permission. Adapted from Skarin. Dana-Farber Cancer Institute Atlas of Diagnostic Oncology

* “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

* 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

* 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)

* 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/mm 3 * lymphocyte count < 600/mm 3 (Hasenclever et al, NEJM 339, ;1998)

* 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

* 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

* 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

* Epidemiology * BIOLOGY * Classification * Approach to the Patient

* 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

* Aggressive 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

* Epidemiology * Biology * CLASSIFICATION * Approach to the Patient

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

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

* Approach dictated mainly by histology * reliable hematopathology crucial * Approach also influenced by: * stage * prognostic factors * co-morbidities

* 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…)

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

* 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

* 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

* 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

* 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

* 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

* 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)

* 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

* 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

* 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

* 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

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

1% of all malignancies 10% of hematological malignancies (2 nd most common) 3-4 per 100,000 population 16,000 new cases/yr; 11,000 deaths/yr Median age: 65 yo; 3%<40 yo M>F Risk: radiation exposure

Monoclonal gammopathy of undetermined significance (MGUS) Asymptomatic (Smouldering) myeloma [Indolent myeloma] Symptomatic myeloma Non-secretory myeloma Solitary plasmacytoma of bone Extramedullary plasmacytoma Multiple, recurrent plasmacytomas Plasma cell leukemia

Fatigue Back pain Increased infections Hypercalcemia Renal insufficiency Hyperviscosity

Bone marrow containing more than 10% plasma cells or a plasmacytoma, plus at least one of the following: 1) a monoclonal protein in the serum, usually more than 30 g/L 2) a monoclonal protein in the urine OR 3) lytic bone lesions

Albumin  1  2   M-protein

Based on Beta 2 microglobulin and albumin I. β2M <3.5 + Alb ≥ 3.5 Med surv 62 m II. In between Med surv 44 m III. β2M >5.5 Med surv 29 m

Calcium (Hypercalcemia) Renal insufficiency Anemia Bone lesions

Often Benign; Over Many Years May Eventually Develop Into Myeloma or Other Lymphoproliferative Disorders; May Be Associated With Tumors Monoclonal Gammopathy M-component Level Igg < 3.5 G/dl Iga < 2.0 G/dl BJ Protein < 1.0 G/24 H Bone Marrow Plasma Cells < 10% No Bone Lesions No Symptoms

no secretion of protein (relatively rare if serum and urine carefully studied for presence of M-protein) prognosis same as myeloma or longer

Solitary plasmacytoma of bone Usually progress, slowly, to myeloma Extramedullary plasmacytoma Upper respiratory tract including nasal cavity, sinuses, nasopharynx, larynx; other sites possible some progress to myeloma

loss of adhesion molecules that localize in marrow (CD56, VLA-5, MPC-1) greater than 20% plasma cells in blood and > 2000/ul more frequent: younger age, hepatosplenomegaly, lymphadenopathy, few lytic lesions, small M-protein, poor prognosis

Amyloid: homogenous, amorphous extracellular material with fibrillar structure; made of low MW proteins that precipitate in tissues

Reactive systemic amyloidosis: Amyloid protein A derived from catabolism of serum amyloid A- related protein (SAA), an acute phase protein; excess production in chronic inflammatory or infectious disorders, may result in deposition in tissues Amyloid Due to an Immunologic-related Disorder Insoluable Catabolic Product of the Variable Region of a Light Chain, Lambda; May Occur As a Result of Myeloma or Waldenstrom’s Macroglobulinemia Primary Amyloidosis Deposits in Joint Capsules, Ligaments, Tongue, Heart (CHF), GI Tract (Diarrhea), Peripheral Nerves (Paresthesias, Weakness, Orthostatic Hypotension), Small Vessel Fragility From Amyloid in Walls (Purpura), Factor X Deficiency Due to Its Binding in the Extracellular Tissues

Peripheral neuropathy usually first sign Papilledema, hyperpigmentation, organomegaly < 5% plasma cells in marrow Association with Castleman’s disease Anemia, rare; usually Hct normal or polycythemia, thrombocytosis Single lytic lesions improved with radiation; may have neurologic improvement as well Gynecomastia, atrophic testes, clubbing

Melphalan/Prednisone VAD (now DVD) Thalidomide/Dexamethasone Lenalidomide/Dexamethasone Bortezomib and combinations Autologous Stem Cell Transplant Minimal myeloablative Allogeneic Transplant Tandem Transplants

New agents needed to address concerns regarding high rate of nonhematologic toxicity seen with thalidomide CC-5013 (lenalidomide) is a potent analogue of thalidomide Promising results in relapsed or refractory MM Significantly fewer nonhematologic toxicities Less peripheral neuropathy, constipation, sedation However, associated with neutropenia and thrombocytopenia Thalidomide CC-5013 (Lenalidomide)

Phase 2 study evaluated use of bortezomib later supplemented with dexamethasone to boost response in newly diagnosed patients with MM Treatment schedule Bortezomib (1.3 mg/m 2, twice weekly for 2 wks) Administered every 3 wks for up to 6 cycles Given alone for first 2 cycles Dexamethasone (40 mg/day) on day of and day after bortezomib Added after 2 cycles if < partial response Added after 4 cycles if < complete response Jagannath S, et al. ASH Abstract 333.

Phase 1/2 trial of frontline bortezomib combined with thalidomide + dex 30 previously untreated patients with MM received Thalidomide ( mg/day) Dexamethasone (20 mg/m 2 ) PO Days 1-4, 9-12, Bortezomib (1.0, 1.3, 1.5, 1.7, 1.9 mg/m 2 ) Days 1, 4, 8, 11 Every 4 wks for 2-3 cycles Alexanian R, et al. ASH Abstract TD alone † All doses ≤ 1.3≥ 1.5 Response Rate*, % VTD P =.18 P =.04 68% 80% 64% 94% † Historical controls from nonrandomized study * Stringent response criteria:  ≥ 75% reduction in serum M protein  ≥ 95% reduction in Bence Jones protein

Multicenter, phase 2 study of pulsed melphalan, dexamethasone, and thalidomide in 50 elderly patients with untreated, symptomatic MM ≥ 75 yrs of age Poor performance status (58% had PS ≥ 2) Advanced-stage disease (58% had ISS 3) Treatment schedule (3 courses every 5 wks, all oral) Melphalan (8 mg/m 2 ) Days 1-4 Dexamethasone (12 mg/m 2 ) Days 1-4 and Intensity less than half that of standard high-dose dexamethasone Thalidomide (300 mg) Days 1-4 and Intermittent dosing used Dimopoulos MA, et al. ASH Abstract 1482.

68.2% of patients responded Partial response, 61.4% Complete response, 6.8% Median time to response, 2 mos (range ) Generally well tolerated 25 infectious episodes 1 fatality Other adverse events Gr 3/4 neutropenia (15%) Gr 3/4 thrombocytopenia (10%) Somnolence (35%) Constipation (30%) Tremors (25%) Xerostomia (15%) Headaches (10%) DVT (10%) Peripheral neuropathy (10%) Dimopoulos MA, et al. ASH Abstract 1482.

MYELOMA: STEM CELL TRANSPLANT