Lymphomas: The Basics

1
Lymphomas The Basics

• Brad Kahl, MD
• Assistant Professor of Medicine
• Director, UW Lymphoma Service

2
Lymphomas NHL vs Hodgkins

• EPIDEMIOLOGY
• Biology
• Classification
• Approach to the Patient

3
Hodgkins 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

4
Hodgkins Disease

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

5
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

6
NHL Epidemiology

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

7
NHL Epidemiology

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

8
Epidemiology

• SEER 5 year survival data
• NHL Hodgkins
• 1974-76 47.2 71.1
• 1977-79 48.1 73.0
• 1980-82 51.1 74.3
• 1983-90 52.0 78.9

9
Hodgkins Disease

• Epidemiology
• BIOLOGY
• Classification
• Approach to the Patient

10
Hodgkins 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 1950s

11
Reed-Sternberg Cell
12
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

13
Hodgkins Disease

• Epidemiology
• Biology
• CLASSIFICATION
• APPROACH TO THE PATIENT

14
Hodgkin Lymphoma Classification

• Classic Hodgkins Disease
• nodular sclerosis
• mixed cellularity
• lymphocyte depleted (very rare)
• classical lymphocyte rich
• HRS cells CD30 and CD15 positive
• nodular lymphocyte predominant
• HRS cells (LH cells) have B cell markers
• CD 20 and surface Immunoglobulin

15
Classic Hodgkin Lymphoma
16
Nodular Sclerosing Hodgkin Lymphoma
17
Approach to the Patient

• Hodgkins 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

18
Hodgkins Disease

• Approach to the Patient
• staging evaluation
• H P
• CBC, diff, plts
• ESR, LDH, albumin, LFTs, Cr
• CT scans chest/abd/pelvis
• bone marrow evaluation
• PET or gallium scan
• lymphangiogram or laparotomy

19
Ann Arbor Staging System

• Stage I single lymph node region (I) or single
  extralymphatic organ or site (IE)
• Stage II gt 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 gt 1 extralymphatic organs (i.e. bone
  marrow)
• (A) or (B) designates absence/presence of B
  symptoms

20
Ann Arbor Staging System for Hodgkin's Disease
and Non-Hodgkin's Lymphoma
Stage I Stage II
Stage III Stage IV
Reprinted with permission. Adapted from Skarin.
Dana-Farber Cancer Institute Atlas of Diagnostic
Oncology. 1991.
21
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 gt 1/3 thorax diameter

22
(No Transcript)
23
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

24
Hodgkin Lymphoma

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

25
Hodgkin Lymphoma

• Independent adverse prognostic factors
• advanced stage (III-IV)
• male sex
• age gt 45
• albumin lt 4 gm/dl
• HgB lt 10.5 mg/dl
• stage IV disease
• WBC count gt 15,000/mm3
• lymphocyte count lt 600/mm3
• (Hasenclever et al, NEJM 339,1506-15141998)

26
Hodgkins 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

27
Hodgkins Disease

• Results of Treatment
• stage 5 year overall survival
• I 90
• II 90
• III 80
• IV 65

28
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

29
Hodgkins 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

30
NHL

• Epidemiology
• BIOLOGY
• Classification
• Approach to the Patient

31
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(814), t(28), t(822) Burkitts
• t(1418) follicular NHL

32
Lymphoma Biology

• 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

33
NHL

• Epidemiology
• Biology
• CLASSIFICATION
• Approach to the Patient

34
NHL Classification

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

35
(No Transcript)
36
NHL Classification

• 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

37
NHL Classification

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

38
NHL

• Epidemiology
• Biology
• Classification
• APPROACH TO THE PATIENT

39
NHL Approach to the Patient

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

40
NHL Approach to the Patient

• Staging evaluation
• History and PE
• Routine blood work
• CBC, diff, plts, electrolytes, BUN, Cr, LFTs,
  uric acid, LDH, B2M
• CT scans chest/abd/pelvis
• Bone marrow evaluation
• Other studies as indicated (lumbar puncture,
  gallium, etc)

41
(No Transcript)
42
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

43
(No Transcript)
44
(No Transcript)
45
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

46
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

47
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

48
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

49
(No Transcript)
50
(No Transcript)
51
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

52
NHL Approach to the Patient

• International Prognostic Index
• Risk Factors (0-5)
• age gt 60
• two or more extranodal sites
• performance status gt 2
• elevated LDH
• stage III-IV
• Age adjusted IPI (0-3)

53
CR and OS stratified by IPI
54
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 gt 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

55
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

56
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

57
Summary

• NHL incidence increasing, Hodgkins decreasing
• Hodgkins 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

58
Lymphoma Clinic

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