NHL Board Review

Brad Kahl, MD

1/20/04

NHL: Outline

Epidemiology Classification Prognostic Factors Treatment Principles Disease by disease breakdown

NHL: Epidemiology

Most common hematologic malignancy– 54,000 new cases annually

– 6th leading cause of cancer death (women)

– 5th in men incidence rising

– overall incidence up by 73% since 1973

– “epidemic”

– 2nd most rapidly rising malignancy

Estimated New Cancer Cases*:

10 Leading Sites, by Sex, United States, 200332% Breast

12% Lung & bronchus

11% Colon & rectum

6% Uterine corpus

4% Ovary

4% Non-Hodgkin’s lymphoma

3% Melanoma of skin

3% Thyroid

2% Pancreas

2% Urinary bladder

20% All other sites

Prostate 33%

Lung & bronchus 14%

Colon & rectum 11%

Urinary bladder 6%

Melanoma of skin 4%

Non-Hodgkin’s 4% lymphoma

Kidney 3%

Oral cavity 3%

Leukemia 3%

Pancreas 2%

All other sites 17%

*Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder.*Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder.Jemal et al. Jemal et al. CA Cancer J Clin.CA Cancer J Clin. 2003;53:5-26. 2003;53:5-26.

Incidence of NHL Is Increasing,

Especially in the Elderly (60 Years)SEER NHL incidence by age, 1975SEER NHL incidence by age, 1975––1977 and 19981977 and 1998–2000–2000 (male, all races) (male, all races)

Ries et al (eds). SEER Cancer Statistics Review, 1975-2000. National Cancer Institute. Bethesda, Md, http://seer.cancer.gov/csr/1975_2000, 2003.

Age at diagnosis (years)Age at diagnosis (years)

00

2020

4040

6060

8080

100100

120120

140140 55 55 –– 99

1010 ––

1414

1515 ––

1919

2020 ––

2424

2525 ––

2929

3030 ––

3434

3535 ––

3939

4040 ––

4444

4545 ––

4949

5050 ––

5454

5555 ––

5959

6060 ––

6464

6565 ––

6969

7070 ––

7474

7575 ––

7979

8080 ––

8484

858

5

19981998––2000200019751975––19771977

No. perNo. per100,000100,000

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

– hair dye-very weak association

– radiation-no association

NHL: Epidemiology

Other risk factors– immunodeficiency states

AIDS, post-transplant, genetic

– Chronic immune stimulation/activation autoimmune diseases

– Sjogrens

– Sprue infections

– H. pylori, EBV, HHV-8

Revised European-American Lymphoma (REAL) Classification: B-Cell Neoplasms

Indolent

• CLL/SLL

• Lymphoplasmacytic/IMC/WM

• HCL

• Splenic marginal zone lymphoma

• Marginal zone lymphoma

– Extranodal (MALT)

– Nodal

• Follicle center lymphoma, follicular, grade I-II

Aggressive

• PLL

• Plasmacytoma/Multiple myeloma

• MCL

• DLCL

• Primary mediastinal large B-cell lymphoma

• Follicle center lymphoma, follicular, grade III

Very Aggressive

• Precursor B-lymphoblastic lymphoma/Leukemia

• Burkitt’s lymphoma/ B-cell acute leukemia

• Burkitt’s-like

• Plasma cell leukemia

Hiddemann. Blood. 1996;88:4085.

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, HIV

– CT scans chest/abd/pelvis

– Bone marrow evaluation

– Other studies as indicated (lumbar puncture, MRI, PET, etc…)

Cancer. 1982;49:2112.

Modified Ann Arbor Staging of NHL

Stage I Involvement of a single lymph node region

Stage II Involvement of 2 lymph node regions on the same side of the diaphragm

Stage III Involvement of lymph node regions on both sides of the diaphragm

Stage IV Multifocal involvement of 1 extralymphatic sites ± associated lymph nodes or isolated extralymphatic organ involvement with distant nodal involvement

Modified Ann Arbor Staging of NHL “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

International Prognostic Index (IPI)

Patients of all ages Risk factors Age > 60 yearsPerformance status (PS) 2-4Lactate dehydrogenase (LDH) level Elevated Extranodal involvement > 1 siteStage (Ann Arbor) III–IV

Patients 60 years (age-adjusted)PS 2-4LDH ElevatedStage III–IV

Shipp. N Engl J Med. 1993;329:987.

IPI Risk Strata

All ages Low (L) 0-1Low-intermediate (LI) 2High-intermediate (HI) 3High (H) 4-5

Age-adjusted L 0LI 1HI 2H 3

RiskFactorsRisk Group

Shipp. Blood. 1994;83:1165.

IPI: Overall Survival by Risk Strata

Adapted from Shipp. N Engl J Med. 1993;329:987.

100

75

50

25

0

0 2 4 6 8 10

H

HILI

L

Pa

tie

nts

(%

)

Year

Age-Adjusted IPI: Overall Survival by Risk Strata

HI

H

LI

L

100

75

50

25

0

0 2 4 6 8 10

Pa

tie

nts

(%

)

Year

Adapted from Shipp. N Engl J Med. 1993;329:987.

Follicular Lymphoma (FL) : Overall Survival

Adapted from Armitage. J Clin Oncol. 1998;16:2780.

Year

8

IPI 0/1

IPI 2/3

IPI 4/5

100

Ov

era

ll S

urv

iva

l (%

)

0 2 5 6 73 41

P < 0.001

60

40

20

0

80

NHL: Approach to the Patient

Approach dictated mainly by histology– reliable hematopathology crucial

Approach also influenced by:– stage

– prognostic factors

– co-morbidities

Treatment Strategies for Indolent NHL

Stage I-II Disease

“Watchful waiting”

Radiation

Stage III-IV Disease

“Watchful waiting”

Purine analogs

Alkylating agents

Combination chemotherapy

MoAbs (conjugated and unconjugated)

Chemotherapy + MoAbs

Intensive chemotherapy + autologous/allogeneic bone marrow (BM) or peripheral blood (PB) transplantation

Indolent NHL: chlorambucil vs W&W

Indolent NHL: What are reasonable first line therapies?

Therapy # ORR CR Median PFS Reference

Chlorambucil 158 90% 63% ? Ardeshna, Lancet 2003

Cytoxan (daily) 119 89% 66% 4.2 yrs Peterson, JCO 2003

Chl-P (pulse) 77 78% 34% 2.5 yrs Baldini, JCO 2003

CVP (which?) (Await E1496)

CHOP (B) 109 93% 60% 3.6 yrs Peterson, JCO 2003

ProM-MOPP 500 83% 47% 3.2 yrs Fisher, JCO 2000

Fludarabine 101 84% 47% 3.0 yrs Zinzani, JCO 2000

FN 78 94% 44% 2.7 yrs Velasquez, JCO 2003

FND 73 98% 79% 3.5 yrs Tsimberidou, Blood 2002

ATT 69 97% 87% 5.0 yrs Tsimberidou, Blood 2002

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

Aggressive NHL: treatment approach– Stage I-II: combined modality therapy

R-CHOP chemotherapy x 3 + IF radiotherapy

– Consider more chemo if bulky, high LDH, stage II– Stage III-IV (also bulky stage II)

R-CHOP chemotherapy x 6-8 cycles

Great lesson in clinical trials

National High Priority Lymphoma Study: Progression-Free Survival

Adapted from Fisher. N Engl J Med. 1993;328:1002.

Pa

tie

nts

(%

)

Years After Randomization

100

80

60

40

20

00 1 2 3 4 5 6

CHOPm-BACODProMACE-CytaBOMMACOP-B

Diffuse Large B-Cell Lymphoma (DLCL): Overall Survival

Pa

tie

nts

(%

)

Year

Adapted from Armitage. J Clin Oncol. 1998;16:2780.

100

60

40

20

0

0 2 5 6 7 83 41

80

IPI 0-1

IPI 2-3

IPI 4-5

P < 0.001

NHL: Approach to the Patient

Role for Stem Cell Transplantation (auto) 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 convincing evidence that patients are cured

– CUP trial suggests survival advantage for ASCT

NHL: Elderly

Indolent histology

– usual principles apply

Aggressive histologies

– trials have consistently shown that prophylactic dose reductions/delays/omissions result in inferior outcomes

– PS predicts outcome rather than chronological age

– routine use of growth factors reduces FN and infections, does not improve survival. NCCN guidelines recommends routine use in patients over age 70 treated with CHOP.

– R-CHOP superior to CHOP in GELA trial for DLBCL

DLBCL

Actually a heterogenous group– 3 subtypes by microarray

Germinal center B cell like Activated peripheral blood B cell like Type 3

DNA Microarray Alizadah et al, Nature,2000:403;503

examined gene expression

profiles in DLCL tumor

samples

compared to profiles of non-

malignant B cells

noted emergence of patterns

DNA Microarray Alizadah et al, Nature,2000:403;503

Reviewed clinical outcome data

Gene expression profiles had prognostic value

Added to IPI

DNA Microarray Rosenwald et al. NEJM 2002:346;1937

DNA Microarray Rosenwald et al. NEJM 2002:346;1937

Biologic Factors

Bcl-2 Predictive Power in DLBCL

Hermine et al. Blood 87:265, 1996 DFS, OS

Kramer et al. JCO 14:2131, 1996 DFS

Hill et al. Blood 88:1046, 1996 DFS

Gascoyne et al. Blood 90:244, 1997 DFS, OS

Kramer et al. Blood 92:3152, 1998 DFS, OS

BCL-2 expression vs survivalBCL-2 expression vs survival

R. Gascoyne et al, Blood 90:244, 1997R. Gascoyne et al, Blood 90:244, 1997

Biology Summary

Microarray studies indicate 3 distinct subtypes of DLBCL based upon gene expression profile

Challenge is to better understand the intracellular derangements unique to each subtype so that new targeted therapies can be developed

Develop easily applicable lab techniques to distinguish the different biological entities (morphology does not do it)

Follicular Center Cell NHL

3 Grades– Grade 1: 0-5 centoblasts/HPF

– Grade 2: 6-15 centroblasts/HPF

– Grade 3: > 15 centroblasts/HPF 3a: no sheets of large cells 3b: sheets of large cells

Characterized by t(14;18)– Overexpression of bcl-2

Flow cytometry: CD10+

MALT

Lymphoma arises in tissue normally devoid of lymphoid tissue– Stomach, lungs, orbit, skin, breast, salivary

glands Gastric MALT unique due to high association

with H. pylori– Often regresses after H. pylori eradication

therapy

– t(11;18) predicts non response to H pylori therapy

T-Cell NHL

Will lack B cell antigens– CD20, sIg

Should have T cell markers– CD3+, CD4+ or CD8+

Harder to tell if clonal– Can’t do simple kappa/lamda

– Can look for clonal T cell receptor gene rearrangements with molecular studies

Small Lymphocytic Lymphoma

Distinction with CLL is arbitrary– > 5000/mm3 circulating lymphs

Characteristic flow pattern– CD5+, dim CD20+, CD23+, dim sIg

Can be confused with MCL– Similar morphology

– CD5+, CD20+, CD23-, bright sIg

– Frequent GI tract involvement Lymphomatous polyposis

Anaplastic large cell (T cell)

CD30+ (Ki-1 positive)– If CD20+, then DLBCL

3 types – Cutaneous

Distinguish from lymphomatoid papulosis

– Systemic ALK+ t(2;5) characteristic

– Systemic ALK- Poor prognosis