Non-Hodgkin's lymphoma

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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 – – 6 th leading cause of cancer death (women) 5 th 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, 2003

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% 32% 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 *Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder.

Jemal et al.

CA Cancer J Clin.

2003;53:5-26.

Incidence of NHL Is Increasing, Especially in the Elderly (

60 Years) SEER NHL incidence by age, 1975 –1977 and 1998–2000 (male, all races) 140 120 1998 –2000 1975 –1977 100 No. per 100,000 80 60 40 20 0 Age at diagnosis (years)

Ries et al (eds).

SEER Cancer Statistics Review, 1975-2000

. National Cancer Institute. Bethesda, Md, http://seer.cancer.gov/csr/1975_2000, 2003.

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 Aggressive Very Aggressive

• CLL/SLL • Lymphoplasmacytic/ IMC/WM • HCL • Splenic marginal zone lymphoma • Marginal zone lymphoma – Extranodal (MALT) – Nodal • Follicle center lymphoma, follicular, grade I-II • PLL • Plasmacytoma/ Multiple myeloma • MCL • DLCL • Primary mediastinal large B-cell lymphoma • Follicle center lymphoma, follicular, grade III • 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…)

Modified Ann Arbor Staging of NHL

Stage I Stage II

Involvement of a single lymph node region Involvement of  2 lymph node regions on the same side of the diaphragm

Stage III Stage IV

Cancer.

1982;49:2112.

Involvement of lymph node regions on both sides of the diaphragm 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

Age Performance status (PS) Lactate dehydrogenase (LDH) level Extranodal involvement Stage (Ann Arbor)

Risk factors

> 60 years 2-4 Elevated > 1 site III –IV

Patients

60 years (age-adjusted)

PS LDH Stage 2-4 Elevated III –IV Shipp.

N Engl J Med.

1993;329:987.

All ages

IPI Risk Strata

Risk Group

Low (L) Low-intermediate (LI) High-intermediate (HI) High (H)

Risk Factors

0-1 2 3 4-5 Age-adjusted L LI HI H Shipp.

Blood.

1994;83:1165.

0 1 2 3

IPI: Overall Survival by Risk Strata

100 75 50 25 0 0 2 4 Adapted from Shipp.

N Engl J Med.

1993;329:987.

Year

6 8

HI L LI H

10

Age-Adjusted IPI: Overall Survival by Risk Strata

100 75 50 25 0 0 2 4 Adapted from Shipp.

N Engl J Med.

1993;329:987.

Year

6 8

L LI HI H

10

Follicular Lymphoma (FL) : Overall Survival

100 80 60 40 20

P

< 0.001

0 0 1 2 3 Adapted from Armitage.

J Clin Oncol.

1998;16:2780.

4

Year

5 6 IPI 4/5 7 IPI 0/1 IPI 2/3 8

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 Chlorambucil Cytoxan (daily) 119 Chl-P (pulse) CVP (which?) # ORR CR 158 90% 63% Median PFS ?

77 89% 78% 66% 4.2 yrs 34% 2.5 yrs CHOP (B) ProM-MOPP Fludarabine FN FND ATT 109 93% 500 83% 101 84% 78 94% 73 69 98% 97% 60% 47% 47% 44% 79% 87% 3.6 yrs 3.2 yrs 3.0 yrs 2.7 yrs 3.5 yrs 5.0 yrs Reference Ardeshna, Lancet 2003 Peterson, JCO 2003 Baldini, JCO 2003 (Await E1496) Peterson, JCO 2003 Fisher, JCO 2000 Zinzani, JCO 2000 Velasquez, JCO 2003 Tsimberidou, Blood 2002 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

100 80 CHOP m-BACOD ProMACE-CytaBOM MACOP-B 60 40 20 0 0 1 2 3 4

Years After Randomization

5 Adapted from Fisher.

N Engl J Med.

1993;328:1002.

6

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

100 80 60 40 20

P < 0.001

0 0 1 2 3 Adapted from Armitage.

J Clin Oncol.

1998;16:2780.

4

Year

5 6 7 8 IPI 0-1 IPI 4-5 IPI 2-3

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 Kramer et al. JCO 14:2131, 1996 Hill et al. Blood 88:1046, 1996 Gascoyne et al. Blood 90:244, 1997 Kramer et al. Blood 92:3152, 1998 DFS, OS DFS DFS DFS, OS DFS, OS

BCL-2 expression vs survival

R. 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/mm 3 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

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