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NHL Board Review

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)

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NHL Board Review

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  1. NHL Board Review Brad Kahl, MD 1/20/04

  2. NHL: Outline • Epidemiology • Classification • Prognostic Factors • Treatment Principles • Disease by disease breakdown

  3. 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

  4. 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 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% *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.

  5. 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 80 No. per100,000 60 40 20 0 5 85 5–9 20–24 45–49 10–14 15–19 25–29 30–34 40–44 65–69 70–74 35–39 50–54 55–59 60–64 75–79 80–84 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.

  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 • hair dye-very weak association • radiation-no association

  7. 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

  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.

  9. 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…)

  10. 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 Cancer. 1982;49:2112.

  11. 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

  12. International Prognostic Index (IPI) Patients of all ages Risk factors Age > 60 years Performance status (PS) 2-4 Lactate dehydrogenase (LDH) levelElevated Extranodal involvement> 1 site Stage (Ann Arbor)III–IV Patients  60 years (age-adjusted) PS 2-4 LDHElevated StageIII–IV Shipp. N Engl J Med. 1993;329:987.

  13. IPI Risk Strata Risk Factors All ages Low (L) 0-1 Low-intermediate (LI) 2 High-intermediate (HI) 3 High (H) 4-5 Age-adjusted L 0 LI 1 HI 2 H 3 Risk Group Shipp. Blood. 1994;83:1165.

  14. IPI: Overall Survival by Risk Strata 100 75 Patients (%) 50 L LI HI 25 H 0 0 2 4 6 8 10 Year Adapted from Shipp. N Engl J Med. 1993;329:987.

  15. Age-Adjusted IPI: Overall Survival by Risk Strata 100 L 75 LI Patients (%) 50 HI H 25 0 0 2 4 6 8 10 Year Adapted from Shipp. N Engl J Med. 1993;329:987.

  16. Follicular Lymphoma (FL) : Overall Survival 100 80 IPI 0/1 60 Overall Survival (%) IPI 2/3 40 20 P < 0.001 IPI 4/5 0 0 1 2 3 4 5 6 7 8 Year Adapted from Armitage. J Clin Oncol. 1998;16:2780.

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

  18. 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 Treatment Strategies for Indolent NHL

  19. Indolent NHL: chlorambucil vs W&W

  20. Indolent NHL: What are reasonable first line therapies?

  21. 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

  22. 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

  23. National High Priority Lymphoma Study: Progression-Free Survival 100 CHOP m-BACOD ProMACE-CytaBOM 80 MACOP-B 60 Patients (%) 40 20 0 0 1 2 3 4 5 6 Years After Randomization Adapted from Fisher. N Engl J Med. 1993;328:1002.

  24. Diffuse Large B-Cell Lymphoma (DLCL): Overall Survival 100 80 IPI 0-1 60 Patients (%) 40 IPI 2-3 IPI 4-5 20 P < 0.001 0 0 1 2 3 4 5 6 7 8 Year Adapted from Armitage. J Clin Oncol. 1998;16:2780.

  25. 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

  26. 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

  27. DLBCL Actually a heterogenous group • 3 subtypes by microarray • Germinal center B cell like • Activated peripheral blood B cell like • Type 3

  28. 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

  29. DNA Microarray Alizadah et al, Nature,2000:403;503 • Reviewed clinical outcome data • Gene expression profiles had prognostic value • Added to IPI

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

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

  32. 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

  33. BCL-2 expression vs survivalR. Gascoyne et al, Blood 90:244, 1997

  34. 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)

  35. 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+

  36. 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

  37. 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

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