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Lymphoma OverviewJohn Gerecitano, M.D., Ph.D.The following material is intended for MSKCC internal medicine housestaff tea...
Incidence of Cancer in the United States*Prostate 29%Lung and bronchus 15%Colon and rectum 10%Urinary bladder 7%Non-Hodgki...
Clinical Courseand REAL/WHO Classification of NHL*RITUXAN® (Rituximab) is approved for the bolded subtypes. Other subtypes...
Evaluating Lymphadenopathy
Lymphadenopathy
Symptoms of Lymphoma• Painless, rubbery, mobile lymphadenopathy• “B Symptoms” (20% of cases)– Drenching Nights Sweats– Fev...
Reactive Lymph Node Follicular Lymphoma
Staging Lymphomas
Staging (the Old Way)
Staging (the Modern way)• CT Scan• PET Scan (for aggressive lymphomas)• Bone Marrow Biopsy
Ann Arbor Staging System for Hodgkins Disease andNon-Hodgkins LymphomaStage I Stage II Stage III Stage IVAdapted from Skar...
The Aggressive Lymphomas
Diffuse Large B Cell Lymphoma• Potentially curable at any age• R-CHOP is standard chemotherapy• PET scanning is important ...
National High Priority Lymphoma Study: Progression-Free SurvivalAdapted from Fisher. N Engl J Med. 1993;328:1002.Patients(...
International Prognostic Index (IPI)Patients of all ages Risk factorsAge > 60 yearsPerformance status (PS) 2-4Lactate dehy...
Age-Adjusted IPI:Overall Survival by Risk Strata (age≤60)HI (30%) = 3H (15%) = 4-5LI (40%) = 2L (15%) = 0-110075502500 2 4...
CD20:A Target for Lymphoma TherapyCD20:• Is a transmembrane protein expressedby 95% of mature B-cell NHLs, but isabsent in...
Antigen Expression DuringB-Cell DevelopmentBone Marrow Periphery (Spleen, Lymph Node)Pro-B Pre-B Immature B Mature B GC BM...
Rituximab:An Anti-CD20 Monoclonal Antibody• Genetically engineered chimericmurine/human antibody– Variable light- and heav...
020406080100Years1 2 3 4 5 60CHOP (n=197)R-CHOP (n=202)%Surviving*Data on file. Genentech, Inc.Feugier P et al. J Clin Onc...
First-Line R-CHOP vs CHOPin DLBCL: Survival SummaryCHOP R-CHOPMedian EFS 1.1 years 2.9 yearsOS at 2 years 58% 69%OS at 5 y...
PARMA Trial: autoSCT for RelapsedDLBCLPhillip et al NEJM 1995: 333(23);1540
The Indolent Lymphomas
Clinical Courseand REAL/WHO Classification of NHL*RITUXAN® (Rituximab) is approved for the bolded subtypes. Other subtypes...
Mantle Cell Lymphomavs. Follicular Lymphoma
Small cells:Panel: CD5,CD10, CD23,cyclin D1,BCL2, BCL6(CD25,CD103)CD5 +CD23 + CLLcyclin D1 –t(11;14) -CD23 -Cyclin D1 +t(1...
Follicular Lymphoma
Follicular NHL• Characteristics– 80% to 90% disseminated atdiagnosis (lymph nodes,spleen, bone marrow,peripheral blood)– S...
Reactive Lymph Node Follicular Lymphoma
Positive• CD20• CD10• BCL2• BCL6Negative• CD3• CD5• ALK• CD30MIB1/Ki67• 50%CD20 BCL2Ki67/MIB1BCL6
Follicular Lymphoma Histology• Numbers of centroblasts (large cells) increase with grade• Criteria for grading*– Grade 1: ...
Comparison of Response Rates, Response Durations and SurvivalTimes After Treatment of Consecutive Recurrences ofFollicular...
NHL: Survival Of Patients WithLow-Grade DiseaseCourtesy of Sandra J. Horning, MD.0204060801000 5 10 15 20 25 30Time (y)Pro...
Survival of Patients with Low GradeNHLTan et al, ASH 2007Abstr 8535
Treatment of Follicular Lymphoma (Grades 1-2)(…and other indolent lymphomas)Modified from National Comprehensive Cancer Ne...
RT for Limited Stage DiseaseWilder et al. Int. J. Radiation Oncology Biol. Phys, 2001
Treatment Options for Advanced StageFollicular LymphomaInterferonAutologousAllogeneic(full or non-myeloablative)Alkylator-...
Immunotherapy
Rituximab:An Anti-CD20 Monoclonal Antibody• Genetically engineered chimericmurine/human antibody– Variable light- and heav...
Principles of Radioimmunotherapy• Targeted delivery of radiation totumor cells• Greater exposure of tumors vssurrounding n...
Cross-fire Enhances MAb ActionNaked Antibody RITCourtesy of Andrew Zelenetz, MD, PhD.
Approaches to Relapsed Patients• Usually includes rituximab ± other agents• Optimal regimen unknown• Optimal duration of t...
Myeloablative allogeneic SCT for FLCIBMTR (Hari et al, BBMT 2008)
Marginal Zone Lymphomas• Gastric MALT– Often associated with H. Pylori– Eradication of H. Pylori can be curative in 2/3 pa...
Gastric MZLEGDMZL +H. Pylori +MZL +H. Pylori –Triple TxRTEGD 3 mo
Gastric MZLEGDMZL +H. Pylori +MZL +H. Pylori –Triple TxRTEGD 3 mo
Gastric MZLEGDMZL +H. Pylori +MZL +H. Pylori –MZL –H. Pylori –Triple TxRTEGD 3 moEGD 3 mo
RT for Gastric MALTSchecter et al. JCO 1998
Waldenstrom’s Macroglobulinemia• = lymphoplasmacytic lymphoma + elevated IgM• Can be associated with hyperviscosity syndro...
Retinopathy inWaldenstroms macroglobulinemia
Waldenstrom’s Macroglobulinemia• Indications for Treatment– Symptomatic hyperviscosity– Anemia, pancytopenia– Bulky adenop...
Lymphoma overview
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  • What we’ll cover:EpidemiologyHistologyTxFLMZLWM
  • http://www.med.cmu.ac.th/dept/pediatrics/06-interest-cases/ic-60-61/supraLN_arrow.jpg
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  • Used DHAP followed by ASCT
  • Transcript of "Lymphoma overview"

    1. 1. Lymphoma OverviewJohn Gerecitano, M.D., Ph.D.The following material is intended for MSKCC internal medicine housestaff teaching purposes only. Thepresentation may not be copies or disseminated. The slides were updated for the LibGuide in 2012-2013.
    2. 2. Incidence of Cancer in the United States*Prostate 29%Lung and bronchus 15%Colon and rectum 10%Urinary bladder 7%Non-Hodgkin’s lymphoma 4%Melanoma of the skin 4%Kidney and renal pelvis 4%Leukemia 3%Oral cavity and pharynx 3%Pancreas 2%All other sites 19%Women678,060Men766,86026% Breast15% Lung and bronchus11% Colon and rectum6% Uterine corpus4% Non-Hodgkin’s lymphoma4% Melanoma of the skin4% Thyroid3% Ovary3% Kidney and renal pelvis3% Leukemia21% All other sites*Excludes basal and squamous cell skin cancers and in situ carcinomas except urinarybladder. Estimated for 2007.American Cancer Society. Cancer Facts & Figures 2007. Atlanta, GA: American Cancer Society; 2007.
    3. 3. Clinical Courseand REAL/WHO Classification of NHL*RITUXAN® (Rituximab) is approved for the bolded subtypes. Other subtypes are not approved RITUXAN indications.Armitage JO, Weisenburger DD. J Clin Oncol. 1998;16:2780-2795; Harris NL et al. Ann Oncol. 1999;10:1419-1432; Hiddemann W et al. Blood.1996;88:4085-4089; Horning SJ. Blood. 1994;83:881-884; Liu Q et al. J Clin Oncol. 2006;24:1582-1589; Fisher RI et al. N Engl J Med.1993;328:1002-1006; Skarin AT, Dorfman DM. CA Cancer J Clin. 1997;47:351-372.FL*PTCL22%Indolent(low grade)Aggressive(intermediate grade)Very aggressive(high grade)• Slowly progressive• 5-year OS ≤95%• Rapid clinical course• 5-year OS ≤50%• Grows rapidly• Survival 0.5-2 years31%6%2%2%6%2%2%6%5%16%Grades I, II- IndolentGrade III- Agressive
    4. 4. Evaluating Lymphadenopathy
    5. 5. Lymphadenopathy
    6. 6. Symptoms of Lymphoma• Painless, rubbery, mobile lymphadenopathy• “B Symptoms” (20% of cases)– Drenching Nights Sweats– Fevers– Unexplained Weight Loss– Fatigue
    7. 7. Reactive Lymph Node Follicular Lymphoma
    8. 8. Staging Lymphomas
    9. 9. Staging (the Old Way)
    10. 10. Staging (the Modern way)• CT Scan• PET Scan (for aggressive lymphomas)• Bone Marrow Biopsy
    11. 11. Ann Arbor Staging System for Hodgkins Disease andNon-Hodgkins LymphomaStage I Stage II Stage III Stage IVAdapted from Skarin. Dana-Farber Cancer Institute Atlas ofDiagnostic Oncology. 1991; with permission.
    12. 12. The Aggressive Lymphomas
    13. 13. Diffuse Large B Cell Lymphoma• Potentially curable at any age• R-CHOP is standard chemotherapy• PET scanning is important in monitoring response• Role of IF-RT?• Autologous transplantation is potentially curative at relapse; rolein upfront Rx?• Mini-allotransplantation is a promising salvage therapy inselected cases
    14. 14. National High Priority Lymphoma Study: Progression-Free SurvivalAdapted from Fisher. N Engl J Med. 1993;328:1002.Patients(%)Years After Randomization1008060402000 1 2 3 4 5 6CHOPm-BACODProMACE-CytaBOMMACOP-B
    15. 15. International Prognostic Index (IPI)Patients of all ages Risk factorsAge > 60 yearsPerformance status (PS) 2-4Lactate dehydrogenase (LDH) level ElevatedExtranodal involvement > 1 siteStage (Ann Arbor) III–IVPatients  60 years (age-adjusted)PS 2-4LDH ElevatedStage III–IVShipp. N Engl J Med. 1993;329:987.
    16. 16. Age-Adjusted IPI:Overall Survival by Risk Strata (age≤60)HI (30%) = 3H (15%) = 4-5LI (40%) = 2L (15%) = 0-110075502500 2 4 6 8 10Patients(%)YearAdapted from Shipp. N Engl J Med. 1993;329:987.
    17. 17. CD20:A Target for Lymphoma TherapyCD20:• Is a transmembrane protein expressedby 95% of mature B-cell NHLs, but isabsent in stem cells, plasma cells, andcells of other lineages• Is a stable target that is not shed,modulated, or internalized upon antibodybinding• May be involved in regulation ofintracellular calcium levels• May be involved in regulation of the cellcycle and apoptosisEinfeld DA et al. EMBO J. 1988;7:711-717.Press OW et al. Blood. 1987;69:584-591.Riley JK, Sliwkowski MX. Semin Oncol. 2000;27(suppl 12):17-24.Tedder TF et al. Proc Natl Acad Sci U S A. 1988;85:208-223.Tedder TF, Engel P. Immunol Today. 1994;15:450-454.
    18. 18. Antigen Expression DuringB-Cell DevelopmentBone Marrow Periphery (Spleen, Lymph Node)Pro-B Pre-B Immature B Mature B GC BMature BMemory BPlasma CellCD19 + + + + + + + –CD10 + + +/– – – + – –CD20 – – –/+ + + ++ + –CD38 ++ ++ + + + ++ + ++CD22 – – + + + + ? –CD52 +Activated B-cellsALL=acute lymphoblastic leukemia; CLL=chronic lymphocytic leukemia, PLL=prolymphocytic leukemia;FL=follicular lymphoma; DLBCL=diffuse large B-cell lymphoma; HCL=hairy cell leukemia; WM=Waldenström’s macroglobulinemia;MM=multiple myeloma.Jaffe ES et al, eds. World Health Organization Classification of Tumours. 2001; Hale G et al.Tissue Antigens. 1990;35:118-127; Freeman GJ et al. J Immunol. 1989;143:2714-2722.PlasmablastWM MMALL CLL, PLLBurkitt’s, FL, DLBCL, HCL
    19. 19. Rituximab:An Anti-CD20 Monoclonal Antibody• Genetically engineered chimericmurine/human antibody– Variable light- and heavy-chainregions from murine anti-CD20antibody– Linked to human IgG1 and κconstant regions• First FDA-approved monoclonalantibody for treatment of cancer inthe United States– Approved November 1997Rituxan [package insert]. South San Francisco, CA; Genentech, Inc; 2006.Pescovitz MD. Am J Transplant. 2006;6:859-866.Rituxan
    20. 20. 020406080100Years1 2 3 4 5 60CHOP (n=197)R-CHOP (n=202)%Surviving*Data on file. Genentech, Inc.Feugier P et al. J Clin Oncol. 2005;23:4117-4126.Median 5-Year Follow-UpFirst-Line R-CHOP vs CHOPin DLBCL: Overall Survival (cont’d)P=.0073HR=0.68* (95% CI, 0.51-0.90)32% risk reduction
    21. 21. First-Line R-CHOP vs CHOPin DLBCL: Survival SummaryCHOP R-CHOPMedian EFS 1.1 years 2.9 yearsOS at 2 years 58% 69%OS at 5 years 46% 58%Rituxan [package insert]. South San Francisco, CA: Genentech, Inc.; 2006.
    22. 22. PARMA Trial: autoSCT for RelapsedDLBCLPhillip et al NEJM 1995: 333(23);1540
    23. 23. The Indolent Lymphomas
    24. 24. Clinical Courseand REAL/WHO Classification of NHL*RITUXAN® (Rituximab) is approved for the bolded subtypes. Other subtypes are not approved RITUXAN indications.Armitage JO, Weisenburger DD. J Clin Oncol. 1998;16:2780-2795; Harris NL et al. Ann Oncol. 1999;10:1419-1432; Hiddemann W et al. Blood.1996;88:4085-4089; Horning SJ. Blood. 1994;83:881-884; Liu Q et al. J Clin Oncol. 2006;24:1582-1589; Fisher RI et al. N Engl J Med.1993;328:1002-1006; Skarin AT, Dorfman DM. CA Cancer J Clin. 1997;47:351-372.FL*PTCL22%Indolent(low grade)Aggressive(intermediate grade)Very aggressive(high grade)• Slowly progressive• 5-year OS ≤95%• Rapid clinical course• 5-year OS ≤50%• Grows rapidly• Survival 0.5-2 years31%6%2%2%6%2%2%6%5%16%Grades I, II- IndolentGrade III- Agressive
    25. 25. Mantle Cell Lymphomavs. Follicular Lymphoma
    26. 26. Small cells:Panel: CD5,CD10, CD23,cyclin D1,BCL2, BCL6(CD25,CD103)CD5 +CD23 + CLLcyclin D1 –t(11;14) -CD23 -Cyclin D1 +t(11;14) +MCLCyclin D1 -t(11;14) -CLLCD5 -CD10 + FLBCL6 +BCL2 +t(14;18) +CD10 -CD103 -Cytoplasmic Ig-- Morphology (MZPattern)-Clinical features(extranodal, splenic)MZLPseudofollicularpattern, clinicalfeatures (BM)CD5 –CLLCytoplasmic Ig + LPL vs MZL-Morphology (MZpattern, plasmacytoidfeatures), genetics (del 7q)-Clinical features(splenomegaly, bonemarrow involvement,paraprotein)Non-Hodgkin’s LymphomasAdapted from NCCN Guidelines
    27. 27. Follicular Lymphoma
    28. 28. Follicular NHL• Characteristics– 80% to 90% disseminated atdiagnosis (lymph nodes,spleen, bone marrow,peripheral blood)– Small B lymphocytes– t(14:18) 90% of cases– Relatively long mediansurvival– Sensitive to chemotherapyand RT– Incurable with conventionaltherapies (possible cureswith allo SCT)• Histologic transformation– Occurs in 30% to 40% ofpatients– Accompanied by newsymptoms, rapidprogression, elevated LDH,increased activity on PET– Generally poor prognosis
    29. 29. Reactive Lymph Node Follicular Lymphoma
    30. 30. Positive• CD20• CD10• BCL2• BCL6Negative• CD3• CD5• ALK• CD30MIB1/Ki67• 50%CD20 BCL2Ki67/MIB1BCL6
    31. 31. Follicular Lymphoma Histology• Numbers of centroblasts (large cells) increase with grade• Criteria for grading*– Grade 1: 0-5 centroblasts/hpf; centrocytes predominate– Grade 2: 6-15 centroblasts/hpf– Grade 3: >15 centroblasts/hpf; centroblasts predominateGrade 1 Grade 2 Grade 3* These images do not reflect individual high power fields.Warnke RA et al. Tumors of the Lymph Node and Spleen. Washington, DC: Atlas of TumorPathology, Armed Forces Institute of Pathology; 1995.Harris NL et al. Ann Oncol. 1999;10:1419-1432.
    32. 32. Comparison of Response Rates, Response Durations and SurvivalTimes After Treatment of Consecutive Recurrences ofFollicular LymphomaJohnson et al., JCO 1995;13(1):140Treatment # Treated RR (%) Duration(years)Survival (years)First 204 88 2.6 9.2Second 110 78 1.1 4.6Third 63 76 1.1 3.5Fourth 37 68 0.5 1.2
    33. 33. NHL: Survival Of Patients WithLow-Grade DiseaseCourtesy of Sandra J. Horning, MD.0204060801000 5 10 15 20 25 30Time (y)Probability(%)1987-1996 (N=668)1976-1987 (N=513)1960-1976 (N=195)
    34. 34. Survival of Patients with Low GradeNHLTan et al, ASH 2007Abstr 8535
    35. 35. Treatment of Follicular Lymphoma (Grades 1-2)(…and other indolent lymphomas)Modified from National Comprehensive Cancer Network. Non-Hodgkin’s lymphoma. Clinical Practice Guidelines inOncology – v.3. 2007. Jenkintown, PA: National Comprehensive Cancer Network; 2007.Workup(Staging)Stage I-IIStage II bulky,or Stage III-IVYes Initial treatmentTreatmentindicated?NoObserveProgressionIndications for treatment• Candidate for clinical trial• Symptoms• Threatened end-organ function• Cytopenia secondary to lymphoma• Bulky disease• Patient preferenceLocalizedLocoregional/extended-fieldradiation
    36. 36. RT for Limited Stage DiseaseWilder et al. Int. J. Radiation Oncology Biol. Phys, 2001
    37. 37. Treatment Options for Advanced StageFollicular LymphomaInterferonAutologousAllogeneic(full or non-myeloablative)Alkylator-basedCVPChlorambucilBendamustineSpecific NonspecificPurine analogsFludarabineFludarabine-basedcombinationChemotherapy-basedAntibody-basedRituximab aloneChemo-immunotherapyRadioimmunotherapyTositumomabIbritumomab tiuxetanBiologic-based TransplantationDiagnosis of low-grade lymphomaneeds treatmentAnthracycline-basedCHOP
    38. 38. Immunotherapy
    39. 39. Rituximab:An Anti-CD20 Monoclonal Antibody• Genetically engineered chimericmurine/human antibody– Variable light- and heavy-chainregions from murine anti-CD20antibody– Linked to human IgG1 and κconstant regions• First FDA-approved monoclonalantibody for treatment of cancer inthe United States– Approved November 1997Rituxan [package insert]. South San Francisco, CA; Genentech, Inc; 2006.Pescovitz MD. Am J Transplant. 2006;6:859-866.Rituxan
    40. 40. Principles of Radioimmunotherapy• Targeted delivery of radiation totumor cells• Greater exposure of tumors vssurrounding normal organs byvirtue of limited path length ofparticle emissions and selectivityof the carrier antibody• Crossfire of particle emissions• Continuous exposure of tumorcells• Retention of anti-tumormechanisms of the antibody
    41. 41. Cross-fire Enhances MAb ActionNaked Antibody RITCourtesy of Andrew Zelenetz, MD, PhD.
    42. 42. Approaches to Relapsed Patients• Usually includes rituximab ± other agents• Optimal regimen unknown• Optimal duration of therapy unknown• Activity of agents unknown in new era• Clinical trial is the standard of care
    43. 43. Myeloablative allogeneic SCT for FLCIBMTR (Hari et al, BBMT 2008)
    44. 44. Marginal Zone Lymphomas• Gastric MALT– Often associated with H. Pylori– Eradication of H. Pylori can be curative in 2/3 patients• Local RT for all others– Patients with t(11:18), API2;MLT have more extensive dz andworse prognosis• Splenic MZL– Usu dx’d based on SM and BM involvement– Splenectomy can yield long term DFS in many patients• Nodal MZL– Worse prognosis, treated like advanced stage FL
    45. 45. Gastric MZLEGDMZL +H. Pylori +MZL +H. Pylori –Triple TxRTEGD 3 mo
    46. 46. Gastric MZLEGDMZL +H. Pylori +MZL +H. Pylori –Triple TxRTEGD 3 mo
    47. 47. Gastric MZLEGDMZL +H. Pylori +MZL +H. Pylori –MZL –H. Pylori –Triple TxRTEGD 3 moEGD 3 mo
    48. 48. RT for Gastric MALTSchecter et al. JCO 1998
    49. 49. Waldenstrom’s Macroglobulinemia• = lymphoplasmacytic lymphoma + elevated IgM• Can be associated with hyperviscosity syndrome– headache, dizziness, vertigo, nystagmus, hearing loss,visual impairment, somnolence, coma and seizures,mucosal hemorrhage (2nd 2 reduced platelet function),CHF (2nd 2 expanded plasma volume), renal failure, andsausage-like beading in the retinal veins
    50. 50. Retinopathy inWaldenstroms macroglobulinemia
    51. 51. Waldenstrom’s Macroglobulinemia• Indications for Treatment– Symptomatic hyperviscosity– Anemia, pancytopenia– Bulky adenopathy– Symptomatic organomegaly– Symptomatic cryoglobulinemia or neuropathy• Treatment Options– Alkylating agents– Nucleoside analogs• 2-CdA• Fludarabine– Clinical trials– Rituximab– Thalomide– Bortezomib

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