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Hodgkin’s Disease and Non-Hodgkin’s Lymphoma

Hodgkin’s Disease and Non-Hodgkin’s Lymphoma. Harold M. Chung, MD Associate Professor of Medicine VCU Medical Center – MCV Hospitals Bone Marrow Transplantation Program November 8, 2011. Why Men Can’t Be Babysitters. Agenda. Discuss Hodgkin’s Disease Discuss Non-Hodgkin’s Lymphoma

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Hodgkin’s Disease and Non-Hodgkin’s Lymphoma

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  1. Hodgkin’s DiseaseandNon-Hodgkin’s Lymphoma Harold M. Chung, MD Associate Professor of Medicine VCU Medical Center – MCV Hospitals Bone Marrow Transplantation Program November 8, 2011

  2. Why Men Can’t Be Babysitters

  3. Agenda • Discuss Hodgkin’s Disease • Discuss Non-Hodgkin’s Lymphoma • Classification Systems • Treatment Options

  4. 2008 Estimated US Cancer Cases* Men720,280 Women679,510 Prostate 33% Lung & bronchus 13% Colon & rectum 10% Urinary bladder 6% Melanoma of skin 5% Non-Hodgkin 4% lymphoma Kidney 3% Oral cavity 3% Leukemia 3% Pancreas 2% All Other Sites 18% 31% Breast 12% Lung & bronchus 11% Colon & rectum 6% Uterine corpus 4% Non-Hodgkin lymphoma 4% Melanoma of skin 3% Thyroid 3% Ovary 2% Urinary bladder 2% Pancreas 22% All Other Sites *Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder. Source: American Cancer Society, 2008.

  5. 2008 Estimated US Cancer Deaths* Men291,270 Women273,560 26% Lung & bronchus 15% Breast 10% Colon & rectum 6% Pancreas 6% Ovary 4% Leukemia 3% Non-Hodgkin lymphoma 3% Uterine corpus 2% Multiple myeloma 2% Brain/ONS 23% All other sites Lung & bronchus 31% Colon & rectum 10% Prostate 9% Pancreas 6% Leukemia 4% Liver & intrahepatic 4%bile duct Esophagus 4% Non-Hodgkin 3% lymphoma Urinary bladder 3% Kidney 3% All other sites 23% ONS=Other nervous system. Source: American Cancer Society, 2008.

  6. B-Cell Neoplasms Precursor B-cell neoplasm Precursor B-lymphoblastic leukemia/lymphoma (precursor B-acute lymphoblastic leukemia) Mature (peripheral) B-neoplasms B-cell chronic lymphocytic leukemia / small lymphocytic lymphoma B-cell prolymphocytic leukemia Lymphoplasmacytic lymphoma‡ Splenic marginal zone B-cell lymphoma (+ villous lymphocytes)* Hairy cell leukemia Plasma cell myeloma/plasmacytoma Extranodal marginal zone B-cell lymphoma of MALT type Nodal marginal zone B-cell lymphoma (+ monocytoid B cells)* Follicular lymphoma Mantle cell lymphoma Diffuse large B-cell lymphoma Mediastinal large B-cell lymphoma Primary effusion lymphoma† Burkitt’s lymphoma/Burkitt cell leukemia§ T and NK-Cell Neoplasms Precursor T-cell neoplasm Precursor T-lymphoblastic leukemia/lymphoma (precursor T-acute lymphoblastic leukemia ‡ Formerly known as lymphoplasmacytoid lymphoma or immunocytoma II Entities formally grouped under the heading large granular lymphocyte leukemia of T- and NK-cell types * Provisional entities in the REAL classification Mature (peripheral) T neoplasms T-cell chronic lymphocytic leukemia / small lymphocytic lymphoma T-cell prolymphocytic leukemia T-cell granular lymphocytic leukemiaII Aggressive NK leukemia Adult T-cell lymphoma/leukemia (HTLV-1+) Extranodal NK/T-cell lymphoma, nasal type# Enteropathy-like T-cell lymphoma** Hepatosplenic γδ T-cell lymphoma* Subcutaneous panniculitis-like T-cell lymphoma* Mycosis fungoides/Sézary syndrome Anaplastic large cell lymphoma, T/null cell, primary cutaneous type Peripheral T-cell lymphoma, not otherwise characterized Angioimmunoblastic T-cell lymphoma Anaplastic large cell lymphoma, T/null cell, primary systemic type Hodgkin’s Lymphoma (Hodgkin’s Disease) Nodular lymphocyte predominance Hodgkin’s lymphoma Classic Hodgkin’s lymphoma Nodular sclerosis Hodgkin’s lymphoma (grades 1 and 2) Lymphocyte-rich classic Hodgkin’s lymphoma Mixed cellularity Hodgkin’s lymphoma Lymphocyte depletion Hodgkin’s lymphoma † Not described in REAL classification § Includes the so-called Burkitt-like lymphomas ** Formerly known as intestinal T-cell lymphoma # Formerly know as angiocentric lymphoma WHO/REAL Classification of Lymphoid Neoplasms

  7. Hematopoietic System

  8. B cell malignancies Lymph node, lymph, blood, bone marrow Lymph node, lymph, blood, bone marrow Bone marrow Bone marrow Progressive B lymphocyte maturation Lymphoid stem cell Mature B cell Plasma cell Maturing B cell many stages Pre-B acute lympho- blastic leukemia B cell lymphoma Chronic lympho- cytic leukemia Multiple myeloma

  9. Boys Need Parents

  10. Hodgkin’s Disease/LymphomaIn the Beginning • First described in 1832 by Dr. Thomas Hodgkin • Neoplasm of B lymphocytes – large pleomorphic prominent nucleolus in a halo - Hodgkin cells • Reed-Sternberg cell – binucleate Hodgkin cell with owl eye appearance • Classification: • Classical Hodgkin’s • Nodular sclerosis – low grade • Mixed cellularity • Lymphocyte rich classical • Lymphocyte depleted. – high grade • Nodular lymphocyte-rich Hodgkin’s 1798-1866

  11. Hodgkin’s Disease/LymphomaIn the Beginning • Bimodal age distribution • first peak between 2nd - 3rd decade of life • second peak between 5th - 6th decade of life • Male: Female 2:1 in kids, adults almost equal M:F • Mixed cellularity (MC) Hodgkin’s Disease is more common at younger ages • More common in immune deficiency patients

  12. Hodgkin’s Disease/LymphomaIn the Beginning Accounts for ~ 30% of all malignant lymphomas Composed of two different disease entities: Lymphocyte-predominant Hodgkin’s (LPHD), making up ~ 5% of cases Classical HD, representing ~ 95% of all HDs. A common factor of both HD types is that neoplastic cells constitute only a small minority of the cells in the affected tissue, often corresponding to < 2% of the total tumor

  13. Fatal disease with 90% of untreated patients dying within 2 to 3 years With chemotherapy, >80% of patients suffering from HD are cured. Pathogenesis of HD is still largely unknown. HD nearly always arises and disseminates in lymph nodes Hodgkin’s Disease/LymphomaIn the Beginning

  14. Hodgkin’s Disease/LymphomaInterest tidbits • Pel-Ebstein Fevers • Pain with alcohol consumption

  15. Hodgkin’s Disease/LymphomaClinical Presentation • Nontender lymph nodes enlargement (localized) • neck and supraclavicular area • mediastinaladenopathy • other (abdominal, extranodal disease) • systemic symptoms (B symptoms) • fever • night sweats • unexplained weight loss (10% per 6 months) • other symptoms • fatigue, weakness, pruritus • cough , chest pain, shortness of breath, vena cava syndrome • abdominal pain, bowel disturbances, ascites • bone pain

  16. Hodgkin’s Disease/LymphomaClinical Presentation SIGNS & SYMPTOMS % OF PATIENTS Lymphadenopathy 90 Mediastinal mass 60 “B” symptoms 30 Fever, weight loss, night sweats Hepatosplenomegaly 25 • Most commonly involved lymph nodes are the cervical and supraclavicular in 75% • Bone marrow is involved in 5% of patients

  17. Reed-Sternberg Cells

  18. CD 30 Immunostain

  19. Hodgkin’s Disease/LymphomaClinical Presentation Stage Definition I Involvement of a single lymph node region (I) or of a single extralymphatic organ or site (IE) II Involvement of two or more lymph node regions on the same side of the diaphragm (II) or localized involvement of an extralymphatic organ or site and one or more lymph node regions on the same side of the diaphragm (IIE) III Involvement of lymph node regions on both sides of the diaphragm (III) which may be accompanied by involvement of the spleen (IIIS) or by localized involvement of an extralymphatic organ or site (IIIE) or both (IIISE) IV Diffuse or disseminated involvement of one or more extra lymphatic organs or tissues with or without associated lymph node involvement B symptoms: fever > 38ºC for three consecutive days, drenching night sweats or unexplained loss 10% or more of weight the preceding 6 months

  20. Hodgkin’s Disease/LymphomaTreatment • Unfavorable prognostic factors: - Stage IIIB, IV - B symptoms - Bulky disease - High ESR >50

  21. Hodgkin’s Disease/LymphomaTreatment • Long term effects of treatment should be taken into consideration: - Treatment-related second neoplasms (i.e. AML, NHL and breast cancer) - Infertility - Growth consideration - Long-term organ dysfunction (i.e., thyroid, heart, lung)

  22. Hodgkin’s Disease/LymphomaTreatment • Adolescent patients who have achieved maximum growth can be treated as adult patients • Chemotherapy alone protocols for localized disease has been used in developing countries with some success Lobo-Sanahuja F: Medical and Pediatric Oncology 22(6);1994

  23. Hodgkin’s Disease/LymphomaTreatment With appropriate treatment about 85% of patients with Hodgkin’s disease are curable • I A,B Radiation Therapy • II A Combination Chemo + Radiotherapy • IIB; IIIA,B; IVA,B Combination Chemo (+/- radiotherapy)

  24. Hodgkin’s Disease/LymphomaTreatment • Radiation therapy (35-40 Gy) 80-90% RC • Mantle field • Paraaortic field • Pelvic field • Combination chemotherapy • ABVD 80% RC • BEACOPP 90% RC

  25. Hodgkin’s Disease/LymphomaTreatment Progress

  26. ABVD vs MOPP vs MOPP/ABVD Failure-free survival Canellos et al, NEJM, 2002 Overall survival

  27. Hodgkin’s Disease/LymphomaTreatment • Almost no MDS/AML (at 15 years 1.0%) (Valagussa ’86) • Oligospermia – 50% complete recovery • Median FSH in normal range (Viviani ’85) • Bleomycin-related pulmonary toxicity ~1/3 have reduced PFT but recover in 3 months; ~20% omit Bleomycin.

  28. Cancer and Leukemia Group B 8251 and 8952: Recurrent Hodgkin's Disease by Treatment Canellos, G. P. et al. J Clin Oncol; 22:1532-1533 2004

  29. Hodgkin’s Disease/Lymphoma – Advanced StageABVD vs MEC vs Stanford V

  30. Stanford, Hoppe et al Hodgkin’s Disease/LymphomaActual Treatment Progress

  31. Causes of Death among 2733 Patients with Hodgkin’s Disease/Lymphoma Hodgkin lymphoma 383 41.2% Secondary cancers 200 21.5% Cardiovascular 148 15.9% Pulmonary 41 4.4% Infection 35 3.8% Trauma/Suicide 16 1.7% MDS 11 1.2% Other/Unknown 96 10.3% Total 930 100.0% Stanford, Hoppe et al

  32. SECOND TUMORS LONG-TERM SURVIVORS OF HODGKIN’S DISEASE/LYMPHOMA (PRIMARY RT OR COMBINED MODALITY) # pts Actuarial Incidence Median Follow-up • Princess Margaret 865 18% (20 years) 20 years Hospital, Toronto • US Pediatric Series 1380 26.3% (30 years) 17 years (JCO 21:4386, 2003) • Harvard/Joint Center 1319 35% (25 years) 12 years (Blood 100:1989, 2002) • Netherlands 1253 27.7% (25 years) 14.1 years (JCO 18:481, 2000) • NIH Survey of 32,591 21.9% (25 years) 10 years Registries and Seer (JCO 20:3474, 2002)

  33. HODGKIN’S DISEASE/LYMPHOMASALVAGE REGIMENS Regimen Patients CR/PR to ASCT DHAP 102 87% 60% (dexamethasone, ara-C, cisplatin) Mini-BEAM 89 77% 82% (BCNU, etoposide, ara-C, melphalan; 2 series) Dexa-BEAM 225 75% 75% (above plus dexamethasone; 3 series) GDP 34 62% 88% (gemcitabine, dexamethasone, oxaloplatin) ICE 65 84% 86% (ifosfamide, carboplatin, etoposide) GND 38 64% -- (gemcitabine, vinorelbine, liposomal doxorubicin)

  34. CALGB 50203 Treatment Plan AVG: • Doxorubicin 25mg/m2 IV d1, D15 • Vinblastine 6mg/m2 IV d1, d15 • Gemcitabine 1,000mg/m2 IV d1, d15 •  800mg/m2 if gr. 4  ANC/plt ct in 2.6 pts Repeat every 28 days x 6 cycles

  35. HODGKIN’S DISEASE/LYMPHOMAAutologous Transplants as Primary Therapy • 1996 - 2002: 7 uncontrolled trials Event-free survival 242/337 patients 72% Median follow-up 42-46 months (30-86 months) • 2003: Prospective Randomized Trial (JCO 21:2320, 2003) 163 83 ASCT 80 (4 more cycles ABVD) CR 89% 92% RFS (5 years) 88% 94% OS (5 years) 88% 88% [no difference]

  36. PROBABILITY OF SURVIVAL AFTER AUTOTRANSPLANTS FOR RELAPSED HODGKIN’S DISEASE/LYMPHOMA, 1996-2001 100 80 60 40 20 0 0 1 2 3 4 5 6 CR1 (N = 226) CR2+ (N = 733) PROBABILITY, % Never in remission (N = 823) Relapse (N = 1,744) P = 0.0001 YEARS

  37. ALLOTRANSPLANTATIONHODGKIN’S DISEASE/LYMPHOMA EBMTR IBMTR JOHNS HOPKINS Patients 45 100 53 Median age 29 28 28 Event-free Survival 15% 15% 26% Median F/U (mos.) 31 36 60 Overall Survival 25% 21% 30% Treatment Mortality 48% 61% 43% GVH - Acute 63% 35% 45% Chronic 55% 45% 17%

  38. HODGKIN’S DISEASE/LYMPHOMANon-Myeloablative Allotransplants7 series (2004-2008) Total Patients = 547 (1.5 – 5-year follow-up) Relapse 43-64% PFS 18-32% OS 28-61% Treatment-Related Mortality 5-24% (The majority failed autotransplantation)

  39. HODGKIN’S DISEASE/LYMPHOMAResidual Masses By PET scan5 series (2001-present) Total Patients 204 Relapses PET negative 144 18 (12.5%) after therapy PET positive 60 35 (58.3%) after therapy ? 40% false positive rate

  40. CTN 0701 • Tandem Transplant • Modeled after myeloma data • High-risk Hodgkin’s Disease • University of Nebraska – Julie Vose, MD

  41. Monoclonal Antibodies

  42. MDX-060 - Anti-CD30 target Anti-CD30 antibody Medarex 2004 – Orphan Drug Status Hodgkin’s Disease/Lymphoma Anaplastic Large Cell NHL

  43. SGN-35 (Seattle Genetics) A Younes et al, N Engl J Med 2010;363:1812-21.

  44. Good Ideas • Cadence Pharmaceuticals • Ofirmev • November 2, 2010 – FDA Approval • IV acetaminophen • $800/IV dose

  45. Boys Need Parents

  46. Non-Hodgkin’s Lymphoma Deep Breath… Stand up… Stretch…

  47. Histologic Classification of Non-Hodgkin’s Lymphomas 1. Rappaport - 1966 2. Lukes and Collins - 1974 3. Kiel - 1974 3. Dorfman - 1974 4. Bennet et al., - 1974 5. Lennert - 1974 6. WHO - 1976 7. Working Formulation - 1982 8. REAL - 1994 9. WHO - 1999

  48. Non-Hodgkin’s LymphomaRappaport Classification Nodular (follicular) Diffuse Indolent Aggressive Small cell Large cell

  49. Non-Hodgkin’s LymphomaRappaport Classification • Small cell, follicular • Small cell, diffuse • Large cell, follicular • Large cell, diffuse

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