Hodgkin’s Diseaseand

Non-Hodgkin’s Lymphoma

Harold M. Chung, MDAssociate Professor of Medicine

VCU Medical Center – MCV HospitalsBone Marrow Transplantation Program

November 8, 2011

Why Men Can’t Be Why Men Can’t Be BabysittersBabysitters

Agenda

Discuss Hodgkin’s Disease

Discuss Non-Hodgkin’s Lymphoma

Classification Systems

Treatment Options

2008 Estimated US Cancer Cases*

*Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder.Source: American Cancer Society, 2008.

Men720,280

Women679,510

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

Prostate 33%

Lung & bronchus 13%

Colon & rectum 10%

Urinary bladder 6%

Melanoma of skin 5%

Non-Hodgkin4% lymphoma

Kidney 3%

Oral cavity 3%

Leukemia 3%

Pancreas 2%

All Other Sites 18%

2008 Estimated US Cancer Deaths*

ONS=Other nervous system.Source: American Cancer Society, 2008.

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%

WHO/REAL Classification of Lymphoid NeoplasmsB-Cell Neoplasms

Precursor B-cell neoplasmPrecursor B-lymphoblastic leukemia/lymphoma

(precursor B-acute lymphoblastic leukemia)Mature (peripheral) B-neoplasmsB-cell chronic lymphocytic leukemia / small

lymphocytic lymphoma

B-cell prolymphocytic leukemiaLymphoplasmacytic lymphoma‡

Splenic marginal zone B-cell lymphoma (+ villous lymphocytes)*

Hairy cell leukemiaPlasma cell myeloma/plasmacytomaExtranodal marginal zone B-cell lymphoma of MALT

typeNodal marginal zone B-cell lymphoma

(+ monocytoid B cells)*Follicular lymphomaMantle cell lymphomaDiffuse large B-cell lymphoma

Mediastinal large B-cell lymphomaPrimary effusion lymphoma†

Burkitt’s lymphoma/Burkitt cell leukemia§

T and NK-Cell NeoplasmsPrecursor 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 neoplasmsT-cell chronic lymphocytic leukemia / small

lymphocytic lymphomaT-cell prolymphocytic leukemiaT-cell granular lymphocytic leukemiaII Aggressive NK leukemiaAdult 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 syndromeAnaplastic large cell lymphoma, T/null cell,

primary cutaneous typePeripheral T-cell lymphoma, not otherwise

characterized Angioimmunoblastic T-cell lymphomaAnaplastic large cell lymphoma, T/null cell,

primary systemic typeHodgkin’s Lymphoma (Hodgkin’s Disease)

Nodular lymphocyte predominance Hodgkin’s lymphomaClassic Hodgkin’s lymphoma

Nodular sclerosis Hodgkin’s lymphoma (grades 1 and 2)Lymphocyte-rich classic Hodgkin’s lymphomaMixed cellularity Hodgkin’s lymphomaLymphocyte 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

Hematopoietic System

B cell malignancies

Pre-B acute lympho-

blastic leukemia

B cell lymphoma Chronic lympho-

cytic leukemia

Multiple myeloma

Progressive B lymphocyte maturation

Bone marrow

Lymph node,

lymph, blood,

bone marrow

Lymph node,

lymph, blood,

bone marrowBone marrow

Lymphoid stem cell Maturing B cellmany stages

Mature B cell Plasma cell

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Hodgkin’s Disease/LymphomaIn the Beginning

1798-1866

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 gradeMixed cellularityLymphocyte rich classical Lymphocyte depleted. – high

grade

Nodular lymphocyte-rich Hodgkin’s

Hodgkin’s Disease/LymphomaIn the Beginning

Bimodal age distributionBimodal age distribution first peak between 2first peak between 2ndnd - 3 - 3rdrd decade of life decade of life second peak between 5second peak between 5th th - 6- 6thth decade of life decade of life

Male: Female 2:1 in kids, adults almost equal M:FMale: Female 2:1 in kids, adults almost equal M:F

Mixed cellularity (MC) Hodgkin’s Disease is more Mixed cellularity (MC) Hodgkin’s Disease is more common at younger agescommon at younger ages

More common in immune deficiency patientsMore common in immune deficiency patients

Hodgkin’s Disease/LymphomaIn the Beginning

Accounts for ~ 30% of all malignant lymphomasAccounts for ~ 30% of all malignant lymphomas

Composed of two different disease entities:Composed of two different disease entities:

Lymphocyte-predominant Hodgkin’s (LPHD), making upLymphocyte-predominant Hodgkin’s (LPHD), making up~ 5% of cases~ 5% of cases

Classical HD, representing ~ 95% of all HDs.Classical HD, representing ~ 95% of all HDs.

A common factor of both HD types is that neoplastic A common factor of both HD types is that neoplastic cells constitute only a small minority of the cells in cells constitute only a small minority of the cells in the affected tissue, often corresponding to < 2% of the affected tissue, often corresponding to < 2% of the total tumorthe total tumor

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

Hodgkin’s Disease/LymphomaInterest tidbits

Pel-Ebstein Fevers

Pain with alcohol consumption

Nontender lymph nodes enlargement (localized)Nontender lymph nodes enlargement (localized) neck and supraclavicular areaneck and supraclavicular area mediastinal adenopathymediastinal adenopathy other (abdominal, extranodal disease)other (abdominal, extranodal disease)

systemic symptoms (B symptoms)systemic symptoms (B symptoms) fever fever night sweatsnight sweats unexplained weight loss (10% per 6 months)unexplained weight loss (10% per 6 months)

other symptoms other symptoms fatigue, weakness, pruritusfatigue, weakness, pruritus cough , chest pain, shortness of breath, vena cava cough , chest pain, shortness of breath, vena cava

syndromesyndrome abdominal pain, bowel disturbances, ascitesabdominal pain, bowel disturbances, ascites bone painbone pain

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

Hodgkin’s Disease/LymphomaClinical Presentation

Reed-Sternberg Cells

CD 30 Immunostain

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

Hodgkin’s Disease/LymphomaTreatment

Unfavorable prognostic factors: Unfavorable prognostic factors: - Stage IIIB, IV- Stage IIIB, IV - B symptoms- B symptoms - Bulky disease- Bulky disease - High ESR >50- High ESR >50

Long term effects of treatment should be Long term effects of treatment should be taken into consideration:taken into consideration:

- Treatment-related second neoplasms - Treatment-related second neoplasms

(i.e. AML, NHL and breast cancer)(i.e. AML, NHL and breast cancer)

- Infertility- Infertility

- Growth consideration- Growth consideration

- Long-term organ dysfunction (i.e., - Long-term organ dysfunction (i.e., thyroid, heart, lung)thyroid, heart, lung)

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

Hodgkin’s Disease/LymphomaTreatment

Lobo-Sanahuja F: Medical and Pediatric Oncology 22(6);1994

With appropriate treatment about 85% of With appropriate treatment about 85% of patients with Hodgkin’s disease are curablepatients with Hodgkin’s disease are curable

I A,B I A,B Radiation TherapyRadiation Therapy II A II A Combination Chemo + Combination Chemo +

RadiotherapyRadiotherapy IIB; IIIA,B; IVA,B IIB; IIIA,B; IVA,B Combination Chemo Combination Chemo

(+/- radiotherapy)(+/- radiotherapy)

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

Hodgkin’s Disease/LymphomaTreatment

Hodgkin’s Disease/LymphomaTreatment Progress

ABVD vs MOPP vs

MOPP/ABVDFailure-free survival

Overall survival

Canellos et al, NEJM, 2002

Almost no MDS/AML (at 15 years 1.0%) Almost no MDS/AML (at 15 years 1.0%) (Valagussa ’86)(Valagussa ’86)

Oligospermia – 50% complete recoveryOligospermia – 50% complete recovery

Median FSH in normal range Median FSH in normal range (Viviani ’85)(Viviani ’85)

Bleomycin-related pulmonary toxicity ~1/3 Bleomycin-related pulmonary toxicity ~1/3 have reduced PFT but recover in 3 months; have reduced PFT but recover in 3 months; ~20% omit Bleomycin.~20% omit Bleomycin.

Hodgkin’s Disease/LymphomaTreatment

Canellos, G. P. et al. J Clin Oncol; 22:1532-1533 2004

Cancer and Leukemia Group B 8251 and 8952: Recurrent Hodgkin's Disease by Treatment

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

Stanford, Hoppe et al

IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII IIIIIII IIIIIII IIII II

IIII III I I II

IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII IIIIII IIIIIII III IIII III I I II

0

20

40

60

80

100

0 5 10 15 20 25 30 35

PR

OB

AB

ILIT

Y

(%)

YEARS

I Observed Survival

I HD Survival

Expected Survival

Hodgkin’s Disease/LymphomaActual Treatment Progress

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

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 yearsHospital, 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 yearsRegistries and Seer (JCO 20:3474, 2002)

HODGKIN’S DISEASE/LYMPHOMASALVAGE REGIMENS

Regimen Patients CR/PR to ASCTDHAP 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)

CALGB 50203 Treatment Plan

AVGAVG::

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

HODGKIN’S DISEASE/LYMPHOMAAutologous Transplants as Primary Therapy

1996 - 2002: 7 uncontrolled trialsEvent-free survival 242/337 patients 72%Median follow-up 42-46 months (30-86 months)

2003: Prospective Randomized Trial (JCO 21:2320, 2003)

16383 ASCT 80 (4 more cycles

ABVD)CR 89% 92%RFS (5 years) 88% 94%OS (5 years) 88% 88% [no difference]

PROBABILITY OF SURVIVAL AFTER AUTOTRANSPLANTS FOR RELAPSED

HODGKIN’S DISEASE/LYMPHOMA, 1996-2001

PR

OB

AB

ILIT

Y,

%

100

0

20

40

60

80

YEARS

P = 0.0001

0 1 2 3 4 65

CR1 (N = 226)

CR2+ (N = 733)

Never in remission (N = 823)

Relapse (N = 1,744)

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%

HODGKIN’S DISEASE/LYMPHOMANon-Myeloablative Allotransplants

7 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)

HODGKIN’S DISEASE/LYMPHOMAResidual Masses By PET scan

5 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

CTN 0701

Tandem Transplant

Modeled after myeloma data High-risk Hodgkin’s Disease University of Nebraska – Julie Vose, MD

Monoclonal Antibodies

MDX-060 - Anti-CD30 target

Anti-CD30 antibody

Medarex 2004 – Orphan Drug Status

Hodgkin’s Disease/Lymphoma

Anaplastic Large Cell NHL

SGN-35 (Seattle SGN-35 (Seattle Genetics)Genetics)

A Younes et al, N Engl J Med 2010;363:1812-21.A Younes et al, N Engl J Med 2010;363:1812-21.

Good IdeasGood Ideas

Cadence PharmaceuticalsCadence Pharmaceuticals OfirmevOfirmev November 2, 2010 – FDA ApprovalNovember 2, 2010 – FDA Approval IV acetaminophenIV acetaminophen $800/IV dose $800/IV dose

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Non-Hodgkin’s Lymphoma

Deep Breath…

Stand up…

Stretch…

Histologic Classification of Non-Hodgkin’s Lymphomas

1. Rappaport - 19662. Lukes and Collins - 19743. Kiel - 19743. Dorfman - 19744. Bennet et al., - 19745. Lennert - 19746. WHO - 19767. Working Formulation - 19828. REAL - 19949. WHO - 1999

Non-Hodgkin’s LymphomaRappaport Classification

Nodular (follicular) Diffuse

Small cell Large cell

Indolent Aggressive

Non-Hodgkin’s LymphomaRappaport Classification

Small cell, follicular Small cell, diffuse Large cell, follicular Large cell, diffuse

Non-Hodgkin’s LymphomaImmunophenotyping

Immunohistochemistry Immunofluorescence Flow cytometry

Identification of CD’s (cluster determinants) CD5 = T cell type CD20 = B cell type

Non-Hodgkin’s Lymphoma

Cluster Determinants

Non-Hodgkin’s LymphomaLukes-Collins & Kiel Classifications

Lukes-Collins System – US Kiel System – Europe

Differentiation of B-cell and T-cell lymphomas

Non-Hodgkin’s LymphomaWorking Classification

Developed in 1980’s NCI Investigators reviewed Rappaport, Lukes-

Collins, and Kiel systems n=1175

Goal was to clarify… now a new system! No consideration to B-cell or T-cell typing Goal was to group lymphomas according to

aggressiveness (low, intermediate, high)

Non-Hodgkin’s LymphomaWorking Classification

Low Grade Small Lymphocytic Follicular small-cleaved cell Follicular mixed small-cleaved and large cell

Intermediate Grade Follicular large cell Diffuse small cleaved cell Diffuse mixed small and large cell Diffuse large cell

High Grade Large cell immunoblastic Lymphoblastic Small non-cleaved cell (Burkitt's and non-Burkitt's type)

HodgkinLymphoma

Non Hodgkin Lymphoma

HighlyAggressive

AggressiveIndolent

B cellFollicularSLL/CLL

Marginal zoneLP (WM)

T/NK cellMycosis fungoidesSezary syndromePrimary cut ALCL

B cellPre-B

lymphoblasticBurkitt

T/NK cellPre-T

lymphoblastic

B cellDLBCL

FLg3 and tFLMantle cell

Primary effusion

T/NK cellALCL

AngioimmunoblasticSubq panniculitis-like

Blastic NKExtnanodal NK/T

nasalEnteropathy-type

HepatosplenicPTCL nos

Classical HL(NS, MC, LR,

LD)

Nodular lymphocyte

Predominant(NLPHL)

MultipleMyeloma

Non-Hodgkin’s LymphomaREAL Classification

Revised European-American Lymphoma Mid 1990’s – International Lymphoma

Study Group (informal group of hematopathologists)

Using immunophenotype, cytogenetics, molecular diagnostics

Reclassified lymphomas by diagnostic criteria and not by risk categories

Indolent (35%)

Diffuse largeB-cell (31%)

Armitage et al. J Clin Oncol. 1998;16:2780–2795

Mantle cell (6%)

Peripheral T-cell (6%)

Other subtypes with a frequency 2% (9%)

Frequency of NHL Subtypes in Adults

Composite lymphomas (13%)

Non-Hodgkin’s LymphomaWHO Classification

Bruce Cheson, MD and the NCI International Working Group reported in January 1999

Adopted in 2001, Revised in 2008

Discredited the Working (non-REAL) Classification Based on REAL (Non-working) Classification

Cheson et al. J Clin Oncol. 1999 Apr;17(4):1244

WHO/REAL Classification of Lymphoid NeoplasmsB-Cell Neoplasms

Precursor B-cell neoplasmPrecursor B-lymphoblastic leukemia/lymphoma

(precursor B-acute lymphoblastic leukemia)Mature (peripheral) B-neoplasmsB-cell chronic lymphocytic leukemia / small

lymphocytic lymphoma

B-cell prolymphocytic leukemiaLymphoplasmacytic lymphoma‡

Splenic marginal zone B-cell lymphoma (+ villous lymphocytes)*

Hairy cell leukemiaPlasma cell myeloma/plasmacytomaExtranodal marginal zone B-cell lymphoma of MALT

typeNodal marginal zone B-cell lymphoma

(+ monocytoid B cells)*Follicular lymphomaMantle cell lymphomaDiffuse large B-cell lymphoma

Mediastinal large B-cell lymphomaPrimary effusion lymphoma†

Burkitt’s lymphoma/Burkitt cell leukemia§

T and NK-Cell NeoplasmsPrecursor 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 neoplasmsT-cell chronic lymphocytic leukemia / small

lymphocytic lymphomaT-cell prolymphocytic leukemiaT-cell granular lymphocytic leukemiaII Aggressive NK leukemiaAdult 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 syndromeAnaplastic large cell lymphoma, T/null cell,

primary cutaneous typePeripheral T-cell lymphoma, not otherwise

characterized Angioimmunoblastic T-cell lymphomaAnaplastic large cell lymphoma, T/null cell,

primary systemic typeHodgkin’s Lymphoma (Hodgkin’s Disease)

Nodular lymphocyte predominance Hodgkin’s lymphomaClassic Hodgkin’s lymphoma

Nodular sclerosis Hodgkin’s lymphoma (grades 1 and 2)Lymphocyte-rich classic Hodgkin’s lymphomaMixed cellularity Hodgkin’s lymphomaLymphocyte 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

Non-Hodgkin’s LymphomaSpecific Types

Time For A Deep Breath…

or an Excedrin

Follicular Lymphoma

Bcl2 Chromosome 18

Mbr (major breakpoint region, 150 bp)

JH

C

Double strand DNA break by RAG1/2

Chromosome 14

Bcl2 C t(14;18) translocation

bcl2 CE C 3’E

Unregulation of Bcl2 expression by IgH enhancers

Translocation takes place in B cell precursors.

Transformation takes placeduring B cell activation in GC.

Bcl2 inhibits apoptosis

cytochrome c

Apaf-1

dATP or ATP

mitochondrion

Apaf-1

Pro-caspase-9

Caspase-9

Pro-caspase-3 Caspase-3

Apoptosis

Bcl-2, Bcl-XL

Bax, Bad

Pro-survival oncogene

Over-expression of Bcl-2 may prevent the apoptosisof germinal center B cells

activation

Germinal center Germinal center

apoptosis

IgH-Bcl2

activation

Germinal center Germinal center

Plasma cells

Memory cells

follicular lymphoma

Apoptosis inhibitedMost follicular lymphoma Ig V regions contain somatic hypermutation.

Non-Hodgkin’s LymphomaFollicular Lymphoma

Low-grade lymphoma Grade 1 – Small cell Grade 2 – Mixed cell Grade 3 – Large cell

Indolent in growth Chemotherapy sensitive Incurable

Non-Hodgkin’s LymphomaCutaneous T-Cell (Mycosis Fungoides)

Low-grade/Indolent lymphoma Radiation therapy sensitive Total Skin Electron Beam Therapy

Control disease for years Peripheralization of lymphoma cells = Sezary Cell Sezary Syndrome

Non-Hodgkin’s LymphomaDiffuse Large Cell

Very Aggressive Curable if chemo-sensitive upfront, not so

if chemo-refractory or relapses within 6 months

Most common of all lymphomas Accounts for ~ 31% of all lymphomas

Non-Hodgkin’s LymphomaMantle Cell

Aggressive Accounts for ~ 6% of all lymphomas Incurable with standard-dose therapy Stem cell transplant is offered often as

front-line consolidation treatment in “younger” patients

Mantle Cell Lymphoma

Morphology

Nodular pattern

Diffuse pattern

Classical Mantle Cell

Blastoid Variant

Mantle Cell - Treatment

CHOP + Rituxan 40 patients (new diagnosis) CR 48%, PR 48% Molecular CR seen in 36% of

patients with PCR detectable cyclin D1/IgH translocation

Median PFS 16.6 months, all patients relapsed by 36 months

No significant difference in PFS for patients having a clinical or molecular CR

Howard, O et al., JCO, 20 (5):1288

Non-Hodgkin’s LymphomaMarginal Zone

Indolent Accounts for ~10% of

all lymphomas Subcategories

MALT (H. pylori) Nodal Extra-Nodal Splenic

Non-Hodgkin’s LymphomaSplenic Lymphoma

Non-Hodgkin’s LymphomaPrimary CNS Lymphoma

Aggressive with poor outcome Accounts for ~ 1-2% of all lymphomas Different chemotherapy treatments Often requires radiation to the brain:

Brain dysfunction in younger patients Dementia in older patients

Non-Hodgkin’s LymphomaAnaplastic Large Cell Lymphoma Aggressive Accounts for ~ 2% of all lymphomas

ALCL ALK-1+ better prognosis, more common in younger patients and children

ALCL ALK-1-negative : as bad as any other T-cell lymphoma

Treatment results of aggressive advanced non-Hodgkin’s lymphomas using different

chemotherapy programs

1. First-generation: CHOP1. First-generation: CHOP

- CR: 50-55%. Long-term survival: 35-50 %.- CR: 50-55%. Long-term survival: 35-50 %.

2. Second-generation: mBACOD, ProMACE-CytaBOM2. Second-generation: mBACOD, ProMACE-CytaBOM

- CR: 70-80%. Long-term survival: 50-60%.- CR: 70-80%. Long-term survival: 50-60%.

3. Third-generation: MACOP-B3. Third-generation: MACOP-B

- CR: 84%. Long-term survival: 75%- CR: 84%. Long-term survival: 75%

Non-Hodgkin’s LymphomaIntergroup 0067 Study

3-year survival Mortality3-year survival Mortality

______%_%_______________________________%%______

CHOPCHOP 4141 1 1

mBACODmBACOD 4646 5 5

ProMACE-CytoBOM ProMACE-CytoBOM 4646 3 3

MACOP-BMACOP-B 4141 6 6

Southwest Oncology Group

Non-Hodgkin’s LymphomaTreatment of Patients Age over 60

Program_Program_______________________________5-year survival %5-year survival %

CHOPCHOP 45 45

mBACODmBACOD 39 39

ProMACE-CytoBOMProMACE-CytoBOM 41 41

MACOP-BMACOP-B 23 23

tt

Non-Hodgkin’s LymphomaPeripheral T-cell Lymphoma

Aggressive Accounts for ~ 7% of all lymphomas Very poor prognosis, often associated with

extra-nodal presentation Often requiring salvage treatment and

transplant

Burkitt’s Lymphoma

myc Chromosome 8

SC

EChromosome 14, 80%IgH

IgChromosome 2

Igchromosome 22

breakpoints

Class switch recombination

V(D)J

Somatic hypermutation

***

mycS

C C3’E

myc C C3’E

SE

t(8:14)

Non-Hodgkin’s LymphomaBurkitt’s NHL

Very Aggressive Curable with standard-dose therapy but

requires very extensive chemotherapy protocol

Translocation t(8,14) Specific Hematopathology Finding

Starry, Starry Night

Burkitt’s LymhomaStarry, Starry Night

Non-Hodgkin’s LymphomaLymphoblastic NHL

Very aggressive Treatment is with acute lymphocytic

leukemia regimen Often requires high-dose therapy and

allogeneic transplantation for relapsed/refractory disease

Gamma Delta-T-cell NHL

Very, very aggressive Very poor outcome with standard-dose

therapy High-dose therapy and allogeneic

transplantation is standard-of-care in first remission

CD57 protein positivity

Double-HitDouble-Hit LymphomasLymphomas

Multiple gene expressions MYC gene t(14,18)

Triple-Hit MYC gene t(14,18) BCL-6 gene

Non-Hodgkin’s LymphomaAggressive chemotherapy regimens

Dose-dense CHOP CHOP-Bleo CEOP-Bleo DexaBEAM HyperCVAD

BMT for Non-Hodgkin’s Lymphoma Indications

1. Refractory disease

2. Relapse

3. High risk in CR

4. Lymphoblastic, Burkitt’s, and gamma delta-t-cell lymphomas

PROBABILITY OF SURVIVAL AFTER AUTOTRANSPLANTS FOR FOLLICULAR

NON-HODGKIN LYMPHOMA

PR

OB

AB

ILIT

Y,

%

100

0

20

40

60

80

YEARS

P = 0.0009

0 1 2 3 4 65

CR1 (N = 174)

CR2+ (N = 322)

Never in remission (N = 418)

Relapse (N = 791)

PROBABILITY OF SURVIVAL AFTER HLA-IDENTICAL SIBLING MYELOABLATIVE

TRANSPLANTS FOR FOLLICULAR NON-HODGKIN LYMPHOMA

PR

OB

AB

ILIT

Y,

%

100

0

20

40

60

80

YEARS

P = NS

0 1 2 3 4 65

CR1-3 (N = 79)

Never in remission (N = 138)

Relapse (N = 193)

PROBABILITY OF SURVIVAL AFTER AUTOTRANSPLANTS FOR

DIFFUSE LARGE CELL LYMPHOMA

PR

OB

AB

ILIT

Y,

%

100

0

20

40

60

80

YEARS

P = 0.0001

0 1 2 3 4 65

CR1 (N = 438)

CR2+ (N = 651)

Relapse (N = 1,443)

Never in remission (N = 986)

PROBABILITY OF SURVIVAL AFTER HLA-IDENTICAL SIBLING MYELOABLATIVE

TRANSPLANTS FOR DIFFUSE LARGE CELL LYMPHOMA

PR

OB

AB

ILIT

Y,

%

100

0

20

40

60

80

YEARS

P = NS

0 1 2 3 4 65

CR1-3 (N = 56)

Relapse (N = 144)

Never in remission (N = 133)

Monoclonal Abs - Rituxan

Radioimmunotherapy with Y-90 Zevalin

IbritumomabIbritumomab Murine monoclonal Murine monoclonal

antibody parent of antibody parent of RituximabRituximab

TiuxetanTiuxetan Conjugated to Conjugated to

antibody, forming antibody, forming strong urea-type strong urea-type bondbond

Stable retention of Y-Stable retention of Y-9090

Y-90 radionuclideY-90 radionuclideBeta Beta radiationradiation

ChelatorChelator

Monoclonal Monoclonal antibodyantibody

New Treatment Options

Velcade + Flavoperidol – MCC Trial Velcade + Darinaparsin

Conclusion

Discussed Hodgkin’s Disease

Discussed Non-Hodgkin’s Lymphoma

Discussed Classification Systems

Discussed Treatment Options