110811 HChunag HD and NHL BMT Core Conf Handout

8/10/2019 110811 HChunag HD and NHL BMT Core Conf Handout

1/99


2/99


3/99

Agenda

Discuss Hodgkins Disease

Discuss Non-Hodgkins Lymphoma

Classification Systems

Treatment Options


4/99


5/99

2008 Estimated US Cancer Deaths*

ONS=Other nervous system.

Source: American Cancer Society, 2008.

Men

291,270

Women

273,56026% Lung & bronchus

15% Breast

10% Colon & rectum

6% Pancreas

6% Ovary

4% Leukemia

3% Non-Hodgkinlymphoma

3% Uterine corpus2% 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%


6/99

WHO/REAL Classification of Lymphoid Neoplasms

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 lymphocyticlymphoma

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 typeNodal 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

Burkitts lymphoma/Burkitt cell leukemia

T and NK-Cell Neoplasms

Precursor T-cell neoplasmPrecursor T-lymphoblastic leukemia/lymphoma

(precursor T-acute lymphoblastic leukemia

Formerly known as lymphoplasmacytoid lymphoma or immunocytomaII 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 / smalllymphocytic lymphoma

T-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 T-cell lymphoma*

Subcutaneous panniculitis-like T-cell lymphoma*

Mycosis fungoides/Szary 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

Hodgkins Lymphoma (Hodgkins Disease)

Nodular lymphocyte predominance Hodgkins lymphoma

Classic Hodgkins lymphoma

Nodular sclerosis Hodgkins lymphoma (grades 1 and 2)Lymphocyte-rich classic Hodgkins lymphoma

Mixed cellularity Hodgkins lymphoma

Lymphocyte depletion Hodgkins 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


7/99

Hematopoietic System


8/99

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 cell

many stages

Mature B cell Plasma cell


9/99

Boys Need Parents


10/99

Hodgkins Disease/Lymphoma

In the Beginning

1798-1866

First described in 1832 by Dr. Thomas Hodgkin

Neoplasm of B lymphocyteslarge pleomorphic prominentnucleolus in a halo - Hodgkin cells

Reed-Sternberg cellbinucleate Hodgkin cell with owl eyeappearance

Classification:Classical Hodgkins

Nodular sclerosislow gradeMixed cellularityLymphocyte rich classicalLymphocyte depleted.high grade

Nodular lymphocyte-rich Hodgkins


11/99


In the Beginning

Bimodal age distribution first peak between 2nd- 3rddecade of life

second peak between 5th - 6thdecade of life

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

Mixed cellularity (MC) Hodgkins Disease is morecommon at younger ages

More common in immune deficiency patients


12/99


In the Beginning

Accounts for ~ 30% of all malignant lymphomas

Composed of two different disease entities:

Lymphocyte-predominant Hodgkins (LPHD), making up ~ 5% of cases

Classical HD, representing ~ 95% of all HDs.

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


13/99

Fatal disease with 90% of untreated patients dyingwithin 2 to 3 years

With chemotherapy, >80% of patients suffering fromHD are cured.

Pathogenesis of HD is still largely unknown.

HD nearly always arises and disseminates in lymphnodes

Hodgkins Disease/LymphomaIn the Beginning


14/99


Interest tidbits

Pel-Ebstein Fevers

Pain with alcohol consumption


15/99

Nontender lymph nodes enlargement (localized) neck and supraclavicular area

mediastinal adenopathy

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 cavasyndrome

abdominal pain, bowel disturbances, ascites

bone pain


Clinical Presentation


16/99

SIGNS & SYMPTOMS % OF PATIENTS

Lymphadenopathy 90

Mediastinal mass 60

B symptoms 30Fever, weight loss, night sweats

Hepatosplenomegaly 25

Most commonly involved lymph nodes are thecervical and supraclavicular in 75%

Bone marrow is involved in 5% of patients




17/99


18/99

CD 30 Immunostain


19/99



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 noderegions on the same side of the diaphragm (IIE)

III Involvement of lymph node regions on both sides of the diaphragm (III) which may beaccompanied by involvement of the spleen (IIIS) or by localized involvement of anextralymphatic organ or site (IIIE) or both (IIISE)

IV Diffuse or disseminated involvement of one or more extra lymphatic organs or tissues withor without associated lymph node involvement

B symptoms: fever > 38C for three consecutive days, drenching night sweats or unexplained loss 10% or more ofweight the preceding 6 months


20/99


Treatment

Unfavorable prognostic factors:

- Stage IIIB, IV

- B symptoms

- Bulky disease

- High ESR >50


21/99

Long term effects of treatment should betaken 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)


Treatment


22/99

Adolescent patients who have achievedmaximum growth can be treated as adultpatients

Chemotherapy alone protocols forlocalized disease has been used indeveloping countries with some success


Treatment

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


23/99


24/99

Radiation therapy (35-40 Gy) 80-90% RC

Mantle field

Paraaortic field

Pelvic field

Combination chemotherapy

ABVD 80% RC

BEACOPP 90% RC


Treatment


25/99


Treatment Progress


26/99


27/99

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

(Valagussa 86)

Oligospermia50% 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.


Treatment


28/99

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


29/99


30/99

Hodgkins Disease/Lymphoma Advanced Stage

ABVD vs MEC vs Stanford V


31/99

Stanford, Hoppe et al

IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII

IIIIIIIIIIIIIIIIIIIIIIIIIII

IIIIIIIIIIIIIIIIII III

IIII IIIIIII II

II II

III

I 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

PROBABILITY

(%)

YEARS

I Observed Survival

I HD Survival

Expected Survival


Actual Treatment Progress


32/99

Causes of Death among 2733 Patients

with Hodgkins 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


33/99

SECOND TUMORS LONG-TERM SURVIVORS OF

HODGKINS DISEASE/LYMPHOMA

(PRIMARY RT OR COMBINED MODALITY)

# pts Actu ar ial Incidence Median Fol low-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)


34/99


SALVAGE 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)


35/99

CALGB 50203 Treatment Plan

AVG:

Doxorubicin 25mg/m2IV d1, D15

Vinblastine 6mg/m2IV d1, d15

Gemcitabine 1,000mg/m2

IV d1, d15 800mg/m2if gr. 4 ANC/plt ct in 2.6 pts

Repeat every 28 days x 6 cycles


36/99

HODGKINS 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]


37/99

PROBABILITY OF SURVIVAL AFTER

AUTOTRANSPLANTS FOR RELAPSED

HODGKINS DISEASE/LYMPHOMA, 1996-2001

P

ROBABILITY,%

100

0

20

40

60

80

YEARS

P = 0.0001

0 1 2 3 4 65

CR1 (N =

226)

CR2+ (N =

733)

Never in r emis sio n (N = 823)

Relap se (N = 1,744)


38/99

ALLOTRANSPLANTATION


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%



39/99

HODGKINS DISEASE/LYMPHOMANon-Myeloablative Allotransplants

7 series (2004-2008)

Total Patients = 547 (1.55-year follow-up)

Relapse 43-64%

PFS 18-32%

OS 28-61%

Treatment-Related Mortality 5-24%

(The majority failed autotransplantation)


40/99


Residual 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


41/99

CTN 0701

Tandem Transplant

Modeled after myeloma data

High-risk Hodgkins Disease

University of NebraskaJulie Vose, MD


42/99

Monoclonal Antibodies


43/99

MDX-060- Anti-CD30 target

Anti-CD30 antibody

Medarex 2004Orphan Drug Status


Anaplastic Large Cell NHL


44/99

SGN-35 (Seattle Genetics)

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


45/99

Good Ideas

Cadence Pharmaceuticals

Ofirmev

November 2, 2010FDA Approval

IV acetaminophen

$800/IV dose


46/99

Boys Need Parents


47/99

Non-Hodgkins Lymphoma

Deep Breath

Stand up

Stretch


48/99

Histologic Classification of

Non-Hodgkins Lymphomas

1. Rappaport - 1966

2. Lukes and Collins - 1974

3. Kiel - 1974

3. Dorfman - 19744. Bennet et al., - 1974

5. Lennert - 1974

6. WHO - 19767. Working Formulation - 1982

8. REAL - 1994

9. WHO - 1999

N H d ki L h


49/99


Rappaport Classification

Nodular (follicular) Diffuse

Small cell Large cell

Indolent Aggressive


50/99

N H d ki L h


51/99


Immunophenotyping

Immunohistochemistry

Immunofluorescence

Flow cytometry

Identification of CDs (cluster determinants)

CD5 = T cell type CD20 = B cell type


52/99

Non-Hodgkins

LymphomaCluster

Determinants

N H d ki L h


53/99


Lukes-Collins & Kiel Classifications

Lukes-Collins SystemUS

Kiel SystemEurope

Differentiation of B-cell and T-cell lymphomas

N H d ki L h


54/99


Working Classification

Developed in 1980s

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)

N H d ki L h


55/99


Working 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)

H d ki


56/99

Hodgkin

LymphomaNon Hodgkin Lymphoma

Highly

Aggressive

AggressiveIndolent

B cell

Follicular

SLL/CLL

Marginal zone

LP (WM)

T/NK cell

Mycosis fungoides

Sezary syndrome

Primary cut ALCL

B cell

Pre-B

lymphoblastic

Burkitt

T/NK cell

Pre-T

lymphoblastic

B cell

DLBCL

FLg3 and tFL

Mantle cell

Primary effusion

T/NK cell

ALCL

Angioimmunoblastic

Subq panniculitis-like

Blastic NKExtnanodal NK/T

nasal

Enteropathy-type

Hepatosplenic

PTCL nos

Classical HL

(NS, MC, LR,LD)

Nodular

lymphocyte

Predominant

(NLPHL)

Multiple

Myeloma


57/99

F f NHL S bt i Ad lt


58/99

Indolent (35%)

Diffuse large

B-cell (31%)Armitage et al. J Clin Oncol. 1998;16:27802795

Mantle cell (6%)

Peripheral T-cell (6%)

Other subtypes with a

frequency 2% (9%)

Frequency of NHL Subtypes in Adults

Composite

lymphomas (13%)

Non Hodgkins Lymphoma


59/99


WHO Classification

Bruce Cheson, MD and the NCI InternationalWorking 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


60/99



61/99


Specific Types

Time For A Deep Breath

or an Excedrin


62/99


63/99


64/99

Over-expression of Bcl-2 may prevent the apoptosis

of 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 containsomatic hypermutation.



65/99

Non-Hodgkin s Lymphoma

Follicular Lymphoma

Low-grade lymphoma

Grade 1Small cell

Grade 2Mixed cell

Grade 3Large cell

Indolent in growth

Chemotherapy sensitive

Incurable



66/99


Cutaneous 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



67/99


Diffuse Large Cell

Very Aggressive

Curable if chemo-sensitive upfront, not soif chemo-refractory or relapses within 6

months

Most common of all lymphomas

Accounts for ~ 31% of all lymphomas


68/99


69/99

Mantle Cell Lymphoma


70/99


71/99

M tl C ll T t t


72/99

Mantle Cell - Treatment

CHOP + Rituxan 40 patients (new diagnosis)

CR 48%, PR 48%

Molecular CR seen in 36% ofpatients with PCR detectablecyclin D1/IgH translocation

Median PFS 16.6 months, allpatients relapsed by 36months

No significant difference in PFSfor patients having a clinical ormolecular CR

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



73/99


Marginal Zone

Indolent Accounts for ~10% of

all lymphomas

Subcategories MALT (H. pylori)

Nodal

Extra-Nodal

Splenic



74/99


Splenic Lymphoma



75/99


Primary 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



76/99


Anaplastic Large Cell Lymphoma

Aggressive

Accounts for ~ 2% of all lymphomas

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

ALCL ALK-1-negative : as bad as any otherT-cell lymphoma

Treatment results of aggressive advanced


77/99

Treatment results of aggressive advancednon-Hodgkins lymphomas using different

chemotherapy programs1. First-generation: CHOP

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

2. Second-generation: mBACOD, ProMACE-CytaBOM

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

3. Third-generation: MACOP-B

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

N H d ki L h


78/99


Intergroup 0067 Study

3-year survival Mortality

___%________________%___

CHOP 41 1

mBACOD 46 5

ProMACE-CytoBOM 46 3MACOP-B 41 6

Southwest Oncology Group



79/99


Treatment of Patients Age over 60

Program________________5-year survival %

CHOP 45mBACOD 39

ProMACE-CytoBOM 41

MACOP-B 23


80/99

t


81/99



82/99

Non Hodgkin s Lymphoma

Peripheral T-cell Lymphoma

Aggressive

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

extra-nodal presentation

Often requiring salvage treatment andtransplant

Burkitts Lymphoma


83/99

Burkitt s Lymphoma

myc Chromosome 8

SC

EChromosome 14, 80%IgH

Ig Chromosome 2

Ig chromosome 22

breakpoints

Class switch recombination

V(D)J

Somatic hypermutation

***

mycS

C C3E

myc C C3E

SE

t(8:14)


84/99


85/99



86/99

Non Hodgkin s Lymphoma

Lymphoblastic NHL

Very aggressive

Treatment is with acute lymphocyticleukemia regimen

Often requires high-dose therapy and

allogeneic transplantation forrelapsed/refractory disease

G D lt T ll NHL


87/99

Gamma Delta-T-cell NHL

Very, very aggressive

Very poor outcome with standard-dosetherapy

High-dose therapy and allogeneictransplantation is standard-of-care in firstremission

CD57 protein positivity

D bl Hit L h


88/99

Double-HitLymphomas

Multiple gene expressions MYC gene

t(14,18)

Triple-Hit

MYC gene

t(14,18)

BCL-6 gene



89/99

g y p

Aggressive chemotherapy regimens

Dose-dense CHOP

CHOP-Bleo

CEOP-Bleo

DexaBEAM

HyperCVAD

BMT f N H d ki L h


90/99

BMT for Non-Hodgkins Lymphoma

Indications

1. Refractory disease

2. Relapse

3. High risk in CR

4. Lymphoblastic, Burkitts, and gamma

delta-t-cell lymphomas



91/99


AUTOTRANSPLANTS FOR FOLLICULAR

NON-HODGKIN LYMPHOMA

PROBABILITY,%

100

0

20

40

60

80

YEARS

P = 0.0009

0 1 2 3 4 65

CR1 (N =

174)CR2+ (N =

322)

Never in rem iss ion (N = 418)

Relaps e (N = 791)

PROBABILITY OF SURVIVAL AFTER HLA-


92/99

IDENTICAL SIBLING MYELOABLATIVE

TRANSPLANTS FOR

FOLLICULAR NON-HODGKIN LYMPHOMA

PROBABILITY,%

100

0

20

40

60

80

YEARS

P = NS

0 1 2 3 4 65

CR1-3 (N =

79)

Never in remissio n (N =

138)

Relaps e (N = 193)



93/99


AUTOTRANSPLANTS FOR

DIFFUSE LARGE CELL LYMPHOMA

PROBABILITY,%

100

0

20

40

60

80

YEARS

P = 0.0001

0 1 2 3 4 65

CR1 (N =

438)

CR2+ (N =

651)

Relaps e (N = 1,443)


PROBABILITY OF SURVIVAL AFTER HLA-


94/99

IDENTICAL SIBLING MYELOABLATIVE

TRANSPLANTS FOR

DIFFUSE LARGE CELL LYMPHOMA

PROBABILITY,%

100

0

20

40

60

80

YEARS

P = NS

0 1 2 3 4 65

CR1-3 (N =

56)

Relaps e (N = 144)



95/99

Radioimmunotherapy with Y-90


96/99

py

Zevalin

Ibritumomab Murine monoclonal

antibody parent of

Rituximab

Tiuxetan Conjugated to

antibody, forming strong

urea-type bond

Stable retention of Y-90

Y-90 radionuclideBetaradiation

Chelator

Monoclonalantibody

New Treatment Options


97/99

New Treatment Options

Velcade + FlavoperidolMCC Trial

Velcade + Darinaparsin

Conclusion


98/99

Conclusion

Discussed Hodgkins Disease

Discussed Non-Hodgkins Lymphoma

Discussed Classification Systems

Discussed Treatment Options


99/99

Documents

110811 HChunag HD and NHL BMT Core Conf Handout