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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

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

agenda
Agenda
  • Discuss Hodgkin’s Disease
  • Discuss Non-Hodgkin’s Lymphoma
  • Classification Systems
  • Treatment Options
2008 estimated us cancer cases
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.

2008 estimated us cancer deaths
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.

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 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
b cell malignancies
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

hodgkin s disease lymphoma in the beginning
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

hodgkin s disease lymphoma in the beginning1
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
hodgkin s disease lymphoma in the beginning2
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

slide13
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 lymphoma interest tidbits
Hodgkin’s Disease/LymphomaInterest tidbits
  • Pel-Ebstein Fevers
  • Pain with alcohol consumption
hodgkin s disease lymphoma clinical presentation
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
hodgkin s disease lymphoma clinical presentation1
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 lymphoma clinical presentation2
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 lymphoma treatment
Hodgkin’s Disease/LymphomaTreatment
  • Unfavorable prognostic factors:

- Stage IIIB, IV

- B symptoms

- Bulky disease

- High ESR >50

hodgkin s disease lymphoma treatment1
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)

hodgkin s disease lymphoma treatment2
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

hodgkin s disease lymphoma treatment3
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)
hodgkin s disease lymphoma treatment4
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
slide26

ABVD vs MOPP vs MOPP/ABVD

Failure-free survival

Canellos et al, NEJM, 2002

Overall survival

hodgkin s disease lymphoma treatment5
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.
slide28

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

stanford hoppe et al
Stanford, Hoppe et al

Hodgkin’s Disease/LymphomaActual Treatment Progress

slide32

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
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)

hodgkin s disease lymphoma salvage regimens
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)

calgb 50203 treatment plan
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

hodgkin s disease lymphoma autologous transplants as primary therapy
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]

probability of survival after autotransplants for relapsed hodgkin s disease lymphoma 1996 2001
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

allotransplantation hodgkin s disease lymphoma
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 lymphoma non myeloablative allotransplants 7 series 2004 2008
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)

hodgkin s disease lymphoma residual masses by pet scan 5 series 2001 present
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

ctn 0701
CTN 0701
  • Tandem Transplant
    • Modeled after myeloma data
    • High-risk Hodgkin’s Disease
    • University of Nebraska – Julie Vose, MD
mdx 060 anti cd30 target
MDX-060 - Anti-CD30 target

Anti-CD30 antibody

Medarex 2004 – Orphan Drug Status

Hodgkin’s Disease/Lymphoma

Anaplastic Large Cell NHL

sgn 35 seattle genetics
SGN-35 (Seattle Genetics)

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

good ideas
Good Ideas
  • Cadence Pharmaceuticals
    • Ofirmev
    • November 2, 2010 – FDA Approval
    • IV acetaminophen
    • $800/IV dose
non hodgkin s lymphoma
Non-Hodgkin’s Lymphoma

Deep Breath…

Stand up…

Stretch…

histologic classification of non hodgkin s lymphomas
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

non hodgkin s lymphoma rappaport classification
Non-Hodgkin’s LymphomaRappaport Classification

Nodular (follicular)

Diffuse

Indolent

Aggressive

Small cell

Large cell

non hodgkin s lymphoma rappaport classification1
Non-Hodgkin’s LymphomaRappaport Classification
  • Small cell, follicular
  • Small cell, diffuse
  • Large cell, follicular
  • Large cell, diffuse
non hodgkin s lymphoma immunophenotyping
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 lukes collins kiel classifications
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 lymphoma working classification
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 lymphoma working classification1
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)
slide56

Hodgkin

Lymphoma

Non Hodgkin Lymphoma

Classical HL

(NS, MC, LR, LD)

Nodular lymphocyte Predominant

(NLPHL)

Indolent

Aggressive

Highly

Aggressive

B cell

Follicular

SLL/CLL

Marginal zone

LP (WM)

T/NK cell

Mycosis fungoides

Sezary syndrome

Primary cut ALCL

B cell

DLBCL

FLg3 and tFL

Mantle cell

Primary effusion

T/NK cell

ALCL

Angioimmunoblastic

Subq panniculitis-like

Blastic NK

Extnanodal NK/T nasal

Enteropathy-type

Hepatosplenic

PTCL nos

B cell

Pre-B lymphoblastic

Burkitt

T/NK cell

Pre-T lymphoblastic

Multiple

Myeloma

non hodgkin s lymphoma real classification
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
frequency of nhl subtypes in adults
Frequency of NHL Subtypes in Adults

Mantle cell (6%)

Peripheral T-cell (6%)

Indolent (35%)

Other subtypes with a frequency 2% (9%)

Composite lymphomas (13%)

Diffuse largeB-cell (31%)

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

non hodgkin s lymphoma who classification
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 neoplasms1
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
non hodgkin s lymphoma specific types
Non-Hodgkin’s LymphomaSpecific Types

Time For A Deep Breath…

or an Excedrin

slide62

Follicular Lymphoma

Mbr (major breakpoint region, 150 bp)

Bcl2

Chromosome 18

Chromosome 14

C

JH

Double strand DNA break by RAG1/2

Translocation takes place in B cell precursors.

Bcl2

t(14;18) translocation

C

Transformation takes place

during B cell activation in GC.

E

3’E

C

bcl2

C

Unregulation of Bcl2 expression by IgH enhancers

slide63

Apaf-1

Apaf-1

Bcl2 inhibits apoptosis

Pro-survival oncogene

mitochondrion

Bax, Bad

Pro-caspase-9

cytochrome c

Bcl-2, Bcl-XL

dATP or ATP

Caspase-9

Caspase-3

Pro-caspase-3

Apoptosis

slide64

Over-expression of Bcl-2 may prevent the apoptosis

of germinal center B cells

Plasma cells

Germinal center

Germinal center

activation

apoptosis

Memory cells

Germinal center

Germinal center

IgH-Bcl2

activation

follicular lymphoma

Most follicular lymphoma Ig V regions contain

somatic hypermutation.

Apoptosis inhibited

non hodgkin s lymphoma follicular lymphoma
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 lymphoma cutaneous t cell mycosis fungoides
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 lymphoma diffuse large cell
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 lymphoma mantle cell
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
morphology
Morphology

Classical Mantle Cell

Nodular pattern

Blastoid Variant

Diffuse pattern

mantle cell treatment
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 lymphoma marginal zone
Non-Hodgkin’s LymphomaMarginal Zone
  • Indolent
  • Accounts for ~10% of all lymphomas
  • Subcategories
    • MALT (H. pylori)
    • Nodal
    • Extra-Nodal
    • Splenic
non hodgkin s lymphoma primary cns 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 lymphoma anaplastic large cell lymphoma
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
slide77
Treatment results of aggressive advanced non-Hodgkin’s lymphomas using different chemotherapy programs

1. 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%

non hodgkin s lymphoma intergroup 0067 study
Non-Hodgkin’s LymphomaIntergroup 0067 Study

3-year survival Mortality

___%________________%___

CHOP 41 1

mBACOD 46 5

ProMACE-CytoBOM 46 3

MACOP-B 41 6

Southwest Oncology Group

non hodgkin s lymphoma treatment of patients age over 60
Non-Hodgkin’s LymphomaTreatment of Patients Age over 60

Program________________5-year survival %

CHOP 45

mBACOD 39

ProMACE-CytoBOM 41

MACOP-B 23

non hodgkin s lymphoma peripheral t cell lymphoma
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
slide83

Burkitt’s Lymphoma

breakpoints

Chromosome 8

myc

IgH

Chromosome 14, 80%

C

***

S

E

V(D)J

IgChromosome 2

Igchromosome 22

Class switch recombination

Somatic hypermutation

3’E

C

C

myc

S

t(8:14)

3’E

C

C

myc

E

S

non hodgkin s lymphoma burkitt s nhl
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
non hodgkin s lymphoma lymphoblastic nhl
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
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 hit lymphomas
Double-HitLymphomas
  • Multiple gene expressions
    • MYC gene
    • t(14,18)
  • Triple-Hit
    • MYC gene
    • t(14,18)
    • BCL-6 gene
non hodgkin s lymphoma aggressive chemotherapy regimens
Non-Hodgkin’s LymphomaAggressive chemotherapy regimens
  • Dose-dense CHOP
  • CHOP-Bleo
  • CEOP-Bleo
  • DexaBEAM
  • HyperCVAD
bmt for non hodgkin s lymphoma indications
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
PROBABILITY OF SURVIVAL AFTER AUTOTRANSPLANTS FOR FOLLICULAR NON-HODGKIN LYMPHOMA

100

80

60

40

20

0

0

1

2

3

4

5

6

CR1 (N = 174)

CR2+ (N = 322)

Never in remission (N = 418)

PROBABILITY, %

Relapse (N = 791)

P = 0.0009

YEARS

slide92
PROBABILITY OF SURVIVAL AFTER HLA-IDENTICAL SIBLING MYELOABLATIVE TRANSPLANTS FOR FOLLICULAR NON-HODGKIN LYMPHOMA

100

80

60

40

20

0

0

1

2

3

4

5

6

Never in remission (N = 138)

CR1-3 (N = 79)

PROBABILITY, %

Relapse (N = 193)

P = NS

YEARS

probability of survival after autotransplants for diffuse large cell lymphoma
PROBABILITY OF SURVIVAL AFTER AUTOTRANSPLANTS FOR DIFFUSE LARGE CELL LYMPHOMA

100

80

60

40

20

0

0

1

2

3

4

5

6

CR1 (N = 438)

CR2+ (N = 651)

PROBABILITY, %

Relapse (N = 1,443)

Never in remission (N = 986)

P = 0.0001

YEARS

slide94
PROBABILITY OF SURVIVAL AFTER HLA-IDENTICAL SIBLING MYELOABLATIVE TRANSPLANTS FOR DIFFUSE LARGE CELL LYMPHOMA

100

80

60

40

20

0

0

1

2

3

4

5

6

PROBABILITY, %

Relapse (N = 144)

CR1-3 (N = 56)

Never in remission (N = 133)

P = NS

YEARS

radioimmunotherapy with y 90 zevalin
Ibritumomab

Murine monoclonal antibody parent of Rituximab

Tiuxetan

Conjugated to antibody, forming strong urea-type bond

Stable retention of Y-90

Radioimmunotherapy with Y-90 Zevalin

Monoclonal antibody

Chelator

Beta radiation

Y-90 radionuclide

new treatment options
New Treatment Options
  • Velcade + Flavoperidol – MCC Trial
  • Velcade + Darinaparsin
conclusion
Conclusion
  • Discussed Hodgkin’s Disease
  • Discussed Non-Hodgkin’s Lymphoma
  • Discussed Classification Systems
  • Discussed Treatment Options
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