Hodgkin Lymphoma Hodgkin Lymphoma

Hodgkin Lymphoma Hodgkin Lymphoma

Seok Jin Kim Department of Medicine Samsung Medical Center Samsung Medical Center Sungkyunkwan University

School of Medicine

School of Medicine

Contents



Classification and pathology



Treatment of classical HL

 Localized disease

 Localized disease

 Advanced disease

T t t f l h t d i t HL



Treatment of lymphocyte predominant HL



Treatment of relapsed/refractory disease p y



New paradigm

New prognostic indicators

 New prognostic indicators

 New agents

Hodgkin lymphoma



Nodular lymphocyte predominant HL (NLPHL)

Different clinical and pathological features including immunophenotypes



Classical HL (CHL)

 Nodular sclerosis

 Mixed cellularity Different clinical and

 Mixed cellularity

 Lymphocyte-rich

pathological features Same immunophenotypes

 Lymphocyte-depleted

CHL



95% of HL



Nodal disease



Nodal disease

 Cervical > mediastinal > axillary > paraaortic LN



Disease of young adults

First peak (15 35 years) and second peak in late

 First peak (15–35 years) and second peak in late



Small number of malignant cells g

 Reed-Sternberg cells << inflammatory cells

Hodgkin and Reed Sternberg cell (HRS)



Hodgkin and Reed-Sternberg cell (HRS)

 B-cell origin tumor cell of this disease



HRS cells of CHL



Immunophenotypes

 CD30: positive in nearly ally

 CD15: positive in

majority (75-85%) Classical HRS

majority (75-85%)

 CD20, CD79a, CD45,

CD68 ti

Classical HRS

CD68: negative

Lacunar type of HRS Lacunar type of HRS

CHL: Morphology

 Nodular sclerosis

 Nodules surrounded by collagen band of fibrosis

 Lacunar type HRS

 Mixed cellularityy

 No bands of fibrosis

 Classical HRS with various non-neoplastic inflammatory cells including NØ, EØ, Histiocytes etc

 Lymphocyte-rich

 Classical HRS with small lymphocytes

 Absence of NØ, EØ

 Lymphocyte-depleted

 Relative predominance of classical HRS in relation to background lymphocytes

CHL: Epidemiology

N d l l i

 Nodular sclerosis

 70% of CHL, Male = female, 15-34 years

M f t i hi h i i t t

 More frequent in high socioeconomic status

 EBV association: 10-40% EBER/LMP1 +

Mi d ll l it

 Mixed cellularity

 20-25% of CHL, Male >70%, median age 38 years

f f

 More frequent in HIV infection and developing countries

 EBV association: > 75% EBER/LMP1 +

L h i h

 Lymphocyte-rich

 5% of CHL, Male > female, 30-50 years, Similar to NLPHL

 EBV association: 50-60% EBER/LMP1 +

 Lymphocyte-depleted

 < 1% of CHL, Male 60-75%, median age 30-37 years

 More frequent in HIV infection and developing countries

CHL: Clinical behavior

 Nodular sclerosis

 Mediastinum > 80%, spleen/lung 8-10%, bone marrow 3%

 Bulky disease > 50%, stage II, B symptoms 40%

 Better prognosis

 Mixed cellularity

 Peripheral LN dominant, spleen 30%, bone marrow 10%

 Frequent B symptoms

 Lymphocyte-richy p y

 Peripheral LN dominant, stage I/II, rare B symptoms

 Similar prognosis to NLPHL

 Lymphocyte-depleted

 Retroperitoneal, abdominal LN, bone marrow invasion frequentp , , q

 Stage III/IV, frequent B symptoms

NLPHL



5% of HL, Male, 30-50 yrs



Localized presentation in peripheral LN: >90%

 Cervical axillary or inguinal LN etc

 Cervical, axillary, or inguinal LN etc

 Mediastinal/BM involvement: rare



LP cell

 “Popcorn” or lymphocyte predominant cell

 Popcorn or lymphocyte predominant cell

 CD20, 79a, BCL6, CD45: positive

 CD15, 30, EBV-associated protein: negative

 Surrounded by CD4+/57+ T cells and small B cellsSurrounded by CD4 /57 T cells and small B cells

LP cells of NLPHL

Unfavorable factors



Localized presentation

 Bulky disease

 Mediastinal massMediastinal mass

 Maximum mass width/maximum intrathoracic diameter > 1/3 in chest X-ray

 Any mass > 10 cm in CT scan

 ESR ≥ 50 if asymptomatic; > 30 if B Sx +

 ESR ≥ 50 if asymptomatic; > 30 if B Sx +

 > 3 lymphoid regions

B t

 B symptoms

 > 1 extranodal site

NCCN v.1. 2010

Unfavorable factors



Advanced presentation

 International Prognostic Score (IPS)

 Albumin < 4 g/dLAlbumin 4 g/dL

 Hemoglobin < 10.5 g/dL

 Male

 Male

 Age ≥ 45 years St IV di

 Stage IV disease

 WBC ≥ 15000/mm³

 Lymphocyte < 8% of WBC and/or lymphocyte count <

600/mm³

Diehl V. NEJM 1998:339:1506-1514

Prognosis in advanced HL

Contents



Classification and pathology



Treatment of classical HL

 Localized disease

 Localized disease

 Advanced disease

T t t f l h t d i t HL



Treatment of lymphocyte predominant HL



Treatment of relapsed/refractory disease p y



New paradigm

New prognostic indicators

 New prognostic indicators

 New agents

Question #1



M/26

 Night sweat, itching E f ti

 Easy fatigue

 ESR 35

 Pathology

 Nodular sclerosis

 Nodular sclerosis

Question #1



What is your choice?

1 ABVD 2 4 l 1. ABVD 2-4 cycle

2 ABVD 2-4 cycle + IFRT 2. ABVD 2-4 cycle + IFRT 3. ABVD 4-6 cycle y

4. ABVD 4-6 cycle + IFRT

5. SD BEACOPP 2-4 cycle

Localized CHL

 IA or IIA & not bulky  High cure rate

 Late complication of irradiation

Cardiovascular disease, Second neoplasm, p

 Complications of chemotherapy

I f tilit t l k i

Infertility, premature menopause, leukemia

 Optimum treatment

Completely eliminate the risk of relapse Completely eliminate the risk of relapse

Minimizing long-term toxicity and complications

Localized CHL



Stage IA/IIA with favorable factors

 Italian Society of Hematology

 ABVD 3-4 cycles + IFRT (30 Gy)ABVD 3 4 cycles IFRT (30 Gy)

 ABVD 2 cycles + IFRT (20 Gy): clinical trial setting

 NCCN 2010

 NCCN 2010

 ABVD 4 cycles or Stanford V 2 cycles (8 weeks) + IFRT: category 1

IFRT: category 1

 ABVD 4-6 cycles: category 2B

Localized CHL



Stage I/II with unfavorable factors

 Italian Society of Hematology

 ABVD 4 - 6 cycles + IFRT (30 Gy with additional 6 GyABVD 4 6 cycles IFRT (30 Gy with additional 6 Gy to bulky disease): category 2

 NCCN 2010

 NCCN 2010

 ABVD 4 - 6 cycles + IFRT

Stanford V 3 cycles (12 weeks) + IFRT (36 Gy to initial

 Stanford V 3 cycles (12 weeks) + IFRT (36 Gy to initial sites > 5cm and residual PET positive sites after

chemotherapy) chemotherapy)

Principles of radiation

NCCN v.1.2010

Contents



Classification and pathology



Treatment of classical HL

 Localized disease

 Localized disease

 Advanced disease

T t t f l h t d i t HL



Treatment of lymphocyte predominant HL



Treatment of relapsed/refractory disease p y



New paradigm

New prognostic indicators

 New prognostic indicators

 New agents

Question #2



F/23

 B symptoms + P th l

 Pathology

 Nodular sclerosis

 Lab

 Albumin 3.8 g/dLg

 Hemoglobin 13.2 g/dL

 WBC 8100/mm³

 WBC 8100/mm

 Lymphocyte 23%

Question #2



What is your choice?

1 ABVD 8 l 1. ABVD 8 cycle

2 ABVD 6 cycle + RT to initial bulky site 2. ABVD 6 cycle + RT to initial bulky site 3. Escalated BEACOPP 8 cycle y

4. Stanford V 4 cycle + RT

Chemotherapy



Anthracycline-based chemotherapy

 Doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD)

 Alternating MOPP/ABVD or MOPP/ABV



Dose intensive chemotherapy

 BEACOPP: German Hodgkin Study Group (GHSG)

 BEACOPP: German Hodgkin Study Group (GHSG)

 CEC: Gruppo Italiano per lo Studio dei Linfomi (GISL)

ChlVPP/PABIOE ChIVPP/EVA U it d Ki d (UKLG)

 ChlVPP/PABIOE, ChIVPP/EVA: United Kingdom (UKLG)



Dose intensive chemotherapy with minimizing py g leukemogenic/gonadotoxic agents

 Stanford V (Stanford Univ )

 Stanford V (Stanford Univ.)

GHSG HD9 trial

N = 288 N = 498 N = 496

Diehl V. NEJM 2003:348:2386-2395

GHSG HD9 trial

I d d BEACOPP lt d

Increased-dose BEACOPP resulted in better tumor control and OS than COPP-ABVD

Diehl V. NEJM 2003:348:2386-2395

UKLG LY09 trial

MDR

Johnson PW. JCO 2005:23:9208-9218

UKLG LY09 trial

Th id f i ifi t diff i EFS OS b t ABVD

There was no evidence of significant difference in EFS or OS between ABVD and MDR in advanced HL.

Johnson PW. JCO 2005:23:9208-9218

GISL HD 2000 trial

BEACOPP

improved PFS than ABVD.

There was no There was no difference in OS.

Federico M. JCO 2009:27:805-811

GISL HD 2000 trial

Federico M. JCO 2009:27:805-811

Intergruppo Italiano Linfomi trial

Overall Survival N = 122

N = 107

ABVD Stanford V

N = 106 ABVD is still the best choice when it is combined with irradiation.

Gobbi PG. JCO 2005:36:9188-9207

Advanced HL



Stage III/IV

 Italian Society of Hematology

 ABVD 6 - 8 cyclesABVD 6 8 cycles

 MOPP or MOPP-like regimens is not recommended

 Escalated BEACOPP only can be recommended in

 Escalated BEACOPP only can be recommended in clinical trials

 Consolidative radiotherapy cannot be justified for

 Consolidative radiotherapy cannot be justified for patients with non-bulky disease achieving CR after anthracycline-containing chemotherapy

anthracycline containing chemotherapy

Advanced HL



Stage III/IV

 NCCN 2010

 ABVD 6 cycles ± RT to initial bulky sitesABVD 6 cycles ± RT to initial bulky sites

 Stanford V 3 cycles (12 weeks) + RT (36 Gy to initial sites > 5cm and spleen if focal nodules are present sites 5cm and spleen if focal nodules are present initially or residual PET positive sites)

 Escalated BEACOPP 8 cycles if IPS ≥ 4 ± RT (30 Gy

 Escalated BEACOPP 8 cycles if IPS ≥ 4 ± RT (30 Gy to initial sites > 5cm and spleen and 40 Gy to residual PET positive sites)p )

UKLG LY09 trial: Role of

consolidation RT in Advanced HL

 Stage III/IV

 Locaized with bulky or B

 Locaized with bulky or B symptoms

 RT: not mandatory

RT i l f i i i l

P < 0.0001

 RT: mainly for initial bulky lesion or residual mass

 300 patients (43%)

 PR to CTx

 RT group > non-RT

 Second malignancy

 Non-RT: 15 (4%) _{P = 0 0014}

 Non RT: 15 (4%)

 RT: 4 (1%) ^{P = 0.0014}

Johnson PW. JCO 2010: May

Contents



Classification and pathology



Treatment of classical HL

 Localized disease

 Localized disease

 Advanced disease

T t t f l h t d i t HL



Treatment of lymphocyte predominant HL



Treatment of relapsed/refractory disease p y



New paradigm

New prognostic indicators

 New prognostic indicators

 New agents

NLPHL



Indolent clinical course

 Frequent relapse rate

 Excellent survival : 10 year OS > 80%

 Excellent survival : 10 year OS > 80%



Watch and wait for localized disease?

 Observation after resection of affected node, especially childrenp y

 No treatment for stage I in France

Ad anced disease nfa orable



Advanced disease: unfavorable

 Progression to DLBCL: 3-5%

NCCN guideline 2010: NLPHL



Stage I/IIA

 IFRT or Regional RT



Stage I/IIB



Stage I/IIB

 CTx ± IFRT or Rituximab ± CTx ± IFRT



After treatment



After treatment

 If CR: observation

 If less than CR with Sx: CTx

 If less than CR without Sx: observation

 If less than CR without Sx: observation

NCCN v.1.2010

NCCN guideline 2010: NLPHL



Stage III/IVA

 CTx ± RT or Rituximab ± CTx

 Observation or Local RT (palliative)

 Observation or Local RT (palliative)



Stage III/IVB

 CTx ± RT or Rituximab ± CTx ± RT



After treatment



After treatment

 If CR: observation

 If less than CR with Sx: CTx or RT

 If less than CR without Sx: observation

NCCN v.1.2010

Hodgkin lymphoma in g y p pregnancy



Diagnosis during the 1

trimester

 Delay treatment until 2^ndd trimester

 If a delay is unacceptable, therapeutic abortion and chemotherapy



Diagnosis Diagnosis during 2 /3 trimester during 2

/3

trimester

 Treatment must be delayed as long as possible in case of localized or stable disease

case of localized or stable disease

 If not possible, ABV or ABVD or CHOP-like regimens

regimens

D l di th til th d f



Delay radiotherapy until the end of pregnancy

Contents



Classification and pathology



Treatment of classical HL

 Localized disease

 Localized disease

 Advanced disease

T t t f l h t d i t HL



Treatment of lymphocyte predominant HL



Treatment of relapsed/refractory disease p y



New paradigm

New prognostic indicators

 New prognostic indicators

 New agents

Question #3



F/17

 B symptoms + P th l

 Pathology

 Nodular sclerosis

 Lab

 Albumin 3.2 g/dLg

 Hemoglobin 9.2 g/dL

 WBC 5340/mm³

 WBC 5340/mm

 Lymphocyte 19%

Question #3

Question #3



What is your choice?

1 R bi

1. Rebiopsy

2 Switch chemotherapy 2. Switch chemotherapy 3. Observation

4. Radiotherapy

Question #3



Rebiopsy

 Non specific

 Non-specific

inflammation with fibrosis

fibrosis

 No evidence of disease

Relapsed/progressed disease



Work-up

 Rebiopsy

 Marrow cytogenetics for MDS prior to ASCT

 Marrow cytogenetics for MDS prior to ASCT



If primary therapy was CTx or CTx/RT

 ASCT ± locoregional RT: category 1

 Salvage CTx ± RT

 Salvage CTx ± RT



If primary therapy was RT alone

 Treat as primary advanced HL

NCCN v.1.2010

Salvage treatment strategy



Salvage

chemotherapy followed by

followed by

autologous stem cell transplantation

transplantation

 Treatment of choice for relapsed HL

Salvage treatment strategy

ASCT improves freedom form treatment failure in chemosensitive first relapse ASCT improves freedom form treatment failure in chemosensitive first relapse.

But they failed to show OS benefit.

Salvage chemotherapy

There are no randomized controlled trials and no consensus on the most effective second-line chemotherapy regimen for relapsed HL most effective second line chemotherapy regimen for relapsed HL.

Kuruvilla J. 2009 ASH meeting

Allo-SCT in relapsed HL: chemo- iti l

sensitive relapse

Patients with suitable donor (n = 122) vs. without donor (n = 63)

Contents



Classification and pathology



Treatment of classical HL

 Localized disease

 Localized disease

 Advanced disease

T t t f l h t d i t HL



Treatment of lymphocyte predominant HL



Treatment of relapsed/refractory disease p y



New paradigm

New prognostic indicators

 New prognostic indicators

 New agents

New prognostic model

Treatment Treatment

success

success + failure

NEJM 2010;362:875-85.

New prognostic model

 Immunohistochemical analysis

- Gene expression signatures associated with macrophage is correlatedGene expression signatures associated with macrophage is correlated with treatment failure (P = 0.002)

 CD68 : significant correlation with treatment outcomesg

NEJM 2010;362:875-85.

New prognostic model

NEJM 2010;362:875-85.

Contents



Classification and pathology



Treatment of classical HL

 Localized disease

 Localized disease

 Advanced disease

T t t f l h t d i t HL



Treatment of lymphocyte predominant HL



Treatment of relapsed/refractory disease p y



New paradigm

New prognostic indicators

 New prognostic indicators

 New agents

Targeting microenvironment



RS surrounded by reactive cells providing survival signals

 Selective depletion of specific cellular

 Selective depletion of specific cellular components

 Monoclonal antibody

 Monoclonal antibody

Microenvironment

Rituximab

 CD20

 Rarely expressed in RS

 Rarely expressed in RS

 Highly expressed in reactive B cells

 Rituximab

 Rituximab

 Depletion of B cells

 Killing CD20+ RSg

 Combined with other chemotherapy regimens

 Rituximab + ABVD

 N = 52, median f/up = 32 months

 EFS 82%: Risk score 0-1 (92%), 3-5 (73%)

 OS 100%

 OS 100%

 Wedgwood AR. (Abstract) Blood 2007: 110:215

 Ongoing phase III: R+ABVD vs. ABVDOngoing phase III: R ABVD vs. ABVD

Targeting intracellular pathway



HDAC inhibitor

 Vorinostat

 Panobinostat (LBH589)

 Panobinostat (LBH589)



Infrequent expression of B-cell antigen in RS

 Epigenetic loss of B cell phenotype

 Epigenetic loss of B-cell phenotype

 Potential therapeutic role of HDAC inhibitor

HDAC inhibitor

 Panobinostat

Phase I including 13 relapsed HL

 Phase I including 13 relapsed HL

 5PR (38%)

 Common SE: fatigue thrombocytopenia etc

 Common SE: fatigue, thrombocytopenia etc

 Phase II is ongoing

 Younes A Haematologica 2009:94:34

 Younes A. Haematologica 2009:94:34

 Vorinostat

 Phase II: SWOG trial

 Phase II: SWOG trial

 N = 25

 200mg bid po for 14 days every 3 weeks

 200mg bid po for 14 days every 3 weeks

 Blood 2007:110:2574

Targeting surface antigen or g g g receptors



CD30 is expressed in RS

 Easily shed to a soluble form

 Soluble CD30 attenuate the therapeutic efficacySoluble CD30 attenuate the therapeutic efficacy

SGN-35



Anti-CD30 antibody conjugate to a synthetic anti-microtuble agent, monomethyl auristatin E

 Phase I

 Phase I

 0.1 – 3.6mg/kg IV every 3 weeks

 45 relapsed HL after ASCT

 45 relapsed HL after ASCT

 DLT: neutropenia/hyperglycemia > 1.8mg/kg RR 37% (6PR 11CR)

 RR: 37% (6PR, 11CR) Younes A. Blood 2008:112:1006

 Phase I:

 1.2mg/kg weekly IV, N = 17

 RR: 47% (1PR or 7CR) ( ) Bartlett N. Proc ASCO 2009:27:8500

Perspective

Frontline treatment Salvage treatment

SGN-35 SGN-35 with ABVD SGN-35 with salvage

chemotherapy chemotherapy

HDAC inhibitor: ? : genotoxicity of Panobinostat with salvage HDAC inhibitor:

Panobinostat

? : genotoxicity of HDAC inhibitor

Panobinostat with salvage chemotherapy

Question #4

What will be the best treatment in What will be the best treatment in the future?

1.

ABVD

2.

SGN-35 + ABVD

3

Rituximab + ABVD

3.

Rituximab + ABVD

4.

Modified BEACOPP

5.

Risk-adapted approach

Question #5

Tonight score? g

1.

1 : 2

0 2

2.

0 : 2

3

2 : 3

3.

2 : 3

4.

1 : 3

5.

0 : 1