Management of Advanced Management of Advanced Stage Hodgkin LymphomaStage Hodgkin Lymphoma

Michael Crump, MD, FRCPCPrincess Margaret Hospital

University of TorontoToronto, Canada

Outline of this presentationOutline of this presentation

• Definition and incidence• Historical results and the need for

change• Recent trials of new approaches• Nodular lymphocyte predominant HL• Late effects in advanced stage HL• Conclusions

Aisenberg, Blood, 1999; Reprinted from Ries; NIH Publ 97-2789, 1997

Decline in mortality rate from HL in North America

MOPPABVD

HL Outcomes – Continued ImprovementBrenner, et al. Blood, 2008

US SEER database: >16,000 pts 1980-2004

Relative survival: 5 y 73% 85%10 y 62% 80%

1980-84 2000-04

all 25-34y >60y

Advanced HL: definitionsAdvanced HL: definitions

• NA intergroup: stage III, IV; relapse after prior extended field radiotherapy

• British: B symptoms (any stage); II with bulky mediastinal mass; stage III, IV

• German Hodgkin Study Group:– Stage IIB + E extension or LMM; III, IV– Early, unfavourable: stage I,II with E lesions,

LMM, ↑ ESR, > 3 sites

Prognostic factors in advanced HLPrognostic factors in advanced HL• Hasenclever-Diehl index NEJM 1998• >5000 patients (13% stage I-IIB)

– Complete data for model: ~1600

• 7 clinical variables:– Age > 45 y– Male sex– Hb <105g/L– Stage IV– Albumen < 40 g/L– WBC > 15– Lymphocytes <0.6 or <8%

Biologic prognostic factors?Biologic prognostic factors?• Epstein-Barr Virus (EBV)

~25-35% +ve by IHC (LMP-1), ISH (EBER-1)More common: males, older age (>45), mixed

cellularity histologyOlder adults → less favourable outcome

• BCL-2• Cytokine levels• Cytokine gene polymorphisms• Tumour microenvironment etc…

Previous Therapeutic Observations in Previous Therapeutic Observations in Advanced DiseaseAdvanced Disease

• ABVD is superior to MOPP, and equal to but less toxic than alternating MOPP-ABVD – Canellos G, et al, NEJM, 1992, 2002

• ABVD is equivalent to alternating and hybrid multidrug regimens, with less toxicity– Johnson PW, et al, JCO 2005

Recent Recent Therapeutic Observations in Therapeutic Observations in Advanced Stage DiseaseAdvanced Stage Disease

ABVD is equivalent to MOPP/ABV but has less serious/fatal toxicity– Duggan D et al; JCO 2006

Esc BEACOPP is superior to COPP-ABVD – Diehl V, et al: NEJM, 2003

Advanced Hodgkin LymphomaABVD vs MOPP/ABV Hybrid

Intergroup CALGB, ECOG, SWOG, NCIC

n 433 419

CR% 76 80 0.16Progression % 10 11

5 y FFS% 63 66 0.425 y OS% 82 81 0.82

ABVD MOPP/ABV p

• Definition and incidence• Historical results and the need for

change• Recent trials of new approaches• Nodular lymphocyte predominant HL• Late effects in advanced stage HL• Conclusions

New concepts evaluated in phase New concepts evaluated in phase II trials to improve results in HLII trials to improve results in HL

• Consolidation with high-dose therapy and ASCT (high risk pts)

• Optimization of combined modality therapy: Stanford V

• Intensification with non-cross-resistant agents, increased dose intensity + G-CSF– escalated BEACOPP, other regimens

Not usefulNot useful• Intensification of COPP-ABV with IMEP

(ifos, MTX, etoposide, prednisone) vs C-AGHSG HD6 trial Ann Oncol 2004

• Intensification with ASCT in high risk HL after CR/PR to ABVD/other x 4 cycles

Federico M, JCO 2003

Recent Randomized Trials of Novel Regimens in Advanced Hodgkin Lymphoma

Esc BEACOPP 466 96 2 87 91 (5)BEACOPP 469 88 8 76 88COPP-ABVD 260 85 10 69 83

ABVD 99 70 12 65 84 (5)BEACOPP 98 81 2 78 92COPP-EBV-CAD 98 69 10 71 91

ABVD 261 67 5 85 90 (5) Stanford V 259 57 6 73 92

N pts CR(%) Progr’n (%) 5 y FFTF OS (yr)

CR: complete response rate; FFTF: freedom from treatment failure; OS: overall survival

BEACOPP Escalated mg/m2 day• Bleomycin 10 IV 8• Etoposide 200 IV 1-3• Doxorubicin 35 IV 1• Cyclophos 1200 IV 1• Vincristine 1.4 IV 8• Procarbazine 100 PO 1-7• Prednisone40 PO 1-14Cycle length 21 days G-CSF day 8-15 

BEACOPP is superior to BEACOPP is superior to COPP-ABVDCOPP-ABVD

• Recent HD9 update: follow-up > 9 yrs • 10 y FTFF and OS favour

escBEACOPP over BEACOPP, COPP-ABVD

Engert A, et al, J Clin Oncol 2009

GISL HD 2000GISL HD 2000BEACOPP v ABVD v CECBEACOPP v ABVD v CEC

Federico M, J Clin Oncol 2009

Should escBEACOPP now be the Should escBEACOPP now be the standard?standard?

…maybe not yet• Toxicity vs (COPP-)ABVD:

– Greater male, female infertility (vs ABVD: fertility is unaffected)

– More significant Hb, plt toxicity; fever/infection– Higher secondary AML risk? (second cancers:

no difference)– Elderly (age >60): more toxic, not more effective

Other trials of this strategyOther trials of this strategy• GHSG HD12:

8 escBEACOPP vs 4 esc + 4 BEACOPPAdvanced disease, age <65No difference in 5 y OS, FFTF

• EORTC-NCIC-GELA HD8:4 esc + 4 BEACOPP vs 8 ABVD--accrual recently completed

ABVD remains the standard for ABVD remains the standard for advanced HLadvanced HL

Doxorubicin 25 mg/m2 d1, 15Bleomycin 10 mg/m2 d1, 15Vinblastine 6 mg/m2 d1, 15Dacarbazine 375 mg/m2 d1, 15

 

ABVD remains the standard for ABVD remains the standard for advanced HLadvanced HLPractical points:• Are pulmonary function tests required?

– Bleomycin lung toxicity: up to 30% of patients; high case fatality rate (esp elderly)

– No PFT at baseline, unless older or underlying lung disease (smokers)

– In follow-up: if symptoms (cough, dyspnea, fever) or if > 6 cycles ABVD planned

– Omission of bleo does not seem to compromise treatment

ABVD remains the standard for ABVD remains the standard for advanced HLadvanced HLPractical points:• Is G-CSF (neupogen) required?

– Not generally: several cohort studies of Rx regardless of treatment-day ANC→ no increase febrile neutropenia

– ? Association with bleomycin toxicity– Should be used for pts at high risk of febrile

neutropenia: elderly, bone marrow involvement, HIV+

– PMH recipe: daily x4-5, starting D5, A cycle• (not needed with each treatment)

Hodgkin Lymphoma Hodgkin Lymphoma Older PatientsOlder Patients

Advanced stage Hodgkin lymphoma

Age > 60

Progression Free Survival (y)

109876543210

Cum

Sur

viva

l

1.0

.8

.6

.4

.2

0.0 MOPP 38

ODBEP 51

ABVD 72HYBRID 38

Data courtesy of J Connors, BCCA

Advanced stage Hodgkin lymphoma

Age > 60

Disease Specific Survival (y)

109876543210

Cum

Sur

viva

l

1.0

.8

.6

.4

.2

0.0

MOPP 38

ODBEP 51

ABVD 72Hybrid 38

Hodgkin Lymphoma Hodgkin Lymphoma Older PatientsOlder Patients

Chemotherapy recommendations– No special regimen superior

• ABVD remains the gold standard• If drugs must be omitted due to underlying organ dysfunction

– Consider 7 – 8 drug combinations, then drop offender(s)

– Anticipate increased toxicity• Hematologic• Neurologic• Pulmonary• Cardiac

– Enhance supportive care• G-CSF

FDG PET?FDG PET?

Gallamini A, J Clin Oncol 2007

Outcome of HL according to interim FDG PET and IPS

RCT of Observation vs RT for Patients with Bulky HL and Negative Post Chemo PET Scan

Bulk: > 5 cm long axis*Chemo: VEBEP 6 cyclesRT: 32 Gy

Negative PET: no uptakePositive PET: “uptake in …abnormal area”

260 patients 2000-2006 n = 160 randomizedstage I, II 2/3B symptoms ½

Radiation: mantle, inv Y, para-aortic

Picardi M, et al. Leuk Lymph, 2007

Relapse:Chemo alone: 11/80 (14%)Chemo + RT: 2/80 (2.5%)

Picardi,et al. Leuk Lymph, 2007

PET Scans and Early Progressionin Advanced Hodgkin Lymphoma

German HL Study Group Trial HD15

Patients: stage IIEB or IIB + LMM; III + IV

esc BEACOPP x 8

esc BEACOPP x 6

BEACOPP-14 x 8

residual> 2.5 cm PET

R

PET +, > 2.5 cm on CT 30 Gy IFRT

Total n: 1788 For analysis: 817Blood 2008

PET Scans and Early Progressionin Advanced Hodgkin Lymphoma

311 patients: <CR after chemo PET scan66 positive (21%) - 63 received XRT

CR

PET-ve

PET+ve

Patients with FDG avid lesions following chemotherapy should have a biopsy, if PET scan is to be used to modify treatment:

Variable false positive rates: 21 +ve scans→10 benign Zinzani, Hematologica 2007

27 +ve scans→ 4 benignSchaefer, Radiology 2007

• Definition and incidence• Historical results and the need for

change• Recent trials of new approaches• Nodular lymphocyte predominant HL• Late effects in advanced stage HL• Conclusions

Pathology:Nodular lymphocyte predominant HL

Marker Classical HL Nodular LP HLCD30 + -CD15 + -CD45 - +CD20 -/+ +PAX5 + +

sIg - +/-EBV LMP1 +/- -

NLPHL: German experienceNLPHL: German experienceNogova, et al. J Clin Oncol 2008

LP HL(%) classical HL(%)

n=394 n= 7904 pCR 8782 .003PD 0.3 3.9 .0001relapse 8.1 8.0

late rel 7.4 4.7 .02death 4.6 9.6 .0004second Ca 2.5 3.7 .27

Nodular LP Hodgkin Nodular LP Hodgkin LymphomaLymphoma • Favourable prognosis with

current therapies according to disease extent

• No increase in relapse vs cHL

• No increase in secondary malignancies

→ treatment as per advanced cHL

GHSG J Clin Oncol 2008

• Definition and incidence• Historical results and the need for

change• Recent trials of new approaches• Nodular lymphocyte predominant HL• Late effects in advanced stage HL• Conclusions

Long-Term Cause-Specific Mortality of Long-Term Cause-Specific Mortality of Patients Treated for Hodgkin’s Disease Patients Treated for Hodgkin’s Disease

J Clin Oncol 2003

GELA H89 Trial: Chemotherapy +/- GELA H89 Trial: Chemotherapy +/- radiation for advanced stage HL;radiation for advanced stage HL;

Causes of DeathCauses of Death• N = 533, median f/u 10 yrs• 129 deaths:

Hodgkin lymphoma PD/rel 60 (46%)– treatment 15– salvage treatment 7Second cancer 24 (19%)Cardiovascular 1Unknown/not spec. 22

Ferme C, Blood 2006

Lung Cancer – Dramatic Effects of Age,Treatment, Smoking History

no no 1.0 6.0yes no 20.2 7.2

no yes 16.8 4.3yes yes 49.1 7.2

>1 ppdsmoker others

RT>5 Gy AA chemo RR RR

Treatment

Change in Systemic Chemotherapy?

Example of secondary AML (JNCI, 2006)

• >35,000 1 yr HL survivors• 14 cancer registries (Nordic, N America)• pts treated 1970-2001

1. Excess absolute risk higher in 1st 10 yrs of follow-up

2. Decline in AML incidence for pts treated after 1985, esp among those getting chemotherapy

--more widespread use of non-alkylator based therapy (ABVD)

General population

ConclusionsConclusions• ABVD 6-8 cycles remains standard for

advanced HL outside of a clinical trial• Use of interim PET to modify therapy is a

question, not the answer• Radiation should not be routinely

administered, nor forgotten: role in LMM, E lesions…

• Decisions re: adopting more toxic regimens involves trade-offs for patients