Management of Advanced Stage Hodgkin Lymphoma Michael Crump, MD, FRCPC Princess Margaret Hospital University of Toronto Toronto, Canada

Outline 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

Decline in mortality rate from HL in North America MOPP ABVD Aisenberg, Blood, 1999; Reprinted from Ries; NIH Publ 97-2789, 1997

HL Outcomes – Continued Improvement Brenner, et al. Blood, 2008 US SEER database: >16,000 pts 1980-2004 all 25-34y >60y 1980-84 2000-04 Relative survival: 5 y 73% 85% 10 y 62% 80%

Advanced 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 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? Epstein-Barr Virus (EBV) ~25-35% +ve by IHC (LMP-1), ISH (EBER-1) More common: males, older age (>45), mixed cellularity histology Older adults → less favourable outcome BCL-2 Cytokine levels Cytokine gene polymorphisms Tumour microenvironment etc…

Previous Therapeutic Observations in Advanced 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 Therapeutic Observations in Advanced 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 Lymphoma ABVD vs MOPP/ABV Hybrid Intergroup CALGB, ECOG, SWOG, NCIC ABVD MOPP/ABV p n 433 419 CR% 76 80 0.16 Progression % 10 11 5 y FFS% 63 66 0.42 5 y OS% 82 81 0.82

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 II 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 useful Intensification of COPP-ABV with IMEP (ifos, MTX, etoposide, prednisone) vs C-A GHSG 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 N pts CR(%) Progr’n (%) 5 y FFTF OS (yr) Esc BEACOPP 466 96 2 87 91 (5) BEACOPP 469 88 8 76 88 COPP-ABVD 260 85 10 69 83 ABVD 99 70 12 65 84 (5) BEACOPP 98 81 2 78 92 COPP-EBV-CAD 98 69 10 71 91 ABVD 261 67 5 85 90 (5) Stanford V 259 57 6 73 92 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 Prednisone 40 PO 1-14 Cycle length 21 days G-CSF day 8-15  

BEACOPP is superior to COPP-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 2000 BEACOPP v ABVD v CEC Federico M, J Clin Oncol 2009

Should escBEACOPP now be the 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 strategy GHSG HD12: 8 escBEACOPP vs 4 esc + 4 BEACOPP Advanced disease, age <65 No 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 advanced HL Doxorubicin 25 mg/m2 d1, 15 Bleomycin 10 mg/m2 d1, 15 Vinblastine 6 mg/m2 d1, 15 Dacarbazine 375 mg/m2 d1, 15

ABVD remains the standard for advanced HL Practical 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 advanced HL Practical 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 Older Patients HL age distribution (y) 16 – 60 80 % > 60 15 % > 70 7 % Characteristic age < 60 > 60 Stage limited:advanced 1:2 2:1 Stage IV % 20 33 B symptoms % 25 Histology- NS:MC 3:1 1:1 Grade 3-4 tox. % 65 Fatal toxicity % 1 - 2 3 - 10

Data courtesy of J Connors, BCCA HYBRID 38 ABVD 72 ODBEP 51 MOPP 38

Hybrid 38 ABVD 72 ODBEP 51 MOPP 38

Hodgkin Lymphoma Older 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?

Outcome of HL according to interim FDG PET and IPS Gallamini A, J Clin Oncol 2007

RCT of Observation vs RT for Patients with Bulky HL and Negative Post Chemo PET Scan Bulk: > 5 cm long axis* Chemo: VEBEP 6 cycles RT: 32 Gy Negative PET: no uptake Positive PET: “uptake in …abnormal area” 260 patients 2000-2006 n = 160 randomized stage I, II  2/3 B 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 Progression in 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: 817 Blood 2008

PET Scans and Early Progression in Advanced Hodgkin Lymphoma 311 patients: <CR after chemo  PET scan 66 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 benign Schaefer, 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 HL CD30 + - CD15 CD45 CD20 -/+ PAX5 sIg +/- EBV LMP1

NLPHL: German experience Nogova, et al. J Clin Oncol 2008 LP HL(%) classical HL(%) n=394 n= 7904 p CR 87 82 .003 PD 0.3 3.9 .0001 relapse 8.1 8.0 late rel 7.4 4.7 .02 death 4.6 9.6 .0004 second Ca 2.5 3.7 .27

Nodular LP Hodgkin Lymphoma 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 Patients Treated for Hodgkin’s Disease J Clin Oncol 2003

GELA H89 Trial: Chemotherapy +/- radiation for advanced stage HL; Causes of Death N = 533, median f/u 10 yrs 129 deaths: Hodgkin lymphoma PD/rel 60 (46%) treatment 15 salvage treatment 7 Second cancer 24 (19%) Cardiovascular 1 Unknown/not spec. 22 Ferme C, Blood 2006

Lung Cancer – Dramatic Effects of Age, Treatment, Smoking History >1 ppd smoker others RT>5 Gy AA chemo RR RR Treatment no no 1.0 6.0 yes no 20.2 7.2 no yes 16.8 4.3 yes yes 49.1 7.2

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

Conclusions 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