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

2. 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

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

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

5. 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

6. 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%

7. 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…

8. 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

9. 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

10. Advanced Hodgkin Lymphoma ABVD vs MOPP/ABV Hybrid
Intergroup CALGB, ECOG, SWOG, NCIC
ABVD MOPP/ABV p n
CR%
Progression % 10 11
5 y FFS%
5 y OS%

11. 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

12. 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

13. 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

14. Recent Randomized Trials of Novel Regimens
in Advanced Hodgkin Lymphoma
N pts CR(%) Progr’n (%) 5 y FFTF OS (yr)
Esc BEACOPP (5)
BEACOPP
COPP-ABVD
ABVD (5)
BEACOPP
COPP-EBV-CAD
ABVD (5)
Stanford V
CR: complete response rate; FFTF: freedom from treatment failure; OS: overall survival

15. BEACOPP Escalated mg/m2 day
Bleomycin 10 IV 8
Etoposide 200 IV 1-3
Doxorubicin 35 IV 1
Cyclophos 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

16. 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

17. GISL HD 2000 BEACOPP v ABVD v CEC
Federico M, J Clin Oncol 2009

18. 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

19. 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

20. 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

21. 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

22. 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)

23. Hodgkin Lymphoma Older Patients
HL age distribution (y)
16 – %
> %
> %
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

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

25. Hybrid 38
ABVD 72
ODBEP 51
MOPP 38

26. 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

27. FDG PET?

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

29. 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 n = 160 randomized
stage I, II  2/3
B symptoms  ½
Radiation: mantle, inv Y, para-aortic
Picardi M, et al. Leuk Lymph, 2007

30. Relapse: Chemo alone: 11/80 (14%) Chemo + RT: 2/80 (2.5%)
Picardi,et al. Leuk Lymph, 2007

31. 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

32. 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

33. 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

34. 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

35. Pathology:Nodular lymphocyte predominant HL
Marker
Classical HL
Nodular LP HL
CD30 + -
CD15
CD45
CD20
-/+
PAX5
sIg
+/-
EBV LMP1

36. NLPHL: German experience Nogova, et al. J Clin Oncol 2008
LP HL(%) classical HL(%) n=394 n= 7904 p CR PD relapse late rel death second Ca

37. 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

38. 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

39. Long-Term Cause-Specific Mortality of Patients Treated for Hodgkin’s Disease J Clin Oncol 2003

40. 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
salvage treatment 7
Second cancer (19%)
Cardiovascular
Unknown/not spec
Ferme C, Blood 2006

41. Lung Cancer – Dramatic Effects of Age, Treatment, Smoking History
>1 ppd
smoker others
RT>5 Gy AA chemo RR RR
Treatment
no no
yes no
no yes
yes yes

42. Change in Systemic Chemotherapy?
Example of secondary AML (JNCI, 2006)
>35,000 1 yr HL survivors
14 cancer registries (Nordic, N America)
pts treated
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)

43. General population

44. 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