The document discusses how PET-guided treatment based on early PET scans after 2 cycles of chemotherapy can help escalate or de-escalate treatment for early and advanced stage Hodgkin lymphoma patients. Studies have shown that escalating treatment to BEACOPP for early stage patients who are PET-positive after 2 cycles significantly improves outcomes, while de-escalating treatment by omitting radiation for early stage PET-negative patients is also effective. Randomized trials are still needed but results so far suggest PET-guided escalation of treatment to BEACOPP for advanced stage PET-positive patients and de-escalation to AB

1. PET-guided treatment of
early and advanced stage
Hodgkin lymphoma
John Raemaekers
Nijmegen/Arnhem, the Netherlands
Session: Hodgkin lymphoma
Sunday, April 9, 2017
V Eurasian Hematology Forum
April 6–9, 2017
St. Petersburg, Russian Federation

2. Introduction
– Cure rates early stages >95%
• Combined modality
– Cure rates advanced stages >75-90%
• ABVD, eBEACOPP
– Toxicity
• Short-term
– neutropenia, anemia, neuropathy, etc
• Long-term
– second malignancies, cardiovascular disease,
pulmonary toxicity, fertility, fatigue, QOL, etc
» based on “historic” treatments

3. The challenge
• Avoid unnecessary failures in patients with
“high-risk” disease
• Avoid unnecessary treatments in patients
with “low-risk” disease
– Distinction risk groups far from optimal
– Discordance in evaluation new approaches
• balance short-term (PFS) vs. long-term (OS)

4. EORTC
GHSG IPS
CD30
TARC
CD68
Gene expression
The challenge
progress?
• imaging• pathology,
biomarker
• site(s) of
disease
• stage
Standard
treatment
Gender
Age
Family
history
cancer
And/or..
Fertility
And/or…..
Individualized Tx?
earlyPET
respons
TREAT
ME
RIGHT

5. PET-guided treatment of early and
advanced stage Hodgkin lymphoma
• Early PET and prognosis
• Early stages
– Escalation
– De-escalation
• Advanced stages
– Escalation
– De-escalation
• Prospects
• Conclusion

6. PET-guided treatment of early and
advanced stage Hodgkin lymphoma
• Early PET and prognosis
• Early stages randomized
– Escalation
– De-escalation
• Advanced stages randomized
– Escalation
– De-escalation
• Prospects
• Conclusion

7. PET score
Deauville criteria
– 1
• No uptake
– 2
• Slight uptake but < mediastinal pool
– 3
• Equal/slightly > blood, but < liver
– 4
• Moderately > liver
– 5
• Markedly > liver
NEG
POS

8. 1. Hutchings M, et al. Blood 2006;107:52–9.
2. Gallamini A, et al. J Clin Oncol 2007;25:3746–52.
3. Kostakoglu L, et al. Cancer 2006;107:2678–87.
4. Hutchings M, et al. Ann Oncol 2005;16:1160–8.
5. Gallamini A, et al. Haematologica 2006;91:475–81.
6. Cerci JJ, et al. J Nucl Med 2010;51:1337–43.
Early PET (PET2) and outcome
Courtesy of Peter Johnson, ASH 2016
And now
use early
PET
Early PETnegative= good prognosis
Early PETpositive = poor prognosis

9. PET-guided treatment of early and
advanced stage Hodgkin lymphoma
• Early PET and prognosis
• Early stages randomized
– Escalation
– De-escalation
• Advanced stages randomized
– Escalation
– De-escalation
• Prospects
• Conclusion
H10

10. Design H10 trial
early PETpositive: escalation
standard
2 ABVD
2 BEACOPPesc+IN-RT 30(+6)
H10F
P
E
T
experimt
2 ABVD
1 ABVD+IN-RT 30 Gy (+6)
-
+
standard
2 ABVD
2 BEACOPPesc+IN-RT 30(+6)
P
E
T
experimt
2 ABVD
2 ABVD+IN-RT 30 Gy (+6)
-
+
HL - CS I/II – supradiaphragmatic -
untreated - 15-70 yrs - no NLPHL
H10U*
R
P
E
T
P
E
T
R
-
or
+
-
or
+
*Unfavorable: CSII ≥4 nodal areas; age ≥50; ESR ≥50, no B-
symptoms; ESR ≥30+B-symptoms; MT ratio ≥0.35
superiority
superiority

11. • N=1950
• Nov 2006  June 2011
• Early PETpositive: 19%
• Median Follow-up: 4.5 yrs
• Cut off at least 3 years after last
patient in
H10 trial
early PETpositive: escalation
Andre et al, J Clin Oncol 2017, March 14 epub

12. H10 trial early PETpositive
BEACOPPesc vs. ABVD
HR (95% CI) = 0.42 (0.23, 0.74); p=0.002
5-yr PFS: 91% vs. 77%
BEACOPPesc+INRT
ABVD+INRT
intention-to-treat
Andre et al, J Clin Oncol 2017, March 14 epub

13. H10 trial early PETpositive
unfavorable vs. favorable
Std.
ABVD
N=192
Exp.
BEACOPPesc
N=169
N (%) N (%)
PD/relapse or death,
whichever first
41 (21.4) 16 (9.5)
-unfavorable 36/138
(26.0)
13/126
(10.3)
-favorable 5/54
(9.2)
3/43
(6.9)
intention-to-treat
Andre et al, J Clin Oncol 2017, March 14 epub

14. H10 trial early PETpositive
BEACOPPesc vs. ABVD
HR (95% CI) = 0.45 (0.19, 1.07); p=0.062
5 yr OS: 96% vs. 89%
BEACOPPesc+INRT
ABVD+INRT
Andre et al, J Clin Oncol 2017, March 14 epub

15. PET-guided treatment of early and
advanced stage Hodgkin lymphoma
• Early PET and prognosis
• Early stages randomized
– Escalation
– De-escalation
• Advanced stages randomized
– Escalation
– De-escalation
• Prospects
• Conclusion
RAPIDH10

16. Design H10 trial
early PETnegative: de-escalation
standard
2 ABVD
2 ABVD
H10F
P
E
T
experimt
2 ABVD
1 ABVD+IN-RT 30 Gy (+6)
-
+
standard
2 ABVD
4 ABVDP
E
T
experimt
2 ABVD
2 ABVD+IN-RT 30 Gy (+6)
-
+
R
H10U*
R
P
E
T
P
E
T
-
or
+
-
or
+
non-inferiority
non-inferiority
*Unfavorable: CSII ≥4 nodal areas; age ≥50; ESR ≥50, no B-
symptoms; ESR ≥30+B-symptoms; MT ratio ≥0.35
HL - CS I/II – supradiaphragmatic -
untreated - 15-70 yrs - no NLPHL

17. • N=1950
• Nov 2006  June 2011
• Early PETnegative: 81%
– Favorable 87%
– Unfavorable 76%
• Median Follow-up: 5.1 yrs
• Cut off at least 3 years after last
patient in
H10 trial early PETnegative
de-escalation
Andre et al, J Clin Oncol 2017, March 14 epub

18. H10 trial early PETnegative
de-escalation
HR (95% CI) = 1.45 (0.8, 2.5)
Non-inferiority p=0.908
5-yr PFS 90% vs. 92%
ABVD+INRT
ABVD
HR: Hazard Ratio ABVD,no INRT vs. ABVD+INRT
intention-to-treat
RT
ABVD
5-yr PFS 87.1% vs. 99%
ABVD+IN
HR (95% CI) = 15.8 (3.79, 66.07)
Non-inferiority p=0.986
5-yr PFS 87.1% vs. 99%
Favorable median FU 5.1 yrs
Raemaekers et al, J Clin Oncol 2014;32:1188; Andre et al, J Clin Oncol 2017, epub
Unfavorable

19. PET3 ABVD
+
-
1 ABVD + IFRT
R
No RT
IFRT
UK/NCRI RAPID trial stage I/IIA
Radford J, et al. N Engl J Med 2015;
• N=602; median follow-up 5 years
• PET(3)negative: 75%
• In fact ”end of treatment”- PET
• PFS primary endpoint
• Study did not show non-
inferiority
• PET3 negative pts have a very
good prognosis, regardless of
additional RT or noRT
3-year PFS
94.6 vs 90.8%
Difference=-3.8%
(95% CI:-8.8 to1.3%)

20. OS (5) 100.0% vs 99.6% OS (5) 96.2% vs 98.1 %
H10
Favorable
H10
Unfavorable
RAPID
No risk factors
OS (3) 97.1% vs 99.5%
Early stages
de-escalation and OS
Radford et al, N Engl J Med 2015; 372:1598
Raemaekers et al, J Clin Oncol 2014;32:1188; Andre et al, J Clin Oncol 2017, epub

21. Summary early PET adaptation
early stages
• Early PETpositive, especially “U”:
– Escalation from ABVD to eBEACOPP significantly
improves PFS, and possibly OS
– Should become new standard of care
• Early PETnegative, especially “F”:
– Combined modality (ABVD+INRT) reduces risk of
relapse
BUT
– Excellent outcome, even after ABVD alone

22. PET-guided treatment of early and
advanced stage Hodgkin lymphoma
• Early PET and prognosis
• Early stages randomized
– Escalation
– De-escalation
• Advanced stages randomized
– Escalation
– De-escalation
• Prospects
• Conclusion
GTIL/FIL HD 0607, GHSG HD 18

23. PET-guided escalation
randomized trials in advanced stages
• GHSG HD 18
– Early PETpositive (40%!!)
• 6/8eBEACOPP vs.
2+4/6eBEACOPP+
Rituximab
• No significant difference
in PFS (3): 91% vs 93%
• GTIL/FIL HD 0607
– Early PETpositive (20%!!)
• 4eBEACOPP+4BEACOPP
vs. 2+2eBEACOPP+
4BEACOPP+ Rituximab
• No significant difference
in PFS (4 ): 69% vs 68%
Borchmann et al, ASH, 2014 Gallamini et al, Haematol Oncol 2015

24. PET-guided escalation
non-randomized data advanced stages
• Israeli H2 Study
– Dann et al
• GTIL study 0607
– Gallamini et al
• US Intergroup S0816
– Press et al
• Italian HD0801
– Zinzani et al
• Indian study
– Ganesan et al
• RATHL
– Johnson et al
• And many other reports
• Mostly start with ABVD and
escalation to eBEACOPP-like or
high-dose Tx
• Historic controls mainly 6-8
cycles ABVD
• Various % early PET positivity
• Assumption: standard
treatment PFS 20-40% (in line
with prognostic studies on
early PET)
• Suggest improved PFS

25. PFS (3) 68%
Johnson et al, N Engl J Med, 2016;374:2419
PET-guided escalation
RATHL trial, non-randomized
2 ABVD
PET
- +
R
4 ABVD 2 AVD
4 eBEACOPP or
6 BEACOPP-14
RATHL
• Stage IIB risk, III, IV
• N=1119
• 16% early PETpositive

26. PET-guided treatment of early and
advanced stage Hodgkin lymphoma
• Early PET and prognosis
• Early stages randomized
– Escalation
– De-escalation
• Advanced stages randomized
– Escalation
– De-escalation
• Prospects
• Conclusion
RATHL, LYSA AHL2011,
GHSG HD 18

27. 2 ABVD
PET
-
R
4 ABVD 4 AVD
2 eBEACOPP
RATHL GHSG HD18
2 eBEACOPP
R
6 eBEACOPP
LYSA AHL2011
Delete drug Reduce # cycles Decrease intensity scheme
Courtesy of Peter Johnson, adapted
PET-guided de-escalation
randomized trials in advanced stages
PET
-
R
4 eBEACOPP 2 eBEACOPP
PET
-
4 ABVD

28. • Stage IIB risk, III, IV
• >=18 yrs
• N=1119 entered
• Stage II: 41.6%
• IPS 0-3: 81.7%
• N=935 (84%): early PETneg
• ABVD, n=470
• AVD, n=465
• Median FU 41.2 mos (2.0-79.7)
Johnson et al, N Engl J Med, 2016;374:2419
PET-guided de-escalation
RATHL trial
PFS(3)
ABVD 85.7% vs.84.4% AVD
OS(3)
ABVD 97.2% vs. 97.6% AVD
2 ABVD
PET
-
R
4 ABVD 4 AVD

29. PET-guided de-escalation
randomized trials in advanced stages
• GHSG HD 18 (n=1005)
– Early(2) PETnegative (60%)
• 6/8eBEACOPP vs.
2eBEACOPP+2eBEACOPP
• Results 2017
• LYSA AHL 2011 (n=782)
– Early(2) PETnegative (88%)
– 6eBEACOPP vs.
2eBEACOPP+4ABVD
PFS(2): 91.6% vs. 88.3% (p=0.79)
Engert, personal communication Casasnovas et al, ASH, 2015

30. PET-guided treatment of early and
advanced stage Hodgkin lymphoma
• Early PET and prognosis
• Early stages randomized
– Escalation
– De-escalation
• Advanced stages randomized
– Escalation
– De-escalation
• Prospects
• Conclusion

31. Prospects
• Results GHSG trials in early (HD16) and
advanced disease (HD18)
– 2ABVD+IFRT vs 2ABVD, no RT: if PET(2) negative
– 6eBEACOPP vs 4 eBEACOPP: if PET(2) negative
• Improve predictive power of PET
– SUVmax, TMTV, TLG
• Very early PET(1) better?
• New treatment modalities
• New prognostic biomarkers?

32. PET-guided treatment of early and
advanced stage Hodgkin lymphoma
• Early PET and prognosis
• Early stages
– Escalation
– De-escalation
• Advanced stages
– Escalation
– De-escalation
• Prospects
• Conclusion
Optimal timing?

33. Conclusion
• Early PET (PET after 2 cycles of chemotherapy) adaptation allows for
escalation and de-escalation
• In early stages
– escalation (ABVD to eBEACOPP) significantly improves outcome in
early PETpositive groups
– de-escalation by omitting RT in earlyPET negative groups, is
defensible in individual pts, though relapse risk is increased
• In advanced stages
– escalation (ABVD to eBEACOPP) in early PETpositive groups is
promising but not well tested in randomized settings
– de-escalation (eBEACOPP to ABVD; ABVD to AVD) in early
PETnegative groups retains efficacy and reduces toxicity
• Early PET adapted treatment is new standard of care for pts
with HL TREAT
ME
RIGHT

34. Acknowledgements
• The H10 trial Intergroup team
– Co-coordinators: Marc Andre, Massimo Federico,
Theodore Girinsky, Catherine Fortpied
– Central data center, data managers
• The financial supports
• The trial patients
• Martin Hutchings
• Peter Johnson