The place and efficasy of allo-HSCT in replace/refrectory classical Hodgkin lymphoma

1. Afanasyev B.V.
СIC 725
The place and efficacy of allo-HSCT
in relapse/refractory
classical Hodgkin lymphoma
8 april, 2017
Sankt-Petersburg
A.Novik Memorial Lecture

2. Microenvironment
in Hodgkin Lymphoma
HD – “chimera” tumor,
infection and inflammation

3. Progress in lymphoma treatment
SEER (Surveillance, Epidemiology and End Results) Cancer Statistics Review,
1975-2008. National Cancer Institute: 2011
Increasing 5-year overall survival5-yearoverallsurvival
Hodgkin
lymphoma
Non-Hodgkin
lymphomas
Multiple
myeloma

4. First-line therapy is able to cure
or allows obtaining long-term remission:
• Burkitt lymphoma >90%
• DLBCL 60%-70%
• Hodgkin lymphoma 75-90%
• Marginal zone lymphomas 90%
• Т-cell lymphomas 40%
• Primary mediastinal lymphoma 80-90%
• Follicular lymphoma
– 5-year complete or partial remission (incurable) 50%
• Mantle cell lymphoma
– 10-year survival (incurable) 50%

5. Hodgkin lymphoma
Rusian Federation
 Incidence: 2.1/100000 people/year
 Russia = 146 267 288 (Russtat , 1st
Jan 2015)
 3164 patients with HD per year in Russia
 Cured by first-line chemotherapy – 2848 patients/year
 Primary resistant up to 10% → 316 patients/year
 Relapse after first-line chemotherapy, up to 30% → 854 patients/year
 Cured by second-line chemotherapy (auto-HSCT) – 427 patients/year
 Second-line chemotherapy unsuccessful* in up to 50% of pts → 427 Patients/year
 Refractory/relapsed HL → 743 patients/year
*relapse/inadequate response
Candidates for allo-HSCT
http://lymphoma.ru
Candidates for allo-HSCT

6. The effect of allo-HSCT directly depends on alloreactivity,
i.e. strength of graft-versus-lymphoma effect
Evidence of graft-versus-lymphoma effect Strength of graft-versus-lymphoma effect
R. Jones et al. 1991
Relapse probablility
auto-HSCT 43%%
allo-HSCT 18%

7. Allo-HSCT Auto-HSCT
Compatible
related donor
Compatible
unrelated donor
(10-9/10)
Alternative donor
(cord blood cells,
haploidentical)
CR1 Generally not
recommended
(III)
Generally not
recommended
(III)
Generally not
recommended
(III)
Generally not
recommended
(I)
Relapse
chemosensitive
No prior auto-HSCT
Developmental
(III)
Developmental
(III)
Generally not
recommended
(III)
Standard of care
(I)
Relapse, prior
auto-HSCT
chemosensitive
Standard of care
(II)
Standard of care
(II)
Clinical option
(III)
Clinical option
(III)
Refractory Developmental
(II)
Developmental
(II)
Developmental
(III)
Clinical option
(III)
A Sureda et al. Indications for allo- and auto-SCT for haematological diseases, solid tumours and immune
disorders: current practice in Europe, 2015. Bone Marrow Transplantation (2015), 1–20
Hodgkin lymphoma
Indications for bone marrow transplantation
EBMT 2015

8. Immunotherapy –
next step in lymphoma treatment
Immunotherapy does not demonstrate cross-resistance to
chemotherapy and radiotherapy! !
Immunotherapy
Targeted
therapy
Activation of immune system
Monoclonal
antibodies:
brentuximab
vedotin,
blinatumomab
Vaccines
Cell therapy
Checkpoint inhibitors
Allogeneic stem cell
transplantation

9. Sarina et al, Blood 2010
Hodgkin lymphoma
Overall survival and progression-free survival:
donor available (allo-HSCT) vs no donor (no allo-HSCT)
PFS OS

10. Immunoadoptive effect
Cytotoxic effect
Dose intensity and toxicity of conditioning
No
No-C
Very low
Micro-allo-SCT
Low
Non-MAC
(mini)
Intermediate
RIC
RTC
High
MAC-C
Very high
MAC-i
Conditioning regimens: immunoadoptive vs cytotoxic effect

11. Conditioning regimens in lymphomas, EBMT 2014
Courtesy to Anna Sureda, LWP Meeting, okt 2015
RIC

12. Fludarabine +Bendamustine (FluBe) conditioning
regimen and PTCY-based GVHD prophylaxis
in allo-HSCT for HL patients
Conditioning regimen = RIC, modified BFR*
-4 -3 -2 -1 0 1 2 3 4 5 6 7
Bendamustine 130 mg/m2
Fludarabine 30 mg/m2
HSCT
Cyclophosphamid
e 50 mg/kg
+/- Tacrolimus 0.03 mg/kg
+/- MMF 15 mg/kg
 Acceptable toxicity (↓ TRM )
 “Maximal” antitumor effect
 Reproducibility
 Economic aspects!
*Khouri et al, Blood, 2014
+
+
+
-

13. Conditioning regimen = RIC
FluBe, modified BFR (n=22)
p=0.004
Progression-free survivalOverall survival
p=0.006
FluBe, 54.5%
Another regimen,
17.9%
FluBe, 86.4%
Another regimen,
39.3%
Time after HSCT, months Time after HSCT, months
Median observation time: 2 years

14. GVHD prophylaxis = PTCY (n=25)
p=0.002
Progression-free survivalOverall survival
p=0.03
PTCY, 44%
ATG, 25%
PTCY, 87.5%
ATG, 37.5%
Time after HSCT, months Time after HSCT, months
Median observation time: 2 years

15. RIC vs MAC allo-HSCT
in relapsed or refractory Hodgkin Lymphoma
Sureda A J Clin Oncol. 2008 Jan 20;26(3):455-62.
Total 168 patients
RIC – 89
MAC – 79
In RIC group:
OS – better
PFS – trend to better
NRM – significantly less

16. Donor type in allo-HSCT for lymphoma
n=917 (2008-2013)
• Diagnosis
– FL n=202
– DLBCL n=221
– MCL n=140
– Т- and NK-cell lymphomas n=155
– Hodgkin lymphoma n=199
• Allogeneic HSCT
– Haplo (PTCY) n=185
– URD (with ATG) n=241
– URD (without ATG) n=491
Kanate A et al. Blood 2016
aGVHD Gr II-IV
2016
cGVHD

17. Non-relapse mortality Relapse /
progression
Progression-free
survival
Overall survival
Donor type in allo-HSCT for lymphoma
n=917 (2008-2013)
Kanate A et al. Blood 2016

18.  n= 26
 pre HSCT: complete
response 35% vs residual
disease 65%
 Haplo-HSCT
 RIC (Baltimore)
 BM
 Post-transplant CY
 CT+DLI (6) post HSCT
Raiola A, Bacigalupo A, Castagna L. et al. Unmanipulated
haploidentical BMT following non-myeloablative conditioning
and post-transplantation CY for advanced Hodgkin’s lymphoma.
Bone Marrow Transplant. 2014;49:190–194.

19. Survival of HL patients after allo-HSCT
according to disease status (n=51)
in the targeted therapy era
Overall survival Progression-free survival
p=0,1
Complete response, 66%
Partial response, 44%
SD/PD г, 22%
Complete response, 100%
Partial response, 77%
SD/PD, 37%
p=0,01
Months after SCT
Median follow-up 1.5 years
Months after SCT
CIC725

20. I.Glimelins and A.Diepstra, J Intern Med 2016; doi:10.11 11/joim.12582
Mechanisms of action of novel targeted drugs

21. Brentuximab vedotin
Younes A et al. N Engl J Med 2010; 363:1812-21 (appendix)

22. Brentuximab vedotin treatment experience
CIC725
Brentuximab vedotin N
Overall
In the treatment of r/r Hodgkin lymphoma
123
«bridge therapy» before allo-HSCT 26
After allo-HSCT 17
 Relapse treatment 13
 Prophylactic 4
Before and after allo-HSCT 14

23. Allo-HSCT in Hodgkin lymphoma patients
R.M.Gorbacheva Memorial Institute experience
Patients characteristics
Total number of patients 51
Age 30 (13-48)
ECOG status 2 (1-4)
Extranodal organs involved 60%
Median time since diagnosis 4 years
Median therapy lines 7 (4-10)
Prior auto-HSCT 34
Brentuximab vedotin as bridge therapy 26
Median number of courses 6 (1-9)
Status at allo-HSCT: Stab/Progr 21
Donor: MRD / MUD / partially matched 16 / 25 /10
Conditioning regimen: Flu+Benda 22
PTCY-based GVHD prophylaxis 25

24. 0
5
10
15
20
25
до BV после BV
полнаяремиссия
частичная ремиссия
стабилизация
прогрессирование
Overall response to BV as “bridge”
therapy before RIC allo-HSCT
Complete remission 42%
Partial remission 42%
Stabilization 11%
Progressive disease 5%
72%
8%
20%
34%
34%
8%
24%
CIC725
Complete remission
Partial remission
Stabilization
Disease progression
Before BV After BV

25. Brentuximab vedotin “bridge” therapy
prior to RIC аllo-HSCT
Patients characteristics CIC 725 CoH/FHCC
Total number 26 19
Median age 21 (17-32) 31 (23-55)
ECOG status 2 (1-3) 1 (0-2)
Extranodal disease 59% -
Median time since diagnosis 3.5 years -
Median therapy lines number 7 (4-10) 5 (3-8)
Prior auto-HSCT 65% 95%
Median number of BV cycles 6 (1-9) 8 (2-16)
CIC725

26. Overall survival in HL patients after BV
treatment: allo vs. no-allo
Time, months
Median survival
27 months
Median survival
not reached
allo-HSCT
no allo-HSCT
n=121
CIC725

27. Overall survival after Brentuximab vedotin
as “bridge” therapy for allo-SCT
Clinical outcome N=19
2 – year OS 79.3 %
Median follow-up 2 years
BV, 73%
No BV, 44%
p=0.016
CIC725

28. Co-stimulatory molecules Co-inhibitory molecules
I.Hude et al, Hematologica: 102(1):30-42, 2017
Potential targets for immune checkpoint
inhibitors on lymphocytes and tumor cells

30. Single center experience CIC 725
93 patients were included in the treatment
of refractory/relapse Hodgkin lymphoma with PD1 inhibitor
1.Patients with relapses after autoHSCT n=11
2.Refractory or relapse after brentuximab therapy n=15
3.Refractory Hodgkin lymphoma in patients, in whom autoHSCT was not done due to
resistant disease and brentuximab was not available n=39
4.Patients with relapses after autoHSCT and brentuximab therapy n=28
The response was evaluated every 3 months by PET/CT

31. PD-1 inhibitors immunotherapy in patients with r/r Hodgkin lymphoma
(R.M.Gorbacheva Institute for Children Hematology, Oncology and Transplantation data)
Patients characteristics CIC725
CheckMate
205
Number of patients (M/F) 93 (48/45) 80 (51/29)
Median age 30 (13-60) 37 (18-72)
Median previous therapy lines number 5 (2-10) 4 (5-15)
Median previous chemotherapy cycles number 18 (8-33) No data
Prior auto-HSCT 11 (12%) 0
Prior brentuximab vedotin 15 (16%) 0
Auto-HSCT +BV 28 (30%) 80 (100%)
No prior auto-HSCT , no brentuximab vedotin 39(41%) 0
Auto-HSCT + BV + allo-HSCT 4 0
Median follow-up, months 8.8 (2-13.5) 8.9
A.Younes et al, ASCO 2016

32. Best overall response during treatment
n=93
CR
PR
Stable
Progression
Indeterminate
response
71%
Response
CIC 725
N=93
(81 effect
was
evaluated)
CheckMate 205 (n=80)
A.Younes et al, Lancet 2016
Researchers IRC
Best overall
response
58 (71%)
58 (73%) 53 (66%)
Complete
response
23 (28%) 22 (28%) 7 (9%)
Partial
response
35 (43%) 36 (45%) 46 (58%)
Stable disease 5 (6%) 18 (23) 18 (23%)
Progression 3 (4%) 3 (4%) 6 (8%)
Indeterminate
response
15 (19%) 1 (1%)
3 (4%)
Alive
100%
Median follow-up 9 months

33. Post
chemo
All
patients
Auto-HSCT
and BV
naïve
(n=39)
Other
(n=54)
Number of
therapy
lines
5 5
Overall
survival
100% 100%
Median PFS,
months
10.7 12.9
CIC 725
Progression-free survival of patients treated with PD-1
inhibitor: patients with previous auto-HSCT and/or
brentuximab vedotin vs patients treated with chemotherapy
only
Median follow-up 9 months
Time, months
Progressionfreesurvival

34. Post allo-HSCT Hodkin lymphoma relapse
treatment
• Immunosuppression withdrawal
• Donor lymphocytes infusion
• New drugs:
- brentuximab vedotin
- nivolumab
• Second allo-HSCT

35. Author Year N Drugs OR (%) Median
PFS, mo
Median OS,
mo
OS (%) GVHD
(%)
Herbaux et al
(present study)
2016 20 Nivolumab 95 Не достиг Not reached 78 (16 mo) 30
Theurich et al 2013 4 DLI+BV 100 11.5 1 died 75
Tsirigotis et al 2016 16 BV +/- DLI (10
patients)
69 6 3 died 31
Carlo-Stella et al 2015 16 BV up to 16
cycles
69 7 25 61% (2
years)
Sala et al 2014 18 Bendamustine
+/- DLI (50%)
55 6 11 50% (4
years)
67
Anderlini et al 2012 27 DLI +/- CT 37 7.5 14 20% (4
years)
82
Peggs et al 2011 24 DLI +/- CT (10
patients)
79 18 Not reached 59%(4 years) 100
Anastasia et al 2014 22 Bendamustine 57 10 7 70%(1 year) No data
Herbaux C. et al, Blood, DOI 10.1182/blood-2016-11-749556
Post allo-HSCT HL relapses therapy

36. Gratwohl A., Baldomero H., Passweg J. Curr Opin Hematol. (2013) Nov;20(6):485-93

37. DLI efficiency according to diagnosis
CIC 725
Efficiency
Diagnosis ALL
(n=91)
NHL
(n=24)
HL
(n=22)
AML+MDS
(n=128)
CML
(n=29)
Overall response
rate
40%
(36/91)
42%
(10/24)
55% (12/22) 44%
(56/128)
62%
(18/29)
Preemptive DLI
(MRD/chimerism
reduction)
47%
(15/32)
2/2 None 37%
(11/30)
75%
(12/16)
Therapeutic DLI
(relapse/progres
sion)
36%
(21/59)
36%
(8/22)
55% (12/22) 46%
(45/98)
46%
(6/13)

38. Brentuximab vedotin for post allo-HSCT
relapses treatment
Patients characteristics CIC 725 Multicenter
N 14 25
Median age 21 (17-32) 32 (20-56)
M/F 8 / 5 13 / 12
ECOG 2 (1-3) 1 (0-2)
Days before progression / relapse 126 days (37 – 298) -
N= chemotherapy, comparison group 6 -
Gopal AK et al. Blood. 2012;120:560–568

39. Overall and progression-free survival in post
allo-HSCT relapse HL patients treated by BV
Chemo 50%
BV 100%
Gopal AK et al. Blood. 2012;120:560–568
P=0.028
BV 50%
Chemo 20%P=0.07
Progression-free survival
1-year overall survival
Progression-free survival 56%
Overall survival 92%
CIC725

40. Immune checkpoint inhibitors for post allo-HSCT
HL relapses treatment
OS = 78%
PFS = 56%
Group CIC 725 Herbaux
et al
Number of
pts
4 20
Overall
response
100% 95%
OS 100% 78%
aGVHD 0% 30%
Median
observation,
months
7 17
Herbaux C et al, Blood 2017

41. Conclusions
1) Allo-HSCT is an effective treatment method in relapsed of
refractory lymphoma patients population
2) Anti-CD30 and anti-PD1 drugs are effective in classic Hodgkin
lymphoma patients:
a. Brentuximab vedotin is effective as pre allo-HSCT “bridge” therapy and
post allo-HCT relapses treatment
b. PD1 inhibitors (nivolumab) are effective in heavily pretreated drug-
resistant Hodgkin lymphoma patients and may be used to increase allo-
HSCT effectiveness
3) Allo-HSCT from haploidentical donor is potentially effective,
especially in the following cases:
a. Use of reduced-intensity conditioning regimen
b. РТСу-based GVHD prophylaxis

42. Thank you for your attention!
Acknowledgements
CIC 725
Special thanks:
Natalia Mikhailova
Kirill Lepilk
Elena Kondakova
Liudmila Zubarovskaya