Allogeneic stem cell transplantation for non-Hodgkin's lymphoma

1. Allogeneic stem cell transplantation
for non-Hodgkin’s lymphoma
N.B.Mikhailova
CIC725

2. Evidence of a Graft-versus-Lymphoma Effect Assotiated
with Allogeneic Bone Marrow Transplantation
R. Jones et al. Blood, 77: 649-653, 1991
alloHSCT
alloHSCT
autoHSCT
autoHSCT
EFS Relapse

3. Conditioning regimen (RIC and MAC) for alloHSCT
in lymphoma , EBMT 2014
Courtesy to Anna Sureda, LWP Meeting, okt 2015

4. Non-Hodgkin’s lymphoma:
alloHSCT in 2001-2011 in Europe
Courtesy to Anna Sureda, LWP Meeting, okt 2015
The number of alloHSCT increased!!!
TCL >180%
FL >80%
DLBCL >80%
MCL 140%

5. DLBCL
alloHSCT
autoHSCT
MRD MUD (10-9/10)
Alternated donor (CBC.,
haplo-)
First remission
(intermedian and high
risk IPI at dx)
Generally not
recommended(III)
Generally not
recommended (III)
Generally not
recommended (III)
Clinical option (I)
Chemosensitive
relapse, CR2
Clinical option (II) Clinical option (II) Developed (III)
Standard
(I)
Chemosensitive
relapse after auto-
HSCT failure
Standard
(II)
Standard
(II)
Clinical option (III)
Generally not
recommended(III)
Resistance Clinical option (II) Clinical option (II) developed (III) Clinical option (II)
Indication for allo- and auto-SCT for Diffuse B-cell large
lymphoma, EBMT 2015
5
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

6. 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
Indication for allo- and auto-SCT
for Mantle Cell lymphoma, EBMT 2015
MCL
alloHSCT
autoHSCT
MRD MUD (10-9/10)
Alternated donor
(CBC., haplo-)
First remission
developed(III) developed (III)
Generally not
recommend (III)
Clinical option (I)
≥ 2CR or PR
without autoHSCT
Clinical option (II) Clinical option (II) Developed (III)
Standard
(I)
≥ 2CR or PR , after
autoHSCT
Standard
(II)
Standard
(II)
Clinical option (III)
Generally not
recommend(III)
Resistance Clinical option (II) Clinical option (II) developed (III)
Generally not
recommend (II)

7. 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
Indication for allo- and auto-SCT
for T-cell Lymphoma, EBMT 2015
T-cell lymphoma
alloHSCT
autoHSCT
MRD MUD (10-9/10)
Alternated donor
(CBC., haplo-)
First remission
Clinical option (II) Clinical option (II)
Generally not
recommended
(III)
Clinical option
(II)
Chemosensitive
relapse, ≥
CR2
Standard
(II)
Standard
(II)
Clinical option (III)
Clinical
options(III)
Resistance Clinical option (II) Clinical option (II)
Clinical options
(III)
Generally not
recommended
(II)

8. Problems:
• Absence of randomized studies on alloHSCT
• Heterogeneous groups of patients in the studies
• Lack of options for cytoreduction before
transplantation
• Poor survival in patients with active disease at
transplantation
• High relapse rate
• High NRM rate
• Weak “Graft-versus-Lymphoma” effect in aggressive B-
cell lymphoma

9. Long-term follow-up of patients with relapsed or
refractory non-Hodgkin’s lymphoma receiving allogeneic
stem cell transplantation
С.S.Link et al, Bone Marrow Transplantation, 1-3, 2016
Aggressive B-cell
lymphoma
T-cell lymphoma
Mantle cell lymphoma
Indolent B-cell lymphoma
Indolent B-cell lymphoma
Mantle cell lymphoma
T-cell lymphoma
Aggressive B-cell
lymphoma

10. Outcome of allogeneic stem cell transplantation in
lymphoma patients
2retrospective single center studies
M.Massoud et al, Rev Bras Hematol Hemoter. 2016; 38(4):314-319
Picleanu A.M.et al, Ann Hematol. 2017 May;96(5):787-796

11. Target and Immunotherapy for B-cell NHL
author IP lymphoma n OR (%) CR (%)
Goebeler M. et al, 2013 Blinatumomab FL, MCL,
DLBCL
35 69 37
Viardot A. et al, 2014 Blinatumomab DLBCL 21 43 19
Jacobsen E. et al, 2015 Brentuximab DLBCL 49 43 17
Jacobsen E. et al, 2015 Brentuximab PMBL 6 17 17
Goebeler ME, et al, Hematol Oncol, 2013,:31:197
Viardot A., et al,Blood, 2014, 124a 4460
Jacobsen E, et al, Blood, 2015,125:1394-1402

12. Single-agent activity of immune check point inhibitors in
R/R different tumors
E. Matsuki & A.Younes; Curr Treat Options in Oncol, 17:31, 2016

13. Types of non-Hodgkin’s lymphomas, transplanted in the
Institute of Children Oncology, Hematology and
Transplantation
Types of lymphomas Number (15)
B-cell lymphomas n=8
Diffuse large B- cell lymphoma 4
Mediastinal lymphoma 2
Mantle cell lymphoma 2
T-cell lymphomas n=7
Anaplastic large cell lymphoma 4
Peripheral T-cell lymphoma, non other
specified
2
Hepatolienal T-cell lymphoma 1

14. Characteristics of r/r lymphoma patients
characteristics В-NHL n=8 Т-NHL n=7
Age at transplantation 36 41
M/F 6/2 4/3
Stage Ann Arbor at Dx
II stage
III stage
IV stage
2-25%
1 (12,5%)
5 (62,5%)
-
2 (28,5%)
5(71,4%)
В-symptoms at Dx 7 (87,5%) 5(71,4%)
Median of chemotherapy lines 4 (2-5) 3(1-4)
autoHSCT 4 (50%) 2 (28.5%)
Patients without autoHSCT:
Primary resistance
Poor mobilizers
3
1
3
2
Median time before alloHSCT (months) 41,2 19,7
Remission status at alloHSCT
Complete response
Partial response
Stabilization/progression
2 (25%)
2(25%)
4 (50%)
2(28,5%)
1(14,2%)
4 (57%)

15. Cytoreduction therapy before alloHSCT in patients with
non-Hodgkin’s lymphoma
cytoreduction B-NHL T-NHL
Chemotherapy+/-
Rituximab
6 4
Brentuximab 1 (mediastinal lymphoma) 3
Ibrutinib+Chemotherapy 1 (mantle cell lymphoma) -

16. AlloHSCT for non-Hodgkin’s lymphoma in the Institute of
Children Oncology, Hematology and Transplantation
Donors for alloHSCT
 MRD : 53%
 MUD: 47%
Год проведения алло-ТГСК
Source of transplant:
 Bone marrow: 66,6%
 PB: 33,3%
1 1 1
2
4
1 1
4
Second alloHSCT: 2 patients
Number of alloHSCT by year

17. Conditioning regimens
RIC : 14 patients
MAC : 1 patient
conditioning number
Flu+Bu 3
Flu+Mel 2
Flu+Bendamustine+/- rituximab 9
-4 -3 -2 -1 0 1 2 3 4 5 6 7
Bendamustine 130 mg/m2
Fludarabine 30 mg/m2.
HSCT
Cy 50 mg/kg
+/- Tacrolimus 0,03 mg/kg
+/- MMF 15 mg/kg
*Khouri et al, Blood, 2014

18. Conditioning regimen BFR vs FCR
Khouri et al., Bone Marrow Transplantation, 2016, 1-6

19. Prophylaxis of GVHD in lymphoma patients in the Institute
of Children Oncology, Hematology and Transplantation
Regimen of GVHD prophylaxis number
CsA+Mtx 3 (20%)
Tacrolimus+Mtx 3(20%)
Tacrolimus+Mycophenolate mofetil 3(20%)
Cyclophosphamide + Tacrolimus+
Mycophenolate mofetil
4 (26,6%)
Cyclophosphamide alone 2 (13,3%)

20. Overall response after alloHSCT in patients with
non-Hodgkin’s lymphoma
Disease status Before
alloHSCT
After
alloHSCT
Complete response 4 9
Partial response 3 1
Stabilization 1 0
Progression 7 5
0
2
4
6
8
10
12
14
16
CR
CR
PR
PR
stable
PD
PD

21. OS and EFS in NHL patients after alloHSCT in the Institute
of Children Oncology, Hematology and Transplantation
0 10 20 30 40 50 60
месяцы
0,0
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0,9
1,0
Общаявыживаемость
OS =66,67%
months
Overallsurvival
0 10 20 30 40 50 60
months
0,0
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0,9
1,0
Event-free-survival
n=15
EFS =46,7%
Median to event 4,7 monthsMedian FU 1year

22. Overall survival of non-Hodgkin’s lymphoma patients with
alloHSCT : B-NHL vs T-NHL
В-NHL
alive -62,5%
Т-NHL
alive 71,4%
0 5 10 15 20 25 30 35 40 45 50
месяцы
0,0
0,2
0,4
0,6
0,8
1,0
Общаявыживаемость
n=8
0 10 20 30 40 50 60
Месяцы
0,0
0,2
0,4
0,6
0,8
1,0
Общаявыживаемость
n=7
Overallsurvival
Overallsurvival

23. GVHD in non-Hodgkin’s lymphoma
Acute GVHD
 skin -6 (5-grade 1; 1-grade 3)
 intestine-2 (grade 1)
 liver -2 ( 1 - grade 1 ; 1 – grade 4)
Chronic GVHD
 skin - 3 (1- grade 1;1- grade 2; 1 – grade 3)
 liver - 2 (grade 1)
 eye (grade 1)
 lung (grade 1)
3
2
1
8
skin
liver
eyes
no GVHD
3
2
8
1
1
skin
liver
no GVHD
eyes
lungs

24. Therapy and prophylaxis of relapse/progression after alloHSCT
patients Status before
alloHSCT
Therapy Outcome
Mediastinal #1 PR Brentuximab, DLI+Brentuximab,
Surgery (confirmed relapse of
lymphoma), radiotherapy,
Blinotumomab
CR, alive
Mediastinal #2 progression Brentuximab+DLI Progression, death
MCL progression DLI Progression, death
Hepatolienal progression DLI, chemotherapy+DLI Progression, death
Sezary stabilization DLI, ECP Progression, death
Anaplastic ALK+ CR DLI, DLI+Brentuximab,
radiotherapy, chemotherapy,
ALK- inhibitor
CR, alive
Prophylaxis
Peripheral T-cell CR DLI CR, alive
Anaplastic CR DLI CR, alive

25. New clinical trials
 A Safety and Effectiveness Study of Nivolumab in Combination With Brentuximab
Vedotin to Treat Non-Hodgkin Lymphomas (CheckMate 436) NCT02581631
 Nivolumab and Lenalidomide in Treating Patients With Relapsed or Refractory Non-
Hodgkin or Hodgkin Lymphoma NCT03015896
 A Study to Evaluate Safety, Pharmacokinetics, pharmacodynamics and Preliminary
Efficacy of the Combination of Ibrutinib With Nivolumab in Participants With
Hematologic Malignancies NCT02329847
 Study of Nivolumab in Patients With Relapsed or Refractory Diffuse Large B-
Cell Lymphoma (DLBCL) That Have Either Failed or Are Not Eligible for Autologous
Stem Cell Transplant (CheckMate 139) NCT02038933
 Study of Combined Check Point Inhibition After Autologous Hematpoietic Stem
Cell Transplantation in Patients at High Risk for Post-transplant Recurrence
(CPIT001) NCT02681302
 Ipilimumab or Nivolumab in Treating Patients With Relapsed Hematologic
Malignancies After Donor Stem Cell Transplant NCT01822509

26. Conclusion
• alloHSCT is effective in patients with NHL if
performed in remission
• Cytoreduction before alloHSCT is a problem
• Known immunotherapy agents have moderate
activity in B-cell NHL before and after alloHSCT

27. Acknowledgments
• CIC725
• Kondakova Elena
Thank you for your attention!