1 ebmt lymphoma working party 11th educational course treatment of malignant lymphoma: state of the...
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EBMT Lymphoma Working Party11th Educational Course
Treatment of Malignant Lymphoma: State of the Art and the Role of Stem Cell
Transplantation25-26 September 2015, Heidelberg, Germany
GVHD & GVL in the lymphoma setting: The case of CLL
Peter DregerDept Medicine VUniversity of Heidelberg
22
The EBMT database 2015Trends in lymphoma transplants
LWP activity report
0
50
100
150
200
250
300
350
400
450
0
200
400
600
800
1000
1200
1400
1600
1800
2000
auto
allo
Absolute numbers 2013
CLL HL TCL DLCL
FL MCL
DLCL HL MCL TCLFL CLL
Total lymphoma transplants 2013 (w/o CLL): allo 1652; auto 5992
CLL FL
TCLHL DLCL
HL FL CLL
- do GVL effects exist ?
GVL vs GVHD in CLL: Key questions
- Plateau after RIC ?
Evidence for GVL: Bullet points
Conditioning Regimens: Immunosuppressive vs anti-tumor activities (adopted from Champlin et al)
Immunosuppression
Mye
losu
ppre
ssio
n / T
oxic
ity
Flu/Cy
Bu/CyTBI12/Cy
BEAM
TBI8/F
TBI4/F
TBI2/F
MEL150/F
Bu8/F
„MAC“
„NMA“
„RIC“
Study GCLLSG Seattle Boston FCGCLL Houston Heidelb. UK/IRL
n 90 82 76 40 86 66 50
Mucositis
3-4
6% 12% na <5% na na na
Infection 3-4 55% 60% na 48% na na na
Early death (< d +100)
<3% <10% <3% 0% 3% 3% 2%
NRM 23% (6y)
23% (5y)
16% (5y)
27% (3y)
17% (1y)
24% (3y)
15% (4y)
Ext. cGVHD 55% 49-53% 48% 42% 56% 53% 48%
Toxicity of RIC alloSCT for CLL
Dreger Blood 2013; Sorror JCO 2008; Brown Leukemia 2013; Michallet Exp Hematol 2013; Khouri Cancer 2011; Hahn EBMT 2014; Richardson BJH 2013
Survival after RIC alloSCT for CLLStudy GCLLSG Seattle Boston FCGCLL Houston Heidelb. UK/IRL
n 90 82 76 40 86 77 50
2-y PFS 50% >50% n.a. 57% 40%* 58% 70% *
5-y PFS 42% 39% 43% 46% 36%* 52% 55%*
2-y OS 75% >60% n.a. 63% 63% 78% 83%
5-y OS 63% 50% 63% 55% 51% 63% 75%
F/U mo 72 (7-129) 11-87 61 28 (3-71) 37 (11-131) 37 (12-101) 51 (11-143)
0 24 48 72 96 1200
50
100
6-y EFS 38% (27, 48)
Months from SCT
Per
cen
t E
FS
Dreger Blood 2013; Sorror JCO 2008; Brown Leukemia 2013; Michallet Exp Hematol 2013; Khouri Cancer 2011; Hahn BMT 2015; Richardson BJH 2013
0 12 24 36 48 60 72 84 960
50
100
5-y EFS 49% (33, 65)
Months from SCT
Per
cen
t E
FS
* Current PFS
- Plateau after RIC- Efficacy of donor lymphocyte infusions
?
Evidence for GVL: Bullet points
0 12 24 36 48 600
25
50
75
100
2-y OS 54% (30, 77)Med OS 37mo
Months from Relapse after HSCT
Pe
rce
nt
Su
rviv
al
Overall survival from relapse after HSCT(n = 25 of 87)
MRD-neg after DLI + R
11.03.2015
- Plateau after RIC- Efficacy of donor lymphocyte infusions- Detrimental effect of T cell depletion
?
Evidence for GVL: Bullet points
AlloBMT for CLL using ex-vivo CD6 TCD(Dana Farber results, n = 25)
Gribben et al, Blood 106:4389 (2005)
- Plateau after RIC- Efficacy of donor lymphocyte infusions- Detrimental effect of T cell depletion- Protective effect of chronic GVHD
?
Evidence for GVL: Bullet points
CLL: Relapse risk and chronic GVHD(EBMT survey, n = 77)
Leukemia 17:841 (2005)
0 12 24 36 480
25
50
75
100
after cGVHD onset
cGVHD always absent
Months from SCT
Per
cen
t w
ith
rel
apse
or
pro
gre
ssio
n
- Plateau after RIC- Efficacy of donor lymphocyte infusions- Detrimental effect of T cell depletion- Protective effect of chronic GVHD- Minimal residual disease (MRD) kinetics ?
Evidence for GVL: Bullet points
CLL: Quantitative MRD assessment by 4 color flow cytometry (MRD-flow)
a = CD19+ B cellsb = exclude doubletsc = CD5- backgroundd = CD5+ CD20low
e = CD43+ CD20low
f = CD43+ CD5+ 10E-4
Böttcher et al, LEUKEMIA 2004; Rawstron et al, LEUKEMIA 2007
Sensitivity 1 in 104
alloSCT for CLL: MRD response patterns
A: MRD- after CSA taper
0 500 1000 1500 2000
days
1E-5
1E-4
1E-3
1E-2
1E-1
1E+0
MR
D l
ev
el
CSA taper
GVHD
Dreger et al, Blood 116:2438 (2010)
MRD- immediately after SCT (16%)
MRD- after CSA taper (42%)
Other pattern (42%)
Ritgen et al, Leukemia 22:1377 (2008)
CLL3X (n=52)
- GVL effects do exist- Are GVL effects durable
?
GVL vs GVHD in CLL: Key questions
Clinical impact of MRD negativity on disease control after alloHSCT (landmark studies)
Farina et al, Haematologica 94:654 (2009)Richardson et al, Br J Haematol 160:640 (2013)
UK (9-month landmark) Milan (6-month landmark)
CLL3X 6-year follow-up: Relapse by MRD negativity at +12mo
(of 38 patients with MRD monitoring and event-free at mo +12)
12 36 60 84 1080
50
100 +12 MRD+ (10)
+12 MRD- (28)
HR 26.2 (6-115); p 0.0001
Months from SCT
Per
cen
t re
lap
sed
Clinical Relapse MRD or clinical relapse
36 60 84 1080
50
100
16% (95%CI 1-50)
Months from SCT
Perc
en
t M
RD
or
clin
ical re
lap
se
Dreger et al, Blood 121:3284 (2013)
12 36 60 84 1080
50
100
16% (95%CI 1-51)
17p-
TP53 mut
NOTCH1 mutSF3B1 mut
no marker
Months from SCT
Pe
rce
nt
no
t in
MR
D-n
eg
ativ
ecl
inic
al r
em
issi
on
CLL3X 6-year follow-up: Relapse by MRD negativity at +12mo
(of 38 patients with MRD monitoring and event-free at mo +12)
Blood 121:3284 (2013)
12 36 60 84 1080
25
50
75
100 +12 MRD+, GVL pattern #4,5 (8)
+12 MRD-, GVL pattern #1 (19)
HR 6.1 (1.3-29.4); p=0.026HR 44.2 (6.1-317); p=0.0002
+12 MRD-, GVL pattern #2,3,5 (24)
HR 6.2 (0.74-51.6);p 0.092
Months from SCT
Per
cen
t re
lap
sed
Clinical Relapse MRD relapse of 43 patients MRD- at 12months
12 36 60 84 1080
50
1005y 26% (95%CI 2-62) GVL pattern #1 (19)
GVL pattern #2,3,5 (24)5y 6% (95%CI 0-68)
HR 4.13 (0.71-24); p 0.12
Months from SCT
Perc
en
t M
RD
rela
pse
Hahn et al, BMT 2015
alloSCT in CLL: long-term disease control by GVL pattern
(Heidelberg; patients with MRD monitoring and event-free at mo +12)
- GVL effects do exist- GVL effects are mostly durable- Can we have GVL w/o (chronic) GVHD
?
GVL vs GVHD in CLL: Key questions
Can we separate GVL from GVHD byT cell depletion?
MRD- immediately after SCT (56%)
MRD- after CSA taper (2%)
Other pattern (25%)
MRD- after DLI (12%)
DLI: 31/50 (62%)
(19 pre-emptive, 12 therapeutic)
Ext. cGVHD 48%
- GVL effects do exist- GVL effects are mostly durable- Can we have GVL w/o GVHD: not yet- Does GVL help in real life
GVL vs GVHD in CLL: Key questions
?
0 12 24 36 48 60 720
25
50
75
100
HR 0.38 (95% CI 0.17-0.85); p=0.014
donor no (14)
donor yes (83)
55% (34%-90%)
78% (95%CI 69%-88%)
Months from 3-month landmark
Per
cen
t al
ive
OS from 3-month landmark after start of search by compatible donor availability
(high-risk CLL; donor vs no-donor comparison, n=97)
Median follow-up 28 months
Herth et al, Ann Oncol 25:200 (2014)
- GVL effects do exist
- GVL effects are mostly durable
- Can we have GVL w/o GVHD: not yet
- Does GVL help in real life: it used to do
- Indications
GVL vs GVHD in CLL: Key questions
?
EBMT CLL transplant consensus
allo-SCT is a reasonable treatmentoption in poor-risk CLL:–.Relapse <24 mo after intensive treatment(purine analogue combinations or auto-SCT)
–.p53 mutation with treatment indication
–.Non-response or early relapse (<12 mo) afterpurine analogue-based therapy(= fludarabine resistance)
VERY
HIGH
HIGH
RISK
Leukemia 21:12-17 (2007)
2929
The EBMT database 2015Trends in lymphoma transplants
LWP activity report
0
50
100
150
200
250
300
350
400
450
-20
-15
-10
-5
0
5
10
15
20
25
0
200
400
600
800
1000
1200
1400
1600
1800
2000
auto
allo
Absolute numbers 2013 % change 2011 -> 2013
CLL HL TCL DLCL
FL MCL
DLCL HL MCL TCLFL CLL
Total lymphoma transplants 2013 (w/o CLL): allo 1652; auto 5992
-60
-50
-40
-30
-20
-10
0
10
20
CLL FL
TCLHL DLCL MCL
HL FL CLLMCLDLCL TCL
Along came…
→ alloHSCT in HR-CLL: Better to be put…
…into the museum?
Months
17p- R/R patients under Ibrutinib (PCYC 1102, n=28) versus
R-Idelalisib (116, n=42) versus HR patients undergoing HSCT (Heidelberg; n=77)
Overall survival until 30-month landmark
0 12 24 36 48 60 72 84 960
25
50
75
100
Months
Per
cen
t S
urv
ival
Months
17p- R/R patients under Ibrutinib (PCYC 1102, n=28) versus
R-Idelalisib (116, n=42) versus HR patients undergoing HSCT (Heidelberg; n=77)
Overall survival until 30-month landmark
0 12 24 36 48 60 72 84 960
25
50
75
100
Months
Per
cen
t S
urv
ival
??
Months
17p- R/R patients under Ibrutinib (PCYC 1102, n=28) versus
R-Idelalisib (116, n=42) versus HR patients undergoing HSCT (Heidelberg; n=77)
Overall survival until 30-month landmark
0 12 24 36 48 60 72 84 960
25
50
75
100
Months
Per
cen
t S
urv
ival
??Consumer health warning:
This is not a fair
comparison!
Refractory CLL and transplantation:
What to do during the
current phase of transition to the BCRi era?
Refractory CLL (FR; early REL; 17p-/TP53_R/R)
Novel agents
No Response Response
Continue NAHSCTFactors favoring options
(if no clinical trial comparing HSCT with novel agent is available)
High disease risk- High-risk cytogenetics (17p-, TP53mut, 11q-)Low transplant risk- Younger age- No comorbidity- Well-matched donor
Lower disease risk- No high-risk cytogenetics
Higher transplant risk- Older age- Significant comorbidity- Mismatched donor
Patient’s desires/expectations
consider (after alternative novel agent)
Blood 2014; 124:3841
Can pathway inhibitors make transplant better?
Median OS after CLL progression after allo-SCT: 36 (24-4) months
5 CLL patients on ibrutinib
(N = 52)(N = 20)
0 12 24 36 48 600
25
50
75
100
2-y OS 54% (30, 77)Med OS 37mo
Months from Relapse after HSCT
Pe
rce
nt
Su
rviv
al
Overall survival from relapse after HSCT(n = 25 of 87)
MRD-neg after DLI + R
11.03.2015
Overall survival from relapse after HSCT(n = 25 of 87)
31.03.2015
0 12 24 36 48 600
25
50
75
100
2-y OS 54% (30, 77)Med OS 37mo
Months from Relapse after HSCT
Pe
rce
nt
Su
rviv
al
MRD-neg after DLI + R
On Ibrutinib
MRD-neg after Ibrutinib + DLI
Thank you CLL3X trialS StilgenbauerR BuschM RitgenS BöttcherD BeelenS CohenJ SchubertN SchmitzM HallekT ZenzH Döhner
LWP/CMWPA BoumendilH FinelC KyriakouJJ LuanAnna Sureda
A van BiezenR BrandD MilliganN KrögerM SobhJ ScheteligT de WitteM Michallet
MRD P CorradiniC MorenoS BöttcherM Ritgen
Med VM Hahn S DietrichL SellnerAD HoT LuftU Hegenbart
…and you for your interest!