1 ebmt lymphoma working party 11th educational course treatment of malignant lymphoma: state of the...

1

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!