Transplantation in CLL · 2013-02-14 · observation PFS . PFS TTRT OS FCR auto . The European Group for Blood and Marrow Transplantation 0 50 100 150 200 250 300 350 400 ... after

Peter Dreger Dept. Internal Medicine V

University of Heidelberg

Gent 25.01.2013

Transplantation

in CLL

http://www.ericll.org/index.php

Allogeneic SCT

= initiation of a permanent

immunotherapeutic process!

graft-vs-tumor effect (GVT/GVL)

Autologous SCT

= supportive measure to compensate

hematopoietic toxicity of single-hit

high-dose therapy

Months from randomisation Months from randomisation

TTRT

ASCT observation

PFS

PFS TTRT OS

FCR

auto

The European Group for Blood and Marrow Transplantation

0

50

100

150

200

250

300

350

400

20002001

20022003

20042005

20062007

20082009

2010

allo auto

EBMT: SCT for CLL 2000-2010 Update January 2012

http://www.ebmt.org/sitemap.html

The European Group for Blood and Marrow Transplantation

0

50

100

150

200

250

300

350

0

50

100

150

200

250

300

350

0

200

400

600

800

1000

1200

1400

1600

1800

Transplant activity for lymphoma

EBMT 2000-2010

auto

allo

Absolute numbers 2010 % increase 2000 -> 2009

CLL HL TCL DLC

L

FL MCL

DLCL HL MCL TCL FL CLL

-100

-50

0

50

100

150

Total lymphoma transplants 2010 (with CLL): allo 1732; auto 5891

The European Group for Blood and Marrow Transplantation The European Group for Blood and Marrow Transplantation The European Group for Blood and Marrow Transplantation

- Do GVL effects exist?

- Therapeutic benefit?

- Indications?

CLL and alloSCT:

Key questions

alloSCT for CLL: MRD response patterns

A: MRD- after CSA taper

CSA taper

GVHD

Ritgen et al, Leukemia 22:1377 (2008)


A: MRD- after CSA taper

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)


Dreger et al, Blood 116:2438 (2010)

MRD- immediately

after SCT (16%)

MRD- after CSA

taper (42%)

Other pattern

(42%)

Hahn et al, EBMT 2013

CLL3X (n=52)

MRD- immediately

after SCT (34%)

MRD- after CSA

taper (35%)

Heidelberg 2005-2012

(n=62)

Are MRD responses durable?

Results from landmark analyses

113

100

90

13 ineligible (no CLL, late

registration, comorbidity etc.)

10 no SCT (Richter‘s, ED,

no donor, refusal)

38 no continuous

MRD sampling

52 13 event <12mo,

CLL3X: Patient flow (MRD)

27 MRD-neg

at +12mo

11 MRD-pos

at +12mo

1 no MRD

at +12mo

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

Perc

en

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

ASH 2012, abstract #966 Dreger et al

ASH 2012, abstract #966 Dreger et al

12 36 60 84 108

0

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

ati

ve

clin

ical re

mis

sio

n

CLL3X 6-year follow-up: Relapse

by MRD negativity at +12mo (of 38 patients with MRD monitoring and event-free at mo +12)

53 3 no continuous

MRD sampling

Heidelberg 2005-2012: Patient flow (MRD)

3 MRD-neg

at +12mo

after REL

2 MRD-pos

at +12mo

after REL

9 MRD-pos

and ev.-free

at +12mo

66 13 too early

7 TRM

29 MRD-neg

and ev.-free

at +12mo

58% (29 of 50)

6% 18% 4%

14%


50

43

Heidelberg CLL 2005-2012:

Relapse by MRD negativity at +12mo (of 38 patients with MRD monitoring and event-free at mo +12)

12 36 60 84

0

25

50

75

100 +12 MRD+ (9)

+12 MRD- (29)

p<0.0001

Months from SCT

Perc

en

t re

lap

sed

Clinical Relapse MRD relapse of patients MRD- at 12months

12 36 60 84

0

50

100

7% (95%CI 0-68)

Months from SCT

Perc

en

t M

RD

rela

pse


Clinical impact of MRD negativity at the

+6mo landmark (Milan data)

Farina et al, Haematologica 94:654 (2009)



yes. Even in poor-risk disease.


- Indications?

CLL and alloSCT:

Key questions

PFS after RIC alloSCT for CLL

Study GCLLSG Seattle Boston FCGCLL Houston

n 90 82 76 40 86

PFS 38% (6y) 39% (5y) 43% (5y) 46% (3y) 36% (5y)

OS 58% (6y) 50% (5y) 63% (5y) 55% (3y) 51% (5y)

NRM 23% (6y) 23% (5y) 16% (5y) 27% (3y) 17% (1y)

Ext. cGVHD 55% 49-53% 64% 42% 56%

F/U mo 72 (7-129) 11-87 61 28 (3-71) 37(11-131)

0 24 48 72 96 1200

50

100

6-y EFS 38% (27, 48)

Months from SCT

Perc

en

t E

FS

GCLLSG ASH 2012; Sorror JCO 2008; Brown Leukemia 2012;

Michallet Exp Hematol 2012; Khouri Cancer 2011

What does that mean in

real life?

I Herth, U Hegenbart, S Dietrich, M Rieger, P Stadtherr, A Bondong, H

Tran, T Zenz, AD Ho, P Dreger

Dept Medicine V, University of Heidelberg, Germany

First evidence that alloSCT can improve the natural

course of poor-risk CLL as defined by the EBMT

consensus criteria:

A retrospective donor vs no donor comparison.

Department of Internal Medicine V

• Design:

Single center retrospective analysis

• Patient eligibility:

All consecutive patients referred

for alloSCT for CLL between June

2005 and July 2011

to the University of Heidelberg

Study design and patients


Eligibility for donor search was either

one of the three EBMT consensus criteria

or

Richter‘s transformation.

• symptomatic 17p-

• fludarabine refractoriness (non-response or relapse within 6 months after the last cycle)

• early relapse after intensive pretreatment (relapse after intensive treatment like FR, FCR, BR, R-CHOP or similar later

than 6 months but within 2 years)


Study population:

patients for whom a 9/10 or 10/10

matched related or unrelated donor could

be found within 3 months

Control population:

patients without 9/10 or 10/10 matched

donor found within 3 months


Overall survival (OS),

measured from the 3-month

landmark after donor search

initiation

(to eliminate the early relapse-

mortality favoring the donor group).

Primary endpoint


Donor

search

indication

(=EBMT risk

or Richter’s)

?

B

Observe OS

yes

Observe OS

8 lost w/i

3 months (6 dead PD, 1

refusal, 1 lost

to f/u)

Heidelberg donor vs no-donor CLL study Patient flow

134 113

3

105 SEARCH

8 No

search 5 refusal,

1 comorbidity,

2 lost to f/u R

E

F

E

R

R

A

L

no

21

MCL 2,

MZL 1

donor 9/10

within 3 Mo

83

no donor 9/10

within 3 Mo

14

Herth et al, EBMT 2012

0 12 24 36 48 60 720

25

50

75

100

p 0.011 ; HR 3.85 (1.36-10.8)

donor yes (83)

donor no (14)

55% (33-85)

78% (65-86)

Months from 3 month after start of search

Perc

en

t alive

Overall survival from 3 months after start of donor

search by donor availability (all patients with donor search completed, n = 97)

Follow-up 25 (0.5-80) months

Medizinische Klinik V


Variable Hazard

ratio Lower CL Upper CL p

Donor yes 0.29 0.15 0.65 0.003

Previous therapies >2 2.88 1.33 6.26 0.008

Age per decade 0.55 0.32 0.94 0.03

Donor availibility and overall survival:

Multivariate analysis Patients with completed search (3-months landmark), n=97

Variables not remaining in the model:

Search indication (EBMT criterion), Binet stage


0 12 24 36 48 60 720

25

50

75

100

p 0.011 ; HR 3.85 (1.36-10.8)

donor yes (83)

donor no (14)

55% (33-85)

78% (65-86)

Months from 3 month after start of search

Perc

en

t alive

Long-term survivors in no-donor group Medizinische Klinik V

m, 55y, early relapse,

5th-line treatment

m, 51y, fludara-refr.,

SCT (late donor),

a&w 55+ months

m, 57y, 17p-,

SCT (2mm donor),

a&w 75+ months




yes.


Yes! Even in poor-risk disease.

-> …but at what price?

- Indications?

CLL and alloSCT:

Key questions


n 90 82 76 40 86

Mucositis 3-4 6% 12% na <5% na

Infection 3-4 55% 60% na 48% na

Early death (< d +100)

<3% <10% <3% 0% 3%

NRM 23% (6y) 23% (5y) 16% (5y) 27% (3y) 17% (1y)

Ext. cGVHD 55% 49-53% 48% 42% 56%

F/U mo 72 (7-129) 11-87 61 28 (3-71) 37(11-131)

Toxicity of RIC alloSCT for CLL




NRM (%) by age groups

0%

10%

20%

30%

40%

50%

60%

100d 6 m 12 m

18-50 yo 51-60 yo 61-70 yo

Lymphoma Registry: Allo-SCT ’06-’10

http://www.ebmt.org/sitemap.html

25% of allografted patients

will suffer from QOL-relevant

chronic GVHD,

but…

0 120 240 360 480 600 720

0

20

40

60

80

100

cGVHD cum. incidence:67% at 12months

cGVHD prevalence:52% at 12months

on immunosuppression:39% at 12months

Days from SCT

Perc

en

t w

ith

cG

VH

D

his

tory

Heidelberg CLL 2005-2012:

Chronic GVHD over time (n=66)


Seattle CLL trial: OS and chronic

GVHD by donor (n=82)

Sorror et al, JCO 26:4912 (2008)

After 5 years, 76% of living patients are off immunosuppression



yes.


Cure! Even in poor-risk disease.

But 15-25% 2y-NRM.

- Indications?

CLL and alloSCT:

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

HI

GH

HI

GH

RISK

Leukemia 21:12-17 (2007)

Still valid in 2013?

EBMT CLL Transplant Consensus 2013

- Is poor-risk CLL still poor risk?

- Can alloSCT improve the outcome of

poor-risk CLL?


- Is poor-risk CLL still poor risk? - 17p-

1st-line treatment results in 17p- CLL

Overall response Median PFS (mo)

CLL

HL

DLCL

FL

MCL

Hallek 2010, Wierda 2011, Hillmen 2007, Stilgenbauer 2012, Badoux 2011, Fischer 2012

0

20

40

60

80

100

R-

FC

O-

FC

CD52 Lena CD52-

Dexa

0 12 24 36 48

R-FC

O-FC

CD52

Lena

CD52-D

R-B

R-Benda

*

* 27% of patients received alloSCT consolidation



- PA refractory

Treatment results in PA-ref CLL

Overall response Median PFS (mo)

CLL

HL

DLCL

FL

MCL

Badoux 2011a, Fischer 2011, Wierda 2010, Stilgenbauer 2012, Badoux 2011b; Lanasa 2010

0

20

40

60

80

100

R-

FC

R-

Ben

da

Ofa Flavo CFAR 0 12 24 36

R-Benda

CD52-D

Ofa

Flavo

CFAR

CD52

R-FC



- PA refractory

- Relapse within 2 years after intensive therapy

Overall survival after 1st salvage after

FC/FCR 1st-line failure: CLL8 data

PFS >24 months

Zenz et al, ASH 2010

OS from 2nd-line therapy (months)

PFS <6 months

PFS 12-24 months

PFS 6-12 months



yes, but

BCR kinase inhibitors:

Is the Gleevec of CLL

approaching?

CLL: B cell receptor signaling downstream

kinase targets and inhibitors

Wiestner et al, Blood Dec 6, 2012

Risk group n Response rate

All patients 61 67% (CR 2%)

PA-refractory 28 61%

17p- 20 65%

Bruton’s tyrosine kinase inhibitor Ibrutinib:

Phase Ib/II study in rel./ref. CLL (O’Brien et al, ASH 2011)

17p Del No (n=36)

17p Del Yes (n=20)

Median follow-up 9-12mo

PCYC-1102-CA

Progression-free Survival

Data cut-off of 19OCT2012

R/R + High-Risk R/R (n=85)

Est. PFS at 26 mo is 75%

Months on Study

+ Censored

Logrank p=0.0256

0 5 10 15 20 25

1.0

0.8

0.6

0.4

0.2

0.0

PF

S P

robabili

ty

50

Relapsed/Refractory patients

(n=85; 24 of them relapsed <24mo after immunohemotherapy)

ASH 2012, abstract #188 Byrd et al

PCYC-1102-CA

Patient Characteristics

TN ≥65 yrs (N=31)

R/R + HR (N=85)

Age, years Median (Range)

71 (65 – 84)

66 (37 – 82)

Fludarabine refractory - 48%

Prognostic Markers, % IgVH unmutated del(17p13.1) del(11q22.3)

55% 7% 3%

85% 35% 39%

51


PCYC-1102-CA


del(17p13.1)/del(11q22.3) Status

Months on Study


del17p (n=28)


del11q (n=23)


No del17p or del11q (n=29)


1.0

0.8

0.6

0.4

0.2

0.0

PF

S P

rob

ab

ility

0 5 10 15 20 25

52

Relapsed/Refractory including High-Risk R/R

+ Censored

Logrank p=0.0437


PCYC-1102-CA


del(17p13.1)/del(11q22.3) Status

Months on Study


del17p (n=28)


del11q (n=23)


No del17p or del11q (n=29)


1.0

0.8

0.6

0.4

0.2

0.0

PF

S P

rob

ab

ility

0 5 10 15 20 25

53

Relapsed/Refractory including High-Risk R/R

+ Censored

Logrank p=0.0437

Months0 6 12 18 24 30 36 42 48 54

0.0

0.2

0.4

0.6

0.8

1.0

CLL2O: Progression free survival

F-refr.: n = 61

17p- relapse: n = 28

17p- 1st-line: n = 42


ASH 2012, abstract #716 Stilgenbauer et al

• Superior disease control in poor-risk

CLL

• Low tox

• Virtually no CRs/mCRs, continuous

progressions in 17p- CLL

• Do they make SCT unnecessary - or

do they help getting patients to

transplant?

BCR kinase inhibitors (Ibrutinib):

The Gleevec of CLL?

↑

↓

↑

?



yes - but might be re-shaped once the

therapeutic value of BCR kinase

inhibitors has been defined

- Can alloSCT improve the outcome of

poor-risk CLL?


Can alloSCT improve the outcome of

poor-risk CLL? - 17p-

Allo-SCT in CLL: Effect of del 17p-

EBMT (retrospective; n=44)

Schetelig et al, JCO 26:5094-5100 (2008)

Allo-SCT in CLL: Effect of del 17p-

EBMT (retrospective; n=44) CLL3X (prospective;

17p- + TP53mut; n=24)

12 MRD-negative at 12mo landmark

MRD-negative at last f/u

Schetelig et al, JCO 26:5094-5100 (2008) Update June 2012

0 24 48 72 96 1200

50

100

TP53 del and/or mut (24)

TP53 normal (49)

1212

*

12

*1212

*12

12

*12

*12

*1212

Months from SCT

Perc

en

t even

t-fr

ee

*




- PA refractory


n 90 82 76 40 86

Higher age ++ (>55) - ++ (>65) - -

HCT-CI na ++ ++ (>0) na -

Unrelated

donor - - - na -

PA ref - - - na na

Active / bulky

CLL at SCT ++ ++ ++ - -

17p- - - - na na

Prognostic factors for PFS in RIC alloSCT for

CLL: Focus on purine analogue refractoriness






- PA refractory

- Relapse within 2 years after intensive therapy

Outcome of RIC alloSCT for CLL (by EBMT indication; Heidelberg 2005-2012, n=64)

0 12 24 36 48 60 72 840

20

40

60

80

100

p53 (22)

F-ref (26)

early rel (13)

Richter (3)

Months from Start of Seach

% P

FS

PFS OS

0 12 24 36 48 60 72 840

20

40

60

80

100

Months from Start of Search

% S

urv

ival


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

HI

GH

HI

GH

RISK

Leukemia 21:12-17 (2007)

Still valid in 2013 !

Conclusions:

- AlloSCT seems to have the potential to

improve the natural course of poor-risk

CLL

- The 2007 EBMT/ERIC CLL transplant

consensus is still valid in 2013

- New agents will hopefully improve but

probably not replace alloSCT

Many Thanks for Invitation and…

Med V

Heidelberg

M Rieger

F McClanahan

U Hegenbart

S Dietrich

M Hahn

I Herth

T Zenz

AD Ho

E Kimby

P Ghia

E Montserrat

C Moreno

EBMT

A van Biezen

H Finel

R Brand

K Cwynarski

D Niederwieser

M Michallet

D Milligan

T de Witte

J Schetelig

DCLLSG

M Ritgen

R Busch

T Zenz

M Hallek

S Böttcher

M Kneba

H Döhner

S Stilgenbauer

http://www.ericll.org/index.php

Documents

Transplantation in CLL · 2013-02-14 · observation PFS . PFS TTRT OS FCR auto . The European Group for Blood and Marrow Transplantation 0 50 100 150 200 250 300 350 400 ... after