Corso nazionale SIE diaggiornamento in ematologia clinica

Il trapianto allogenico nella LLC

Bolzano, 18-19 giugno 2009

Francesco Zaja - Clinica Ematologica, Udine

Curative strategy for CLL

Induction Flu-CYT + Rituximab

PCR- PCR+

Consolidation Campath-1H

PCR- PCR+

Eradication Transplant

M. Keating

Leucemia Mieloide Acuta Leucemia Linfatica Acuta

Leucemia Linfatica Cronica Leucemia Mieloide CronicaMielMult/Plasmacell Linfomi

Tumori Solidi MDS/MPS

Errori genetici Anemia AplasticaImmunodeficienze Talassemia

AD

n=26 n=56

AAThal

AD

LMA

LLALLC

LMC

MM/PCD

LYST

MDS/MPS

n=12

n=66n=1

n=41n=78

n=393 n=275n=26n=188n=256

n=3

ID

GITMO Trapianto AllogenicoNumero Trapianti per principali Patologie (N= 1467)

Attività 2008IE

3%

• La più frequente forma leucemica dell’adulto (25% delle leucemie)

• Incidenza pari a 2-6 x 100.000 abitanti anno (paesi occidentali), ma13 x 100.000 abitanti anno a 65 anni e circa 30 x 100.000 abitantianno dopo i 70 anni

• Età mediana di insorgenza 65 anni

• M/F: 2/1

• 30% dei pazienti ha un’età < 60 anni

• 10-15% dei pazienti ha un’età < 50 anni

Epidemiologia CLL

Rationale of SCT in CLL

CLL in relapsed/advanced stage or with high risk features:- poor prognosis- conventional therapies not curative

Potentially curative in CLL:- Stem cell source free of tumour contamination- Graft vs leukemia effect

Who are poor risk patients?

Outcome of conventional salvagefor fludarabine-refractory CLL

Source n Salvage OSKeating, L&L 2002 147 various 10 moO'Brien, JCO 2001 28 FC 12 moKeating, Blood 2002 93 Campath iv 16 moStilgenbauer, ASH 2004 46 Campath sc 17 mo

Survival from Time of Diagnosis (n=325)

13q- single

Survival in Months

11q-

+12

17p-

36 72 108 144 180

20

40

60

80

100

00

Overall survival ofCLL patients by FISHkaryotype

Döhner, NEJM 2000

Prognostic impact ofFISH karyotype in CLL

SopravvivenzamedianadeipzconLLCinrapportoallostatomutazionaleIgVHedespressioneZAP-70

Hamblin et al Blood 1999 Crespo et al, 2003

Definition of poor risk patients fortherapeutic purpose

• NR or early relapse (within 12 months) after purine analogue containing therapy• Relapse within 24 months from ASCT• p53 deletion/mutation requiring therapy

Dreger et al Leukemia 2007 (EBMT consensus)

Years

0 2 61 3 4 5

Probability of survival after Probability of survival after autologousautologous and andHLA-identical sibling SCT for CLL, 1998HLA-identical sibling SCT for CLL, 1998––20062006

Autotransplant (N=394)

CONV (N=382) RIC (N=529)

P<.0001.

0

20

40

60

80

100

10

30

50

70

90

0

20

40

60

80

100

10

30

50

70

90

Probab

ility

of Surv

ival

, %

CIBMTR

PFS after auto-SCT in CLL:retrospective studies

Years

Probability 0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

Auto

Allo

24% (±7)

42% (±9)

Esteve 2001

n = 124

Gribben 2005

n = 137

TCDTCDn = 25

Allo-SCT in CLL: key issues

Dreger et al Leukemia 2007 (EBMT consensus)

1. Does GVL activity in CLL exist?

2. What is the success rate of SCT (disease controlvs. toxicity)?

3. Is it effective in high-risk disease?

4. Indications for allo-SCT in CLL?

1. Does GVL activity in CLL exist?

Evidence for GVL in CLL: relapse rate• Few late relapses after allo-SCT in contrast to auto-SCT (Esteve ’01)

•• MRD kinetics correlate to immune intervention MRD kinetics correlate to immune intervention ((RitgenRitgen ’’04)04)

Years

Probability

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

Auto

Allo

24% (±7)

42% (±9)

Esteve 2001

n = 124 n = 137

auto

allo

Evidence for GVL in CLL: detrimental effect of TCD

PFS:auto vs. TCD-alloSCT

n = 137

Gribben et al 2005

n = 25

Evidence for GVL in CLL:beneficial effect of DLI

• 1 x 107 CD4+ cells/kg or 3 x 107 CD4+ cells/kg • 6/7patients responded to DLI

Gribben et al 2005

Dreger, Leukemia ’03; Ritgen, Leukemia ’08; Schetelig, JCO ’08; Corradini, Haematologica ’09

Evidence for GVL in CLL:favorable effect of cGVHD

0 12 24 36 48

0

25

50

75

100

after cGVHD onset

cGVHD always absent

Months from SCT

Percent with relapse or

progression

Dreger et al. Leukemia 2003

Higher incidence of PCR negativity in patients with

cGvHD (75% vs 46%)

2. in PCR neg pts with a delayed clearance of MRD, the onset

of GvHD preceded the achievement of molecular remission;

3. overall GvHD was more frequent in patients who did not

relapse (p=0.04): the crude incidence of grade 2-4 acute

and chronic GvHD was 22% in relapsed and and 70% in

not relapsed patients.

Evidence for GVL in CLL:favorable effect of cGVHD

Corradini, Haematologica 2009

CLL3x: m (sib) p# 05001

-180 180 360 540SCT

10 -5

10 -4

10 -3

10 -2

10 -1

10 0

0

25

50

75

100

CSA

start of cGVHD

BLOOD 2004;104:2600

Chimerism

Does GVL activity in CLL exist?

Yes

2. What is the success rate of SCT

(disease control vs. toxicity)?

Survival After SCT

Years

Pro

bab

ility 0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

Auto

Allo

63% (±7)

56% (±7)

Auto=124 (28 dead)

Allo=46 (20 dead)

Esteve et al, ASH 2001

100 days CONV allo-TRM: 31%

CONV Allo-SCT with in CLL

Dreger et al. Leukemia ’07

EBMT survey on RIC allografting for CLL:Treatment-related mortality (n=77)

0 12 24 36 480

25

50

75

100

18% (9;27)

Months from SCT

Percent TRM

Dreger et al Leukemia 2003

RIC allo-SCT: CLL-specific trials

Study Seattle GCTSG CLL3X

n 64 30 44

TRM 22%(2y) 15%(5y) 7%(3y)

OS 60%(2y) 69%(5y) 75%(3y)

REL 18%(2y) 30%(5y) 24%(3y)

REL >2y 2 4 2

F/U (mo) 24 72 19

Sorror JCO 2005; GCLLSG 2005; Schetelig JCO 2003, 2005

Allo-SCT in CLL (EBMT):

Population-matched analysis

- 73 RIC cases (survey), 82 MC cases (registry)

- matched for age, donor, remission status, sex

- by serial Cox modeling

- RIC reduces TRM (HR 0.4; p 0.025)

- RIC increases relapse (HR 2.7; p 0.054) (?)

- no influence on EFS and OS

Prospective controlled studies are needed!

Dreger et al Leukemia 2005

RIC allo-SCT on CLL:MRD vs. MUD

Study Seattle CLL3X

MRD MUD MRD MUD

n 44 20 25 25

TRM (2y) 22% 20% 0% 14%

OS (2y) 56% 74% 87% 77%

REL (2y) 34% 5% 13% 23%

GCLLSG 2005; Sorror JCO 2005

CLL3X: PFS according to MRDnegativity (n=26)

0 12 24 36 48 60 720

25

50

75

100

HR 0.06; p 0.0002

not MRD neg at 12 mo

MRD neg at 12 mo

Months post SCT

% progression-free

CLL3X: TRM

0 12 24 36 48 60 720

25

50

75

100

11% (0, 23%)

Months from allo-SCT

Perc

ent T

RM

RIC allo-SCT in CLL: results from theGCLLSG CLL3X trial

• Molecular response ≥ 50% of the pts with high-risk CLL• Prognostic impact of MRD negativity at +12 month

Ritgen et al Leukemia 2008

Corradini et al Haematologica 2009

p=0.012

p=0.031

Role of molecular response at + 6 monthafter RIC allo-SCT in CLL:

What is the success rate of SCT

(disease control vs. toxicity)?

• Allo SCT active

• Molecular remission

• RIC associated with reduced TRM

3. Is it effective in high-risk disease?

RIC allo-SCT in CLL: impact of 17p-

44 patients from EBMT database (1995-2006)• median age: 54 years (35-64)• 60% fludarabine refractory• status at SCT: 14% CR, 39% PR, 48% SD/PD• 24 sibling / 20 alternative donor• 89% RIC• aGVHD grade 2-4: 43%• extensive cGVHD: 53%

Schetelig, JCO 2008

RIC allo-SCT in CLL: impact of 17p-

3-year OS 44% 3-year PFS 37%

3-year relapse 30%3-year TRM 32%

Schetelig et al JCO 2008

Dreger 2005

CLL3X: Relapse incidence byFISH karyotype (n=42)

0 12 24 36 48 60 720

25

50

75

100

other

del 11q- / del 17p-

Months post SCT

% relapsed

RIC allo-SCT in CLL:Impact of poor-risk factors

Other adverse prognostic factors like VH genemutational status or ZAP-70 espression seem to

have no major influence on the outcome afterallogeneic SCT.

Ritgen, Blood 2004; Moreno, JCO 2005 (VH gene); Caballero, Clin Cancer Res 2005;Khouri, BJH 2007 (ZAP-70)

Is it effective in high-risk disease?

• Yes.

• Allo SCT has the potential toinduce long-term DFS in patientswith 17p-CLL.

• Detrimental effect of TCD.

4. Indications for allo-SCT in CLL?

EBMT guidelines for SCT in CLL

Dreger et al. Leukemia ’07 (EBMT consensus panel)

Allo-SCT in poor-risk CLL including:• Fludarabine resistence – non response or early relapse (<12 months) after purine analogue-based tx• Relapse <24 months after purine analogue combinations or auto-SCT (+ high risk genetics)• p53 mutation with treatment indication

Auto-SCT indicated in clinical trial only.

Criteri di eleggibilità per ricerca MUD.Standard IBMDR maggio ’09

Linfomiaggressivi in

francaprogressione

Frontline

Ricaduto/resistenteall’autologo e/o

polichemioterapiadi età ≤ 65 anni

LNH/LLC

Categoria Csenza

indicazione

Categoria Bsperimentale

Categoria Acomprovata

Patologia

Pazienti 66-70 anni:• Nell’ambito di protocolli clinici• Specifica richiesto al registro

Allo SCT in CLL

RIC

CONV

PRO vs CONS

++

--

Proposal for alloSCT in poor risk CLL

• Good disease control• Older• Comorbidities

RIC

• Refractory• Younger (???)• No comorbidities

CONV

• 3.986 patients with CLL/SLL (1975-2005, MDACC)• 204 patients (5.1%): possible RS• 148 patients (3.7%): biopsy proven RS• 20 patients underwent alloSCT

Richter’s syndrome

AM Tsimberidou et al. JCO 2006

Patients who received alloSCT as postremission therapyhad longer survival than patients who achieved remissionand received no additional therapy or patients who underwent allo or autoSCT as salvage therapy (P = .019).

AM Tsimberidou et al. JCO 2006