Integrazione del profilo clinico-biologico con le nuove opzioni terapeutiche

Francesca R MauroDipartimento di Biotecnologie Cellulari ed EmatologiaUniversità “ La Sapienza” Roma

FCR the golden standard therapy for all patients?

AgeCytogenetic abnormalities &

CLL8: Genetic effect on PFS

FC FCR

17p-

17p-

13q-

normal

11q-

+12

11q-

+12

normal

13q-

Outcome of 11q- patients: FCR vs FC

p <.001 p <.05

PFS OS

FCR

FC

%CR

FCR FC

61.5 14

p< .001

FCR

FC

Outcome of 17p- patients: FCR vs FC

p <.001

PFS OS%CR

FCR FC

19 4.5

p= ns FCR

FC

53% vs 41% p=ns

30% vs 0%p<0.05

FCR

FC

FCM-R for Previously Untreated CLL

%

ORR 93

CR MRD - 46

CR MRD + 36

PR 11

Response

82%

MTX 6 mg/m2

FAMP 25 mg/m2

CTX 200 mg/m2

Rituximab 375 (1°)500mg/m2 (2°-6°)

R

D1 D2 D3

CR/PR

Rituximab 375mg/m2

every 3 months

%

CR

%

MRD-

CR

13q- 82 50

+12 100 50

11q- 87 62

17p- 26 0

Bosh, JCO 2009

Response

ORR 77%

CR 14.5%

81 patients with relapsed or refractory CLL

Fischer et al., ASH 2008

Toxicity

Leucopenia 12%

Infections 5%

Rituximab375 mg/m2 (course 1) 500 mg/m2 (courses 2-6)

X 6 courses

Bendamustine 70 mg/m2 d1-2

11q- 92% 8%17p- 44% -

Bendamustine and Rituximab (BR) for Patients with Relapsed CLL: a Multicentre Phase II Trial of the German CLL Study Group

(GCLLSG- CLL2M Study)

ORR CR

Ofatumumab (HuMax-CD20), a Novel CD20 Monoclonal Antibody, is an Active Treatment for Patients with CLL Refractory to Both Fludarabine

and Alemtuzumab or Bulky Fludarabine-Refractory Disease: Results from the Planned Interim Analysis of an International Pivotal Trial

Österborg et al. ASH 2008

DR

%OR

BFR

%OR

11q- (40) 63 64

17p- (31) 41 14

17p Deletion Predicts for Inferior Overall Survival after Fludarabine ± CTX First Analysis of Genetics in the CLL4 Trial of the GCLLSG

17p- significant adverse impact on:

Response (p=0.001)

PFS (P=0.001)

Survival (P<0.001)

17p-: 4.9% of CLL patients

Stilgenbauer et al., ASH 2005

no 17p-

17p-

CLL4 study: effect of FISH abnormalities

Survival Proportion of 17p-cells and response

p53+ fludarabine-refractory CLL: Campath-1H

Short response duration (4-8 months)

regimen No

pts

%OR (CR)

Lozanski et al.,

Blood 2004Campath-1H 15 40 (0)

Stilgenbauer et al.,

CLL2H GCSG

Blood 2004 [Abstr. #478

Campath-1H 13 54 (0)

Osuji et al.,

Haematologica 2005Campath-1H 8 50 (0)

Sayala et al.,

ASH 2006, abstr.#34Campath-1H 38 58

Pettitt et al.,

Leukemia 2006Campath-H - HDMP 5 100 (3/7)

Wierda et al.,

ASH 2005 abstr.#31CFAR 32 44

Mauro et al.,

ASH 2006 abstr.#2830FandCam 4 3/4

Sc Campath-1H for fludarabine refractory CLL patientsGCLLSG-CLL2H study

Stilgenbauer et al., JCO 2009

NCRI- UKCLL206- CamPred regimen

PI: A Pettitt

– 50% ORR - Relapse post-remissional therapy

p53 deletion ≥ 20% of cells

HMP HMP HMP HMP

Campath T-cell depletion: the only significant adverse factor for PFS at multivariate analysis

EBMT transplant consensus: allogeneic SCT reasonable option for CLL patients with p53+ abnormalities requiring treatment

Allogeneic Hematopoietic SCT for CLL with 17p deletion: a retrospective analysis of the EBMT

Schetelig et al., JCO 2008

Sc Campath and oral Dexamethasone, followed by Campath maintenance or Allogeneic SCT

in CLL associated with 17p deletion or refractory to fludarabine (CLL2O protocol) GCLLSG – FCLLSG-

sc Campath: 30 mg TTWoral Dexamethasone 40 mg d 1–4 40 mg d15–18

sc Campath 30 mg/14 days max. 2 years

CR or max.

3 cycles

F-refractory

(11)

17p-

(19)

OR 4 (36%) 17 (84%)

CR - 4 (21%)

Allo/maintenance 4/3 7/10

CMV react, 4/14 3/33

Grade 3-4 infections 6/14 11/33

% DFS at 16 mos 60% 60%

Allogeneic SCT

NCRI- UKCLL210 - CamPred regimen

Lenalidomide

p53+ CLL

patients

EFFICACY AND SAFETY OF A FIRST-LINE COMBINED THERAPEUTIC APPROACH FOR YOUNG CLL PATIENTS

STRATIFIED ACCORDING TO THE BIOLOGIC PROGNOSTIC FEATURES:

GIMEMA MULTICENTER LLC0405 STUDY

Low Risk patients: PFS

FC 23%FCR 45%

High Risk patients: PFS

High Risk patients: post-induction therapy

FCR: median age of patients•1st-line (CLL8) 61 yrs•2nd-line (REACH) 62 yrs

FCR and age

193 previously treated patients - median age 70 yrs 100 pts fludarabine 25 mg/m2 d1-d5 x 6 courses 93 pts chlorambucil 0.4 mg/kg d1-d15, 0.8 mg/kg increase every 15 days, x 12 months

Fludarabine

Chlorambucil

p= ns

Flu CB

OR 72% 52% <.01

CR 7% 0% <.05

mPFS 19 m 18 m

First-line fludarabine compared with chlorambucil does not result ina major benefit for elderly patients with advanced CLL

Eichhorst et al., Blood 2009

Multivariate analysis shorter PFS and OS: 1. elevated β2 microglobulin 2. ≥ 2 comorbidities R

FCR. median age of patients•1st-line 61 yrs• 2nd-line 62 yrs

Chlorambucil + CD20 Mab for elderly CLL patients

UK: CLL207 study ITALY: ML21445 study

GCLLSG CLL11 studyOMB110911 study

Lenalidomide-based therapies for elderly CLL patients

>

FCR the new standard treatment for physically fit patients

Specific treatments for patients with selected cytogenetic entities.

Specific treatments for elderly patients under investigation

Conclusions