John GribbenProfessor of Experimental Cancer Medicine, Director of the Experimental Cancer Medicine Centre and Director of Stem Cell Transplantation at St Bartholomew’s

Hospital, Queen Mary’s School of Medicine, University of London, UK

Former Research Fellow in Haematology at University College London, UK

Former Associate Professor of Medicine at Harvard Medical School, Boston, Massachusetts, USA

Former Attending Physician at the Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Boston, Massachusetts, USA

Author of more than 300 manuscriptsand book chapters

Founding member of the CLL Research Consortium

Associate Editor of Blood St Bartholomew’s Hospital

Management of relapsed CLL: why rituximab?

John GribbenSt Bartholomew’s Hospital,

Queen Mary’s School of Medicine

University of London, UK

Introduction

Fludarabine-based therapy is the standard first-line treatment for fit patients

Ultimately, all patients treated for CLL progress and require subsequent therapy

A significant proportion of patients become fludarabine resistant

Clonal evolution is observed with accumulation of negative molecular biology features

The majority of patients are aged >65 years

Allogeneic SCT is effective in some patients with relapsed CLL– use is limited in patients with advanced age

and/or comorbidities

CLL = chronic lymphocytic leukaemia; SCT = stem cell transplantation

Relapsed versus refractory CLL

Relapse or progression – response to therapy: PR at least, lasting more than

6 months

Fludarabine-refractory disease– no response to therapy– or progression on therapy– or progression within 6 months of completion of

fludarabine therapy

PR = partial response

Fludarabine-based regimens for relapsed/refractory CLL

Study Regimen n

Refractory patients

(%)

OR/CRnon-refractory

(%)

OR/CR refractory

(%)

Keating et al.1 F 78 64 93/57 38/28

O’Brien et al.2 FC 74 31 80/12 39/3

Bosch et al.3 FCM 60 58 72/32 34/6

Mauro et al.4 FAND 23 61 100/78 50/29

OR = overall response;CR = complete response;A = ara-C; C = cyclophosphamide;D = dexamethasone; F = fludarabine;M = mitoxantrone; N = novantrone;

1Keating M, et al. Blood 1993;81:2878–842O’Brien SM, et al. J Clin Oncol 2001;19:1414–20

3Bosch F, et al. Br J Haematol 2002;119:976–844Mauro FR, et al. Haematologica 2002;87:926–33

Poor prognosis of advanced, relapsed CLL

Survival (years)

Responsive to both alkylating agents and fludarabine 2–3

Alkylator refractory 1–2

Fludarabine refractory (17p-) <1

Thomas D, et al. In: Cheson B, editor. Chronic lymphoid leukemias. M Dekker, 2001. p. 275–335

There is therefore an outstanding need for more effective,feasible therapies in relapsed/refractory CLL

Rituximab in relapsed/refractory CLL: rationale

Rituximab is an active targeted therapy that acts via CD20 to eradicate lymphoma cells

Rituximab is generally well tolerated

Rituximab demonstrates good clinical activity

Rituximab demonstrates synergistic activity with fludarabine

R-FC for previously treated CLL: regimen and patient characteristics

179 patients with pretreated CLL

– rituximab (R) 375mg/m2 cycle 1, 500mg/m2 cycles 2–6

– F 25mg/m2 days 1–3 every 4 weeks x 6

– C 250mg/m2 days 1–3 every 4 weeks x 6

– infectious prophylaxis during treatment and 2 months after

Patient characteristics

– mean age: 59 years (36–81 years)

– Rai stage III/IV: 49%

– median number of prior treatments: 2 (1–10)

– 46% of patients completed 6 cycles; 37% 3 cycles

Wierda W, et al. J Clin Oncol 2005;23:4070–8

R-FC for previously treated CLL:median survival over 3 years

Outcome nPatients at t=0

(n)

Died 80 177

Relapsed 60 129

Months

Overall survival (OS)

Time to progression (TTP)

Median OS: 42 months

Median TTP: 28 months

0 6 12 18 24 30 36 42 48 54

Pro

bab

ility

1.0

0.8

0.6

0.4

0.2

0

Rituximab doseCycle 1: 375mg/m2

Cycles 2–6: 500mg/m2

R-FC for previously treated CLL:TTP by response status

Pro

bab

ility

0 6 12 18 24 30 36 42 48 54

1.0

0.8

0.6

0.4

0.2

0

Months

n ResponseMedian

(months)

45 CR 39

28 Nodular CR 33

56 PR 15

Wierda W, et al. J Clin Oncol 2005;23:4070–8

NR = no response; ED = early death

n ResponseMedian

(months)

51 CR 45+

28 Nodular CR 30+

56 PR 39

42 NR 11

6 ED 2

R-FC for previously treated CLL:OS by response status

Wierda W, et al. J Clin Oncol 2005;23:4070–8

Pro

bab

ility

0 6 12 18 24 30 36 42 48 54

1.0

0.8

0.6

0.4

0.2

0

Months

R-FC is well tolerated in patients with previously treated CLL

Tolerability – no serious infusion-related adverse events– grade 3/4 neutropenia 62% of courses – grade 3/4 thrombocytopenia 17% of courses– major infection 5% of courses

Wierda W, et al. J Clin Oncol 2005;23:4070–8

R-FC in relapsed/refractory CLL: response by treatment regimen

Patients (%)

F ± P*(n=251)

FC*(n=111)

R-FC(n=143)

CR 13 12 28

Nodular PR 25 16 14

PR 21 39 30

NR 28 24 24

Early death 11 7 4

Wierda W, et al. Cancer 2006;106:337–45

*Historical controlsP = prednisone

59 67 72

R-FC in relapsed/refractory CLL: OS by treatment regimen

Wierda W, et al. Cancer 2006;106:337–45

1.0

0.8

0.6

0.4

0.2

00 24 48 72 96 120 144 168 192 216

Pro

po

rtio

n s

urv

ivin

g

Patients Died

Median survival (months) Protocol p value

251 241 20 F ± P

111 87 31 FC

143 669 49 R-FC

<0.01

0.05

Months

Increasing response rates in relapsed/refractory CLL

ORR (%) CR (%)

Chlorambucil/CAP 22–35 0–6

Fludarabine 32–59 3–37

FC 40–80 3–15

R-FC 73 25

Gribben J. Hematology (ASH Education Book) 2005;292–8O’Brien S, et al. J Clin Oncol 2001;19:1414–20

Wierda W, et al. J Clin Oncol 2005;23:4070–8

ORR = overall response rateCAP = cyclophosphamide, doxorubicin, prednisone

The REACH trial: R-FC versus FC in relapsed CLL

• CLL• Binet B or C• >18 years• Relapsed disease,

excluding fludarabine-refractory

RANDOMISE

R-FC every 3 weeks x 3

FC every 3 weeks x 3

RESTAGE

R-FC every 3 weeks x 3

FC every 3 weeks x 3

SD, PD off study

CR, PR

Rituximab doseCycle 1: 375mg/m2

Cycles 2–6: 500mg/m2

SD = stable disease; PD = progressive disease

Other rituximab combinations in relapsed/refractory CLL

Rituximab plus alemtuzumab Regimen

– rituximab 375mg/m2 (day 1) and 500mg/m2 ondays 8, 15, and 22

– alemtuzumab 15mg (days 2–7) and 30mg on days 3 and 5 of weeks 2–4

20 patients with relapsed/refractory CLL– six (30%) were refractory to both fludarabine and

alkylators– all had prior exposure to rituximab and two (10%)

had prior exposure to alemtuzumab

ORR 55%, CRR 30% Faderl S, et al. Blood 2005;106 (Abstract 2963)CRR = complete response rate

R-FCA in relapsed CLL: treatment regimen

R 500mg/m2 on day 2*

F 25mg/m2 on days 3–5

C 250mg/m2 on days 3–5

A 30mg on days 1, 3, and 5

A R CFA CF CFA

Day Every 28 days for 6 cycles

*375mg/m² dose adjustment for cycle 1 onlyA = alemtuzumab

1 2 3 4 5

Wierda WG, et al. Blood 2006;108:31 (Abstract 2839)

R-FCA in relapsed CLL: response by previous treatment

No. of patients (n=78)

CR after R-FCA (%)

ORR afterR-FCA (%)

FC

First line

Salvage

3

7

0

14

100

43

R-FC

First line

Salvage

20

25

30

16

65

48

SCT 4 25 75

Wierda W, et al. Blood 2006;108:14a (Abstract 31)

R-FCA in relapsed CLL: progression-free survival

Pro

port

ion

1.0

0.8

0.6

0.4

0.2

00 6 12 18 24 30 36Months

27 months10 months

Patients Relapsed Response

19 5 CR

32 14 PRp<0.001

CR

PR

Wierda W, et al. Blood 2006;108:14a (Abstract 31)

R-FCA in relapsed CLL: OSP

rop

ort

ion

1.0

0.8

0.6

0.4

0.2

0 0 6 12 18 24 30 36 42Months

Patients Died Response19 2 CR32 21 PR27 22 SD/PD

0.007

0.008

p value

Wierda W, et al. Blood 2006;108:14a (Abstract 31)

R-PC in relapsed/refractory CLL

Regimen (all drugs administered on day 1 of a 3-week cycle for a total of 6 cycles)– R 375mg/m2 – P 4mg/m2

– C 600mg/m2

32 patients with relapsed/refractory CLL– eight patients fludarabine-refractory

ORR 75%, CRR 25%– six of eight fludarabine-refractory patients responded

with one CR

Of three patients with 17p deletion, two achieved a CR and one a PR

Lamanna N, et al. J Clin Oncol 2006;24:1575–81 R-PC = rituximab, pentostatin, cyclophosphamide

Case study 56-year-old woman presents in 1997 with

– cervical lymphadenopathy

– no B symptoms

– WBC WNL CT scan

– cervical and inguinal lymphadenopathy

– no splenomegaly LN biopsy: small lymphocytic lymphoma BM biopsy: diffuse infiltrate with CD19+CD5+CD23+

small B cells FISH of BM sample reveals del 13qWBC = white blood cell; WNL = within normal limits; CT = computed tomographyLN = lymph node; BM = bone marrow; FISH = fluorescence in-situ hybridisation

Case study (cont’d) Watch and wait approach explained to patient

Over the next 3 years, slowly progressive disease

– watch and wait

November 2000 presents with increased cervical, axillary, and inguinal adenopathy

– largest nodes increased to 7cm

Peripheral blood

– WBC 1,4000/µL with lymphocytosis

– Hgb 9.5g/dL

– platelets 8,9000/µL

No B symptoms, but uncomfortable with degree of adenopathy

Case study (cont’d)

Commenced on therapy with FCR

Tolerated first cycle well – notes marked decrease in lymph nodes

Returns for third cycle – notes increasing lymphadenopathy

Restaging after three cycles shows no response

Autologous and allogeneic SCT for poor-risk CLL

Gribben J, et al. Blood 2005;106:4389–96

1.0

0.8

0.6

0.4

0.2

0

Pro

bab

ility

1.0

0.8

0.6

0.4

0.2

0

Pro

bab

ility

OS Progression-free survival

0 1 2 3 4 5 6 7 8 9 10 1112 13 14 15 0 1 2 3 4 5 6 7 8 9 10 1112 13 14 15

Years Years

Allogeneic

Autologous

Allogeneic

Autologous

p=0.96 p=0.04

Sorror M, et al. J Clin Oncol 2005;23:3819–29

Outcome after reduced-intensity conditioning transplantations for CLL

Related recipients Unrelated recipients

Months after HCT

Per

cen

tag

e

100

80

60

40

20

0

Months after HCT

Per

cen

tag

e

OS

DFSNRM

Relapse-related mortality

OS

DFS

NRM

Relapse-related mortality

100

80

60

40

20

00 6 12 18 24 30 36 42 480 6 12 18 24 30 36 42 48

NRM = non-relapse mortalityDFS = disease-free survival

FK506; short-course MTX

FC versus R-FC for non-myeloblative SCT conditioning in CLL: MD Anderson experience

Cohort 1 (1996–1999): FC

Day –13 –5 –4 –3 0 +8

Rituximab 1,000mg/m2 Fludarabine 30mg/m2

Cyclophosphamide 750mg/m2

Cohort 2 (2000–2002): R-FC

Day –13 –6 –5 –4 –3 0 +1 +8

FK506; short-course MTX

Khouri IF, et al. Exp Hematol 2004;32:28–35MTX = methotrexate

FC versus R-FC for NST conditioningin CLL: outcome (MD Anderson)

FC R-FC p value

n 7 10

2-year REL (%) 14 20 ns

2-year OS (%) 57 100 0.03

ext. chr. GVHD (%) 81 36 0.04

2-year TRM (%) 43 0 0.03

Khouri IF, et al. Exp Hematol 2004;32:28–35

REL =relapse rate; ns = not significantext. chr. = extensive chronicGVHD = graft versus host diseaseTRM = treatment-related mortality

Allogeneic transplantation for relapsed/refractory CLL

CLL transplant consensus Allogeneic SCT is a reasonable treatment option for

younger patients with– non-response or early relapse (<12 months)

after purine analogue-based therapy– relapse <24 months after purine analogue

combinations or auto-SCT (plus high-risk genetics)– p53 mutation with treatment indication

Dreger P, et al. Leukemia 2007;21:12–17

Case study: outcome

Underwent RIC allogeneic transplant fromHLA-matched unrelated donor

Early withdrawal of immunosuppressive therapy because of disease – concomitant with development of GVHD – good

evidence of GVL effect

Remains in CR – now 5 years post transplant

RIC = reduced-intensity conditioning GVL = graft versus leukaemia

Case study: tumour burden after non-myeloablative allogeneic SCT

1E+07

1E+06

1E+05

1E+04

1E+03

1E+02

1E+01

1E+00

GVHD grade 3 skin

IgH

/GA

PD

H c

op

y n

um

ber

12 months post SCT

Limit of detection

0 3 6 9 48

Conclusions

Immunochemotherapy is becoming standard treatment for relapsed/refractory CLL– the REACH trial will provide further information

Allogeneic SCT is an option for selected patients

Best supportive care and the testing of novel therapies remain very important for relapsed/refractory CLL patients