B-CLL

DIAGNOSIS

PROGNOSIS

CLINICAL MANAGEMENT

MRD MONITORING

THERAPY

CLL TherapyGeneral Considerations

• Treat only patients with symptomatic or progressive disease

• Treatment based on biological factors not justified

• Include patients in trials whenever possible• Never forget that the ultimate goal of therapy is

to prolong survival • Treat the patient, not the disease

CLL TherapyIndici di attività

• Sintomi B (febbre, sudorazione notturna, perdita di peso)

• Insufficienza midollare (-Hb, -Plt, -Neu)

• Splenomegalia progressiva

• Adenomegalie progressive

• LDT < 6 o 12 mesi

CLL TherapyCriteri di Risposta (NCI WG, 1996

Remissione Completa• assenza di adenopatie, splenomegalia ed epatomegalia • assenza di sintomi sistemici • linfociti inferiori a 4000/µL • neutrofili superiori o uguali a 1500/µL • piastrine superiori a 100000/ µL • Hb uguale o superiore a 11g/dL • alla biopsia osteomidollare normale cellularità e infiltrato linfatico inferiore al 30%

Remissione Parziale• riduzione delle adenopatie pari o superiore al 50% • riduzione della splenomegalia o dell'epatomegalia pari o superiore al 50% • riduzione della linfocitosi pari o superiore al 50% • >più uno o più dei seguenti:• - neutrofili pari o superiori a 1500/µL, o miglioramento del 50% rispetto ai valori di base

- piastrine superiori a 100000/µL o miglioramento del 50% rispetto ai valori di base- Hb superiore a 11 g/dL o miglioramento del 50% rispetto ai valori di base- assenza di sintomi sistemici

Malattia Stabile• Non RP nè progressione

010

20304050

60708090

100

1970 1980 1990 2000

CR%

Chlorambucil

COP, CHOP

FludarabineFludarabine

Fludarabine-combined regimens

Year

Symptoms palliation

Higher response rate(vs. Chlorambucil)

Prolonged FFPProlonged FFP

MRD (-)? Prolonged survival

? Cure

CLL: CR rate and treatment goals over the years

E. Montserrat - Inside Blood 2005

CLL Treatment in a Nutshell

RANDOMIZED STUDIES

• Fludarabine (Cladribine) > Chlorambucil• Fluda + Cyclophosphamide > Fluda• Fluda + Cyclo (oral) = Fluda + Cyclo (i.v)

SINGLE ARM STUDIES• Fluda + Rituximab• FCR• FCM…

Risultati CLB I linea

Trials Dosaggio Risultati

FRE-CLL-80

( 278 pz )0,1 mg/die CR: 45%

PR: 31%NR: 24%

FRE-CLL-85

( 437 pz )

0,3 mg/Kg d 1-5 +PDN 40/mq d 1-5

CR: 28%PR: 41%NR: 31%

RISULTATI CLB I linea IGCI CLL-01 trial

Risposta Alte dosi Dosi intermedie

CR 70 % 31 %

PR 19 % 19 %

NR 11 % 50 %

Risultati CLB mantenimento

Riferimenti Dosaggio Risultati

Jaksic et al. Nouv Rev Fr Hematol, 1988

15 mg 2 volte settimana/ 3 anni

Migliora la durata della risposta e la sopravvivenza

Risultati CLB II linea

Riferimenti Popolazione Risultati

Robak et al. Blood, 2000

Resistenti agli analoghi delle purine

OR: 33%

Ray et al.N Engl J Med, 2000

Resistenti alla FAMP

OR: 7%

HD-CLB versus CHOP mod.

• Arruolati 228 pazienti in stadio avanzato

• OR HD-CLB: 89,5% CHOP: 75% p<0,001

• CR HD-CLB: 59,5% CHOP: 30,4%

• OS HD-CLB: 68 m. CHOP: 47 m. P<0,005

Jaksic et al. Cancer,1997

CHOP versus COP• French Cooperative Group on CLL:

“Long- term results of the CHOP regimen in stage C chronic lymphocitic leukaemia”.

Br J Haematol, 1989

OS mediana = 22 mesi COP OS mediana = 62 mesi CHOP ( p = 0,001 )

ANALOGHI PURINICIANALOGHI PURINICI

1)1) FludarabinaFludarabina (9- (9---arabinosil-2-fluoroadenina) arabinosil-2-fluoroadenina)

2)2) 2CdA 2CdA (2-cloro-2’-(2-cloro-2’-deossiadenosina)deossiadenosina)

3)3) dCFdCF (2’-deossicoformicina) (2’-deossicoformicina)

MECCANISMO DI AZIONEMECCANISMO DI AZIONE

1)1) effetto inibitorio su enzimi effetto inibitorio su enzimi implicati nella riparazione e implicati nella riparazione e sintesi del DNAsintesi del DNA– DNA primasi, ligasi e polimerasiDNA primasi, ligasi e polimerasi– Reduttasi ribonucleotidica Reduttasi ribonucleotidica

2)2) danno diretto della membrana danno diretto della membrana dei mitocondridei mitocondri

3)3) inibizione della sintesi di RNAinibizione della sintesi di RNA

FAMP IN PAZIENTI FAMP IN PAZIENTI PRETRATTATI PRETRATTATI

Refer. RC OR

OS media

naN°pz.

GreverNouv Rev Fr

Hematol: 1988

3%

(13%)12%

(32%)13 m

32(31)

KeatingBlood 74:

1989

13%(13%)

57%(48%)

11 m68

(48)Johnson Ann Oncol

142 [a277]:1994

5% 26% 12.7 m 123

Sorensen JCO 15:1997

3% 32% 13 m 724

2-CDA IN PAZIENTI 2-CDA IN PAZIENTI PRETRATTATI PRETRATTATI

Refer. RC OROS

medianaN°pz

PiroBlood

72:19880 22%

Non riportata

18

SavenLeuk Lymph

5: 19934% 40%

Non riportata

90

JuliussonAnn Oncol

7:199631% 58%

36 m (CR) 28 m (PR)

52

RobakBr J Hematol

108:200012% 48% 12 m 184

FAMP FRONT-LINEFAMP FRONT-LINE

Trattamento

N° pz. RC OR PFS mediana

OS median

a

Ref.

FAMP 25-30 mg/m2 d 1-5 (71 pz) opp.

FAMP 30 mg/m2 d 1-5 + PDN 30

mg/m2 (103)

174I/II 108III/IV 66

29% 78%

31 mRC = 37

m p=0.02RP = 30

m

63 mKeating Blood

92:1998

FAMP 25 mg/m2 d 1-5 16 31% 100% Non

riportata

Non riportat

a

Clavio EurJHem61:1998

FAMP 30 mg/m2 d 1-5 17 65% 94%

n.r. [FUP 13

m (2-38)]

Non riportat

a

Stelitano Haemat84:1999

FAMP FRONT-LINEFAMP FRONT-LINE

Keating MJ et al. Blood 92:1998

OS by treatment OS by response

PFS by response

2-CDA FRONT-LINE2-CDA FRONT-LINE

RC ORRFS

medianaOS

medianaMorti

Popolazione totale194 pz

45.4%

82.5%

12 (3-54) 18 m 63

2-CdA 0.12 mg/kg d 1-

543 pz

37.2%

72.1%

16 (3-54) 19 m 15

2-CdA+PDN 30 mg/m2

d1-5151 pz

47.7%

85.4%

12 (3-43) 18 m 48

Robak T et al. Br J Haem 108:2000p=0.04

FAMP FAMP vsvs CHL CHLTrattamento N°

pz.RC RP RFS OS Ref.

FAMP 25 mg/m2

Chl 40 mg/m2 ogni 28 gg.

170

181

20%p<0.001

4%

43%p<0.00

1

33%

25 mp<0.00

1

14 m

66 mp=0.

156 m

Rai et al. NEJM

24: 2000

FAMP 25 mg/m2 x 6

Chl 30 mg/m2 g 1 e 15+PDN 40 mg/m2 g 1-5 e 15-19 ogni 28 gg

69 73

46%p-NC

37%

25%p-NC

34%

28 mP=0.00

7

21 m

NCSpriano Hematol

Cell Ther Abs 2000

FAMP 25 mg/m2

ogni 21 gg (per 18 sett)Chl 10 mg/m2/d

per 18 sett

39

35

39%p=0.29

43%

36%p=0.29

43%

p=0.92 p=0.3

Jaksic Hematol

Cell Ther Abs 2000

FAMP FAMP vsvs CHL CHL

Rai et al. NEJM, 343: 24, 2000

RFS p<0.001

PFS p<0.001

OS p<0.21

FAMP + CY (non comparativi)FAMP + CY (non comparativi)

Trattamento

N° pz.

Stadio

RC OR PFS mediana Ref.

FAMP 30 mg/m2 d 1-3+ CY 300

mg/m2 d 1-3

128(34*)

III-IV 47%

17% (35%)

74% (88%)

12-38 m Non

raggiunta

O’ Brien JCO

19:2001

FAMP 30 mg/m2 d 1-3

+CY 250 mg/m2 d 1-3

32(15*)

A 3%B

50%C

47%

16% 91%

Durata mediana

della risposta non

raggiunta dopo FUP 14

m

Hallek,B J

Haemat114:200

1

FAMP per os 30

mg/m2 d 1-5 +CY per os 200 mg/m2

d 1-5 x 6

59*

B 79%

C 21%

47% 78% Non riportata

Cazin [a772] Blood

98:2001

* non pre-trattati

TTP FAMP TTP FAMP vsvs FAMP+CY FAMP+CY

O’ Brien S et al. JCO 19: 2001

FAMP+CY: TTP mediano n.r.

FAMP: TTP mediano 30 mesi

FAMP ORALEFAMP ORALE

Trattamento

N° pz.

RC OR PFS mediana

OS mediana

Ref.

FAMP 40 mg/m2 d 1-5 x 6-8 cicli

78* 21% 46%Non

riportata

Non riportat

a

Boogaerts JCO

15:2001

FAMP 40 mg/m2 d 1-5 x 6-8 cicli

81 37% 72% 28 m Non

riportata

Rossi JF JCO

22:2004FAMP per

os 30 mg/m2 d 1-5 +CY per os 200 mg/m2 d 1-5

x 6 cicli

59 47% 78%Non

riportata

Non riportat

a

Cazin [a772] Blood

98:2001

* Pretrattati con alchilanti (rec+res)

MoAbs citotoxic mechanisms

Effector cells/Complement

Apoptosis Radionuclide Toxin/Antibiotic

MoAbs for CLLMoAbs for CLL

Antibody Antigen

Alemtuzumab (Campath-1H) CD52

Rituximab (Rituxan, Mabthera) CD20

Epratuzumab (LymphoCide) CD22

Hu-1D10 (Apolizumab) HLA-DR

IDEC-152 (Lumiliximab) CD23

IDEC-114 CD80

Bevacizumab (Avastin) VEGF

BL-22 CD22( conjugate with Pseudomonas)

Alemtuzumab (anti-CD52) antibody

IgG1 humanised antibody:Low immunogenicity

CD52 antigen: Highly expressed on

all lymphocytesmonocytes and macrophages

spermatozoaeosinophils

Not expressed on haemopoietic stem cells

Does not modulate/shed Also expressed on the

majority of malignant lymphocytes

Number of fludarabine-refractory pts 36 Pts with p53 mutations or deletions 15 (42%) Clinical responses in p53 mutated/deleted 6/15 (40%) Clinical responses in pts without 4/21 (19%) Median duration of response 8 months

- Alemtuzumab is active in CLL pts with p53 mutations or deletions

Lozanski G et al, Blood,2004

Alemtuzumab in B-CLL with p53 mutations and deletions

patients: number: 41; 38 evaluable for Response age: 66 (44-75) Rai: I: 10%; II: 21%; III: 54%; IV: 15% B-symptoms: yes: 63%; no: 37%

therapy: Dosis escalation from 3-10-30 mg s.c. Campath-1H in week 1; 30 mg 3x /week s.c. (week 2 - 18) duration: 12-18 weeks prophylaxis: Cotrimoxazol, Acyclovir, Fluconazol

Lundin et al, Blood,2002

CAMPATH-1H AS FIRST LINE TREATMENT OF CLL

subcutaneoussubcutaneous

First line treatment of CLL with CAMPATH-1H results

Response: 87% (19% CR, PR 68%) Rai stage I-II 100% <65 y 83%; > 65 y 90%

TTF: 18+ months (7 - 44+ months)

side effects: -fever: 70% (68% Gr. 1-2; 2% Gr. 3) -skin reactions: 90% (88% Gr. 0-II; 2% Gr. 3) -infections: 4x CMV-reactivation, no severe

bacterial infection

Lundin et al,Blood, 2002

Eradication of MRD in B-CLL after alemtuzumab (ALZ) therapy is associated

with prolonged survival

Patients: 91 pretreated (44 refractory to purine analogs) Treatment: 30 mg i.v. TIW, 9 weeks Response: 32 CR (36%), 17 PR (19%), 42 NR (46%)

22/44 (50%) refractory to PA responded Longer median survival in MRD-negative pts Longer TFS in MRD-negative pts, not reached; MRD+CRs, 20

months; PRs, 13 months; NR, 6 months (P<0.0001) OS in 18 pts MRD- CR was 84% at 60 months.

MRD-negative CR in CLL is achievable with ALZ, leading to an improved OS and TFS

Moreton P, et al,JCO, 2005

CMV infection during alemtuzumab treatment

• Monitoring for CMV

• Usually fever without pneumonitis, rapidly responding to ganciclovir

• Incidence: CLL ≈ 10-40%

• If patient is well and CMV test is positive:

– Confirm CMV test

– If second CMV test is positive it is recommended that alemtuzumab is stopped and patient is treated with ganciclovir

• If patient is symptomatic:

– Treat at once if patient is CMV PCR positive

– Perform bronchoscopy and broncho-alveolar lavage if patient is CMV PCR negative

MabThera®: a chimeric murine/human MoAb

Variable murine regions bounding CD20 on B cells

Human kappa costant regions

Human domain IgG1 Fc, synergistic with human effector mechanisms

Chimeric IgG1

Rituximab monotherapy in CLL (375mg/m2/wk x 4)

Investigator, year

No of Pts

Prior Rx ORR (% )

CR (% )

Itala, 2002 24 Yes 35 -

Huhn, 2001 29 Yes 23 -

Winkler, 1999

10 Yes 10 -

Nguyen, 1999

15 Yes 7 -

Hainsworth, 2003

44 No 51 4

Rituximab monotherapy in CLL (schedules other than

375mg/m2/wk x 4)

Investigator, year

No of Pts

Regimen mg/ m2/ wk

Prior Rx ORR (% )

CR (% )

O’Brien, 2001 40 375 x 1

500 – 2250 x 3

Yes 22-75 -

Byrd, 2001 33 250-375 x3/ w x 4

Yes and No

45 3

Hainsworth, 2003

44 375 x 4 + 4 No 51/ 58 4/ 9

Thomas, 2001

31 375 x 8 No 90 19

Summary of response data in Phase II studies of rituximab plus

chemotherapyInvestigator, Yr No of Pts Regimen Prior Rx ORR (% ) CR

(% )

Schulz, 2002 31 F (25 mg/ m2 ) q5 d x 2 then FR (375 mg/ m2) x 2 then R x 2

Yes and No

87 33

Byrd, 2003 53

51

Sequential F x 6 then R x 4

Concurrent F and R x 6

No 77

90

28

47

Lamanna, 2003 30 Sequential F (25 mg/ m2 ) q5 d x 6, then HDC (3 g/ m2) q1 x 3 then R (375 mg/ m2) x 4

No 86 57

Keating, 2005

JCO

224

FCR: Cycle 1: R -375 mg/ m2 d1; std doses C, F d 2 - 4. Cycles 2-6: R-500 mg/ m2 d1; C, F d 1 - 3

No 95 70

Wierda, 2005

JCO

177

FCR: Cycle 1: R -375 mg/ m2 d1; std doses C, F d 2 - 4. Cycles 2-6: R-500 mg/ m2 d1; C, F d 1 - 3

Yes 73 25

Keating et al, JCO 2005

Keating et al, JCO 2005

PATIENT CHARACTERISTICS I o Observation time 1998-2004o N° of patients 60o M/F 30/30o Median age (range) 59 (37-74) o Modified Rai stage:

Low risk (0) 5 Intermediate risk (I + II) 52 High risk (III + IV) 3

o ECOG (Performance Status): 0 37 1 19 2 4

PATIENT CHARACTERISTICS II o B symptoms 17o Time since first diagnosis:

1 year 17 2-5 years (I + II) 29 > 5 years 14

o Infiltration pattern BM: Nodular 4 Mixed 10 Diffuse 46

FLUDARABINE + RITUXIMAB FOR PREVIOUSLY UNTREATED

CLL

patients with CR, PR, or stable disease

received

Rituximab (375mg/m2

weekly x 4)

Fludarabine

25mg/m2

MabThera

375mg/m2

Weeks

40 days Range 30- 155

1 5 9 13 17 21 1 2 3 4

Weeks

MATERIALS AND METHODS

ZAP-70 protein TK and CD38 antigen were determined by multicolor flow cytometric methods (Crespo et al, 2003; Del Poeta et al,2001).

A cut-off of 20% was used for ZAP-70 and CD38.

The threshold for MRD positivity was set at >5% CD19+CD5+CD79b- CLL cells in bone marrow.

MRD flow analysis after chemotherapy with fludarabine CD19+CD5+ = 0.6%

0 256 512 768 1024

B aldas s a ri A . pos tC HT.002FSC -Height ->

10 10 10 10 100 1 2 3 4

B aldas s a ri A . pos tC HT.002C D19 PerC P ->

10 10 10 10 100 1 2 3 4

B aldas s a ri A . pos tC HT.002C D79b FITC ->

10 10 10 10 100 1 2 3 4

B aldas s a ri A . pos tC HT.002C D79b FITC ->

10 10 10 10 100 1 2 3 4

B aldas s ari A. pos tC HT.002C D79b FITC ->

10 10 10 10 100 1 2 3 4

B aldas s ari A. pos tC HT.002C D19 PerC P ->

10 10 10 10 100 1 2 3 4

B aldas s ari A. pos tC HT.002C D20 PE ->

TOXICITY (WHO)

Grade 0

Grade 1

Grade 2

Grade 3 Grade 4

Fever/Chills 0 5 0 0 0Anemia 0 0 3 0 0Neutropenia

0 7 5 19 10

Thrombocytopenia

0 2 2 2 1

InfectionsHerpes simplexHerpes zosterPneumoniaAcute hepatitis

77

3

3

2

2

1

1

78,3%

15,0%6,7%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

p

a

t

i

e

n

t

s

CR PR NR

RESPONSE TO RITUXIMAB AND FLUDARABINE

NCI criteriaNCI criteria

((47/60)47/60)

FLUDARABINE AND RITUXIMABFLUDARABINE AND RITUXIMAB

((9/60)9/60) ((4/60)4/60)

CLINICAL OUTCOME I Median follow up duration was 27 months (9/56 pts Median follow up duration was 27 months (9/56 pts [[16%16%] have experienced a relapse).] have experienced a relapse).

Median duration of CR and PR was not reachedMedian duration of CR and PR was not reached..

Progression-Free Survival

Months from Treatment

Rate

wit

h c

on

tin

uin

g r

esp

on

se

0,0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1,0

0 12 24 36 48 60

68% at 3 years

CLINICAL OUTCOME II Among the 60 pts enrolled, 6 have died: 1 in CR Among the 60 pts enrolled, 6 have died: 1 in CR (fulminant B hepatitis), 2 resistant to fludarabine for PD, 3 (fulminant B hepatitis), 2 resistant to fludarabine for PD, 3 for PD after protocol therapy).for PD after protocol therapy).

Overall Survival

Months from Treatment

Cu

mu

lati

ve P

rop

ort

ion

Su

rviv

ing

0,0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1,0

0 12 24 36 48 60 72 84

85% at 5 years

2832

19

41

15

45

0

10

20

30

40

50

p

a

t

i

e

n

t

s

ZAP- 70+

ZAP- 70-

CD38+

CD38-

MRD+

MRD-

INCIDENCE OF ZAP-70, CD38 AND MRDINCIDENCE OF ZAP-70, CD38 AND MRD

MRDMRDCD38CD38ZAP-70ZAP-70

46.746.7%%

31.731.7%%

25%25%

57

97

58

88

0

10

20

30

40

50

60

70

80

90

100

C

R

(%)

ZAP- 70+

ZAP- 70-

CD38+

CD38-

CR (%) BY ZAP-70 AND CD38 CR (%) BY ZAP-70 AND CD38

P = P = 0.020.02

P = P = 0.00090.0009

Min-Max

25%-75%

Median value

CD20 MFI and Response to Rituximab

Response to Rituximab

CD

20 M

FI

0

40

80

120

160

200

0 1 2 3CRPR/NR

P = 0.007

PROGRESSION FREE SURVIVAL BY ZAP-70, CD38 and MMR

ZAP70 -

ZAP70+

Months from Treatment

Cu

mu

lati

ve P

rop

ort

ion

Pro

gre

ssin

g

0,0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1,0

0 12 24 36 48 60

P = 0.00005

CD38 -

CD38+

Months from Treatment

Cu

mu

lati

ve P

rop

ort

ion

Pro

gre

ssin

g

0,0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1,0

0 12 24 36 48 60

P = 0.0002

MMR-

MMR+

Months from Treatment

Cu

mu

lati

ve P

rop

ort

ion

Pro

gre

ssin

g

0,0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1,0

0 12 24 36 48 60

P = 0.001

OVERALL SURVIVAL BY ZAP-70, CD38 and MMR

ZAP70-

ZAP70+

Months from Treatment

Cu

mu

lati

ve P

rop

ort

ion

Su

rviv

ing

0,0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1,0

0 12 24 36 48 60 72 84

P = 0.006

CD38-

CD38+

Months from Treatment

Cu

mu

lati

ve P

rop

ort

ion

Su

rviv

ing

0,0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1,0

0 12 24 36 48 60 72 84

P = 0.05

MMR-

MMR+

Months from Treatment

Cu

mu

lati

ve P

rop

ort

ion

Su

rviv

ing

0,0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1,0

0 12 24 36 48 60 72 84

P = 0.002

CONSIDERATIONS CONSIDERATIONS

The The additionaddition of MoAbs, such as of MoAbs, such as rituximabrituximab, to , to chemotherapychemotherapy, allowed us a , allowed us a better outcomebetter outcome in B-CLL exerting a key in B-CLL exerting a key role to role to eradicate MRDeradicate MRD..

The The stratification stratification of patients in of patients in different different risk classesrisk classes using using ZAP-70ZAP-70 and and CD38CD38, , allowed us to distinguish different clinical allowed us to distinguish different clinical outcome subsets: we can offer more outcome subsets: we can offer more tailored treatmenttailored treatment strategies based on this strategies based on this approach.approach.

TransplantationTransplantation procedures or procedures or experimental therapiesexperimental therapies should be should be specifically reserved to specifically reserved to “high risk” “high risk” ((ZAP-ZAP-70+ or CD38+70+ or CD38+)) B-CLL subsets.B-CLL subsets.

N

um

ber

CLL Autologous

CLL Allogeneic

0

50

100

150

200

250

1993 1994 1995 1996 1997 1998 1999 2000 2001 2002

Year

Stem-cell transplants in CLL - EBMT

Allogeneic SCT for CLLWhy?

• Increasing number of patients treated with “best” chemo- chemo/immunotherapies upfront difficult to be “rescued” with conventional therapies

• Autologous transplantation– not indicated (patients do not achieve CR)

– all patients relapse

– risk of MDS/AML

Auto Allo

Upper age limit 70 50 - 60

TRM (4 yrs) 10% 25-50%

RR (4 yrs) 50% 10-25%

Survival (4 yrs) 40-70% 40-60%

Survival (8 yrs) 30-40% 35-55%

Plateau no yes

Stem-cell transplants in CLL

Overall survival after stem cell transplantation

AlloSCT (n = 46)

AutoSCT (n = 139)

0 2 4 6 8 10 12 14 16 18

Years

0

0.2

0.4

0.6

0.8

1

Pro

bab

ility

Montserrat E, Hematol Oncol Clin N Am 2004; 18:915–926.

0 2 4 6 8 10 12 14 16

Years

1

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

Ris

k o

f re

lap

se

Auto - SCT (n=122)

Allo - SCT (n=38)

Montserrat E, Hematol Oncol Clin N Am 2004; 18:915–926.

Relapse rate after stem cell transplantation

CLL Treatment Goals/Interventions

Palliation Chlorambucil, Epo, etc.

Response Fludarabine + Cycloph.

MRD - FCR, FCM (R-FCM)

Cure Allogeneic SCT