B-CLL

1
B-CLL

• DIAGNOSIS
• PROGNOSIS
• CLINICAL MANAGEMENT
• MRD MONITORING
• THERAPY

2
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

3
CLL TherapyIndici di attività

• Sintomi B (febbre, sudorazione notturna, perdita
  di peso)
• Insufficienza midollare (-Hb, -Plt, -Neu)
• Splenomegalia progressiva
• Adenomegalie progressive
• LDT lt 6 o 12 mesi

4
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
• gtpiù 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

5
CLL CR rate and treatment goals over the years
? Cure
Fludarabine-combined regimens
MRD (-) ? Prolonged survival
CR
Fludarabine
Prolonged FFP
COP, CHOP
Higher response rate (vs. Chlorambucil)
Chlorambucil
Symptoms palliation
Year
E. Montserrat - Inside Blood 2005
6
CLL Treatment in a Nutshell

• RANDOMIZED STUDIES
• Fludarabine (Cladribine) gt Chlorambucil
• Fluda Cyclophosphamide gt Fluda
• Fluda Cyclo (oral) Fluda Cyclo (i.v)
• SINGLE ARM STUDIES
• Fluda Rituximab
• FCR
• FCM

7
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
8
RISULTATI CLB I linea IGCI CLL-01 trial
Risposta Alte dosi Dosi intermedie
CR 70 31
PR 19 19
NR 11 50
9
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
10
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
11
HD-CLB versus CHOP mod.

• Arruolati 228 pazienti in stadio avanzato
• OR HD-CLB 89,5 CHOP 75 plt0,001
• CR HD-CLB 59,5 CHOP 30,4
• OS HD-CLB 68 m. CHOP 47 m. Plt0,005
• Jaksic et al.
  Cancer,1997

12
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 )

13
ANALOGHI PURINICI

1. Fludarabina (9-b-arabinosil-2-fluoroadenina)
2. 2CdA (2-cloro-2-deossiadenosina)
3. dCF (2-deossicoformicina)

14
MECCANISMO DI AZIONE

• effetto inibitorio su enzimi implicati nella
  riparazione e sintesi del DNA
• DNA primasi, ligasi e polimerasi
• Reduttasi ribonucleotidica
• danno diretto della membrana dei mitocondri
• inibizione della sintesi di RNA

15
FAMP IN PAZIENTI PRETRATTATI
Refer. RC OR OS mediana Npz.
Grever Nouv Rev Fr Hematol 1988 3 (13) 12 (32) 13 m 32 (31)
Keating Blood 74 1989 13 (13) 57 (48) 11 m 68 (48)
Johnson Ann Oncol 142 a2771994 5 26 12.7 m 123
Sorensen JCO 151997 3 32 13 m 724

16
2-CDA IN PAZIENTI PRETRATTATI
Refer. RC OR OS mediana Npz
Piro Blood 721988 0 22 Non riportata 18
Saven Leuk Lymph 5 1993 4 40 Non riportata 90
Juliusson Ann Oncol 71996 31 58 36 m (CR) 28 m (PR) 52
Robak Br J Hematol 1082000 12 48 12 m 184

17
FAMP FRONT-LINE
Trattamento N pz. RC OR PFS mediana OS mediana Ref.
FAMP 25-30 mg/m2 d 1-5 (71 pz) opp. FAMP 30 mg/m2 d 1-5 PDN 30 mg/m2 (103) 174 I/II 108 III/IV 66 29 78 31 m RC 37 m p0.02 RP 30 m 63 m Keating Blood 921998
FAMP 25 mg/m2 d 1-5 16 31 100 Non riportata Non riportata Clavio EurJHem611998
FAMP 30 mg/m2 d 1-5 17 65 94 n.r. FUP 13 m (2-38) Non riportata Stelitano Haemat 841999
18
FAMP FRONT-LINE
OS by response
OS by treatment

PFS by response
Keating MJ et al. Blood 921998
19
2-CDA FRONT-LINE
RC OR RFS mediana OS mediana Morti
Popolazione totale 194 pz 45.4 82.5 12 (3-54) 18 m 63
2-CdA 0.12 mg/kg d 1-5 43 pz 37.2 72.1 16 (3-54) 19 m 15
2-CdAPDN 30 mg/m2 d1-5 151 pz 47.7 85.4 12 (3-43) 18 m 48
p0.04
Robak T et al. Br J Haem 1082000
20
FAMP vs CHL
Trattamento N pz. RC RP RFS OS Ref.
FAMP 25 mg/m2 Chl 40 mg/m2 ogni 28 gg. 170 181 20 plt0.001 4 43 plt0.001 33 25 m plt0.001 14 m 66 m p0.1 56 m Rai et al. NEJM 24 2000
FAMP 25 mg/m2 x 6 Chl 30 mg/m2 g 1 e 15PDN 40 mg/m2 g 1-5 e 15-19 ogni 28 gg 69 73 46 p-NC 37 25 p-NC 34 28 m P0.007 21 m NC Spriano 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 p0.29 43 36 p0.29 43 p0.92 p0.3 Jaksic Hematol Cell Ther Abs 2000
21
FAMP vs CHL
RFS plt0.001
PFS plt0.001

OS plt0.21
Rai et al. NEJM, 343 24, 2000
22
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 192001
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 Haemat 1142001
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 982001
non pre-trattati
23
TTP FAMP vs FAMPCY

FAMPCY TTP mediano n.r.
FAMP TTP mediano 30 mesi
O Brien S et al. JCO 19 2001
24
FAMP 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 riportata Boogaerts JCO 152001
FAMP 40 mg/m2 d 1-5 x 6-8 cicli 81 37 72 28 m Non riportata Rossi JF JCO 222004
FAMP 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 riportata Cazin a772 Blood 982001
Pretrattati con alchilanti (recres)
25


26
MoAbs citotoxic mechanisms
Effector cells/ Complement
Apoptosis
Radionuclide
Toxin/Antibiotic
27

MoAbs 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)
28
Alemtuzumab (anti-CD52) antibody

• IgG1 humanised antibody
• Low immunogenicity
• CD52 antigen
• Highly expressed on
• all lymphocytes
• monocytes and macrophages
• spermatozoa
• eosinophils
• Not expressed on haemopoietic stem cells
• Does not modulate/shed
• Also expressed on the majority of malignant
  lymphocytes

29
Alemtuzumab in B-CLL with p53 mutations and
deletions

• 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
30
CAMPATH-1H AS FIRST LINE TREATMENT OF
CLL subcutaneous

• 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
31
First line treatment of CLL with CAMPATH-1H
results

• Response 87 (19 CR, PR 68)
• Rai stage I-II 100
• lt65 y 83 gt 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
32
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
  MRDCRs, 20
• months PRs, 13 months NR, 6 months (Plt0.0001)
• 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
33
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

34
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
35
Rituximab monotherapy in CLL (375mg/m2/wk x 4)
36
Rituximab monotherapy in CLL (schedules other
than 375mg/m2/wk x 4)
37
(No Transcript)
38
Summary of response data in Phase II studies of
rituximab plus chemotherapy
39


Keating et al, JCO 2005
40


Keating et al, JCO 2005
41
PATIENT CHARACTERISTICS I

• Observation time 1998-2004
• N of patients 60
• M/F 30/30
• Median age (range) 59 (37-74)
• Modified Rai stage
• Low risk (0) 5
• Intermediate risk (I II) 52
• High risk (III IV) 3
• ECOG (Performance Status)
• 0 37
• 1 19
• 2 4

42
PATIENT CHARACTERISTICS II

• B symptoms 17
• Time since first diagnosis
• ? 1 year 17
• 2-5 years (I II) 29
• gt 5 years 14
• Infiltration pattern BM
• Nodular 4
• Mixed 10
• Diffuse 46

43

FLUDARABINE RITUXIMAB FOR PREVIOUSLY UNTREATED
CLL

Fludarabine 25mg/m2
MabThera 375mg/m2
40 days Range 30- 155
1 2 3 4
1 5 9 13 17 21
Weeks
Weeks
patients with CR, PR, or stable disease received
Rituximab (375mg/m2 weekly x 4)
44
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 gt5
  CD19CD5CD79b- CLL cells in bone marrow.

45
TOXICITY (WHO)

Grade 0 Grade 1 Grade 2 Grade 3 Grade 4
Fever/Chills 0 5 0 0 0
Anemia 0 0 3 0 0
Neutropenia 0 7 5 19 10
Thrombocytopenia 0 2 2 2 1
Infections Herpes simplex Herpes zoster Pneumonia Acute hepatitis 7 7 3 3 2 2 1 1
46

FLUDARABINE AND RITUXIMAB
(47/60)

NCI criteria
(9/60)
(4/60)
47

CLINICAL OUTCOME I

• Median follow up duration was 27 months (9/56
  pts 16 have experienced a relapse).
• Median duration of CR and PR was not reached.

48

CLINICAL OUTCOME II

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

49




INCIDENCE OF ZAP-70, CD38 AND MRD
31.7
25
46.7

MRD
CD38
ZAP-70
50




CR () BY ZAP-70 AND CD38





P 0.0009
P 0.02
51

52
PROGRESSION FREE SURVIVAL BY ZAP-70, CD38 and
MMR
53
OVERALL SURVIVAL BY ZAP-70, CD38 and MMR
54
CONSIDERATIONS

• The addition of MoAbs, such as rituximab, to
  chemotherapy, allowed us a better outcome in
  B-CLL exerting a key role to eradicate MRD.
• The stratification of patients in different risk
  classes using ZAP-70 and CD38, allowed us to
  distinguish different clinical outcome subsets
  we can offer more tailored treatment strategies
  based on this approach.
• Transplantation procedures or experimental
  therapies should be specifically reserved to
  high risk (ZAP-70 or CD38) B-CLL subsets.

55
Stem-cell transplants in CLL - EBMT
250
CLL Autologous
200
150
Number
100
50
CLL Allogeneic
0
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
Year
56
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

57
Stem-cell transplants in CLL
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

58
Overall survival after stem cell transplantation
1
0.8
AlloSCT (n 46)
0.6
Probability
AutoSCT (n 139)
0.4
0.2
0
0
2
4
6
8
10
12
14
16
18
Years
Montserrat E, Hematol Oncol Clin N Am 2004
18915926.
59
Relapse rate after stem cell transplantation
Auto - SCT (n122)
Allo - SCT (n38)
Montserrat E, Hematol Oncol Clin N Am 2004
18915926.
60
CLL Treatment Goals/Interventions
Palliation Chlorambucil, Epo, etc.
Response Fludarabine Cycloph.
MRD - FCR, FCM (R-FCM)
Cure Allogeneic SCT