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
8
RISULTATI CLB I linea IGCI CLL-01 trial
9
Risultati CLB mantenimento
10
Risultati CLB II linea
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

• Fludarabina (9-b-arabinosil-2-fluoroadenina)
• 2CdA (2-cloro-2-deossiadenosina)
• 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

16
2-CDA IN PAZIENTI PRETRATTATI

17
FAMP FRONT-LINE
18
FAMP FRONT-LINE
OS by response
OS by treatment

PFS by response
Keating MJ et al. Blood 921998
19
2-CDA FRONT-LINE
p0.04
Robak T et al. Br J Haem 1082000
20
FAMP vs CHL
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)
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
Pretrattati con alchilanti (recres)
25


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

MoAbs for CLL
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)

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