b cll
Download
Skip this Video
Download Presentation
B-CLL

Loading in 2 Seconds...

play fullscreen
1 / 60

B-CLL - PowerPoint PPT Presentation


  • 202 Views
  • Uploaded on

B-CLL. DIAGNOSIS PROGNOSIS CLINICAL MANAGEMENT MRD MONITORING THERAPY. CLL Therapy General Considerations. Treat only patients with symptomatic or progressive disease Treatment based on biological factors not justified Include patients in trials whenever possible

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about 'B-CLL' - chancellor


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
b cll
B-CLL
  • DIAGNOSIS
  • PROGNOSIS
  • CLINICAL MANAGEMENT
    • MRD MONITORING
  • THERAPY
cll therapy general considerations
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 therapy indici di attivit
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 therapy criteri di risposta nci wg 1996
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
cll cr rate and treatment goals over the years
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

cll treatment in a nutshell
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…
hd clb versus chop mod
HD-CLB versus CHOP mod.
  • Arruolati 228 pazienti in stadio avanzato
  • ORHD-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
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 purinici
ANALOGHI PURINICI
  • Fludarabina (9-b-arabinosil-2-fluoroadenina)
  • 2CdA (2-cloro-2’-deossiadenosina)
  • dCF (2’-deossicoformicina)
meccanismo di azione
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
famp front line18
FAMP FRONT-LINE

OS by response

OS by treatment

PFS by response

Keating MJ et al. Blood 92:1998

2 cda front line
2-CDA FRONT-LINE

p=0.04

Robak T et al. Br J Haem 108:2000

famp vs chl21
FAMP vs CHL

RFS p<0.001

PFS p<0.001

OS p<0.21

Rai et al. NEJM, 343: 24, 2000

slide23
TTP FAMP vs FAMP+CY

FAMP+CY: TTP mediano n.r.

FAMP: TTP mediano 30 mesi

O’ Brien S et al. JCO 19: 2001

famp orale
FAMP ORALE

* Pretrattati con alchilanti (rec+res)

moabs citotoxic mechanisms
MoAbs citotoxic mechanisms

Effector cells/

Complement

Apoptosis

Radionuclide

Toxin/Antibiotic

slide28
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
slide29
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/deleted6/15 (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

slide30
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

slide31
First line treatment of CLL with CAMPATH-1H results
  • Response:87% (19% CR, PR 68%)
  • Rai stage I-II100%
  • <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

eradi cation of mrd in b cll after alemtuzumab alz therapy is associated with prolonged survival
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

slide33
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
MabThera®: a chimeric murine/human MoAb

Variable murine regions bounding

CD20 on B cells

Human kappacostant regions

Human domain IgG1 Fc, synergistic

with human effector mechanisms

Chimeric IgG1

patient characteristics i
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
patient characteristics ii
PATIENT CHARACTERISTICS II
  • B symptoms 17
  • Time since first diagnosis:
    •  1 year 17
    • 2-5 years (I + II) 29
    • > 5 years 14
  • Infiltration pattern BM:
    • Nodular 4
    • Mixed 10
    • Diffuse 46
slide43
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)

materials and methods
MATERIALS AND METHODS
  • ZAP-70 protein TK and CD38 antigen were determined by multicolor flow cytometricmethods (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.
slide46
FLUDARABINE AND RITUXIMAB

(47/60)

NCI criteria

(9/60)

(4/60)

slide47
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.
slide48
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).
slide49
INCIDENCE OF ZAP-70, CD38 AND MRD

31.7%

25%

46.7%

ZAP-70

CD38

MRD

slide50
CR (%) BY ZAP-70 AND CD38

P = 0.0009

P = 0.02

considerations
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.
stem cell transplants in cll ebmt
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

allogeneic sct for cll why
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
stem cell transplants in cll
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

overall survival after stem cell transplantation
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;18:915–926.

slide59
Relapse rate after stem cell transplantation

Auto - SCT (n=122)

Allo - SCT (n=38)

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

cll treatment goals interventions
CLL Treatment Goals/Interventions

Palliation Chlorambucil, Epo, etc.

Response Fludarabine + Cycloph.

MRD - FCR, FCM (R-FCM)

Cure Allogeneic SCT

ad