B-CLL DIAGNOSIS PROGNOSIS CLINICAL MANAGEMENT MRD MONITORING THERAPY.

Presentazione sul tema: "B-CLL DIAGNOSIS PROGNOSIS CLINICAL MANAGEMENT MRD MONITORING THERAPY."— Transcript della presentazione:

1 B-CLL DIAGNOSIS PROGNOSIS CLINICAL MANAGEMENT MRD MONITORING THERAPY

2 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 Never forget that the ultimate goal of therapy is to prolong survival Treat the patient, not the disease

3 CLL Therapy Indici di attività
Sintomi B (febbre, sudorazione notturna, perdita di peso) Insufficienza midollare (-Hb, -Plt, -Neu) Splenomegalia progressiva Adenomegalie progressive LDT < 6 o 12 mesi

4 CLL Therapy Criteri 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 / 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 /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) > Chlorambucil Fluda + Cyclophosphamide > Fluda Fluda + Cyclo (oral) = Fluda + Cyclo (i.v) SINGLE ARM STUDIES Fluda + Rituximab FCR FCM…

7 Risultati CLB I linea Risultati ( 278 pz ) ( 437 pz ) Trials Dosaggio
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 % 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% 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

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
Refer. RC OR OS mediana N°pz. Grever Nouv Rev Fr Hematol: 1988 3% (13%) 12% (32%) 13 m 32 (31) Keating Blood 74: 1989 13% 57% (48%) 11 m 68 (48) Johnson Ann Oncol 142 [a277]:1994 5% 26% 12.7 m 123 Sorensen JCO 15:1997 32% 13 m 724

16 2-CDA IN PAZIENTI PRETRATTATI
Refer. RC OR OS mediana N°pz Piro Blood 72:1988 22% Non riportata 18 Saven Leuk Lymph 5: 1993 4% 40% 90 Juliusson Ann Oncol 7:1996 31% 58% 36 m (CR) 28 m (PR) 52 Robak Br J Hematol 108:2000 12% 48% 12 m 184

17 FAMP FRONT-LINE Trattamento N° pz. RC OR PFS mediana OS mediana Ref.
FAMP mg/m2 d 1-5 (71 pz) opp. FAMP 30 mg/m2 d PDN 30 mg/m2 (103) 174 I/II 108 III/IV 66 29% 78% 31 m RC = 37 m p=0.02 RP = 30 m 63 m Keating Blood 92:1998 FAMP 25 mg/m2 d 1-5 16 31% 100% Non riportata Clavio EurJHem61:1998 FAMP 30 mg/m2 d 1-5 17 65% 94% n.r. [FUP 13 m (2-38)] Stelitano Haemat 84:1999

18 FAMP FRONT-LINE Keating MJ et al. Blood 92:1998 OS by response
OS by treatment OS by response PFS by response Keating MJ et al. Blood 92:1998

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-CdA+PDN 30 mg/m2 d1-5 151 pz 47.7% 85.4% 12 (3-43) 48 p=0.04 Robak T et al. Br J Haem 108:2000

20 Spriano Hematol Cell Ther Abs 2000 Jaksic Hematol Cell Ther Abs 2000
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% p<0.001 4% 43% 33% 25 m 14 m 66 m p=0.1 56 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 ogni 28 gg 69 73 46% p-NC 37% 25% 34% 28 m P=0.007 21 m NC Spriano Hematol Cell Ther Abs 2000 ogni 21 gg (per 18 sett) Chl 10 mg/m2/d per 18 sett 39 35 39% p=0.29 36% p=0.92 p=0.3 Jaksic Hematol Cell Ther Abs 2000

21 FAMP vs CHL Rai et al. NEJM, 343: 24, 2000 RFS p<0.001
PFS p<0.001 OS p<0.21 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 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 Haemat 114:2001 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

23 FAMP+CY: TTP mediano n.r.
TTP FAMP vs FAMP+CY FAMP+CY: TTP mediano n.r. FAMP: TTP mediano 30 mesi O’ Brien S et al. JCO 19: 2001

24 FAMP per os 30 mg/m2 d 1-5 +CY per os 200 mg/m2 d 1-5 x 6 cicli
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 Boogaerts JCO 15:2001 81 37% 72% 28 m Rossi JF JCO 22:2004 FAMP per os 30 mg/m2 d 1-5 +CY per os 200 mg/m2 d 1-5 x 6 cicli 59 47% 78% Cazin [a772] Blood 98:2001 * Pretrattati con alchilanti (rec+res)

25

26 MoAbs citotoxic mechanisms
Once bound to cancer cells, MoAbs can exert tumoricidal effects through a variety of mechanisms. Antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) may work in synergy with MoAbs to destroy tumor cells.75 Induction of apoptosis (programmed cell death) and inhibition of cell proliferation following antibody binding have been demonstrated in vitro.24,96 Antibodies that lack the ability to interact with the host immune system can be conjugated to radionuclides or toxins to produce a cytotoxic effect.24,60 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 Pts with p53 mutations or deletions (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 mg s.c. Campath-1H in week 1; 30 mg 3x /week s.c. (week ) duration: 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% <65 y 83%; > 65 y 90% TTF: months ( 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: 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

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 MabThera® binds to the CD20 antigen present on normal and malignant pre-B and B cells.95 MabThera® is an engineered immunoglobulin (Ig) produced from the variable regions (Fab) of a mouse (murine) anti-CD20 MoAb and human IgG1 and kappa constant regions (Fc). The human Fc domain and kappa constant regions may contribute to the infrequency of host antibody response. 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

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 N° of patients M/F /30 Median age (range) (37-74) Modified Rai stage: Low risk (0) Intermediate risk (I + II) High risk (III + IV) ECOG (Performance Status):

42 PATIENT CHARACTERISTICS II
B symptoms Time since first diagnosis:  1 year 2-5 years (I + II) > 5 years Infiltration pattern BM: Nodular Mixed Diffuse

43 FLUDARABINE + RITUXIMAB FOR PREVIOUSLY UNTREATED CLL
Fludarabine 25mg/m2 MabThera 375mg/m2 40 days Range 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 >5% CD19+CD5+CD79b- CLL cells in bone marrow.

45 TOXICITY (WHO) 5 3 7 19 10 2 1 Fever/Chills Anemia Neutropenia
Grade 0 Grade 1 Grade 2 Grade 3 Grade 4 Fever/Chills 5 Anemia 3 Neutropenia 7 19 10 Thrombocytopenia 2 1 Infections Herpes simplex Herpes zoster Pneumonia Acute hepatitis

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% ZAP-70 CD38 MRD

50 CR (%) BY ZAP-70 AND CD38 P = 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 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 Year

56 Allogeneic SCT for CLL Why?
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 TRM (4 yrs) 10% % RR (4 yrs) 50% % 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 2 4 6 8 10 12 14 16 18 Years Montserrat E, Hematol Oncol Clin N Am 2004; 18:915–926.

59 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.

60 CLL Treatment Goals/Interventions
Palliation Chlorambucil, Epo, etc. Response Fludarabine + Cycloph. MRD FCR, FCM (R-FCM) Cure Allogeneic SCT