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B-CLL DIAGNOSIS PROGNOSIS CLINICAL MANAGEMENT MRD MONITORING THERAPY.

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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 CR% Chlorambucil COP, CHOP Fludarabine Fludarabine-combined regimens Year Symptoms palliation Higher response rate (vs. Chlorambucil) Prolonged FFP MRD (-) ? Prolonged survival ? Cure CLL: CR rate and treatment goals over the years 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 TrialsDosaggio Risultati FRE-CLL-80 ( 278 pz ) 0,1 mg/dieCR: 45% PR: 31% NR: 24% FRE-CLL-85 ( 437 pz ) 0,3 mg/Kg d PDN 40/mq d 1-5 CR: 28% PR: 41% NR: 31%

8 RISULTATI CLB I linea IGCI CLL-01 trial RispostaAlte dosiDosi intermedie CR70 %31 % PR19 % NR11 %50 %

9 Risultati CLB mantenimento RiferimentiDosaggioRisultati Jaksic et al. Nouv Rev Fr Hematol, mg 2 volte settimana/ 3 anni Migliora la durata della risposta e la sopravvivenza

10 Risultati CLB II linea RiferimentiPopolazioneRisultati 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 1) Fludarabina (9- -arabinosil-2- fluoroadenina) 2) 2CdA (2-cloro-2-deossiadenosina) 3) dCF (2-deossicoformicina)

14 MECCANISMO DI AZIONE 1)effetto inibitorio su enzimi implicati nella riparazione e sintesi del DNA –DNA primasi, ligasi e polimerasi –Reduttasi ribonucleotidica 2)danno diretto della membrana dei mitocondri 3)inibizione della sintesi di RNA

15 FAMP IN PAZIENTI PRETRATTATI Refer.RCOR OS median a N°pz. Grever Nouv Rev Fr Hematol: % (13%) 12% (32%) 13 m 32 (31) Keating Blood 74: % (13%) 57% (48%) 11 m 68 (48) Johnson Ann Oncol 142 [a277]:1994 5% 26%12.7 m123 Sorensen JCO 15:1997 3% 32%13 m724

16 2-CDA IN PAZIENTI PRETRATTATI Refer.RCOR OS mediana N°pz Piro Blood 72: % Non riportata 18 Saven Leuk Lymph 5: %40% Non riportata 90 Juliusson Ann Oncol 7: % 58% 36 m (CR) 28 m (PR) 52 Robak Br J Hematol 108: % 48%12 m184

17 FAMP FRONT-LINE TrattamentoN° pz.RCORPFS mediana OS mediana Ref. FAMP mg/m 2 d 1-5 (71 pz) opp. FAMP 30 mg/m 2 d PDN 30 mg/m 2 (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/m 2 d %100% Non riportata Clavio EurJHem6 1:1998 FAMP 30 mg/m 2 d % 94% n.r. [FUP 13 m (2-38)] Non riportata Stelitano Haemat 84:1999

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

19 2-CDA FRONT-LINE RCOR RFS mediana OS mediana Morti Popolazione totale 194 pz 45.4 % 82.5 % 12 (3-54)18 m63 2-CdA 0.12 mg/kg d pz 37.2 % 72.1 % 16 (3-54)19 m15 2-CdA+PDN 30 mg/m 2 d pz 47.7 % 85.4 % 12 (3-43)18 m48 Robak T et al. Br J Haem 108:2000 p=0.04

20 FAMP vs CHL TrattamentoN° pz. RCRPRFSOSRef. FAMP 25 mg/m 2 Chl 40 mg/m 2 ogni 28 gg % p< % 43% p< % 25 m p< m 66 m p= m Rai et al. NEJM 24: 2000 FAMP 25 mg/m 2 x 6 Chl 30 mg/m 2 g 1 e 15+PDN 40 mg/m 2 g 1-5 e ogni 28 gg % p-NC 37% 25% p-NC 34% 28 m P= m NC Spriano Hematol Cell Ther Abs 2000 FAMP 25 mg/m 2 ogni 21 gg (per 18 sett) Chl 10 mg/m 2 /d per 18 sett % p= % 36% p= % p=0.92p=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

22 FAMP + CY (non comparativi) FAMP + CY (non comparativi) TrattamentoN° pz. StadioRCORPFS medianaRef. FAMP 30 mg/m 2 d CY 300 mg/m 2 d (34*) III-IV 47% 17% (35%) 74% (88%) m Non raggiunta O Brien JCO 19:2001 FAMP 30 mg/m 2 d 1-3 +CY 250 mg/m 2 d (15*) A 3% B 50% C 47% 16%91% Durata mediana della risposta non raggiunta dopo FUP 14 m Hallek, B J Haemat 114:200 1 FAMP per os 30 mg/m 2 d 1-5 +CY per os 200 mg/m 2 d 1-5 x 6 59* B 79% C 21% 47% 78%Non riportata Cazin [a772] Blood 98:2001 * non pre-trattati

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

24 FAMP ORALE TrattamentoN° pz. RCORPFS mediana OS mediana Ref. FAMP 40 mg/m 2 d 1-5 x 6-8 cicli 78* 21 % 46% Non riportata Boogaerts JCO 15:2001 FAMP 40 mg/m 2 d 1-5 x 6-8 cicli % 72% 28 m Non riportata Rossi JF JCO 22:2004 FAMP per os 30 mg/m 2 d 1-5 +CY per os 200 mg/m 2 d 1-5 x 6 cicli % 78% Non riportata Cazin [a772] Blood 98:2001 * Pretrattati con alchilanti (rec+res)

25

26 MoAbs citotoxic mechanisms Effector cells/ Complement ApoptosisRadionuclide Toxin/Antibiotic

27 MoAbs for CLL AntibodyAntigen Alemtuzumab (Campath-1H)CD52 Rituximab (Rituxan, Mabthera)CD20 Epratuzumab (LymphoCide)CD22 Hu-1D10 (Apolizumab)HLA-DR IDEC-152 (Lumiliximab)CD23 IDEC-114CD80 Bevacizumab (Avastin)VEGF BL-22CD22 ( 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 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 without4/21 (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

30 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 CAMPATH-1H AS FIRST LINE TREATMENT OF CLLsubcutaneous

31 First line treatment of CLL with CAMPATH-1H results Response:87% (19% CR, PR 68%) Rai stage I-II 100% 65 y 90% TTF:18+ 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: 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

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 IgG 1 Fc, synergistic with human effector mechanisms Chimeric IgG 1

35 Rituximab monotherapy in CLL (375mg/m 2 /wk x 4)

36 Rituximab monotherapy in CLL (schedules other than 375mg/m 2 /wk x 4)

37

38 Summary of response data in Phase II studies of rituximab plus chemotherapy

39 Keating et al, JCO 2005

40

41 PATIENT CHARACTERISTICS I o Observation time o N° of patients 60 o M/F 30/30 o 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):

42 PATIENT CHARACTERISTICS II o B symptoms 17 o Time since first diagnosis: 1 year years (I + II) 29 > 5 years 14 o Infiltration pattern BM: Nodular 4 Mixed 10 Diffuse 46

43 FLUDARABINE + RITUXIMAB FOR PREVIOUSLY UNTREATED CLL patients with CR, PR, or stable disease received Rituximab (375mg/m 2 weekly x 4) Fludarabine 25mg/m 2 MabThera 375mg/m 2 Weeks 40 days Range Weeks

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) Grade 0Grade 1Grade 2Grade 3Grade 4 Fever/Chills Anemia Neutropenia Thrombocytopenia Infections Herpes simplex Herpes zoster Pneumonia Acute hepatitis

46 NCI criteria ( 47/60) FLUDARABINE AND RITUXIMAB ( 9/60) ( 4/60)

47 CLINICAL OUTCOME I Median follow up duration was 27 months (9/56 pts [16%] have experienced a relapse). Median follow up duration was 27 months (9/56 pts [16%] have experienced a relapse). Median duration of CR and PR was not reached. 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). 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 MRD CD38ZAP % 31.7% 25%

50 CR (%) BY ZAP-70 AND CD38 P = 0.02 P =

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

55 Number CLL Autologous CLL Allogeneic Year Stem-cell transplants in CLL - EBMT

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 AutoAllo Upper age limit 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% Plateaunoyes Stem-cell transplants in CLL

58 Overall survival after stem cell transplantation AlloSCT (n = 46) AutoSCT (n = 139) Years Probability Montserrat E, Hematol Oncol Clin N Am 2004; 18:915–926.

59 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

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


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