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B-CLL

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

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B-CLL

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  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 < 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% • >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

  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

  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 • 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

  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 92:1998

  19. 2-CDA FRONT-LINE p=0.04 Robak T et al. Br J Haem 108:2000

  20. FAMP vs CHL

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

  22. FAMP + CY (non comparativi) * non pre-trattati

  23. 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 ORALE * Pretrattati con alchilanti (rec+res)

  25. MoAbs citotoxic mechanisms Effector cells/ Complement Apoptosis Radionuclide Toxin/Antibiotic

  26. MoAbs for CLL

  27. 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

  28. 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

  29. 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

  30. 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

  31. 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

  32. 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

  33. 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

  34. Rituximab monotherapy in CLL (375mg/m2/wk x 4)

  35. Rituximab monotherapy in CLL (schedules other than 375mg/m2/wk x 4)

  36. Summary of response data in Phase II studies of rituximab plus chemotherapy

  37. Keating et al, JCO 2005

  38. Keating et al, JCO 2005

  39. 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

  40. 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

  41. 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)

  42. 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.

  43. TOXICITY (WHO)

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

  45. 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.

  46. 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).

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

  48. CR (%) BY ZAP-70 AND CD38 P = 0.0009 P = 0.02

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