SIMPOSIO - Leucemia Linfatica Cronica: presente e futuro nella gestione del paziente refrattario

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1 42 Congresso Nazionale SIE ottobre Milano Convention Centre SIMPOSIO - Leucemia Linfatica Cronica: presente e futuro nella gestione del paziente refrattario Paolo Ghia Lab of B Cell Neoplasia - Div. of Molecular Oncology Lymphoma Unit Department of Oncology Università Vita-Salute San Raffaele Istituto Scientifico San Raffaele

2 Chronic Lymphocytic Leukemia Homogeneous phenotype: CD5 +, CD23 +, sigm low CD19 CD5 CD5 CD20 CD79b Kappa

3 Chronic Lymphocytic Leukemia Homogeneous phenotype: CD5 +, CD23 +, sigm low Heterogeneous clinical course Indolent course Aggressive course Survival: years Therapy: No or late need during the clinical course Survival: 3-5 years Therapy: Early and frequent during the clinical course Classic Prognostic factors Clinical Stage (Rai/Binet) Bone Marrow Histology LDT Reflect disease burden

4 Chronic Lymphocytic Leukemia Homogeneous phenotype: CD5 +, CD23 +, sigm low Heterogeneous clinical course Indolent course Aggressive course Survival: years Therapy: No or late need during the clinical course Survival: 3-5 years Therapy: Early and frequent during the clinical course New biological Prognostic factors IGHV mutational status CD38 expression ZAP70 expression Genomic abnormalities Predict prognosis at diagnosis

5 IGHV Mutation status predicts clinical course in CLL 98% Hamblin et al, 1999 Time from diagnosis Damle et al, 1999

6 Chromosomal abnormalities in CLL 13q deletion: 36% Trisomy 12: 16% 11q deletion: 18% 17p deletion: 7% Dohner et al. 2000

7 Chromosomal abnormalities and survival Patients surviving (%) q- 13q- 17p- Time (months) Dohner et al. 2000

8 Chomosomal abnormalities and survival Patients surviving (%) p- 11q- 13q- Time Krober et al. 2002

9 Chromosomal abnormalities in CLL? mir-15a mir q deletion: 36% Trisomy 12: 16% p53 ATM? 11q deletion: 18% 17p deletion: 7% Dohner et al. 2000

10 Treatment related decisions Clinical Stage (Rai/Binet) Stage A (0) Stage B (I-II) Stage C (III-IV) Treatment strategy Wait and watch Treat if progression Treat at onset IGHV mutations CD38 ZAP-70 FISH

11 Treatment related decisions Clinical Stage (Rai/Binet) Stage A (0) Stage B (I-II) Stage C (III-IV) Treatment strategy Is early therapy beneficial? Which treatment? IGHV mutations CD38 ZAP-70 FISH Prospective clinical trials Hallek et al, Blood 2009

12 ESMO guidelines Eichhorst B, et al. Ann Oncol 2008 Time of first relapse/progression > 12 months after first-line therapy < 12 months after first-line therapy The first line treatment may be repeated Alternative therapy should be used

13 iwcll definition of Refractory CLL Hallek M, et al. Blood Treatment failure (<PR) or - disease progression within 6 months of the last anti-leukemic therapy

14 Increasing complete remissions in CLL 80 CR according to NCI criteria, 1996 Percent of patients Chlorambucil Fludarabine Alemtuzumab CAP CHOP FC FCM FCR Rai et al Leporrier et al Lundin et al O Brien et al Bosch et al Tam et al. 2008

15 Survival of fludarabine-refractory CLL cases Fludarabine-refractory CLL patients treated with first salvage therapy have a poor prognosis: 22% of patients had a response to therapy Median survival of the entire population was ~10 months Early death rate was 13% Most common cause of death was infection Proportion Surviving Pts Months Keating MJ, et al. Leuk Lymphoma. 2002

16 Impaired p53 pathway in CLL ATM 11q- / ATM Mutation MDM2 p21 p53 mir-34a Puma 17p- / TP53 Mutation mir-34 CDKs, CCND1, BCL2, E2F, MYCN, SIRT1, etc Cell cycle arrest Apoptosis Kind courtesy of T. Zen

17 UKCLL202: Fludarabine-refractory CLL p- and 11q- 11q- 17p- 28/46 (61%) 17p- &/or 11q normal N/A 23/31 ( 74%) of patients had unmutated IGHV genes Kind courtesy of P. Hillmen

18 TP53 mutations and del17 Abnormalities may be acquired with time Zenz et al. Blood 2008

19 Patients 17p - may have stable disease Best et al, Leukemia 2009

20 iwcll definition of Refractory CLL Hallek M, et al. Blood Treatment failure (<PR) or - disease progression within 6 months of the last anti-leukemic therapy Most patients are not refractory, particularly in the era of immunochemotherapy

21 Increasing complete remissions in CLL 80 CR according to NCI criteria, 1996 Percent of patients Chlorambucil Fludarabine Alemtuzumab CAP CHOP FC FCM FCR Rai et al Leporrier et al Lundin et al O Brien et al Bosch et al Tam et al. 2008

22 GLLSG CLL8: Response to treatment FC FCR p CR 22.9% 44.5% <0. 01 CR u 5.1% 3.3% 0.22 CR i 1.9% 2.6% 0.52 npr 4.9% 2.8% 0.15 PR 50.4% 39.6% <0.01 SD 6.7% 3.9% 0.08 PD 8.1% 3.3% <0.01 Hallek et al. ASH, 2008

23 CLL8 - Progression free survival Median observation time 25.5 months p< p= Median PFS: 32.3 months for FC vs 42.8 months for FCR Hallek et al. ASH, 2008

24 Tam, C. S. et al. Blood 2008;112: CLL therapy: is there standard of care? 1.0 Proportion Alive Rx Pts. Died F+/-P FM/FC FCR Years

25 CLL8 Genetic Analyses: OS FC FCR 25 Stilgenbauer S. Et al, ASH 2008

26 CLL8 Treatment Effect: OS 11q- group P= Stilgenbauer S, ASH 2008

27 CD20: A B cell Target for Therapeutic MoAbs CD20 Expressed 1-3 : Exclusively on B-cells On most B-cells in periphery On most malignant B-cells Stable on B-cell surface, allowing sustained MoAb binding 1-3 Some reports indicate that it is infrequently shed or modulated (either by internalisation or down-regulation) B-Cell Function not well understood but believed to contribute to B-cell growth, proliferation, differentiation, and activation 1-3 No known ligand May form a membrane ion channel and play a role in calcium flux Involved in B-cell receptor activation and signaling 1 Cragg MS, et al. Curr Dir Autoimmun. 2005; 2 Hotta, Acta Histochem Cytochem. 2002; 3 Teeling JL, et al. J Immunol

28 Expression of target antigens on CLL cells 400, ,303 MESF units (n=5) 300, , , CD20 CD22 CD52 Rossmann et al. Hematol J 2001;2:300

29 1. Keating MJ, et al. Blood Dreger P, et al. Leukemia 2007 Treatment options for refractory patients Licensed Alemtuzumab (fludarabine refractory) 1 Experimental Other anti-cd20 Mabs Other Mabs Bcl-2 inhibitors Signalling pathway inhibitors (Syk, PI3K, HSP90) Autologous Stem-cell transplantation (not curative) Allogeneic Ste-cell transplantation (high toxicities)

30 Allo-SCT for 17p- CLL: EBMT survey year OS 52% 3-year PFS 44% Median follow-up: 23 months (2 90) Probability Progression-free survival Overall survival Years after HCT Schetelig J, et al. JCO 2008

31 CLL3X: Allo-SCT after Dose-reduced Conditioning 100 Overall Survival N=37 Survival: 80% Follow-up: 15 months Patient characteristics Age (years) 53 F-refractory 47% 11q- / 17p- 50% VH unmutated 94% Months Dreger et al., GCLLSG, 2004

32 CLL3X: Allo-SCT after Dose-reduced Conditioning 11q- or 17p- 17p- Percent EFS p- or 11q- (39) other(32) p- (13) other(58) HR 0.89 ( ) HR 0.81 ( ); p Months from SCT Months from SCT Dreger P, et al unpublished 2009

33 Alemtuzumab alone in refractory CLL Study Tumor type Disease phase No. of patients Response rate Response duration (mo.) Österborg et al 1 CLL Alkylating-agent refractory 29 42% 12 Keating et al 2 CLL F- refractory 93 33% 9 Rai et al 3 CLL F-refractory % Not stated Lozanski et al 4 CLL F- refractory, p53 mutation Stilgenbauer et al 5 CLL F-refractory (SC) Karlsson et al 6 CLL F-refractory (SC) 15 40% % % 14 1 Österborg et al. J Clin Oncol 1997; 2 Keating et al. Blood 2002; 3 Rai et al. ASH 2002; 4 Lozanski et al. Blood 2004; 5 Stilgenbauer et al. J Clin Oncol 2009; 6 Karlsson et al, Br J Hematol, 2009

34 CLL2H trial: alemtuzumab s.c. Fludarabine-refractory CLL Alemtuzumab subcutaneous 3 x 30 mg/week 4 12 weeks Genetics (FISH, VH), CD38, ZAP-70, TK, ß2-MG 17p- 29% 11q- 19% +12 6% Unmut. VH 66% Dreger P et al. JCO 2009

35 CLL2H: survival (n=103) % survival Median OS: 19.1 months Median PFS: 7.7 months Time (months) Compare: Keating et al Alemtuzumab iv Median OS: 16 months Median PFS: 4.7 months Infections (grade 3-4) Non-CMV: 29% CMV: 8% Dreger P et al. JCO 2009 Keating MJ, et al. Leuk Lymph 2002

36 CLL2H: Survival by genetics 100 Overall survival 100 Progression-free survival p- 17p- 11qother 11q- 11qother 17p- 11qother p- 11qother 17p Time (months) Time (months) Dreger P et al. JCO 2009

37 CAM-PRED regimen (Pettitt et al.) IV alemtuzumab 30 mg thrice weekly after dose escalation SC alemtuzumab 30 mg thrice weekly from week 5 IV methylprednisolone 1.0 g/m 2 day 1 5 repeated every 28 days Infection surveillance and prophylaxis!!! Kind courtesy of P. Hillmen

38 CAMPRED protocol (UK CLL206) Patients requiring therapy and with >20% 17p-deleted cells 39 patients (22 de novo; 17 pre-treated with 1-5 regimens) Response assessment by IWCLL criteria, 2008 CR/CRi rate: All patients 24%, De novo patients 37% MRD negative: 3 patients Toxicity CMV reactivation in 23% Non-CMV infection in 41% Steroid-related toxicity in 38% Pettitt AR, et al. EHA 2009

39 CLL2O Trial for 17p- or F-refractory CLL Off study (other salvage protocol) PD PD PD 4 week Alem + Dexa Staging PR SD 4 week Alem + Dexa Staging PR SD 4 week Alem + Dexa Staging CR CR SD/PR CR Consolidation: Option A: OR: Option B: Alemtuzumab maintenance (30 mg / 14 days, max 2 years) Allogeneic SCT (CLLX2 etc) Kind courtesy of S. Stilgenbauer

40 Fludarabine+Cyclophosphamide+Campath: FCC Protocol Dose escalation course 2 course Kind courtesy of M. Montillo

41 FCC: efficacy RESPONSE N % RC 7 31 RP 9 39 ORR 74% RPN 1 4 STABLE DISEASE 3 13 PROGRESSIVE DISEASE 2 9 EARLY DEATH 1 4 Characteristics of patients: response Unmutated : 61% 86% del17p and del11q: 42% 75% Toxicity: Non-CMV infections : 6/31 19% CMV reactivation: 6/31 19% Montillo M, ASH 2007

42 Lenalidomide in Relapsed CLL Lenalidomide 25 mg PO QD x 21 (q 28 days) Treatment continued until CR or PD 45 pts with relapsed CLL (median age 64 y) 64% stage Rai III-IV 51% Fludarabine refractory Response rate: 47% CR 9 %, PR 38% Side Effects Grade 3-4 : neutropenia 70%, thrombocytopenia 45% Flare reaction grade 3-4 was seen in 8% of pts Chanan-Khan A et al. JCO 2006

43 Lenalidomide: response in poor risk CLL Subgroup Number Response 17p- 6 3 PR, 1 SD, 2 NE 11q CR, 3 PR *, 4 SD, 2 NE F-refractory 23 1 CR, 6 PR, 3 SD ZAP CR, 2 PR, 2 SD, 2 NE 44% 30% 60% Chanan-Khan AA, et al. ASH 2007 Ferrajoli A, et al. ASH 2007

44 UKCLL210 trial: Cam-Dex-Rev For p53 deleted and fludarabine refractory CLL Candidate for allosct Allograft Campath Dexamethasone Lenalidomide (CamDexRev) CR/PR NR/PD No allosct option?lenalidomide Off study Kind courtesy of Pettitt et al.

45 Flavopiridol in Relapsed CLL 30-minute loading dose followed by 4 hours of infusion weekly for 4 of 6 weeks 3 cohort ( loading 30+ inf 30; L 40+I 40; L30+ I 50) 117 pts with relapsed CLL (median age 60 y) Fludarabine refractory: 73% Response rate: 48% (CR 1%) 50% response in 17p del pts (20/40); 59% response in 11q del pts (29/49) 48% bulk lymphoadenpathies (41/85) Side Effects Grade 3 : tumor lysis syndrome Grade 3-4 : neutropenia, thrombocytopenia Lin et al. ASH 2008

46 Treatment options for refractory patients Tsimberidou and Keating, Cancer 2009

47 Salvage therapy in refractory CLL Need for active, new agents Poor prognosis for fludarabine-refractory CLL 1 Worse outcomes if also refractory to alemtuzumab, or with bulky lymph nodes 2 Response with salvage regimens ORR 23%; median TTF 2-3 mo Median OS: 9 mo Major infections: 54% Early death*: 13% *Death within 8 weeks of start of salvage treatment Keating et al. Leuk Lymphoma 2002; 2. Tam et al. Leuk Lymphoma 2007

48 Ofatumumab: Characteristics Ofatumumab binding site Rituximab binding site Human CD20 mab Binds a small-loop epitope of CD20 Potent lysis of B cells More effective in vitro CDC versus rituximab Effective CDC of cells with low CD20 expression, including CLL cells Promising activity in pilot CLL study: ORR 50% in high-dose group (n=27) Teeling et al. J Immunol 200; 2. Teeling et al. Blood 2004; 3. Coiffier et al. Blood 2008

49 FA and BF refractory CLL International, open-label, single-arm study in EC and US Fludarabine- and alemtuzumabrefractory (FA-ref) Refractory to fludarabinecontaining regimen ( 2 cycles) Refractory to alemtuzumabcontaining regimen ( 12 doses) Fludarabine-refractory with bulky lymph nodes (BF-ref) Refractory to fludarabinecontaining regimen ( 2 cycles) Less suitable for alemtuzumab due to bulky nodes (>5 cm) Screening, baseline characteristics Ofatumumab 300 mg Ofatumumab 2000 mg Week

50 Ofatumumab in refractory CLL Overall response rate 100 ORR (%) %* 47%* 99% CI *p< versus H 0 20 H 0 : ORR = 15% 0 FA-ref (N=59) BF-ref (N=79) All PRs except one CR in BF-ref group. *The null hypothesis of ORR=15% was tested against the corresponding two-sided alternative hypothesis ORR 15% using an exact test. Osterborg and Wierda, EHA, 2009

51 Grade 3-4 related adverse events* Adverse events FA-ref N=59 BF-ref N=79 n % n % Infections Neutropenia Fatigue Cough Anemia Diarrhea Dyspnea Nausea Rash Fever *Adverse events judged by investigators to be related to ofatumumab among the most common adverse events that occurred in 10% of patients from the first infusion of ofatumumab to within 30 days of the last infusion. 51 Osterborg and Wierda, EHA, 2009

52 Ofatumumab in refractory CLL Summary of early deaths Early deaths ( Week 8) occurred in 6 patients (4%) 4 patients in FA-ref group: sepsis (n=1), pneumonia (n=2), fusarium infection (n=1) 2 patients in BF-ref group: sepsis (n=1), myocardial infarction (n=1) Early deaths with salvage regimens: FA-ref patients BF-ref patients Tam et al study Tam et al study 16% 7% 10% 3% Tam et al. Leuk Lymphoma 2007 Osterborg and Wierda, EHA, 2009

53 Ofatumumab in refractory CLL Time to response and duration Time to response Duration of response* Median 1.8 mo Median 1.8 mo Median 7.1 mo Median 5.6 mo *Time from initial response to progression (assessed by IRC) or death. 53 Osterborg and Wierda, EHA, 2009

54 Ofatumumab in refractory CLL Survival outcomes Progression-free survival* Overall survival** Median 15.4 mo Median 5.7 mo Median 13.7 mo Median 5.9 mo *Time from start of treatment to progression (assessed by IRC) or death. **Time from start of treatment to death. 54 Osterborg and Wierda, EHA, 2009

55 Ofatumumab in refractory CLL Overall survival by response FA-ref BF-ref Median not reached Median not reached Median 9.8 mo Median 10.2 mo Osterborg and Wierda, EHA, 2009

56 Summary of Ofatumumab in refractory CLL Ofatumumab as a single-agent produces high response rates in fludarabine-refractory CLL ORR 58% in FA-ref group, 47% in BF-ref group Response correlates with significantly improved survival Effective independent of prior rituximab 1 Meaningful improvements in disease symptoms, organomegaly, and hematologic parameters Well tolerated with no unexpected adverse events Results compare favorably with historic outcomes with current salvage therapies in this setting Osterborg and Wierda, EHA 2009; 2. Tam et al. Leuk Lymphoma 2007

57 Novel Treatments for refractory CLL Combinations Ofatumumab Lenalidomide Alemtuzumab F-based therapies Flavopiridol Pre-clinical drugs (MAbs, inhibitors)

58 Università Vita-Salute San Raffaele Istituto Scientifico San Raffaele Department of Oncology - Division of Molecular Oncology Uppsala Richard Laboratory Rosenquist of B Cell Neoplasia Claudia Fazi, Agnieszka Janus, Maria Gounari, Giorgia Simonetti, Elisa ten Haken Paris Laboratory of Lymphoid Malignancies Frédéric Davì Cristina Scielzo, Marta Muzio, Sabrina Bertilaccio, Benedetta Apollonio Federico Caligaris-Cappio Barcelona Carol Moreno IMGT, Montpellier Thessaloniki Marie-Paule Lefranc, Veronique Kostas Giudicelli Stamatopoulos Athens Chrysoula Belessi CERTH, Thessaloniki Milano Nikos Darzentas