II SESSIONE: LLC dalla Biologia alla Clinica ATTUALI APPROCCI TERAPEUTICI Dott. L. Trentin CONVEGNO INTERREGIONALE SIE PADOVA, 12 maggio 2011 Predicting clinical outcome in CLL: how and why survival from diagnosis of 2474 Mayo Clinic patients diagnosed with CLL since January 1995 as compared with the agematched general Minnesota population survival from diagnosis of 1282 Mayo Clinic patients diagnosed with Rai stage 0 CLL since January 1995 as compared with the age matched general Minnesota population Tait D. Shanafelt Factors affecting the prognosis of CLL patients IgVH ZAP70 CD38 Cytogenetics Telomere length Telomerase TK Response β2-microglobulin Patient-related Disease-related Treatment related BIOMARKERS Age Gender Performance status/comorbilities Stage Marrow failure Transformation Immunodeficiency/autoimmunity Biomarkers Type of therapy Minimal residual disease status Telomerase Activation of telomerase is essential for unlimited cell growth and plays a critical role in tumorigenesis Telomerase activity is significantly higher in B-CLL patients with progressive disease than in patients with stable disease Telomerase expression in B-cell chronic lympocytic leukemia predicts survival and delineates subgroups of patients with the same IgVH mutation status and different outcome Terrin et al., Leukemia 2007 173 pazienti con LLC sono stati valutati per Telomerasi 1. Determinazione di telomerasi e lunghezza dei telomeri 2. Analisi dei dati e comparazione con - citogenetica - SHM - ZAP70 e CD38 SHM muta) non muta) CD38 pos neg % % 59.9 40.1 31.2 68.8 Citogene)ca Alterata/normale del 11, 17 del 13 63.2/36.8 6.4 33.6 Time to first treatment 11q- 17p- +12 13q- normal- ZAP70 pos neg 48.4 51.6 Doubl.)me <6mesi 11.3 tris. 12 10.4 M/F 67/33
Telomerasi Telomerasi Time to first treatment AT>, TS< AT>, TS> AT: TELOMERASE TS: TELOMERE LENGHT AT<, TS> AT<, TS< CLL therapy timeline 1960 1970 1980 1990 2000 Goals of CLL therapy overtime 5% 5% Alkylatinng agents -Chlorambucil -Cyclophosphamide. 20-30% Purine analogs -Fludarabine -Pentostatin -Cladibrin 35% Purine analogs and alkylators 50-70% Chemoimmunotherapy 1970 Palliation 1980 Palliation, Higher Response rate 1990 2000,, PFS Freedom from progression 2010 PFS, MRD- F as first line treatment in CLL at M.D. Anderson Cancer Center F as first line treatment in CLL at M.D. Anderson Cancer Center Overall survival after response Time to progression after response FL-cytometry neg Pneg P lowpos Ppos FL-cytometry pos Tam C S et al. Blood 2008;112:975-980 Tam C S et al. Blood 2008;112:975-980
Definition of complete remission Response definition after treatment for patients with CLL general practice - blood lymphocytes < 4000/ml - BM lymphoid cells < 30% * MRD+ MRD- In clinical trials with as an endpoint: -CT negative -MRD assessment -BM biopsy PR MRD+ MRD- : all the criteria have to be met, and patients have to lack disease-related constitutional symptoms; PR: at least 2 of the criteria of group A plus one of the criteria of group B have o be met; SD is absence of PD and failure to achieve at least a PR; PD: at least one of the above criteria of group A or group B has to be met. Hallek et al., Blood 2008 Improved PFS in MRD negative patients Fludarabine-Based Regimens in Previously Untreated Chronic Lymphocytic Leukemia Reference Regimen Phase No Pts ORR Mean PFS (Months) Median OS (Months) Johnson, 1996[155] Flu III 52 23 71 NR NR CAP 48 17 60 7 54 Rai, 2000 [169] Flu III 170 20 63 20 66 CLB 181 4 37 14 56 Flu + CLB 123 20 61 N/A 55 Leporrier, 2001[173] Flu III 341 40 71 32 69 CHOP 357 30 72 30 67 CAP 237 15 58 28 70 Flinn, 2000 [182] Flu + Cy II 17 51 92 N/A N/A O'Brien, 2001[183] Eich horst, 2006[93] p=0.2 Flu + Cy II 34 35 88 NR NR Flu III 182 7 83 20 NR Flu + 180 24 95 48 NR Cy Flu + Cy 136 5 59 19 NR Catv osky, 2005[202] CLB III 387 7 72 N/A N/A Flu 194 15 80 N/A N/A Flu + Cy 196 39 94 N/A N/A Moreton et al. JCO 2005 Byrd, 20 03[232] Flu + Ritu x Ran II 51 47 90 NR NR Flu th en Ritu x 53 28 77 NR NR Rai et al., NEJM 2000 Keatin g, Flu + Cy + II 300 72 94 NR NR What is the impact of therapy on and PFS? CLL8 Study Chlorambucil Cam path Ben da Fludarabine Fludarabine Cyclophospahamide RFC PFS PFS Hallek et al., Lancet 2010
CLL8 STUDY CLL8 STUDY Progression free survival P<.0001 FC R-FC Proportion surviving P=.012 FC R-FC Hallek et al., Lancet 2010 Hallek et al., Lancet 2010 REACH TRIAL REACH TRIAL P<.001 R-FC FC Robak et al., JCO 2010 Robak et al., JCO 2010 CLL therapy: open questions after CLL8 and REACH trial CLL therapy: open questions after CLL8 and REACH trial 1. Therapy for unfit patients 2. How to improve current treatments 3. Therapy in relapsed/refractory disease 4. Therapy for high risk CLL 5. Maintenance therapy for CLL 1. Therapy for unfit patients 2. How to improve current treatments 3. Therapy in relapsed/refractory disease 4. Therapy for high risk CLL 5. Maintenance therapy for CLL
Definition of Ultra High-Risk Chronic Lymphocytic Leukemia OS in High-Risk Chronic Lymphocytic Leukemia no CLL8 trial Zenz et al. J Clin Oncol. 2010 Stilgenbauer and Zenz, Hematology 2010 Refractory CLL Refractory CLL to Disease that fails to respond to a therapy ( / PR not achieved) Disease progressed within 6 months in patients who had achieved / PR Patients progressing or relapsing shortly (within 12 months) after stem-cell transplantation NCI IWCLL Guidelines 2008 Chlorambucil Fluda Fluda + Cytoxan Fluda-Rituxan RFC Treatment becomes more difficoult when aggressive therapies are used upfront Fludarabine in Combination with Alemtuzumab in Relasped/Refractory CLL: Phase II Trial Response to Alemtuzumab in Relapsed/Refractory CLL (N=91) Partial response 19% 18/91 (20%) MRD negative 46% 35% No response Complete Remission T. Elter et al., J. Clin. Oncol. 23: 7024 (2005) P. Moreton et al., J. Clin.Oncol. 23: 2971-9 (2005)
Limitations of Alemtuzumab German CLL Study Group CLL2H Trial Alemtuzumab sc. in fludarabine-refractory Patients Treatment: sc alemtuzumab 30 mg TIW, 12 weeks 60 PR Response (%) 50 40 30 Toxicity - Fever - Rigors - Immunosuppression - Infections 20 10 0 Lymphadenopathy all 17p13 11q23 others Cytogenetics VH unmut S. Stilgenbauer et al., J. Clin. Oncol. 27: 3994 (2009) Consolidation with alemtuzumab improves progression-free survival in CLL patients CMV reactivation Rationale for using MoAbs in combinations Variable expression of epitopes on CLL B cells of individual patients Synergistic activity in anatomic compartments (Rituxan/Campath: Lymph nodes/marrow) Engagement of distinct intracellular signaling pathways resulting in apoptotic cell death C.D. Schweighofer et al., Br. J. Haematol. 144: 95 (2008) Fludarabine, Cytoxan, Alemtuzumab and Rituximab (CFAR) in High-Risk CLL Combinations using Fludarabine and Campath T. Robak, Blood 115: 437-438 (2010)
HSC Transplantation Autologous SCT Allogeneic SCT RIC Allogeneic SCT Is a procedure with evidence-based efficacy in poor-risk CLL Is a reasonale option for younger patients - with non-response or early relapse after purine analogues; - with p53 abnormalities and treatment indication; - with relapse within 24 months after having achieved a response with intensive treatment, including autologous transplantation Transplant strategies may vary on an individual basis (choice of conditioning, etc.) Limitations of Transplantation Procedures Advanced age of many CLL patients Comorbilities High Transplant Related Mortality and QoL-related problems (GvHD) Best salvage and conditioning regimens not determined Ultra High-Risk Chronic Lymphocytic Leukemia 17p-/TP53 mutation (treatment indication, 1 or>treatment line) F-refractory (no PR/ or PR/< 6 months) Refractory to Fludarabine and Alentuzumab Short PFS< 24 (-36) months after (or similar regimen, e.g. P, FR, BR), And absnce of 17p-/TP53 mutation (exclude clonal evolution by retesting) Option 1: treatment in clinical trial (clinical trial of novel agents/combinations with evidence for activity) Option 2: treatment outside trial alentuzumab Ofatumumab Prior response to F (or similar) /npr: F (ORR 70%) Prior response to F (or similar) : Alternative regimens (ORR with F 30%) Consolidation (if PR/ achieved) Fit patients: allo SCT after reduced-intensity conditioning Patients not eligible for allo-sct: consolidation therapy in clinical trial New agents for CLL Monoclonal antibodies in CLL therapy
Ofatumumab: characteristics Human CD20 MoAb Binds to small loop of CD20 Potent lysis of B cells More effective in vitro CDC vs rituximab Effective CDC of cells expressing low CD20 FA-ref: Fludarabine-alentuzumab refractory BF-ref: Bulky fludarabine refractory Wierda et al. Blood First Edition Paper
Ofatumumab trials Wierda et al. Blood First Edition Paper Flavopiridol in Refractory high-risk CLL Flavopiridol in high-risk CLL 42 Patients fludarabine refractory High risk disease 30 Patients with del(17p) or del (11q) 64 Patients with Genetically High-Risk Disease 21 Patients with del(17p) 28 Patients with del(11q) 27 Patients with complex karyotype Partial Response 45% Partial Response 47% Complete Response 1,6% Median Duration Response 12 months Response in 57% Patients with del(17p) 50% Patients with del(11q) J.C. Byrd et al., Blood 109: 399 (2007) T.S. Lin et al., J. Clin. Oncol. 27: 6012 (2009)
Bendamustine in CLL Rituximab and Bendamustine in Relapsed/Refractory CLL Pazienti refrattari a FC Pazienti con AEA (Coombs+) Pazienti con molteplici infezioni opportunistiche Pazienti con insufficienza renale Pazienti anziani con comorbidità Pazienti (%) 100 80 60 40 20 0 PR/ npr ORR = 77% (n = 62) 63 15 Tutti i pazienti n = 41 ORR 71 n = 9 Fischer K. et al., Blood 112: Abs. 330 (2008) n = 39 78 74 n = 13 92 Fludarasensibilrefrattari non Fludara- IgV H 11q del mutato n = 9 44 17p del Phase I to II Multicenter Study of Oblimersen Sodium, a Bcl-2 Antisense Oligonucleotide, in Patients With Avanced B-CLL 40 Patients (69% Fludarabine refractory) Reduction in splenomegaly 41% Complete disappearence of hepatomegaly 29% Reduction in circulating lymphocyte counts 50% Adverse events included transient hypotension, fever, fatigue, night sweats, diarrhea, nausea, vomiting, hypokalemia, cough. S.M. O Brien et al., J. Clin. Oncol. 23: 7697 (2005) Randomized phase III trial of Fludarabine plus Cyclophosphamide with or without Oblimersen in patients with relapsed or refractory CLL 100 90 80 70 60 50 40 30 20 10 0 % fo patients alive at 36 months 70% (14/20) 45% (13/29) 7% (5/71) Fluda+CTX and oblimersen O Brien S. et al., J. Clin. Oncol. 25: 1114-1120 (2007) 38% (3/8) 33% (15/46) Fluda + CTX PR < PR 9% (6/67) Randomized phase III trial of Fludarabine plus Cyclophosphamide with or without Oblimersen in patients with relapsed or refractory CLL 5-Year Survival Lenalidomide in CLL Lenalidomide 25mg p.o. (1 through 21 of a 28-day cycle) until progression, unacceptable toxicity,, or 45 patients; mean age 64 yrs (42-75) Rai III-IV 64% Fludarabine refractory 51% Overall Response: 47 % (58%*) Complete Response: 9 % (18%*) Partial Response: 38 % Responding patients (i.e., patients with a complete or partial response; n = 103) S. O Brien et al., J. Clin. Oncol. 27: 5208-5212 (2009) Only 3 patients needed addition of Rituxan * Updated results A. Chanan-Khan et al., J. Clin. Oncol. 24: 5343-49 (2006)
Progression-free Survival of Patients with CLL with High-risk Cytogenetics after Lenalidomide Therapy CLL therapy: new agents (-) del(11q)(q22.3) patients; ( ) del(17p)(p13.1) patients T. Sher et al., Leuk. Lymph. 51: 85 (2010)