Chronische lymphatische Leukämie. Michael Hallek

Transcription

1 Chronische lymphatische Leukämie Michael Hallek

2 Themen Wandel der Prognose CLL8 Follow up CLLM1 Neue Substanzen Ibrutinib CAL101 CLL-Therapie 2013 Studien der DCLLSG

3 Cancer 1981

4 Clinical Stage and Prognosis of CLL in 2001 (Barcelona data) Courtesy of Emili Montserrat et al. 1,0 Binet A Binet B Binet C 15.5 y 5.5 y 3 y 0,5 Binet A Binet B 0, Years Binet C

5 Improved survival of advanced CLL 1981 versus 2011 Binet stage A Survival after 5 years: 87.8% Binet stage C Survival after 5 years: 72.8% HR: 2.6 (95% CI: ) Binet stage B Survival after 5 years: 74.0% HR: 2.7 (95% CI: )

6 Overall survival and clinical stage updated results of several gcllsg Trials, 2011 (N= 1948) Jasmin Bahlo, Natali Pflug Abstract 4.13, IWCLL 2011 Abstract book, Page S225 Binet stage B Survival after 5 years: 74.0% HR: 2.7 (95% CI: ) Binet stage A Survival after 5 years: 87.8% Binet stage C Survival after 5 years: 72.8% HR: 2.6 (95% CI: ) 6

7 435 EXTENDED FOLLOW UP OF THE CLL8 PROTOCOL, A RANDOMIZED PHASE-III TRIAL OF THE GERMAN CLL STUDY GROUP (GCLLSG) COMPARING FLUDARABINE AND CYCLOPHOSPHAMIDE (FC) TO FC PLUS RITUXIMAB (FCR) FOR PREVIOUSLY UNTREATED PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) Kirsten Fischer, MD, Jasmin Bahlo, Anna-Maria Fink, MD, Raymonde Busch, Sebastian Böttcher, MD, Jiri Mayer, MD, Peter Dreger, MD, Christian Maurer, Anja Engelke, Michael Kneba, MD, PhD, Hartmut Döhner, MD, Barbara F. Eichhorst, MD, Clemens-Martin Wendtner, MD, Stephan Stilgenbauer, MD, and Michael Hallek, MD 54th Annual Meeting of the American Society of Hematology (ASH), Atlanta, December 10, 2012

8 CLL8 Study, Design Hallek et al., Lancet 2010; 376: Patients with untreated, active CLL and good physical fitness (CIRS 6, creatinine clearance 70 ml/min) R FCR FC 6 courses C1 C2 C3 C4 C5 C6 Follow up Updated results of the 3rd analysis, July 2010 Median observation time 47,4 months.

9 Patient Characteristics (N=817) FC (N=408) FCR (N=409) Median age Binet stage A 5% 4% B 63% 64% C 31% 31% Mutational status IGHV unmutated 63% 63% Cytogenetic abnormalities 17p- 10% 7% 11q- 22% 27% Hallek M et al. Lancet 2010

10 ADDITION OF RITUXIMAB TO FLUDARABINE AND CYCLOPHOSPHAMIDE Progression free survival (PFS)* 2009 Median observation time 3.2 years Median PFS FCR 52 months FC 33 months HR 0.56, 95% CI p < Hallek M et al. Lancet 2010

11 ADDITION OF RITUXIMAB TO FLUDARABINE AND CYCLOPHOSPHAMIDE Progression free survival (PFS)* 2012 Median observation time 5.9 years Median PFS FCR 57 months FC 33 months HR 0.59, 95% CI p < *Fischer K et al. ASH 2012

12 ADDITION OF RITUXIMAB TO FLUDARABINE AND CYCLOPHOSPHAMIDE Progression free survival (PFS)* 2012 Binet stage A Binet stage B Binet stage C p < p = 0.07 p = 0.02 Median PFS FCR not reached FC 34 months Median PFS FCR 58 months FC 32 months Median PFS FCR 43 months FC 33 months *Fischer K et al. ASH 2012

13 ADDITION OF RITUXIMAB TO FLUDARABINE AND CYCLOPHOSPHAMIDE Overall survival (OS)* 2009 Median observation time 3.2 years FCR 85.0% alive Median not reached FC 80.0% alive Median not reached HR 0.66, 95% CI p=0.013 Hallek M et al. Lancet 2010

14 ADDITION OF RITUXIMAB TO FLUDARABINE AND CYCLOPHOSPHAMIDE Overall survival (OS)* 2012 Median observation time 5.9 years FCR 69.4% alive Median not reached FC 62.3% alive Median 86 months HR 0.68, 95% CI p=0.001 *Fischer K et al. ASH 2012

15 ADDITION OF RITUXIMAB TO FLUDARABINE AND CYCLOPHOSPHAMIDE Overall survival (OS) in genetic subgroups of FCR patients* 2012 N Pts alive, % Median OS, months +12q NR 13q NR 11q NR Not** NR 17p ** not 17p- / 11q- / +12q / 13q- acc. to Döhner et al. NEJM 2000 ** Courtesy of Stilgenbauer S.

16 ADDITION OF RITUXIMAB TO FLUDARABINE AND CYCLOPHOSPHAMIDE Toxicities during treatment (N=800)* 2009 Neutropenias N % p value FCR < FC Infections N % p value FCR FC Hallek M et al. Lancet 2010

17 ADDITION OF RITUXIMAB TO FLUDARABINE AND CYCLOPHOSPHAMIDE Toxicities after end of treatment (N=800)* 2012 Late neutropenias 2 months after end of treatment N % p value FCR FC Late neutropenias 12 months after end of treatment N % p value FCR FC *Fischer K et al. ASH 2012

18 ADDITION OF RITUXIMAB TO FLUDARABINE AND CYCLOPHOSPHAMIDE Toxicities after end of treatment (N=800)* 2012 Secondary malignancies** N % p value FCR FC Secondary malignancies** N % Solid tumor Richters` transformation AML or MDS ** Mean time to onset, 2.4 years (range 2.0 days 7.4 years) *Fischer K et al. ASH 2012

19 ADDITION OF RITUXIMAB TO FLUDARABINE AND CYCLOPHOSPHAMIDE Late toxicities after end of treatment (N=800)* 2012 Solid tumor N % p value FCR FC Richters` transformation N % p value FCR FC AML or MDS N % p value FCR FC *Fischer K et al. ASH 2012

20 CLL8: DEFINITION OF HIGH RISK AFTER FCR (= PATIENTS RELAPSING WITHIN 2 YEARS) (FINK ET AL., ASH AND IWCLL 2011) MRD levels >10-2 or MRD levels >10-4 -<10-2 combined with del(17p) or TP53 mutation or unmutated IGHV

21 CLL8 SHORT PFS IS RELATED WITH SHORT OS Total n=143, HR n=40, LR n=103 median OS High risk 57 months Low risk not reached (HR 5.758, 95%CI: , p<0.0001)

22 CLLM1-STUDY DESIGN Physically fit and previously untreated patients with treatment requiring disease Firstline investigator s choice (FCR, BR, FR (FC) 200 patients 2:1 randomization Double blind Arm A L-maintenance 133 patients High Risk Of Early PD Start Q3/2012~700 Screening patients Arm B Placebo 67 patients A phase 3, multicenter, randomized, double-blind, placebo-controlled, study of the efficacy and safety of lenalidomide as maintenance therapy for high-risk patients with chronic lymphocytic leukemia following first-line therapy Follow up 25. Arbeitstreffen der DCLLSG, Petersberg, Königswinter 14. September 2012

23 Die Zukunft

24 Therapeutic modulation of B-cell receptor-dependent signaling in CLL pre-bcr Ig Ig CD19 P Lyn P Syk P P PI3K Btk Ibrutinib CAL-101, GS-1101, idelalisib PLC- PLC- P PIP 2 IP 3 DAG Ca 2+ PKCβ IKK ERK NF-κB

25 189 The Bruton s Tyrosine Kinase (BTK) Inhibitor Ibrutinib (PCI ) Promotes High Response Rate, Durable Remissions, and Is Tolerable in Treatment Naïve (TN) and Relapsed or Refractory (RR) Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL) Patients Including Patients with High-Risk (HR) Disease: New and Updated Results of 116 Patients in a Phase Ib/II Study John C. Byrd, MD 1, Richard R. Furman, MD 2, Steven Coutre, MD 3, Ian W. Flinn, MD, PhD 4,5, Jan A. Burger, MD, PhD 6, Kristie A. Blum, MD 7*, Jeff P. Sharman, MD 8*, Barbara Grant, MD 9*, Jeffrey A. Jones, MD, MPH 7, William G. Wierda, MD, Ph.D. 10, Weiqiang Zhao, MD PhD 11*, Nyla A. Heerema, PhD 11, Amy J. Johnson, PhD 12, Anh Tran 13*, Fong Clow, ScD 14*, Lori Kunkel, MD 15, Danelle F. James, M.D 13 and Susan O'Brien, MD 16*

26 Patient cohorts Cohort Population Dose mg/day Group Size 1 relapsed/refractory treatment-naïve; aged 65 years relapsed/refractory High Risk - relapsed or refractory 5 treatment-naïve; aged 65 years a

27 Study Population (N=116) Patients in the 3 Cohorts Treatment naive, age >= 65yrs (cohort 2 & 5) Relapsed or Refractory (cohort 1 & 3) High risk (cohort 4) Number of pts Median f/u, months (range) 16.6 (1.4, 23.2) 17.3 (0.3, 22.4) 10.3 (1.1, 11.5) Age (range) 71 (65, 84) 64 (40, 81) 68 (37, 82) Median # prior Tx 0 4 (1,12) 4 (1,11) (range) Hgb <11 g/dl OR 61% 57% 63% Plt <100,000 µl b2m >3 mg/l 8/ 31 (26%) 30/ 57 (53%) 9/ 23 (39%) IgVH unmutated 17/ 31 ( 55%) 50/ 58 (86%) 19/ 23 ( 83%) (UM) del 17p 2/ 30 ( 7%) 21/ 57 ( 37%) 7/ 23 ( 30%) del 11q 1/ 30 ( 3%) 23/ 57 ( 40%) 8/ 23 ( 35%)

28 Treatment response Study Population (N=116) Treatment naive, age >= 65yrs (cohort 2 & 5) Relapsed or Refractory (cohort 1 & 3) High risk (cohort 4) Number of pts IWCLL ORR (CR + 71% 67% 50% PR) CR 10% 3% 0 PR 61% 64% 50% PR with 10% 20% 29% lymphocytosis SD 13% 5% 8% PD 0 2% 4% Not evaluable 6% 7% 8%

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31 191 Combinations of the Selective Phosphatidylinositol 3-Kinase- Delta (PI3Kdelta) Inhibitor GS 1101 (CAL-101) with Rituximab and/or Bendamustine Are Tolerable and Highly Active in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL): Results From a Phase I Study Steven E. Coutre, MD 1, John P. Leonard, MD 2, Richard R. Furman, MD 2, Jacqueline C. Barrientos, MD 3, Sven de Vos, MD, PhD 4*, Ian W. Flinn, MD, PhD 5, Marshall T. Schreeder, MD, MPH 6*, Nina D. Wagner-Johnston, MD 7, Jeff P. Sharman, MD 8*, Thomas E. Boyd, MD 9*, Nathan H Fowler, MD 10, Leanne M. Holes 11*, Brian J. Lannutti, PhD 11, Dave M. Johnson 11, Langdon L Miller, MD 11* and Thomas M. Jahn, MD/PhD 11 *

32 Patients Regimen Parameter GS-1101/R N=19 GS-1101/B N=17 GS-1101/BR N=15 Age, median [range], years 65 [40-84] 59 [38-81] 59 [48-76] Sex, males/females, % 68/32 41/59 60/40 Patients with bulky adenopathy, % Prior therapies Median [range], n 2 [1-8] 3 [1-9] 4 [1-10] Patients with prior R/B, % 100/47 94/41 100/40 Pts with refractory disease, % GS-1101 doses Pts at 100 mg/dose BID, n 4 4 n/a Pts at 150 mg/dose BID, n

33 Side effects Regimen Parameter GS-1101/R N=19 GS-1101/B N=17 GS-1101/BR N=15 GS-1101 minimum follow-up, weeks Pts with Grade 3 adverse events, % Anemia Neutropenia Febrile neutropenia Thrombocytopenia Infections Pneumonia/pneumonitis Rash Diarrhea Hepatic transaminase elevation

34 Response Parameter GS-1101/R N=19 Regimen GS-1101/B N=17 GS-1101/BR N=15 Pts with decrease in adenopathy, % Max. decrease in adenopathy, median Pts with lymph node response (decrease 50%), % Best on-treatment response rate 2, CRu 3 /PR/SD/PD/NE, % 0/78/11/11/0 0/82/6/0/12 7/80/0/0/13 Intent-to-Treat ORR, % Year PFS, %

35 Therapiestandard 2013

36 Ersttherapie der CLL Stage Fitness del(17p) p53mut Therapy Binet A-B, Rai 0-II, inactive Irrelevant Irrelevant None Active disease or Binet C or Rai III-IV Go go Slow go No Yes No FCR Allo-SCT CLB + anti-cd20- Mab (R oder GA-101) Yes Al, HD R or O

37 Rezidivtherapie der CLL Response to First-Line Therapy Fitness Therapy Standard Alternatives (trials) Go go Al-Dex, FA, FCR Allo SCT Lenalidomide, BR, BR 2 Combination with kinase inhibitors Refractory or progress within 2 years Slow go Change therapy (if possible, include in trial) Al for del(17p), FCRlite, BR, bendamustine, lenalidomide, ofatumumab, HD rituximab Progress after 2 years All Repeat first-line therapy

38 Registerstudie Thrombopenie T-PLL Rezidivtherapie Transplantation Primärtherapie Nicht behandlungsbedürftig Binet C, behandlungsbedürftiges Binet B und A Binet A CLLM1 CLL2P CLL13 CLL14 CLL12 Go Go High Risk Lenalidomid- Erhaltung vs. Placebo Go Go Bendamustin Lenalidomid Rituximab Go Go Slow Go Risk of Early Progression Ibrutinib vs. Placebo Low Risk w&w CLL2P CLLR1 CLLR2 CLLR3 CLLX4 Rezidiv Max. 3 Vortherapien Bendamustin Lenalidomid Rituximab Rezidiv Mind. 1 Vortherapie Ibrutinib plus Bendamustin plus Rituximab Rezidiv Slow Go (oder tox. KM- Insuff.) Rituximab plus CAL101 vs. Rituximab plus Placebo Rezidiv Max. 3 Vortherapien FC-GA101 vs. B-GA101 plus GA101- Erhaltung Slow Go Allo TX in High Risk Ofatumumab in Induktion und Erhaltung Register CLL2S T-PLL2 Bei Thrombopenien Langzeitbeobachtung Firstline und Rezidiv CLL, SLL, B- PLL, T-PLL, LGL, Richter Syndrom Eltrombopag 0-3 Vortherapien FCM+ Cam, gefolgt von Cam- Erhaltung

39 Trials of the GCLLSG, Generation 3.1: Risk, Stage and Fitness Adapted Inactive Binet A Active disease CLL12 CLLM1 CLL11 Which is the best score to define high risk? Go go Slow go no yes BR/FR/FCR MRD+ High risk W&W W&W treat L W&W CLB CLB + R CLB + GA101 Disease (MRD) eradication Longer survival Symptom control Longer disease-free survival

40 Trials of the GCLLSG, Generation 4.0: Risk, Stage and Fitness Adapted Inactive Binet A Active disease CLL12 CLL13 CLL14 Definition of a biological & genetic risk score Go go Slow go Low, intermed High, very high iate CLB + B + W&W W&W treat GA101 GA101 BR BR+TKI (B+)TKI GA101 Disease (MRD) eradication Longer survival Long-term disease-control with minimal side effects