Imatinib dose intensification, combination therapies. Andreas Hochhaus Universitätsklinikum Jena, Germany

Transcription

1 Imatinib dose intensification, combination therapies Andreas Hochhaus Universitätsklinikum Jena, Germany

2 Apperley JF. Lancet Oncol. 2007

3 High OCT-1 activity is associated with faster MMR in imatinib treated CML patients White DL et al. Blood 2007

4 Imatinib 400 mg vs 800 mg in CML-CP: Complete Cytogenetic Response Rates % Patients Achieving CCyR P= P= mg 800 mg 0 6 Months 12 Months Time of Cytogenetic Assessment Cortes et al., ASH 2008

5 % Patients Achieving MMR Imatinib 400 mg vs 800 mg in CML-CP: Time to First MMR by Treatment Arm Treatment Arm Median Time to MMR 400 mg 13.6 months 800 mg 8.4 months Cortes et al., ASH 2008 Months Since Randomization P=0.0038, Log-rank test

6 Imatinib 400 mg vs 800 mg in CML-CP: Patient Disposition at 12 Months Disposition 400 mg N=157 No. (%) 800 mg N=319 Still on treatment 145 (92.4) 288 (90.3) Discontinued treatment 12 (7.6) 31 (9.7) Adverse events 2 (1.3) 18 (5.6) Abnormal laboratory values 1 (0.6) 1 (0.3) Unsatisfactory therapeutic effect 6 (3.8) 6 (1.9) Protocol violation 2 (1.3) 1 (0.3) Subject withdrew consent 0 2 (0.6) Lost to follow-up 0 2 (0.6) Administrative problems 1 (0.6) 1 (0.3) Cortes et al., ASH 2008

7 German CML IV Trial: Time to MMR by therapy Hehlmann et al., ASH 2009

8 Standard Interferon Pegylated Interferon

9 CCyR after IFN α therapy EICML metaanalysis Bonifazi, F. et al. Blood 2001;98:

10 High vs. low dose IFN Kluin Nelemans et al. Blood 2004

11 MRD Levels Predict Relapse After 10 IFN-α Induced CCR Minimal residual disease during complete remission: Ratio BCR-ABL/ABL (%) Follow-up: Relapse to blastic phase (n=4) Relapse to chronic phase (n=16) Continuing complete remission (n=47) Undetectable n=67 Continuing complete Relapse, remission, n=47 n=20 MRD = minimal residual disease; CCR = complete cytogenetic response. Hochhaus et al. Blood P<0.0001

12 Phase I/II Imatinib + Pegasys combination study # 1 n=7 Imatinib 400 mg Phase I # 2 n=6 Imatinib 400 mg PEGASYS 90 µg # 3 n=8 Imatinib 300 mg PEGASYS 180 µg # 4 n=4 Imatinib 300 mg PEGASYS 180 µg Cohort # 5 n=7 Imatinib 400 mg PEGASYS 90 µg PEGASYS 180 µg 300 mg Maintenance phase 2 weeks 4 w. 4 w. 4 w. 4 w. 4 w. 8 w. Hochhaus et al., ASH 2005

13 Imatinib vs. combinations, high dose imatinib ± transplantation CML Study IV, n=1400 (Hehlmann et al., ASH 2009) Pilot Phase Main Phase Imatinib 400 mg+arac* Imatinib 400 mg after IFN* ** high risk: primary imatinib 800 mg R Imatinib 400 mg Imatinib 400 mg ctd. Imatinib 400 mg + IFN Imatinib 400 mg + IFN ctd. Imatinib 800 mg*** Years from start of study * Recruitment terminated 7-11/2005; ** no high risk patients; *** Full recruitment started 7/2005

14 Median dose per actual therapy day* Imatinib 400 mg: Imatinib 400 mg+ifn: Imatinib 800 mg: 400 mg/d ( mg/d) Imatinib: 400 mg/d ( mg/d) IFN: 1.7 Mio I.U./d ( Mio I.U./d) 646 mg/d ( mg/d) * IFN 3 days/week (imatinib+ifn) Hehlmann et al., ASH 2009

15 Adverse events (WHO grade I-IV, total time of therapy) IM 800 mg n=240 IM 400 mg n=276 IM 400 mg + IFN n=280 Edema Myalgia Neurological AEs 33% 26% 20% 23% 20% 19% 12% 14% 21% Gastrointestinal AEs 42% 29% 30% Fatigue 15% 12% 19% Hehlmann et al., ASH 2009

16 Major Molecular Responses at 24 months BCR-ABL/ABL 0.1% IS patients (ITT) 71% 71% Guilhot et al., ASH 2009

17 Continuous molecular remission after imatinib withdrawal in case of IFN pretreatment Pts IFN Sokal M0 M3 M6 M12 M18 M24 (months) 1 0 L 4 0 L 8 9 H I I I 3 32 I 6 33 L L 7 71 L I Rousselot et al. Blood 2007 PCR negativity Molecular relapse Imatinib retreatment Molecular response

18 STop IMatinib study (MULTICENTER TRIAL ESTIMATING THE PERSISTANCE OF MOLECULAR REMISSION IN CML AFTER STOPPING IMATINIB) (ClinicalTrials.gov number, NCT [ClinicalTrials.gov]) 40 pts relapsed (loss of CMR) within the first 6 months and one patient relapsed at M7. At M12, the probability of being in CMR is 41% (95% CI: 29-52%) Mahon et al., ASH 2009

19 STIM Study: Results according to Sokal score 55% 36 % 14% Mahon et al., Blood (ASH Annual Meeting Abstracts), Nov 2009; 114: 859

20 Stable remission on IFN maintenance therapy (n=20) after imatinib withdrawal IFN after Imatinib/IFN combination % relapse Years after imatinib withdrawal Burchert et al., JCO 2010

21 Level of residual disease at stop of imatinib and during IFN maintenance therapy Pt. no mo Complete molecular remission, CMR 11 BCR-ABL <0.01% 12 <0.1% 13 <1% 14 <10% = Relapse, R R R R R R >10% Burchert et al., JCO 2010

22 Increase of the proportion of PR1 cytotoxic T lymphocytes on IFN monotherapy. n=9 HLA A2+ patients PR1 CTL (%) Pretherapy Imatinib/IFN IFN only PR1 PE 0.01% <0.01% 0.11% CD8 FITC Burchert et al., JCO 2010

23 IFNα may also activate dormant CML stem cells making them sensitive to imatinib IFNα CML- SC CML- SC CML- SC Expansion Expansion Dormant CML-SCs are resistant to imatinib Activated CML-SCs may be sensitive to imatinib More differentiated CML cells are effectively eliminated by imatinib M. Essers et al. Nature, 2009

24 IFNα may also activate dormant CML stem cells making them sensitive to imatinib IFNα priming Imatinib Long term cure? Dormant CML-SCs are resistant to imatinib Activated CML-SCs may be sensitive to imatinib More differentiated CML cells are effectively eliminated by imatinib M. Essers et al. Nature, 2009

25 New German CML-Study V >18 mo. assessment confirmed MMR >12 mo. CMR Nilotinib 2x300 mg cont. Nilotinib --- R Nilotinib + IFN 3x3 Mill/week IFN 3x3 Mill/week --- Nilo dose acc. to pilot phase Nilo intolerance -> Imatinib Nilo resistance -> Transplantation/Dasatinib No MMR after 18 mo. -> Treatment cont. Induction therapy Maintenance therapy Cure?

26 Andreas Hochhaus Universitätsklinikum Jena Jena, Germany

27 Andreas Hochhaus Universitätsklinikum Jena Jena, Germany

28 Andreas Hochhaus Universitätsklinikum Jena Jena, Germany