Future of CML treatments – Are they getting us closer to cure? Andreas Hochhaus Universitätsklinikum Jena, Germany.

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Presentation transcript:

Future of CML treatments – Are they getting us closer to cure? Andreas Hochhaus Universitätsklinikum Jena, Germany

3 Melo, Ross, 2011

Long term prediction – model patient Prediction to imatinib  MRD eradication after about 30years continuous therapy. Löffler, Roeder et al., 2012

CFU Apoptosis Kumari et al. Blood, 2012 Response to imatinib depends on BCR-ABL expression level.

JAK2-Mediated Extrinsic Survival of CML Stem Cells Stromal cells protect CML stem/progenitors cells by producing cytokines which activate JAK2 pathway: rational for combining Bcr-Abl and JAK2 inhibitor Traer E, Mackenzie R, Snead J et al. Blood 2010; 116: abstract 199

? IFN

Activated CML-SCs may be sensitive to imatinib More differentiated CML cells are effectively eliminated by TKIs Dormant CML-SCs are resistant to imatinib IFN  may activate dormant CML stem cells making them sensitive to Imatinib TKIs CML- SC CML- SC Expansion CML- SC CML- SC CML- SC CML- SC IFN  priming SC=stem cell. Modified from Essers et al., Nature 2009

Stable remission with IFN after imatinib plus IFN combination (n=20) IFN after Imatinib/IFN combination Yearsafterimatinibwithdrawal % relapse Burchert A, et al. J Clin Oncol 2010;28(8):1429–1435.

Increase of the proportion of PR1 cytotoxic T lymphocytes on IFN monotherapy Pretherapy IFN only Imatinib/IFN 0.01% 0.11% <0.01% n=9 HLA A2+ patients PR1 PE PR1 CTL (%) CD8 FITC Burchert A, et al. J Clin Oncol 2010;28(8):1429–1435.

Variables for discontinuation studies Duration of TKI therapy Duration of MR 4, MR 4.5 …. Time to MR 4, MR 4.5 …. IFN maintenance? Prognostic scores TKI (Imatinib vs. second generation) …

EURO-SKI Main objective Evaluation of molecular relapse-free survival after stopping TKI (survival without molecular relapse) Definition of relapse defined as BCR-ABL >0.1% (loss of MMR) on the IS at one time point

Design of EURO-SKI 13 QPCR Screening phase (Confirming MR 4 ) Stop TKI Year 1Year 2Year 3 TKI treatment at least 3 years MR 4 at least 1 year q4wq6w every 3 months (Restart TKI at molecular relapse) STOP

R Induction therapy > 24 mo. assessment Nilotinib 2x300 mg + PEG-IFN  2b confirmed MMR cont. Nilotinib PEG-IFN Nilotinib 2x300 mg Maintenance therapy --- Cure? >12 mo. MR 4 Nilo dose acc. to pilot phase Nilo intolerance -> Imatinib Nilo resistance -> Transplantation/Dasatinib Suboptimal response: -> Nilotinib 400 mg BID > 36 mo. therapy CML V (TIGER) Study

Pathways to blastic transformation Adapted from: Perrotti D, et al. J Clin Invest 2010; 120;2254

Nilotinib (n=10+8) E450G (n=1) T315I (n=3) M244V (n=4) M351T (n=2) F359C/I/V (n=4) G250E (n=1) H396R (n=1) Y253H (n=2) Y253H (n=3+2) D276G (n=2) Imatinib (n=20) BCR-ABL 2 BCR-ABL mutations each had 3 patients on Nilotinib 300 mg BID, 2 patients on nilotinib 400 mg BID and 3 patients on imatinib. ENESTnd: BCR-ABL mutations detected in patients with lack or loss of MMR E355G (n=1) E459K (n=2) G250E (n=1) Q252H (n=1) E255K/V (n=1+3) F359V (n=4+2) E459K (n=1) T315I (n=3+2) SH2 domain P-loopA-loop SH3 domain Hochhaus et al., ASH 2010

BELA – Molecular Response Rates at Specified Times on Therapy: ITT Population MMR, major molecular response; CMR, complete molecular response. *Indicates a P value 0.05, which was considered statistically significant. P values at all time points with the exception of Month 12 were considered exploratory. * * * * * 3 months 6 months 9 months 12 months 18 months 24 months Cumulative by 24 months Bosutinib MMR CMR Imatinib MMR CMR 41% 27% 46% 38% 7% 3% 28% 11% 35% 19% 61% 50% 49% 42% Cortes et al. Blood (ASH) 2011;118: Abstract 455

BELA – Rates of Treatment Failure: ITT Population 18 AP, accelerated phase; BP blast phase. a Treatment failure/disease progression includes both on-treatment transformation to AP/BP and lack of efficacy. Patients were followed for up to 8 years from randomization (treatment plus long-term follow-up phases). a No new on-treatment transformations to AP/BP CML have occurred on bosutinib since the 12-month primary analysis, compared with 3 new events on imatinib The majority of deaths (bosutinib, n = 5/7; imatinib, n = 9/13) occurred more than 28 days after treatment discontinuation – Deaths due to CML progression occurred in 6/7 patients receiving bosutinib and 10/13 patients receiving imatinib Cortes et al. Blood (ASH) 2011;118: Abstract 455

Conservative treatment: Stopping TK inhibitor Hydroxyurea Allo SCT Experimental treatment: New inhibitors (Ponatinib) DCC-2036 Omacetaxine (?)

PACE Initial Results Response CP-CML Cohorts 20 Response n Response / N Evaluable (%) OverallR/I CohortT315I Cohort CHR248/271 (92)193/207 (93)55/64 (86) MCyR*116/248 (47)79/191 (41)37/57 (65) CCyR96/248 (39)63/191 (33)33/57 (58) MMR51/265 (19)31/205 (15)20/60 (33) *MCyR is the primary endpoint Cortes et al. Blood (ASH) 2011;118: Abstract 109 (Data as of 02 Dec)

Concepts for a cure Optimize TKI treatment (combination with IFN, dose- schedule optimization) Define maintenance protocols Include new more broadly active drugs, e.g. against T315I Improve sensitivity for deep MR assessment Increase proportion of patients with durable “CMR” Discontinue TKI after long-term “CMR”

New studies (1) Discontinuation of therapy after TKI only after IFN maintenance („silencing“) after combination of TKI with stem cell active drug after rotation of TKI High dose IFN bolus therapy followed by TKI for good responders („exhaustion“)

New studies (2) Response optimization New inhibitors targeting T315I (Ponatinib...) New combinations for suboptimal responders Studies targeting residual disease in case of optimal response

Change of endpoints Survival Progression free survival Cytogenetic response MRD: RT-PCR MRD: genomic PCR

Prevalence increasing First line therapy improving Tailoring treatment according to molecular milestones feasible Selection of second line therapies based on patient history and molecular parameters Option for discontinuation of TKI Life long surveillance needed Long term management of CML patients: Response consolidation >1 year Targeting detectable or undetectable residual disease with acceptable toxicity profile. TKI discontinuation Continuous MR Follow up IFN ? MR Response induction Most active BCR-ABL inhibitor Combinations >2 years Diagnosis