Outlook CML 2016: What is being done on the way to cure

Transcription

1 New Horizons 2011 Outlook CML 2016: What is being done on the way to cure Gianantonio Rosti Dept. Of Hematology and Oncology St. Orsola-Malpighi University Hospital Bologna (Italy) GIMEMA CML Working Party

2 Definition of "Cure" (to Cure) Etymology: from Latin, care (care, concern) 1. Spiritual charge 2. Recovery or relief from a disease Something (as a drug or treatment) that cures a disease Complete or permanent solution or remedy 3. Process or method of curing Synonyms: to heal, to preserve, to correct

3 CML: What Is Cure? Sustained CMR (MMR?) with/without TKI therapy And 100% CML-related survival And QoL comparable to age-matched population

4 Projection of CML Prevalence Up to 2050 Assumptions: population 500 million, mortality 2% per year, incidence increasing by about 0.01/100,000 per year 20%-25% increase per year in projected prevalence Year

5 CML: What Is Cure? Sustained CMR (MMR?) with/without TKI therapy And 100% CML-related survival And QoL comparable to age-matched population

6 CML: What Is Cure? Sustained CMR (MMR?) with/without TKI therapy And 100% CML-related survival And QoL comparable to age-matched population

7 Definition of "Cure" (to Cure) Etymology: from Latin, care (care, concern) 1. Spiritual charge 2. Recovery or relief from a disease Something (as a drug or treatment) that cures a disease Complete or permanent solution or remedy 3. Process or method of curing Synonyms: to heal, to preserve, to correct

8 IRIS Trial: 8-Year Follow-up on Imatinib Among patients randomized to imatinib, after 8 years 81% event-free survival 85% overall survival 86% had achieved MMR 92% not progressed to AP/BC Rate of progression to AP/BC in years 4 to 8 0.9%, 0.5%, 0%, 0%, 0.4% No pt in MMR at 12 months subsequently progressed Deininger et al. Blood. 2009;114:142. Abstract 1126 (poster).

9 Imatinib Frontline The egimema Experience e (61 Centres enrolled 1 Pt between Jan 04 and Apr 07) DATA LOCK N = 559 Age, years; median (range) 52 (18-84) 65 years or older; n (%) 115 (21%) Relative Risk; n (%) Low Intermediate High Sokal Hasford 219 (39%) 243 (43%) 216 (39%) 277 (50%) 124 (22%) 39 (7%) Variant Translocations; n (%) CCA Ph+; n (%) Der(9) deletions; n (%) 400 mg; n (%) 800 mg; n (%) 30 (5%) 21 (4%) 60 (11%) 423 (76%) 136 (24%) Follow-up, months; median (range) 60 (2-83) F. Castagnetti for GIMEMA, 2011 (unpublished) GIMEMA CML WP

10 Estimated OS, PFS, FFS, EFS Events Failures Progressions Deaths N F. Castagnetti for GIMEMA, 2011 (unpublished) GIMEMA CML WP

11 Estimated OS, PFS, FFS, EFS Events Failures Progressions Deaths N F. Castagnetti for GIMEMA, 2011 (unpublished) GIMEMA CML WP

12 Estimated OS, PFS, FFS, EFS Events Failures Progressions Deaths N F. Castagnetti for GIMEMA, 2011 (unpublished) GIMEMA CML WP

13 European LeukemiaNet recommendations GCT9310 Optimal Response Suboptimal Response Failure Warnings Baseline NA NA NA High risk CCA/Ph+ a 3 Months CHR and at least minor CyR (Ph+ 65%) No CyR (Ph+ > 95%) Less than CHR NA 6 Months At least PCyR Less than PCyR No CyR (Ph+ 35%) (Ph+ > 35%) (Ph+ > 95%) 12 Months CCyR PCyR (Ph+ 1-35%) Less than PCyR (Ph+ > 35%) 18 Months MMR b Less than MMR b Less than CCyR NA NA Less than MMR b Any time Stable or improving MMR b Loss of MMR b Mutations c Loss of CHR Loss of CCyR Mutations ti d CCA/Ph+ a Any rise in transcript levels CCA in Ph- cells a CCA/Ph+, clonal chromosome abnormalities in Ph+ cells; CCA/Ph+ is a warning factor at diagnosis although its occurrence during treatment (ie, clonal progression) is a marker of treatment failure. Two consecutive cytogenetic tests are required and must show the same CCA in at least 2Ph+ cells. b MMR indicates a ratio of BCR-ABL1 to ABL1 or other housekeeping genes, 0.1% on the international scale. c BCR-ABL1 kinase domain mutations still sensitive to imatinib. d BCR-ABL1 kinase domain mutations poorly sensitive to imatinib. Baccarani M, et al. J Clin Oncol. 2009;27:

14 Higher MMR Leads to Lower Progression to Advanced Disease for Nilotinib Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD P< P< P= % MMR MMR = AP/BC Num mber of patients with event P= MMR - Month 12 0 Progression to AP/BC No patient who progressed to AP/BC achieved MMR on study

15 GIMEMA Protocol CML 0307 Nilotinib 400 mg BID Time to first CMR (CMR 4.0 : 0.01% BCR-ABL IS with 10,000 ABL transcripts ) 79% 50% 58% 36% 19% Rosti et al, ASH 2010 GIMEMA CML WP

16 RQ PCR is the Only Technique That Can Assess Major Molecular Response (MMR) and Complete Molecular Response (CMR) CMR MMR CCyR CHR Leukocytosis Ph chromosome pos RQ PCR positive RQ PCR negative Number of leuke emia cell ls (log 10 ) Decreasing residual leukemia 1 0

17 CML Stem Cells Survive Imatinib Treatment In Vitro imatinib + imatinib CD34 4-PE Imatinib-insensitive CML stem cells CFSE Mechanisms of resistance of stem cells: expression of BCR-ABL mrna and protein and kinase activity, it expression of IL-3 and GM-CSF, expression of OCT1, expression ABCB1 and ABCG2 Graham et al. Blood. 2002;99: Holtz et al. Blood. 2002;99: Jiang et al. Leukemia. 2007;21:

18 Detection of DNA BCR-ABL in CMR 1 2 RNA DNA RNA DNA BCR-ABL not detected BCR-ABL detected 3 RNA DNA 4 RNA DNA 5 RNA DNA Months since imatinib cessation Months since imatinib cessation Ross et al Leukemia 2010

19 CML: What Is Cure? Sustained CMR (MMR?) without any treatment after a COMBINATION OF TKI AND Stem Cell Minded Therapy And 100% CML-related survival And QoL comparable to age-matched population

20 Hypothetical Model of CML persistence and recurrence versus extinction The eradication of the leukemic clone may depend on inherent features of the disease or on the duration of therapy, or both. Deininger, M. Nat. Rev. Clin. Oncol. advance online publication 1 February 2011; doi: /nrclinonc

21 Properties and targets of the CML Leukemia Stem Cell GCT9310 Self renewal Inhibition of Hedgehog Wnt/b-cathenin mtor pathway 5-LO pathway Omacetaxine BCR ABL + CD34 + CD38 Lin cell Resistance to apoptosis Inhibition of Histone deacetylase Farnesyl- transferase/pkcb activation Autophagy Sesquiterpene oils Fingolimod Quiescence Inhibition Of: Interferon αα SDF-1/CXCR4 Vaccines PML (As 2 O 3 ) SCT Interferon-a Immunotolerance 21

22 New Horizons 2011 Outlook CML 2016: What is being done on the way to cure Gianantonio Rosti Dept. Of Hematology and Oncology St. Orsola-Malpighi University Hospital Bologna (Italy) GIMEMA CML Working Party

23 GCT9310 Targeting g Minimal Residual Disease Despite achievement of complete molecular response, residual disease can remain Essers MA, et al. Nature. 2009;458(7240): Jorgensen HG, et al. Blood. 2007;109(9): Graham SM, et al. Blood. 2002;99(1):

24 Targeting the niche: the CXCR4/CXCL12 axis Imatinib up regulates CXCR4 in CML LSC, so increasing their ability to home in the bone marrow environment. 1 Inhibition of CXCR4/CXCL12 axis (Plerixafor ) may mobilize BCR ABL + into the bloodstream. CXCL12 CXCR4 G CSF may prime LSC breaking their dormancy. Ina experimental model intermittentexposure exposure of primitive quiescent CML stem cells to G CSF enhances their elimination by imatinib. 2 However, in the clinical setting the addition of G CSF to imatinib failed to demonstrate so far the capability of eradicating CML LSC. 3 1 Jin L, et al. Mol Cancer Ther, Jorgensen HG, et al. Clin Cancer Res, Drummond MW, et al. Leukemia, 2009