Contemporary and Future Approaches in CML. Emory Meeting; Sea Island August 2014 Hagop Kantarjian, M.D.

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1 Contemporary and Future Approaches in CML Emory Meeting; Sea Island August 2014 Hagop Kantarjian, M.D. 1

2 CML. Historical vs. Modern Perspective Parameter Historical Modern Course Fatal Indolent Prognosis Poor Excellent 10-yr survival 10% 84-90% Frontline Rx Allo SCT; IFN-α Imatinib; nilotinib; dasatinib Second line Rx? New TKIs; 2 allo SCT

3 CML Survival by Era Harrison s Principles of Internal Medicine. 2014

4 Population-Based CML Outcome in Sweden 3173 pts Dx in ; median age 62 yrs 80% 54% 37% 23% 21% Bjorkholm, JCO 29: 2514; 2011

5 CML Transformation. Survival by Era

6 Poor Prognostic Factors in CML Older age Splenomegaly Anemia Thrombocytosis, thrombocytopenia Blasts, promyelocytes, basophils Marrow fibrosis Cytogenetic clonal evolution Prognostic Models: Sokal, Hasford (Euro), MDACC 6

7 Kantarjian. Blood 119:1981;2012

8 IRIS. PFS Associated With CGCR At 12 Mos, Not With Sokal Risk % without PD to AP/BC Low risk Intermediate risk High risk Estimated rate at 60 months n= % n= 91 95% n= 49 95% } } p=0.16 p=0.09 p=0.200 (overall) Months since randomization 8

9 Developmental Therapeutics in CML FDA Approval Agent Salvage Frontline Interferon Imatinib Nilotinib Dasatinib Ponatinib 2012 Bosutinib 2012 Omacetaxine 2012 Kantarjian. NEJM 346:645;2002. Kantarjian. NEJM 354:2542;2006. Talpaz. NEJM 354; 2531: Kantarjian. NEJM 362:2260:2010. Kantarjian. Lancet Oncol 12: 841; Cortes. NEJM 367: 2075; Cortes. Blood 120: 2573; Cortes. AJH e-pub 2/2013.

10 Therapy of CML in 2014 Frontline - imatinib 400 mg daily - nilotinib 300 mg BID - dasatinib 100 mg daily Second / third line - nilotinib, dasatinib, bosutinib, ponatinib, omacetaxine - allogeneic SCT Other - decitabine, pegasys - hydrea, cytarabine, combos of TKIs and with TKIs - investigational: hedgehog inhibitors, JAK2 inhibitors, IL3-DT

11 Results with Imatinib in Early CP CML The IRIS Trial at 8-Years 304 (55%) patients on imatinib on study Projected results at 8 years: - CCyR 83% - 82 (18%) lost CCyR, 15 (3%) progressed to AP/BP - Event-free survival 81% - Transformation-free survival 92% - If MMR at 12 mo: 100% - Survival 85% (93% CML-related) Annual rate of transformation: 1.5%, 2.8%, 1.8%, 0.9%, 0.5%, 0%, 0%, & 0.4% Deininger. Blood 114: abst 1126, 2009

12 Frontline Rx with Dasatinib or Nilotinib at MDACC Parallel studies with nilotinib (400 mg BID) or dasatinib (100 mg QD or 50 mg BID) Nilotinib Dasatinib % Response N=100 N=93 CGCR by 12 mos MMR by 12 mos yr Survival yr TFS yr EFS yr FFS Rx discontinuation 11 9 Quintas-Cardama. Blood 118: abst 454, Pemmaraju. Blood 118; abst 1700; 2011

13 Jain. Blood 122: abst 2728; 2013 TKI Frontline Therapy in CML Long-Term Outcome By Response Time Event-Free Survival Transformation-Free Survival p<0.001

14 ENEST-nd. Study Design Nilotinib 300 mg BID (n = 282) N = centers 35 countries R A N D O M I Z E D * Nilotinib 400 mg BID (n = 281) Imatinib 400 mg QD (n = 283) Kantarjian. Blood 120:abst 1676;2012 * Stratification by Sokal risk score. 10 years of follow-up are planned

15 Saglio. Blood 122: abst 92; 2013 Nilotinib vs Imatinib in Newly Diagnosed Chronic Phase CML 846 pts randomized to nilotinib 300 mg BID (n=282), nilotinib 400 mg BID (n=281), or imatinib 400 mg QD (n=283) Minimum follow-up 5 years Outcome Nil 300 Nil 400 IM 400 % CCyR* % MMR** % BCR-ABL %** % Transformed AP/BP % 5-yr EFS % 5-yr OS * by 24 months, ** by 60 months (K-M)

ENESTnd. Progression to AP/BC on Core Rx P =.0185 P =.0059 P =.0085 P =.0009 4.2% 0.7% 1.1% 6.0% 1.1% 1.

16 ENESTnd. Progression to AP/BC on Core Rx P =.0185 P =.0059 P =.0085 P = % 0.7% 1.1% 6.0% 1.1% 1.8% Imatinib 400 mg QD (n = 283) Nilotinib 300 mg BID (n = 282) Nilotinib 400 mg BID (n = 281) Saglio. Blood 122: abst 92; 2013

17 Nilotinib vs. Imatinib in CML-CP. Adverse Events and Grade 3/4 Myelosuppression Fluid retention Diarrhea Headache Muscle cramps Rate difference (imatinib - nilotinib) with 95% CI Favors imatinib Favors nilotinib (300 mg BID) Any grade Grade 3/4 Nausea Pruritus Rash Vomiting Anemia Neutropenia Thrombocytopenia Hochhaus. Haematologica. 2010;95(s2):459 [abst 1113]

18 ENEST-nd.Cardiac and Vascular Events by 4 Years (All Grades) Patients With an Event, n (%) Nilotinib 300 mg BID n = 279 Nilotinib 400 mg BID n = 277 Imatinib 400 mg QD n = 280 IHD 11 (3.9) 21 (7.6) 5 (1.8) PAOD 4 (1.4) 6 (2.2) 0 (0) Saglio. Blood 120: abst 92; 2013

19 Kantarjian. NEJM. 362: 2260, 2010 Dasatinib Versus Imatinib Study In Treatmentnaïve CML (DASISION). Trial Design N= centers 26 countries Dasatinib 100 mg QD (n=259) Randomized* Imatinib 400 mg QD (n=260) *Stratified by Hasford risk score Follow-up 5 years Primary endpoint: Confirmed CCyR by 12 months Secondary/other endpoints: Rates of CCyR and MMR; times to confirmed CCyR, CCyR and MMR; time in confirmed CCyR and CCyR; PFS; overall survival

20 Dasatinib vs Imatinib in Newly Diagnosed Chronic Phase CML 519 pts randomized to dasatinib 100 mg QD (n=259) or imatinib 400 mg QD (n=260) Minimum follow-up 48 mo Outcome Das 100 IM 400 % CCyR* % MMR** % BCR-ABL %** % Transformed AP/BP 5 7 % 4-yr PFS % 4-yr OS * by 24 months, ** by 48 months (K-M) Cortes. Blood 122: abst 653; 2013

21 DASISION. Transformation to AP/BP CML by 4 Years Patients, n Dasatinib 100 mg QD 8 (3.1%) On Study 14 (5.4%) Imatinib 400 mg QD 12 (4.6%) 18 (6.9%) Including Follow-up Beyond Discontinuation (ITT) Cortes. Blood 122: abst 653; 2013

22 Kantarjian. JCO. 29:abst 6510; 2011 DASISION. Forest Plot Comparing Differences in AE Rates for Dasatinib and Imatinib Any grade Grade 3/4 Fluid retention Superficial edema Pleural effusion Myalgia Nausea Vomiting Diarrhea Fatigue Headache Rash Neutropenia Thrombocytopenia Anemia Rate Difference (dasatinib-imatinib) with 95% CI Favors dasatinib Favors imatinib

23 CML. Relative Risks of Uncommon Events Imatinib RR Dasatinib RR Nilotinib RR Marrow/ tumor bleed Conjunct. bleed Pleural effusion 9.4 Pericardial effusion Femoral artery necrosis PAOD 191 Effusionascites PAH 4.0 Coronary stenosis 185 Anginas 7.2 MI 4.9 Arterial ischemia 4.0

24 CML. What Happens in 2015? Parameter Imatinib 2 nd TKIs Efficacy excellent even better Tolerance excellent even better Cost ($/yr) 2-10, ,000 %5 10 yr survival survival 80 90? > 90 EFS 50-60??? the difference at 5 yrs in EFS and OS determines frontline Rx

25 CML- Possible Future Rxs Most differences in events in ENEST-nd and DASISION are in intermediate-high risk Sokal. Most differences in transformation in first 1-2 yrs Achieving PCR 10% at 3-6 mos and CGCR by 6 mos protects against events Possible strategies 1) imatinib in low-risk Sokal 2) nilotinib-dasatinib in higher risk Sokal for 1 year on until CGCR then change to imatinib

26 MSD and MUD SCT in CP-CML 3514 MDS & 1052 URD SCT from CIBMTR from 1988 to 2003 All in CP1; median age Overall Survival Leukemia-Free Survival Arora. JCO 2009; 27:

27 Gratwohl. Lancet 1998; 352: Risk Assessment for SCT in CML Risk factor Group Score Donor type HLA-identical sibling 0 MUD 1 Stage CP 0 AP 1 BP, 2 nd CP 2 Age < >40 2 Sex match All other 0 M-rec/F-don 1 Time from Dx <12 mo 0 >12 mo 1

28 Outcome After SCT by EBMT Score Score % with score % at 5 years LFS OS TRM RI Gratwohl. Lancet 1998; 352:

29 This image cannot currently be displayed. Overall Survival With TKI After Imatinib Failure or With SCT 100 % alive % 75% 20 ~55% Dasatinib Dasatinib Shah. Blood; 2014[E-pub ahead of print] Kantarjian. Blood 2009; 114: Abs # 1129; Gratwohl. Lancet 1998; 352: % Alive Months Nilotinib 87% Months Since Start of Treatment

30 CML. Role and Timing of allo SCT Status TKIs Allo SCT AP-BP Interim Rx to MRD ASAP IM failure in CP, T315I IM failure in CP no CE, no mutations, good initial response IM failure in CP CE, bad mutations, no CG response Older post IM failure Ponatinib interim Rx to MRD Long-term second line TKIs Interim Rx to MRD Long-term ASAP Third line post second TKI failure Second line May forgo allo SCT for many yrs of 30 QOL

31 CML Monitoring Establish confirmed CGCR in first year (BM at 6-12 mo) In CGCR - FISH and QPCR every 6 mos - If MMR (QPCR < 0.1%), may monitor with QPCR only (watch for false results) - If QPCR by log and/or loss of MMR (PCR> 0.1%) monitor more frequently Mutations studies if resistance / need to change TKIs Change TKI only for loss of CGCR, not based on MMR/QPCR 31

32 When to Look For Mutations? Mutation analysis in 1301 pts receiving imatinib or 2 nd generation TKI (GIMEMA) Clinical condition % Positive Failure 27 No CHR at 3 mo 19 No CyR at 6 mo 11 No PCyR at 12 mo 17 No CCyR at 18 mo 17 Loss CCyR 31 Loss CHR 50 Suboptimal 5 No CyR at 3 mo 7 No PCyR at 6 mo 5 No CCyR at 12 mo 8 No MMR at 18 mo 0 Loss MMR 4 Soverini. Blood 118:1208 and abst 112, 2011

33 Analysis of Mutations in CML If CG or hematologic relapse, mutations studies help No role for mutation studies pre-rx or in imatinib responding patients T315I: no role for new TKIs; allo SCT or others (HU, ara-c, HHT, T315I inhibitors ) Y253H, E255K/V, F359V/C/I : dasatinib V299L,T315A, F317L/V/I/C : nilotinib Kantarjian. Blood 111:1774, Soverini. Blood 118 : 1208,

34 New Criteria for Failure and Warning Baccarani. Blood 2013;122:

35 MDACC Retrospective Analysis: CCyR at 12 Months Associated With PFS Kantarjian H. Cancer. 2008;112:

36 EFS and Survival by 12-month Response-CCyR with vs without MMR with TKI Frontline Rx (Landmark)

37 % Survival/TFS by Early Molecular Response Study QPCR < 10% QPCR > 10% Marin ( 8-yr) MD Anderson (10-yr) ENEST-nd DASISION BELA Marin JCO 30: 232; Jain. Blood 120: abst 70,2012; Hochhaus. Blood 120:abst 167; 2012; Saglio. Blood 120: abst 1675; 2012;Brummendorf. Blood 120: abst 69; 2012.

38 The Problem with the 3 Months Response Transcripts 10% Myelosuppression Rash Non-adherence Are these the same? Are these the same? 3 mo Time

39 BCR-ABL Transcripts < 10% at 6 mos Associated with Better Outcome Response 3 Mo 6 Mo No. % Survival % PFS % FFS > > > > 10 > Brandford. Blood 122: abst 254; 213

40 Criteria for Response/Failure and Time (mo) Change of Rx Imatinib 3-6 Major CG; QPCR 10% Second TKIs CG CR; QPCR 1% 12 CG CR CG CR Later CG CR CG CR CG 35% QPCR 10% CGCR QPCR 1%

41 Important Response Categories in CML Response Translates into: CCyR MMR CMR Significantly improved survival Modest improvement in EFS; possible longer duration CCyR; no survival benefit Possibility of Rx discontinuation (clinical trials only)

42 My Golden Rules in CML Monitoring Do not discard a TKI unless there is loss of CGCR (not MMR) at the maximum tolerated adjusted dose that does not cause grade 3-4 or chronic grade 2 (affecting QOL) toxicities Dose ranges imatinib mg/D (rarely 200mg/D) nilotinib mg BID (rarely 200mg/D) dasatinib mg/D Mutation studies only if CG or hematologic relapse 42

43 Imatinib Treatment Discontinuation STIM1 and STIM2 STIM1 STIM2 100 pts Median follow-up 55 mo (range, 9-72) 127 pts Median follow-up 16 mo (range, 0-27) Mahon et al. ASH 2013; Abstracts #255 & 654

44 Inhibition of Bcr-Abl Bcr-Abl ATP-binding Abl & Src T315I-active Non-kinase Inhibition Imatinib Dasatinib Ponatinib Omacetaxine Nilotinib Bosutinib Decitabine INNO-406 AZD 0530

45 Survival with Dasatinib in CML-CP Post IM Failure 70-76% Shah. Blood. 123: 2317; 2014

46 Ponatinib (AP24534). Pan-BCR-ABL Inhibitor Rationally designed inhibitor of BCR-ABL Active against T315I mutant - Unique approach to accommodating gatekeeper residue Potent activity against an array of BCR-ABL variants Also targets other therapeutically relevant kinases: - Inhibits FLT3, FGFR, VEGFR and PDGFR, and c-kit Once-daily oral activity in murine models Ile315 Imatinib Ponatinib Avoids T315I Ponatinib O Hare T. Cancer Cell. 2009;16:

47 Ponatinib in CML-CP (PACE) 267 pts Rx; 93% failed 2 TKI, 58% failed 3 TKI Response Rate % Cytogenetic response 67 MCyR 56 CCyR 46 MMR 34 MR % MCyR sustained at 12 mos Cortes. Blood 122: abst 650; 2013

48 Ponatinib Phase 2 Study. PFS and OS in CP-CML Probability of PFS (%) 100 No. at risk Total R/I (N=203) 20 T315I (N=64) 10 Total (N=267) Months PFS at 2 years: 67% (median 29 months) Probability of OS (%) 100 No. at risk Total R/I (N=203) 20 T315I (N=64) 10 Total (N=267) Months OS at 2 years: 86% (median not reached) Cortes. Blood 122: abst 650; 2013

49 Ponatinib Toxicities of Concern CML Therapy? Optimal dose: 30 vs. 45 mg daily? Incidence of toxicities of concern Pancreatitis 7% Skin rashes 40%; severe 4-7% Vasoocclusive disorders (cardiac, CNS, PAOD) 12% Hypertension 67%; severe 20%

50 Response to Bosutinib 2 nd Line Therapy Dual Src & Abl inhibitor, no effect over c-kit or PDGFR 286 pts with imatinib failure Median follow-up 24.8 mo ( mo) Response, % IM resistant (n = 196) IM intolerant (n = 90) Total (n = 286) CHR MCyR CCyR yr MCyR Dur yr Transformation yr Progression/Death % remain on therapy Brumendorf et al. Blood 2013; Asbtract #2723

51 Bosutinib in CML post imatinib failure PFS and survival Cortes. Blood 118: 4567;2012

52 Take Home Message CML 2014 Great therapy for CML CGCR is endpoint of Rx = improves survival Early response (3 months) predictive Should not change at 3 months Monitor at 6 months and decide Deeper molecular responses improve eventfree survival No impact on transformation or survival No clear benefit for CMR (except discontinuation?) Excellent new drugs: ponatinib, bosutinib, omacetaxine

53 Leukemia Questions? Pager:

Contemporary and Future Approaches in Management of CML. Disclosures

Winship Cancer Institute of Emory University Contemporary and Future Approaches in Management of CML Hagop Kantarjian, MD Chairman and Professor, Department of Leukemia University of Texas M. D. Anderson