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 Cancer Center Disclosures • Received research funding: – Ariad, BristolMyers Squibb, Novartis, and Pfizer 1
Cure of CML (Almost…). Brief Perspective • IFN – α induced CGCR in 10-30%; CGCR associated with long-term survival; potential cure 5-7% (1983; 1990) • Ph and BCR-ABL molecular events identified (1980s) • BCR-ABL abnormalities caused CML in animal models (1990); BCR- ABL legitimate Rx target • Development of TKIs → CGCR 80- 90%; 10-yr survival 80-95% CML. Historical vs. Modern Perspective Parameter Historical Modern • Course Fatal Indolent • Prognosis Poor Excellent • 10-yr survival 10% 84 - 90% • Frontline Rx Allo SCT; Imatinib; nilotinib; IFN- dasatinib • Second line Rx ? New TKIs; allo SCT 4 2
CML Survival by Era Harrison’s Principles of Internal Medicine. 2014 Population-Based CML Outcome in Sweden • 3173 pts Dx in 1973-2008; median age 62 yrs 80% 54% 37% 23% 21% Bjorkholm, JCO 29: 2514; 2011 3
CML - Increasing Prevalence Over Time 200000 180000 Number of Cases 160000 140000 120000 100000 • Incidence 4700 per year 80000 • Age-matched mortality ratio vs normal population = 1.50 60000 • Accounts for increased US 40000 population to 410 million in 2050 20000 2000 2005 2010 2015 2020 2025 2030 2035 2040 2045 2050 Year Huang. Cancer 118:3123;2012 CML Transformation. Survival by Era 4
CML Ph-Associated CG and Molecular Events BCR-ABL Expression Sufficient for CML Induction LTR LTR BCR/ABL STEM CELL CML (Daley et al., Science 1990) 10 5
Do We Need Bone Marrow At Dx? • Assess % of blasts and basos (10- 15% have CML transformation at Dx) • Confirm Ph by CG; detect clonal evolution • FISH can be falsely positive • QPCR can be falsely positive or negative 11 Hyper CVAD + TKIs in CML Lymphoid BP • 42 pts; HCVAD and imatinib (n=27) or dasatinib (n=15) • CR 90%, CGCR 58%, CMR 25%, FCM-MRD negative 42% • Median remission 14 mos; median survival 17 mos; 18 (47%) had allo SCT. 12 Strati. Cancer 120: 373; 2014 6
Poor Prognostic Factors in CML • Older age • Splenomegaly • Anemia • Thrombocytosis, thrombocytopenia • Blasts, promyelocytes, basophils • Marrow fibrosis • Cytogenetic clonal evolution 13 Prognostic Models: Sokal, Hasford (Euro), MDACC Kantarjian. Blood 119:1981;2012 7
IRIS. PFS Associated With CGCR At 12 Mos, Not With Sokal Risk 100 90 % without PD to AP/BC 80 70 60 50 40 Estimated rate at 60 months p=0.09 30 n= 179 99% Low risk p=0.16 n= 91 95% Intermediate risk 20 High risk n= 49 95% 10 p=0.200 (overall) 0 0 6 12 18 24 30 36 42 48 54 60 66 15 Months since randomization Developmental Therapeutics in CML FDA Approval Agent Salvage Frontline Interferon 1986 1986 Imatinib 2001 2002 Nilotinib 2007 2010 Dasatinib 2006 2010 Ponatinib 2012 Bosutinib 2012 Omacetaxine 2012 Kantarjian. NEJM 346:645;2002. Kantarjian. NEJM 354:2542;2006. Talpaz. NEJM 354; 2531: 2006. Kantarjian. NEJM 362:2260:2010. Kantarjian. Lancet Oncol 12: 841; 2011. Cortes. NEJM 367: 2075; 2012. Cortes. Blood 120: 2573; 2012. Cortes. AJH e-Pub 2/2013. 8
CML. So Many Choices 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 9
CML. The Next Questions • Frontline CML Rx: imatinib vs. second TKIs • Can we cure CML molecularly? Is it necessary? • Role and timing of allo SCT • Monitoring of CML • Others: prevalence, pregnancy CG abn., Rx DC 19 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 10
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 93 99 MMR by 12 mos 73 83 3-yr Survival 100 99 3-yr TFS 97 100 3-yr EFS 91 91 3-yr FFS 78 80 Rx discontinuation 11 9 Quintas-Cardama. Blood 118: abst 454, 2011. Pemmaraju. Blood 118; abst 1700; 2011 TKI Frontline Therapy in CML Long-Term Outcome By Response Time Event-Free Survival Transformation-Free Survival p<0.001 Jain. Blood 122: abst 2728; 2013 11
ENEST-nd. Study Design Nilotinib 300 mg BID (n = 282) R A N • N = 846 D • 217 centers O Nilotinib 400 mg BID (n = 281) M • 35 countries I Z E D * Imatinib 400 mg QD (n = 283) * Stratification by Sokal risk score. 10 years of follow-up are planned Kantarjian. Blood 120:abst 1676;2012 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* 87 85 77 % MMR** 77 77 60 % BCR-ABL ≤ 0.0032%** 54 52 31 % Transformed AP/BP 3.5 2.1 7.1 % 5-yr EFS 92 95 91 % 5-yr OS 94 96 92 * by 24 months, ** by 60 months (K-M) Saglio. Blood 122: abst 92; 2013 12
ENESTnd. Progression to AP/BC on Core Rx P = .0085 P = .0185 P = .0009 P = .0059 1.1% 1.8% 4.2% 0.7% 1.1% 6.0% Nilotinib 300 mg BID (n = 282) Imatinib 400 mg QD (n = 283) Nilotinib 400 mg BID (n = 281) Saglio. Blood 122: abst 92; 2013 Nilotinib vs. Imatinib in CML-CP. Adverse Events and Grade 3/4 Myelosuppression Rate difference (imatinib - nilotinib) with 95% CI Favors imatinib Favors nilotinib (300 mg BID) Fluid retention Diarrhea Headache Muscle cramps Any grade Nausea Pruritus Rash Vomiting Anemia Neutropenia Grade 3/4 Thrombocytopenia -0.5 -0.3 -0.2 -0.1 0 0.1 0.2 0.4 0.5 -0.4 0.3 Hochhaus. Haematologica. 2010;95(s2):459 [abst 1113] 13
ENEST-nd.Cardiac and Vascular Events by 4 Years (All Grades) Nilotinib Nilotinib Imatinib 300 mg 400 mg 400 mg Patients With BID BID QD an Event, n = 279 n = 277 n = 280 n (%) 11 (3.9) 21 (7.6) 5 (1.8) IHD 4 (1.4) 6 (2.2) 0 (0) PAOD Saglio. Blood 120: abst 92; 2013 Dasatinib Versus Imatinib Study In Treatment- naïve CML (DASISION). Trial Design Dasatinib 100 mg QD (n=259) • N=519 Follow-up • 108 centers Randomized* 5 years • 26 countries Imatinib 400 mg QD (n=260) *Stratified by Hasford risk score ● 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 Kantarjian. NEJM. 362: 2260, 2010 14
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* 86 82 % MMR** 74 60 % BCR-ABL ≤ 0.0032%** 34 21 % Transformed AP/BP 5 7 % 4-yr PFS 90 90 % 4-yr OS 93 92 * by 24 months, ** by 48 months (K-M) Cortes. Blood 122: abst 653; 2013 DASISION. Transformation to AP/BP CML by 4 Years Dasatinib 100 mg QD Imatinib 400 mg QD 20 18 (6.9%) 18 16 14 (5.4%) 14 Patients, n 12 (4.6%) 12 10 8 (3.1%) 8 6 4 2 0 On Study Including Follow-up Beyond Discontinuation (ITT) Cortes. Blood 122: abst 653; 2013 15
DASISION. Forest Plot Comparing Differences in AE Rates for Dasatinib and Imatinib Fluid retention Superficial edema Pleural effusion Myalgia Nausea Any grade Vomiting Diarrhea Fatigue Headache Rash Neutropenia Grade 3/4 Thrombocytopenia Anemia –40 –20 0 20 40 Rate Difference (dasatinib-imatinib) with 95% CI Favors dasatinib Favors imatinib Kantarjian. JCO. 29:abst 6510; 2011 CML. Relative Risks of Uncommon Events Imatinib RR Dasatinib RR Nilotinib RR Marrow/ 14-27 Pleural 17-60 Femoral 409 tumor effusion artery bleed necrosis Conjunct. 9.4 Pericardial 10 PAOD 191 bleed effusion Effusion- 4.5-5.6 PAH 4.0 Coronary 185 ascites stenosis Anginas 7.2 MI 4.9 Arterial 4.0 ischemia 16
Frontline Rx with Imatinib vs. Second Generation TKIs 2 nd TKIs Parameter Imatinib • Efficacy excellent even better • %12-mo CGCR 65-70 80-85 MMR 20-25 40-45 AP- BP 3.5 0.4-2 • Tolerances excellent even better • Follow up (yrs) 10 6-7 • Cost ($/yr) 90,000 90,000 – 120,000 CML. What Happens in 2015? 2 nd TKIs Parameter Imatinib • Efficacy excellent even better • Tolerance excellent even better • Cost ($/yr) 2-10,000 90-120,000 • %5 – 10 yr survival survival 80 – 90 ? > 90 EFS 50-60 ??? → the difference at 5 yrs in EFS and OS determines frontline Rx 17
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