CML-A Functionally Curable Disease Hagop Kantarjian, MD The University of Texas M. D. Anderson Cancer Center Houston, Texas, United States Middle East Forum on Hematologic Malignancies Dubai April 2013 CML. Historical vs. Modern Perspective Parameter •Course •Prognosis •10-yr survival •Frontline Rx •Second line Rx Historical Fatal Modern Indolent Poor Excellent 10% 84 - 90% Allo SCT; IFN- Imatinib; nilotinib; dasatinib New TKIs; 2 allo SCT ? Survival in Early Chronic Phase CML TKI Interferon Chemotherapy Kantarjian . Blood 119:1981; 2012. Population-Based CML Outcome in Sweden • 3173 patients diagnosed between 1973-2008 - Median age 62 yrs 80% 54% 37% 23% 21% Bjorkholm. JCO. 29 2514, 2011 Therapy of CML in 2013 •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 Available TKIs in CML TKI Target Imatinib Bcr-Abl Nilotinib Bcr-Abl post IFN; frontline 400 BID post IM CP,AP frontline Dasatinib Src-Abl 100 Src-Abl Bcr-Abl T315I Omacetaxine -- 500 45 Bosutinib Ponatinib Dose (mg/D) FDA Approval in CML Unique AEs 400 post IM all phases frontline salvage salvage pancreas; LFT; rash ↓ PLT; effusions diarrhea; LFT Pancreatitis PLT↓ 6 salvage 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 7 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 Frontline Rx with Dasatinib or Nilotinib at MDACC • Parallel studies with nilotinib (400 mg BID) or dasatinib (100 mg QD or 50 mg BID) % Response CGCR by 12 mos MMR by 12 mos 3-yr Survival 3-yr TFS 3-yr EFS 3-yr FFS Rx discontinuation Nilotinib N=100 93 73 100 97 91 78 11 Dasatinib N=93 99 83 99 100 91 80 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 Alattar et al. ASH 2011; Abstract #745 ENEST-nd. Study Design Nilotinib 300 mg BID (n = 282) • N = 846 • 217 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) * 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 48 mo Outcome % CCyR* % MMR** % BCR-ABL ≤0.0032%** % Transformed AP/BP % 4-yr EFS % 4-yr OS * by 24 months, ** by 48 months Kantarjian. Blood 120;abst 1676: 2012 Nil 300 Nil 400 IM 400 87 85 77 76 73 56 40 37 23 3.2 2.1 6.7 95 97 93 94 97 93 ENEST-nd.Progression to AP/BC Core Rx P = .0009 25 P = .0059 P = .0085 P = .0185 Percentagen Patients, 20 17 15 12 10 5 5 0 2 0.7% 3 1.1% 3 4.2% 1.1% 1.8% 6.0% Including Clonal Evolution Nilotinib 300 mg BID Nilotinib 400 mg BID Kantarjian. Blood 120:abst 1676;2012 Imatinib 400 mg QD ENEST-nd.Progression to AP/BC on Study (Including After Treatment Discontinuation) Nilotinib 300 mg BID P = .0497 HR = 0.5 (0.2-1.0) P = .0074 Patients, n HR = 0.3 (0.1-0.8) 19 Nilotinib 400 mg BID Imatinib 400 mg QD 9 6 3.2% 2.1% 6.7% On Core or Extension Treatment or After Discontinuation Kantarjian. Blood 120:abst 1676;2012 ENEST-nd. Cumulative Incidence of MMR Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD 100 Patients With MMR, % n 282 281 283 90 By 4 Years 80 By 1 Year 76%, P < .0001 70 55%, P < .0001 73%, P < .0001 Δ 17%-20% 60 50 51%, P < .0001 40 Δ 24%-28% 56% 30 27% 20 10 0 0 6 12 18 24 30 36 42 Time Since Randomization, Months Kantarjian. Blood 120:abst 1676;2012 48 54 60 ENEST-nd. Cumulative Incidence of MR4.5 Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD Patients With MR4.5, % 100 80 By 4 Years By 1 Year 60 40%, P < .0001 40 37%, P = .0002 Δ 14%-17% Δ 6%-10% 20 11%, P < .0001 23% 7%, P < .0001 1% 0 0 6 12 18 24 30 36 42 48 54 Time Since Randomization, Months Kantarjian. Blood 120:abst 1676;2012 60 % With MR4.5 Nilotinib vs. Imatinib in CML (ENEST-nd). MR 4.5 by 3 Years According to Sokal Risk 50 45 40 35 30 25 20 15 10 5 0 P = .0003 P = .0468 40 P = .0099 30 24 18 17 9 n= 103 Low 104 Nilotinib 300 mg BID Saglio. Blood 118; abst 452, 2011 101 101 Intermediate 78 High Imatinib 400 mg QD 78 Nilotinib vs. Imatinib in CML (ENEST-nd). Survival After Progression to AP/BP Progressed = 34 Died = 23 Alive = 11 100 90 80 Median survival 10.5 months % Alive 70 60 50 40 30 20 10 0 0 6 12 18 24 Months Since Progression Saglio. Blood 118; abst 452, 2011 30 36 42 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 Grade 3/4 Neutropenia Thrombocytopenia -0.5 -0.4 -0.3 -0.2 -0.1 0 0.1 Hochhaus. Haematologica. 2010;95(s2):459 [abst 1113] 0.2 0.3 0.4 0.5 Dasatinib Versus Imatinib Study In Treatmentnaïve CML (DASISION). Trial Design • N=519 • 108 centers • 26 countries Dasatinib 100 mg QD (n=259) Randomized* Follow-up 5 years 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. JCO. 29:abst 6510; 2011 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 36 mo Outcome* % CCyR % MMR % BCR-ABL ≤0.0032% % Transformed AP/BP % 3-yr PFS % 3-yr OS Das 100 86 68 22 4 91 94 IM 400 82 55 12 6 91 93 * by 24 months Hochhaus. JCO 30: abst 6504; 2012. DASISION. Cumulative Incidence of CCyR 100 By 12 months 85% 80 % By 24 months 86% 82% 73% 60 Dasatinib 100 mg QD Imatinib 400 mg QD 40 20 0 0 • 10 20 30 Months cCCyR rate by 24 months for dasatinib vs imatinib was 80% vs 74% Kantarjian. JCO. 29:abst 6510; 2011 40 DASISION - Cumulative Incidence of MMR and MR4.5 Dasatinib 100 mg QD MR4.5 MMR 100 P<0.0001 40 P=0.00069 64% 60 68% 46% 55% 40 46% 20 % with MR4.5 80 % with MMR Imatinib 400 mg QD 30 22% 17% 20 3% 10 12% 23% 9% 0 0 0 12 24 Months 36 2% 0 12 24 36 Months MMR = BCR-ABL ≤0.1% MR4.5 = BCR-ABL ≤0.0032% Hochhaus, JCO 30: abst 6504; 2012 DASISION. Transformation to AP/BP CML by 3 Years Dasatinib 100 mg QD Imatinib 400 mg QD Number of patients, n 16 13 11 8 N 259 260 On study Hochhaus. JCO 30: abst 6505;2012 259 260 Including follow-up beyond discontinuation (ITT) 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 –40 l l l l l l l l l l l l l –20 0 20 40 Rate Difference (dasatinib-imatinib) with 95% CI Favors dasatinib Favors imatinib Kantarjian. JCO. 29:abst 6510; 2011 CML Frontline Rx. Toxicities of TKIs • Bothersome chronic side-effects less frequent with nilotinib than with imatinib: nausea, cramps, aches, weight gain, fluid retention, periorbital edema • Rashes, headaches more frequent with nilotinib • Pleural effusions, cytopenias more frequent with dasatinib Frontline TKI for CML AP • 58 pts with ≥15% blasts (n=8), ≥20% • • basophils (n=22), platelets <100 x109/L (n=3), or CE (n=22) Rx: Imatinib 36, nilotinib 17, dasatinib 5. CCyR 82%: imatinib 75%, nilotinib 95% − − At 12 mo: imatinib 74%, nilotinib 83% CE 91%, other 76% − 4 pts transformed to BP (none had CyR @ 12 mo) • MMR 68%: imatinib 66%, nilotinib 71% • 24 mo EFS 90%, TFS 92%, OS 100% Ohanian et al. ASH 2011; Abstract #3779 Risk Assessment for SCT in CML Risk factor Donor type Stage Age Sex match Time from Dx Group HLA-identical sibling MUD CP AP BP, ≥2nd CP <20 20-40 >40 All other M-rec/F-don <12 mo >12 mo Score 0 1 0 1 2 0 1 2 0 1 0 1 Gratwohl. Lancet 1998; 352: 1087-92 Outcome After SCT by EBMT Score % with Score score 0 2 1 18 2 28 3 28 4 15 5 7 6 2 LFS 62 61 44 34 28 37 15 % at 5 years OS TRM 76 21 73 21 59 35 49 47 38 53 39 45 19 81 RI 26 23 32 31 28 41 32 Gratwohl. Lancet 1998; 352: 1087-92 Overall Survival With TKI After Imatinib Failure or With SCT 100 80 % alive 91% 60 40 ~55% 20 Dasatinib 0 0 3 6 9 12 15 18 Months 21 24 27 30 100 90 80 % Alive 70 87% 60 50 40 30 20 Shah. Hematologica 2010 [E-pub ahead of print] Kantarjian. Blood 2009; 114: Abs # 1129; Gratwohl . Lancet 1998; 352: 1087-92 Nilotinib 10 0 0 3 6 9 12 15 18 21 24 27 Months Since Start of Treatment 30 33 36 CML. Role and Timing of allo SCT Status TKIs Allo SCT AP-BP Interim Rx to MRD ASAP IM failure in CP, T315I Ponatinib interim Rx to MRD ASAP IM failure in CP – no CE, no mutations, good initial response IM failure in CP – CE, bad mutations, no CG response Older ≥65 – 70 post IM failure Long-term second line TKIs Third line post second TKI failure Interim Rx to MRD Second line Long-term May forgo allo SCT for many yrs of 32 QOL CML in US. Incidence vs. Prevalence The Changing Demographics of CML •Incidence 5,000 cases/yr •Prevalence plateaus when incidence = annual mortality 2% Annual Mortality X Incidence of 5000 cases = 100 Prevalence of 5000 X 100 ÷ 2 = 250,000 cases Kantarjian. CML Chapter. Abeloff’s Clinical Oncology 4th Edition, 2279, 2008. CML - Increasing Prevalence Over Time Number of Cases 200000 180000 160000 140000 120000 100000 • • 80000 60000 • 40000 20000 2000 2005 2010 2015 Incidence 4700 per year Age-matched mortality ratio vs normal population = 1.50 Accounts for increased US population to 410 million in 2050 2020 2025 2030 2035 2040 2045 2050 Year Huang. Cancer 118:3123;2012 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 0.5 – 1 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 35 based on MMR/QPCR Take Home Message – CML 2013 • Great therapy for CML • Early response (3 months) predictive of response • Should not change at 3 months • Monitor at 6 months and decide • Deeper molecular responses improve event-free survival • No impact on transformation or survival • No clear benefit for CMR (except discontinuation?) • Few patients can discontinue safely • New approaches: IFN, AZA, JAK2 inhibitors, etc • Excellent new drugs: ponatinib, bosutinib, omacetaxine Leukemia Questions? • Pager 713-404-3387 • [email protected] Hagop Kantarjian, MD