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4/24/2018 TKI Resistance in Chronic Myeloid Leukemia Updates and Challenges in the Management of Chronic Myeloid Leukemia April 19, 2018 Michael Deininger MD PhD Disclosures Ariad Blueprint Galena Biopharma Incyte Novartis Pharma Pfizer, Inc. Paid Advisory Paid Research Board Consultant Funding yes no no yes no no yes no no yes yes no yes yes yes yes yes yes IRIS Study: 10-year Follow-up Hochhaus et al, NEJM 2017 1 4/24/2018 2G TKIs vs Imatinib in Treatment-Naïve CP-CML ENESTnd R A N D O M I Z E DASISION R A N D O M I Z E Nilotinib 300mg BID (N = 282) Nilotinib 400mg BID (N = 281) Imatinib 400 mg QD (N = 283) BFORE R A N D O M I Z E Dasatinib 100 mg QD (N = 259) Imatinib 400 mg QD (N = 260) Bosutinib 400 mg QD (N = 246) Imatinib 400 mg QD (N = 241) Saglio et al. NEJM 2017; Kantarjian et al. NEJM 2010; Cortes et al. JCO 2017 No Difference in Overall Survival – ENESTns as an Example Approved frontline dose Imatinib 400 mg QD (n = 283) Estimated 5-year PFS, % Nilotinib 300 mg BID (n = 282) 91.1 92.0 Nilotinib 400 mg BID (n = 281) 95.3 Progressions and deaths, n 23 22 11 Hazard ratio (95% CI) — 0.92 (0.51-1.65) 0.46 (0.23-0.95) .77 .03 P value Estimated 5-year OS, % 91.6 93.6 96.0 Total deaths, n 21 18 10 Deaths in patients with advanced CML, nb 15 6 4 Hazard ratio (95% CI) — 0.84 (0.45-1.58) 0.46 (0.22-0.98) P value — .58 .04 The Community Experience: High Rate of Imatinib Failure 88 newly diagnosed patients in NW UK Lucas et al, BJH 2008 28 27 2 4/24/2018 Disease Burden & Monitoring on the International Scale (IS) ? Deep MR DASISION: Cumulative Incidence of MMR Dasatinib 100 mg QD Imatinib 400 mg QD N 259 260 NIL 300 BID 77% 100 p=.0022 90 By 4 years 80 By 2 years 70 % With MMR By 5 years By 3 years 76% 73% 67% 64% By 1 year 60 64% 60% 55% 50 46% 46% 40 30 28% 20 10 0 0 6 12 18 24 30 36 Months Since Randomization 42 48 54 60 Cortes JC, et al. Blood. 2014 DASISION: Cumulative Incidence of MR4.5 100 Dasatinib 100 mg QD Imatinib 400 mg QD 90 N 259 260 NIL 300 BID 54% 80 % With MR4.5 70 p=.0251 By 5 years 60 By 4 years 50 42% By 3 years 40 34% By 2 years 30 24% By 1 year 20 23% 19% 8% 10 33% 13% 5% 0 3% 0 6 12 18 24 30 36 Months Since Randomization 42 48 54 60 Cortes JC, et al. Blood. 2014 3 4/24/2018 Therapeutic Milestones NCCN vs. ELN Baccarani et al. Blood. 2013;122(6):872-84. Radich et al. J Natl Compr Canc Netw. 2014;12(11):1590-610 Challenges Remain Failure with 1st line TKI imatinib ~10% on studies Failure with 1st line dasatinib/Nilotinib/bosutinib* ~5% on studies 2G TKIs have long-term toxicities Treatment free remission limited to minority % BCR-ABL1 (IS) Cases in the US 181000 105000 Restarted therapy Stopped therapy 2018 2050 Year Months * Limited follow-up with the new initial dose of 400mg daily Recognizing TKI Failure Failure to reach milestones Loss of CHR Loss of CCyR Confirmed loss of MMR CCA/Ph+ Do not rush to conclusions! Non-compliance or drug interaction? Laboratory error or imprecision? No Complete diagnostic workup Physical exam Bone marrow aspirate/biopsy Karyotyping BCR-ABL1 mutation screen 4 4/24/2018 Mechanisms of TKI Resistance BCR-ABL Reactivation? No Yes Factors Influencing Selection of Salvage Therapy Disease phase BCR-ABL1 mutation analysis Previous TKI exposure and response(s) Past medical history ABL1 Kinase Inhibitors DCC-2036 asciminib ponatinib approved failed in trials 5 4/24/2018 Resistance Due to BCR-ABL1 Point Mutations TKI Resistance Imatinib Single BCR-ABL1 Mutants Nilotinib Bosutinib Dasatinib T315I Ponatinib* Relatively resistant Completely resistant * FDA-approved 12/2012 O’Hare et al. Cancer Cell 2009. Past Medical History Impacts Therapy Selection IM NIL DAS BOS Diabetes PON Problems Potential POAD Low CHF Somewhat elevated Prolonged QT Elevated PHT Typically contraindicated GI Bleeding IBS Pancreatitis Impaired LF Thrombembolism Few absolute contraindications Many better or worse picks Clinical judgment crucial Relative Activity Profile of Various TKIs in Imatinib-Resistant Mutants But: In vitro sensitivity is imperfect correlate of in vivo efficacy. Eiring et al. Genome Biol. 2014;15(9):461 6 4/24/2018 Treatment History and Salvage Therapy – Likelihood of CCyR 1. Line therapy Imatinib 2. Line therapy 3. Line therapy Dasatinib Dasatinib Nilotinib Nilotinib Nilotinib Ponatinib T315I Bosutinib Dasatinib Bosutinib 70% Ponatinib Omacetaxine Treatment History and Salvage Therapy – Likelihood of CCyR 1. Line therapy Imatinib 2. Line therapy 3. Line therapy Dasatinib Dasatinib 20% Nilotinib Nilotinib Bosutinib Dasatinib 5070% Ponatinib 20% 10% Ponatinib Nilotinib Bosutinib Omacetaxine Binders at the Myristoylation Site Allosterically Enforce Autoinhibition Hantschel O. Haematologica. 2012;97:195-97 7 4/24/2018 Asciminib: Allosteric BCR-ABL1 Inhibition Binds with high affinity to the myristoyl pocket of ABL1 kinase to mimic the native myristate ligand Ba/F3 BCR-ABL1 IC50: ~3 nM Demonstrates an extremely selective kinase profile Currently in Phase 1/2 Wylie et al. Nature. 2017;543(7647):733-737 Activity of Asciminib in Comparison with Catalytic Site TKIs Myristate pocket Wylie et al. Nature. 2017;543(7647):733-737 Responses in Patients With CML Treated With Single-Agent BID ABL001 With ≥ 3 Months Exposure on Study Patients With Response, % 100 Hematologic Response Within 6 mo Cytogenetic Response Within 6 moa CHR: 88% (14/16) CCyR: 75% (9/12) Molecular Response Within 6 moa,b Molecular Response Within 12 mob,c 90 80 70 60 50 40 30 20 MMR: 20% (10/50) 10 0 Hematologic Disease (CHR relapse) Cytogenetic Disease (> 35% Ph+) ≥ 1-log reduction: 30% (10/33) Molecular Disease (> 0.1% IS) (≤ 10% IS) MMR: 42% (16/38) ≥ 1-log reduction: 48% (12/25) Molecular Disease (> 0.1% IS) (≤ 10% IS) Disease Status at Baseline Hughes et al. ASH 2016, abstract # 625 8 4/24/2018 Other BCR-ABL1 Inhibitors of Potential Interest carbon in nilotinib Radotinib K0706 Axitinib Chemically almost identical to nilotinib Similar activity Approved in South Korea Structure unpublished Active against BCR-ABL1T315I Phase 1/2 study in refractory CML is ongoing (Sponsor: Sun Pharmaceuticals) Main targets VEGFR1-3; KIT; PDGFR Approved for RCC Selective activity against BCR-ABL1T315I vs. native BCR-ABL1 (Pemovska et al. Nature 2015; Zabriskie et al. Leukemia 2015) T315I-Inclusive Compound Mutations Confer Universal TKI Resistance Zabriskie et al. Cancer Cell 2014 Cellular BCR-ABL1 TKI Sensitivity Zabriskie et al. Cancer Cell 2014 9 4/24/2018 Rationalizing Resistance due to E255V/T315I Zabriskie et al. Cancer Cell 2014 Efficacy of Ascminib alone and in Combination with Nilotinib Efficacy Against Single BCR-ABL1 Mutants Efficacy in Combination with Nilotinib Single Mutants ENU-based Mutagenesis Assay Y253H/E255V E255V/T315I 100000 2000 1600 ABL001 IC50 [ nM] ABL001 IC5 0 [nM] 10000 1000 8000 6000 4000 1200 800 400 2000 0 ABL A BL0 001 01 0 12000 5000 10000 1 Niloti nib IC50 [nM] 3000 2000 8000 6000 4000 2000 1000 0 ib il otin 1 N L00 nM ilotin Nilo N tinib Q + ib + 250 250 nM Nilo tinib W M T 24 G 4V 25 0 25 E Y2 2H 5 E2 3H 5 V2 5V 99 F3 L 1 T 3 1I 1 F3 5I 1 M 7L 35 H3 1T 96 R 0 ABL001 001 Ni lotini b IC50 [nM] 4000 10 ABL 100 AB ABL001 IC50 [nM] 12000 10000 Nilo Nilo+ABL001 O’Hare T, Zabriskie M, Deininger M, unpublished How far can we get with BCR-ABL1 Inhibition? Responses to Ponatinib 45mg vs. Imatinib 400mg Daily (EPIC Trial) Imatinib Ponatinib 44 43 33 Nilotinib 300mg BID (ENESTnd) Ponatinib: Potent Very long on-target time Long half-life Vascular toxicity 9 Cave: Low numbers at 9, 12 months due to study closure Lipton et al. Lancet Oncol. 2016. 17(5):612-21 10 4/24/2018 Mechanisms of TKI Resistance BCR-ABL Reactivation? No Yes Alternative Survival Pathways in CML LSC Hedgehog Wnt/b-catenin PI3K/AKT/FOXO3A/BCL6 JAK/STAT/PP2A O’Hare, Zabriskie, Eiring, Deininger, Nat Rev Canc 2012 Instead of a Summary: How CML Works Chronic Phase Blast Phase BCR-ABL1 Dependence MRD Progression 11 4/24/2018 Acknowledgments Deininger/O’Hare Lab Tony Pomicter Will Heaton Phillip Clair Anya Senina Jonathan Ahmann Anna Eiring Dongqing Yan Matt Zabriskie Anca Franzini Srinivas Tantravahi Ami Patel Funding Source The Leukemia & Lymphoma Society NIH/NCI Aspire Mechanism V Foundation 12 4/24/2018 Multi-drug Resistant and Intolerant CML: What to do? Michael J. Mauro, MD Leader, Myeloproliferative Neoplasms Program Memorial Sloan Kettering Cancer Center, New York, NY Five Things • What are we aiming for and what trips us up • Approaching the ‘failing patient’: why? mutations, adherence, other? • ABL001 • PF-114 • K0706 ‘Shrinking the iceberg’: response expectations International Standard (IS) qPCR Early Molecular Response: <10% or 1-log (10x) drop from starting level Complete Cytogenetic Response: <1% or 2-log (100x) drop Major Molecular Response: <0.1% or 3-log (1000x) drop 4-log drop (<0.01%) 4.5 log drop, ‘MR4.5’, Complete Molecular Remission: <0.0032%; below the level of detection for standard labs 10% Early Molecular Response Early Molecular Response 1% Complete Cytogenetic Response Complete Cytogenetic Response Major Molecular Response Major Molecular Response 0.1% 0.01% 0.0032% MR5-6? MR4 MR4 MR4.5 ‘CMR’ eligible for ‘treatment free remission’ trials MR4.5 ‘CMR’ Plainly stated: 1. PCR at diagnosis = very important, like a timing chip when you run a race (where did you start?) 2. Early response at 3mo should be ‘on track’, 10x lower than start, ~10% (if you start ~100%) 3. Complete cytogenetic response (~1% on the PCR scale; 100x lower) is very important and protective 4. Major molecular response (MMR, ~0.1% on the PCR scale; 1000x lower) adds further protection 5. Deep Molecular remission: aiming for 0.01% or lower (10,000x lower than start) and staying that way 1 4/24/2018 Impact of BCR-ABL values ≤10% @ 3 months Overall Survival Progression-Free Survival ≤ 10% > 10% Failure-Free Survival ≤ 10% > 10% Major Molecular Response ≤ 10% > 10% Complete Molecular Response ≤ 10% > 10% ≤ 10% > 10% Branford S et al. Blood 2014;124:511-518 Value of MMR in prolonging remission Loss of CCyR (%) 100 80 Response at 12 months n Loss of CCyR CCyR without MMR 95 24% CCyR plus MMR 32 3% 60 40 P = 0.04 20 0 0 6 12 18 24 30 36 42 48 54 Months Since Start of Imatinib Therapy 60 Hughes T, et al. Blood 2010; 116(19):3758-65; Cortes J et al. Clin Cancer Res 2005;11:3425-3432; Marin D, et al. Blood 2008; 112(12):4437-44 Aside from being a launching point for ‘TFR’ trials, does ‘CMR’ add value for CML patients? EFS FFS 1.0 1.0 CCyR+MMR+CMR+ p = 0.00124 0.6 CCyR+MMR+CMR- Failure Free Survival Event Free Survival CCyR+MMR+CMR+ 0.8 p < 0.0001 p < 0.0001 0.4 CCyR+MMR- 0.2 p = 0.0335 0.8 CCyR+MMR+CMR- 0.6 p < 0.0001 p < 0.0001 CCyR+MMR- 0.4 0.2 0.0 0.0 0 20 40 60 80 Follow-up (Months) 100 120 0 Number at risk CCvR+MMRCCvR+MMR+CMRCCvR+MMR+CMR+ 20 40 60 80 Follow-up (Months) 100 120 Number at risk 23 92 65 11 81 63 5 60 53 1 33 35 0 10 15 0 3 3 0 0 2 CCvR+MMRCCvR+MMR+CMRCCvR+MMR+CMR+ 23 92 65 11 81 63 5 60 53 1 33 35 0 10 15 0 3 3 0 0 2 EFS = event-free survival; FFS = failure-free survival. CMR Defined as undetectable BCR-ABL with a sensitivity of at least 4.7 logs on 2 consecutive analyses at least 2 months apart. Etienne G et al. Haematologica 2014;99:458-464 2 4/24/2018 Choosing your tools: comparing TKI toxicity in CML Issue Imatinib Dasatinib Bosutinib Ponatinib Dosing QD/BID, with BID, without food food (2h) Nilotinib QD, w/ or w/o food QD, with food QD, w/ or w/o food Long term safety Most extensive Extensive; Emerging toxicity Extensive; Emerging toxicity Extensive, No emerging toxicity More limited but increasing; Emerging toxicity Heme toxicity intermediate least Most severe; ASA-like effect; lymphocytosis ~dasatinb in 2nd, 3rd line; ~nilotinib in 1st line thrombocytopenia ASA-like effect NonHeme toxicity Edema, GI effects, Phos lipase, bili, Pleural / chol, glu pericardial Black box: QT effusions prolongation; screening req’d Diarrhea; transaminitis lipase, pancreatitis; rash; hypertension; Black box: vascular occlusion, heart failure, and hepatotoxicity Emerging toxicities early question re: CHF; ?late renal effects Vascular events (ICVE, IHD, PAD) ? Mild renal effects Vascular events (ICVE, IHD, PAD, VTE) PAH (pulmonary arterial hypertension) Post-Imatinib: 2nd Generation TKIs offer similar benefits Dasatinib Bosutinib Nilotinib Months follow-up >24 Median of 24 >24 Complete Hematologic Response 89% 86% 77% Major Cytogenetic Response 59% 54% 56% Complete Cytogenetic Response 44% 41% 41% 2-year Progression Free Survival 80% 79% 64% 2-year Overall Survival 91% 92% 87% Shah et al. Haematologica 2010; 95: 232-40, Kantarjian et al. Blood 2011; 117: 1141-45; Cortes et al. Blood 2011; 118; 4567-76 3rd line therapy: Switch to alternate 2nd gen agent versus ponatinib? Lipton J, et al. ASH 2013. Abstract 4010. 3 4/24/2018 The most significant ‘late effects’: CML TKI Associated Cardiovascular Adverse Effects Cerebrovascular Disease Cardiomyopathy Congestive Heart Failure Endothelial Dysfunction? Atherosclerosis? Cardiomyocyte Injury? Pulmonary Arterial Hypertension Coronary Heart Disease Myocardial Infarction Endothelial Dysfunction? Endothelial Dysfunction? Atherosclerosis? Venous Thrombosis Peripheral Arterial Disease Platelet dysfunction? Prothrombotic state? Endothelial Dysfunction? Atherosclerosis? Other: • Fatigue • Musculoskeletal Sx / Cramping • Exercise-Induced Symptoms Morbidity and mortality; ? Effect on survival observations in front-line studies? Kantarjian, ? Delay/deferral of advantageous therapy both in front-line and salvage et al. Blood. 2012;119:1981-1987. 10 Omacetaxine for CML After Failure of ≥2 TKIs Response, % Primary endpoint(s) Median duration, months Median Progression Free Survival, months Median Overall Survival, months • • • CP N=81 AP N=41 Major Cytogenetic Response: 20% 17.7 Major Hematologic Response: 27% Complete Hematologic Response: 24% 9 9.6 4.7 33.9 16 Complete Cytogenetic Response: 10% 11 patients (9 chronic phase, 2 accelerated phase) ongoing response Median 35 cycles over median 39 months Median response duration: • 14 months for chronic phase, 24 months for accelerated phase Kantarjian. Blood 120: abst 2767; 2012 Resistance to TKIs: point mutations • >100 mutations described in imatinib and subsequent generation TKI treated patients; only a handful (~10) account for the vast majority (~85%) of clinically observed mutations • Single and compound mutations are found in the same subset of 12 key positions 4 4/24/2018 Likelihood mutation testing will influence TKI choice Branford S et al, Blood 2009 Adherence 6-year probability of MMR according to the measured adherence rate p<0.001 Marin D, et al. J Clin Oncol 2010; 28(14): 2381–2388. 5 4/24/2018 6-year probability of CMR according to the measured adherence rate p=0.002 Marin D, et al. J Clin Oncol 2010; 28(14): 2381–2388. Adherence and the achievement of MMR are the only independent predictors for outcome 1.0 1.0 p<0.0001 0.9 MMR, n=53 0.8 p=0.003 Probability of imatinib failure Cumulate incidence of loss of CCyR 0.9 CCyR, no MMR, Adherence Rate ≤85%, n=11 0.7 CCyR, no MMR, Adherence Rate >85%, n=23 0.6 0.5 0.4 0.3 p<0.0001 0.2 p=0.0009 0.8 0.7 0.4 0.3 0.1 0.0 12 Months from enrolment 18 24 MMR, n=53 0.2 0.0 6 p<0.0001 0.5 0.1 0 p<0.0001 0.6 CCyR, no MMR, Adherence Rate ≤85%, n=11 CCyR, no MMR, Adherence Rate >85%, n=23 0 6 12 18 Months from enrolment 24 Marin D, et al. J Clin Oncol 2010; 28(14): 2381–2388. Practical approach to a patient with resistance (or intolerance +/- resistance) • First, determine what the disease state requires – disease phase – prior TKI exposure – mutational status • T315I unique • Select mutations may support role of specific 2nd generation TKIs • Predictive potential imprecise • ‘iceberg’ phenomenon • More detailed assays not routinely incorporated (deep sequencing, etc) • Next, balance therapy risk and toxicity potential with known comorbidities – are there true ‘contraindications’? – does risk outweigh benefit expected from therapy? – can risk be mitigated or anticipated? – enlist the patient’s insight, trust, and awareness 6 4/24/2018 What is the role of allografting in CML? Status TKIs Transplant Accelerated or Blast transformation has occurred Interim treatment to best response/minimal residual disease ASAP Imatinib failure in chronic Ponatinib with caution, If no response to phase, T315I (+) ABL001 (experimental) Ponatinib/ABL001 Imatinib failure in chronic Long-term second line phase without clonal TKIs evolution, mutations, good response Third line post second TKI failure or beyond IM failure in chronic phase with clonal evolution, mutations, poor response Interim treatment to best response Second line, taken case by case Older age (≥65 – 70) post imatinib failure Long-term second line TKIs May forgo allo SCT for many yrs of QOL New Agents: ABL001, PF-114, K0706 At present, five oral, small molecular kinase inhibitors approved in the US for Ph+ Leukemia: a ‘spoil of riches’; more on the way? 2001 Novartis (1st line) 1st Gen. TKI Imatinib (STI571) Nilotinib (AMN107) Dasatinib (BMS354825) South Korea only 2007/2010 Novartis (1st, 2nd line) 2007/2010 BMS (1st, 2nd line) 2nd Gen. TKIs Radotinib (IY5511) 2012/2015 IL-YANG: (1st, 2nd line) 2012 Pfizer (2nd/3rd line) Bosutinib (SKI606) 2017: 1st/2nd/3rd line 3rd Gen. TKI 2012 Ariad (2nd?/3rd line) Others: K0706; PF-114 4th Gen. TKI (allosteric): ABL001 Ponatinib (AP24534) 7 4/24/2018 4th generation TKI ABL001 Allosterically Inhibits BCR-ABL1 Kinase Activity BCR t(9;22) SH3 SH3 SH2 SH2 SH2 Kinase BCR Kinase ABL001 INACTIVE ACTIVE • Developed to gain greater BCR-ABL1 inhibition, with activity against BCR-ABL1 mutations conferring resistance to TKIs • Potential to combine with TKIs for greater pharmacological control of BCR-ABL1 ABL001 Ottmann et al, ASH 2015 Abstract #138 ABL001X2101: Study Design A multicenter, phase 1, first-in-human study Dose Escalation Bayesian Logistic Regression CML—completed ABL001, po, BID Dose Expansion CML (20 mg, 40 mg)–completed T315I mutation (150 mg)–ongoing MTD RDE Dose Escalation CML ABL001, po, QD Dose Escalation Ph+ ALL/CML-BP 47 of 77 (61%) patients with CML treated with singleagent ABL001 BID were resistant to their last TKI Primary outcome: estimation of MTD/RDE Secondary outcomes: safety, tolerability, preliminary anti-CML activity, pharmacodynamics, pharmacokinetic profile ALL, acute lymphocytic leukemia; BID, twice daily; BP, blast phase; CML, chronic myeloid leukemia; MTD, maximum tolerated dose; Ph+, Philadelphia chromosome-positive; po, peroral; QD, once daily; RDE, recommended dose for expansion Dose Expansion Ph+ ALL/CML-BP MTD RDE Combo Dose Escalation CML ABL001+nilotinib MTD RDE Expansion Combo Dose Escalation CML ABL001+imatinib MTD RDE Expansion Combo Dose Escalation CML ABL001+dasatinib MTD RDE Expansion Hughes TP, et al. Blood. 2016; 128 (22): [abstract 625]. Responses in Patients With CML Treated With Single-Agent BID ABL001 With ≥3 Months Exposure on Study 100 Patients With Response, % • • Dose Expansion CML MTD RDE Hematologic Response Within 6 mo Cytogenetic Response Within 6 moa Molecular Response Within 6 moa,b Molecular Response Within 12 mob,c 80 Low blood counts and pancreas enzyme elevation are main side effects of higher intensity seen to date 70 13.3% and 37.5% achieved MMR by 6 and 12 months 60 29.4% and 42.9% achieved ≥1-log reduction by 6 and 12 mo 90 50 40 30 CHR: 88% (14/16) CCyR: 75% (9/12) 20 MMR: 20% (10/50) 10 0 8 of 10 (80%) patients with >35% Ph+ achieved CCyR by 6 mo Hematologic Disease (CHR relapse) Cytogenetic Disease (>35% Ph+) ≥1-log reduction: 30% (10/33) Molecular Disease (>0.1% IS) (≤10% IS) MMR: 42% (16/38) ≥1-log reduction: 48% (12/25) Molecular Disease (>0.1% IS) (≤10% IS) Disease Status at Baseline CCyR, complete cytogenetic response; CHR, complete hematologic response; IS, International Scale; MMR, major molecular response; mo, months aPatients had ≥6 months of treatment exposure or achieved response within 6 months bBCR-ABL1IS reduction achieved cPatients had ≥12 months of treatment exposure or achieved response within 12 months Hughes TP, et al. Blood. 2016; 128 (22): [abstract 625]. 8 4/24/2018 ABL001 Bosutinib 500 mg QD • • Lack of response Failure/Intolerance 2:1 Randomization 40 mg BID CML CP patients (N = 222 planned), previously treated with ≥ 2 ATP binding TKIs Lack of response Failure/Intolerance Survival follow-up CABL001A2301 (Planned): Study Design A phase 3, Multicenter, Open-label, Randomized Study of ABL001 Versus Bosutinib Primary endpoints: Major Molecular Response (MMR) rate at 24 weeks Key secondary endpoint: MMR rate at 96 weeks BID, twice daily; CML, chronic myeloid leukemia; CP, chronic phase; QD, once daily; TKI, tyrosine kinase inhibitor PF-114 phase 1 study PF-114 – Novel 3rd Generation Inhibitor of Bcr-Abl • PF-114: 3rd generation Abl inhibitor, close structural analog of ponatinib • PF-114 rationally designed to avoid inhibition of numerous off-target kinases and potentially avoid life-threatening side effects PF-114 Structure-inspired disruption of off-target interactions with kinases like VEGFR2 and B-Raf PF-114 kinase inhibition profile (100 nM) Cortes J et al, ASH 2017 PF-114 phase 1 study Pre-clinical Characterization of PF-114 • Cytotoxicity to Ph+ ALL PDLTC and BaF3 cells with native BCR/ABL and mutant variants Cell line Bcr-Abl variant IC50, nM* PDLTC, VB p210 15 PDLTC, PH P185 3 PDLTC, CM p210 7 PDLTC, KW p185 5 PDLTC, DW p185 7 PDLTC, BV p185 3 PDLTC, KO p185, T315I 75 BaF3 p185, Y253F 25 BaF3 p185, E255K 25 BaF3 p185, F317L 100 *Medical Clinic of • Xenograft K562 CML cell line model Ponatinib Dose 25 mg/kg AUC 24uM*h PF-114 Dose 40 mg/kg AUC 15uM*h AUC 15uM*h Orthotopic murine BaF3 cell model of T315I+ CML NSG Mice iv xenograft of human T315I Ph+ALL Ghoethe University, Frankfurt, Germany Cortes J et al, ASH 2017 9 4/24/2018 PF-114 phase 1 study Phase 1 Study Design and Outcome Measures • Design – 3+3 dose escalation till MTD (DLT during 1-st 28-day cycle) – Expanded cohorts (10-15 pts each) at ≤MTD; total enrollment ~44 pts • Eligibility – CML CP or CML AP patients who failed ≥2 TKIs, or intolerant of TKIs, or with T315I • Primary endpoints – DLT(s) during 1-st 28-day cycle – MTD • Secondary endpoints – Incidence of AEs – PK – Rates of hematologic, cytogenetic, molecular responses • Exploratory endpoints – Pharmacodynamic response (p-CrkL/CrkL) – Pharmacogenetic relations (response across BCR/ABL mutant forms) Cortes J et al, ASH 2017 PF-114 phase 1 study Preliminary Analysis of Safety: Hematologic Adverse Drug Reactions n of patients with adverse drug reactions Blood and lymphatic system disorders Gr 1 Gr 2 Gr 3 4/24 1/24 3/24 neutropenia 2 thrombocytopenia 2 anemia 1 1 Gr 4 2 2 Cortes J et al, ASH 2017 PF-114 phase 1 study Non-Heme AEs n of patients with adverse drug reactions Gr 1 Gr 2 Gr 3 Gr 4 Skin and subcutaneous tissue disorders 18/24 13/24 4/24 13 10 3 psoriasiform skin lesions 5 1 dry skin 2 1 itching 1 1 1 rash 1 1 hyperemia 7/24 1/24 Gastrointestinal disorders 6 1 diarrhea 2 abdominal pain 1 nausea 1 stomatitis 1 pain in the right hypochondrium General disorders and administration site 1/24 conditions 1 fever 2/24 Nervous system disorders 1 dizziness 1 headache Cortes J et al, ASH 2017 10 4/24/2018 PF-114 phase 1 study Biochemical AEs n of patients with adverse drug reactions Investigations hypophosphatemia increase of cholesterol increase of LDL decrease of HDL increase of ALT increase of AST increased level of creatinine Gr 1 Gr 2 4/24 2/24 1 1 1 1 1 1 1 1 Gr 3 Gr 4 Cortes J et al, ASH 2017 PF-114 phase 1 study Preliminary Analysis of Efficacy of PF-114 Phase of CML Chronic Acceleration Blast BCR/ABL Total number mutation of patients status Rate of CHR Rate of MCyR % n*/N** % T315I 9 40 2/5 80 n*/N*** 4/5 All 21 36 4/11 40 4/10 T315I 1 0 0/1 0 0/1 All 2 50 1/2 0 0/2 T315I 1 100 1/1 0 0/1 n*- number of patients who achieved response during treatment N** - number of patients evaluable for hematologic response assessment: were not in CHR at enrollment N*** - number of patients evaluable for cytogenetic response assessment: were not in MCyR at enrollment and completed at least 3 cycles Cortes J et al, ASH 2017 PF-114 phase 1 study Conclusions • PF-114 mesylate exhibits anti-leukemia activity in a heavily pretreated CML patients including those with T315I mutation • MTD has not been reached – 50, 100, 200, 400, 500 mg dose cohorts have been studied – 600 mg cohort is currently being studied • A single DLT of grade 3 erythematous rash observed • No cardiovascular events have been observed • A Phase 2 multicenter international study is planned for 2018 Cortes J et al, ASH 2017 11 4/24/2018 K0706: Program K0706: Novel BCR-ABL tyrosine kinase inhibitors for treatment of Chronic Myeloid Leukemia (CML) K0706: equipotent to Ponatinib in CML cellular* & in vivo efficacy assays with limited potential for off-target effects based on the long term toxicity studies K0706: as an efficacious, tolerable and safer treatment alternative for Chronic Myeloid Leukemia or Ph+ Acute Lymphoid Leukemia patients who have failed ≥ 2 lines of therapies and/or ineligible due to comorbidities which limit the administration of other TKIs Courtesy of Sun Pharma / personal communication SUN-K0706: Preclinical Data Summary In vitro In vivo 3000 K0706 (10 mg/kg, o.d., 21 days) IC50 SUNK706 Ponatini b 0.9 0.7 Abl Abl(T315I) 8 2 Abl (M351T) 0.8 0.3 Abl (Q252H) 0.8 0.4 Abl(Y253F) 1 0.3 2500 Tumor volume (mm3) IC50 (nM) Kinases Ponatinib (10 mg/kg, o.d., 21 days) 2000 Vehicle 1500 1000 500 0 1 4 6 8 1012151821 1 3 4 7 101417222428313539424549525459 Days post treatment initiation Caused tumor regression in an imatinib- Effective against the wild type resistant xenograft model and mutation bearing CML cell lines Courtesy of Sun Pharma / personal communication K0706:Long-term monitoring of K562 xenograft growth Tumor volume (mm3) 3500 K0706 (1 mg/kg, p.o., o.d., 21 days) K0706 (3 mg/kg, p.o., o.d., 21 days) Imatinib (150 mg/kg, p.o., o.d., 21 days) Ponatinib (3 mg/kg, p.o., o.d., 21 days) Placebo (p.o., o.d., 21 days) K0706 (10 mg/kg, p.o., o.d., 21 days) 3000 2500 2000 1500 1000 500 0 1 4 6 8 10 12 15 18 21 24 28 32 35 38 43 45 49 52 56 60 63 66 70 74 77 80 Days after treatment initiation K0706: Demonstrates comparable long term tumour control with Ponatinib Courtesy of Sun Pharma / personal communication 12 4/24/2018 Part B: Subject Profile & Disposition Toxicity: ICH in BP patient, tenosynovitis with successful rechallenge % Country wise enrolment 40% 36% Female 36% 27% 30% BCR-ABL Mutation 25% Male 64% 18% 20% 15% 9% 9% 5% 0% France Korea Belgium 81% 1 Subject: T315I mutation 1 Subject: F359V mutation 1 Subject: T315I mutation status under investigation 10% India Native BCRABL 18% 35% USA Cohort/Dose level Disposition of Subject Subjects enrolled (N) Received study medication (N) 12 mg 1 1 Subjects completing Cycle 1 (N) No of Cycles completed Subjects discontinued (N) 24 mg 1 1 48mg 6 6 66mg 3 3 All Subjects 11 11 1 1 5 2 10 Cycle 9 Nil Cycle 5 Nil Cycle 3 1 (SAE) Cycle 1 NA 1 (SAE) Courtesy of Sun Pharma / personal communication Efficacy Hematological response 80,000 Subjects: Study entry in Haematological response Subjects: Study entry : Loss of haematological response 70,000 9,000 60,000 7,000 40,000 6,000 Cells/mL Cells/mL 8,000 50,000 30,000 20,000 5,000 4,000 3,000 2,000 10,000 1,000 0 Screening C1D8 C1D15 C122 35600501 (Refractory) 0 C1D28 Screening C1D8 C1D15 C122 C1D28 35600503 (Refractory) 35600102 (Refractory) 5600101 (Intolerant) 25000201 (Refractory) 41000103 (Refractory) 35600101 (Intolerant) 41000101 (Intolerant) 5600201 (Intolerant) 25000201 (Refractory) 84000201 (Intolerant and Refractory) 9/11 Subjects demonstrated complete hematological response by end of Cycle 1 3/11 Achieved; 6/11 Maintained Transient self-limiting grade 1 /2 neutropenia associated with study drug was observed in 2/11 subjects This was self-limiting and recovered by end of Cycle 1 without intervention Courtesy of Sun Pharma / personal communication 38 SPARC Presentation Confidential Efficacy 100% 35600501 90% 5600101 80% 41000102 70% 41000103 60% 35600102 50% 35600503 40% 25000201 30% 20% 10% * % Philadelphia Cell Positivity % Philadelphia Cell Positivity Cytogenetic response 100% 35600101 90% 5600201 80% 41000101 70% 60% 50% 40% 30% 20% 10% 0% Screening 0% Screening C3D28 C3D28 C6D28 C6D28 Subjects: Study entry :Loss of cytogenetic response Subjects: Study entry: Complete cytogenetic response Cytogenetic response data in maturing process Subject with loss of cytogenetic response transition: Partial cytogenetic response & evolving cytogenetic response Subjects with complete cytogenetic response: Maintained cytogenetic response *: Not applicable; Subject discontinued from study SPARC Presentation Confidential Courtesy of Sun Pharma / personal communication 13 4/24/2018 In CP and AP CML, No Early Gain in Overall Survival with SCT vs Ponatinib *P-value <0.05. OS = overall survival; IQR = interquartile range; NR = not reached. FE. Nicolini et al., ASH 2015 Abst. #480; Blood, submitted Conclusions • • • • CML is highly treatable; ‘functional cure’ appears feasible Generic imatinib is here; more TKIs still in development Early response increasingly predictive of long term success Resistance based in mutations can drive treatment choice but is likely quite complex; Novel agents in study (ABL001) • Second /third line therapy effective, needs to be carefully chosen (risk/benefit of ponatinib vs other alternatives) • SCT still needed as an option • New options/new drugs on the horizon Many TKIs Response Remission Cure? = Long, Happy, Healthy Life! Thank you for your attention! Questions? maurom@mskcc.org 212-639-3107 14 4/24/2018 Upfront Treatment Strategies for Patients with CML Daniel J. DeAngelo, MD, PhD Adult Leukemia Program Dana-Farber Cancer Institute Brigham and Women’s Hospital Associate Professor of Medicine Harvard Medical School Boston, MA 2017 Master Class Course Presenter Disclosure Information The following relationships exist related to this presentation: • Dr. Daniel DeAngelo has served as a consultant for Amgen, Celgene, Incyte, Novartis, Pfizer, Shire and Takeda Pharmaceuticals • I have also received research funding from Glycomimetics and Blueprint Pharmaceuticals Off-Label/Investigational Discussion In accordance with CME policy, faculty have been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations. CML: Management in the Era of Multiple Tyrosine Kinase Inhibitors 1 4/24/2018 Life Expectancy of Patients with CML Approaches the General Population Bower et al., J Clin Oncol 2016 34: 2851-7. CML Current Status: 2018 Imatinib Nilotinib Dasatinib Bosutinib Nilotinib Dasatinib Bosutinib Generic imatinib finally here! Other: Omacetaxine Refractory response Suboptimal response Relapse Intolerance Ponatinib SCT Refractory response Suboptimal response Relapse Intolerance T315I What Can We Expect From Front-line Imatinib in CP CML? IRIS Trial Data 2 4/24/2018 MMR A Hochhaus, RA Larson, F Guilhot, et al. New Engl J Med 2017 376: 917-27. • There are consistent data from multiple studies demonstrating that patients who have very rapid responses with any TKI have excellent long term outcomes and that some patients with slower responses fare more poorly. • Responses are faster with “second” generation TKIs ENESTnd: Nilotinib vs Imatinib in Newly Diagnosed Chronic Phase CML • Primary endpoint: MMR at 12 mos, defined as ≤ 0.1% BCR-ABL(/ABL ratio) on International Scale • Secondary endpoint: CCyR by 12 mos • Other endpoints: time/duration of MMR and CCyR; EFS, PFS, time to AP/BP, OS • Stratification by Sokal risk Newly Diagnosed CML-CP (N = 846) 217 centers; 35 countries R A N D O M I Z E Nilotinib 300 BID (n = 282) Nilotinib 400 BID (n = 281) Imatinib 400 QD (n = 283) Saglio G, et al. N Engl J Med. 2010;362(24):2251-2259. 3 4/24/2018 ENESTnd: Cumulative Incidence of MMR aP values are nominal. For each arm, the curve stops at the latest time point at which a patient first achieved MMR. Hochhous A, et al. Leukemia. 2016: 1044-1054. Dasatinib vs Imatinib in Treatment-naive CML: DASISION Dasatinib 100 mg QD (n = 259) N = 519 Follow-up Randomized* 108 centers 5 years Imatinib 400 mg QD (n = 260) 26 countries *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 H, et al. N Engl J Med. 2010;362(24):2260-2270. DASISION: Cumulative MMR Rates Over Time N 259 260 Dasatinib 100 mg QD Imatinib 400 mg QD 100 By 5 years By 4 years 90 By 3 years 80 % With MMR b By 2 years 70 64% 60% By 1 year 55% 46% 50 76% 67% 64% 60 p=0.0022 73% 46% 40 28% 30 20 10 0 0 6 12 18 24 30 36 Months Since Randomization 42 48 54 60 Cortes et al. J Clinic Oncol 2016: 2333-2340 4 4/24/2018 BFORE Study Design: First-line Bosutinib vs Imatinib in CML ▪ BFORE (NCT02130557) is an ongoing (expected duration 5 years), multinational, randomized, openlabel, two-arm, phase 3 study ▪ Prespecified primary endpoint: Eligibility Bosutinib 400 mg once daily (n=268) • ≥18 years of age • New molecular diagnosis of BCR-ABL1+ (Ph+ or Ph−) CP CML − MMR at 12 months in the mITT population ▪ mITT population: Ph+ patients with e13a2/e14a2 transcripts, excluding Ph− patients and those with unknown Ph status and/or BCR-ABL transcript type* − Bosutinib: n=246 − Imatinib: n=241 ▪ Current analysis based on ≥18 months of follow-up† 1:1 • ECOG PS 0 or 1 • No prior medical treatment for CML N=536 Imatinib 400 mg once daily (n=268; 3 not treated) Stratification • Sokal risk group • Geographic region • * 12 Ph‒ patients (ie, 0 of ≥10–99 metaphases at baseline; n=6 in each arm), 8 patients with atypical transcripts (n=3 in bosutinib arm; n=5 in imatinib arm), and 31 patients with unknown Ph status (n=13 in bosutinib arm; n=18 in imatinib arm [includes 2 patients also listed as having atypical transcripts]). • † All P values, except MMR at 12 months and CCyR by 12 months in the mITT population, are for descriptive purposes only; no adjustments for multiple comparisons. • CCyR=complete cytogenetic response; CML=chronic myeloid leukemia; CP=chronic phase; ECOG PS=Eastern Cooperative Oncology Group performance status; mITT=modified intent-to-treat; MMR=major molecular response; Ph=Philadelphia chromosome Gambacorti-Passerini et al., ASH 2017, abstract #896 Cumulative Incidence of Response (mITT Population) BFORE: First-line Bosutinib vs Imatinib in CML 100 HR=1.36 (95% CI: 1.09–1.69); P=0.0079† 80 60 40 Bosutinib Imatinib 20 0 0 12 24 36 48 60 72 84 Weeks Patients at risk, n Cumulative Incidence of CCyR* Probability of CCyR (%) Probability of MMR (%) Cumulative Incidence of MMR* 100 HR=1.33 (95% CI: 1.10–1.62); P=0.0049† 80 60 40 Bosutinib Imatinib 20 0 0 12 24 36 48 60 72 84 Weeks Patients at risk, n Bosutinib 246 232 206 119 94 75 58 39 Bosutinib 246 229 121 50 20 8 5 2 Imatinib 241 235 204 151 116 87 62 38 Imatinib 241 229 149 70 40 20 12 2 * 18-month data shown; data after 72 weeks subject to change to due to incomplete follow-up. † Gray’s test P-value. CI=confidence interval; CML=chronic myeloid leukemia; CCyR=complete cytogenetic response; HR=hazard ratio; mITT=modified intent-to-treat; MMR=major molecular response Gambacorti-Passerini et al., ASH 2017, abstract #896 BUT…. • NO SURVIVAL ADVANTAGE with nilotinib, dasatinib or bosutinib in randomized trials • Only about 60-65% of patients remain on their initial drug • And then there are the toxicities… 5 4/24/2018 LONGER TERM FOLLOW-UP OF SECOND and THIRD GENERATION TKIs • Dasatinib - late pleural effusions, pulmonary hypertension; T/NK cells • Nilotinib – hyperglycemia, peripheral arterial occlusive disease, other arterial thromboses • Bosutinib – less information; diarrhea and transaminitis • Ponatinib - MAJOR arterial thrombotic issues CML Molecular Response Milestones BCR-ABL1 (IS) 3 months > 10% YELLOW 1% - 10% 6 months 12 months > 12 months RED GREEN YELLOW 0.1% - 1% RED GREEN < 0.1% YELLOW GREEN Clinical Considerations RED YELLOW GREEN Treatment options Evaluate compliance and drug interactions Mutation testing Switch to alternate TKI Consider screen for HSCT Same as above Consider switch to alternate TKI or continue (may increase dose of imatinib to 800 mg) Monitor response and toxicity Continue same TKI NCCN 2017 Guidelines CML Monitoring Frequency The 3 month QRT-PCR may be uniquely important in defining long term outcome! If these criteria aren’t met (primary resistance, ~15% on imatinib): check for ABL TKD mutation and switch therapy Repeat marrow exams are not necessary once CCyR achieved (check at 6 months and 6 months thereafter prn) (PB FISH also reasonable) Check QPCR q 3 months x 3yrs, then q 3-6 months thereafter or if increase by 1 log after MMR achieved, then repeat in 1-3 months When to check for ABL TKD mutation and switch therapy: loss of response (heme or cytog relapse) or disease progression to AP/BP confirmed 1 log increase in bcr-abl1 transcript and loss of MMR NCCN Guidelines 2017; Mahon et al., Lancet Oncol 2010; 11: 1029–35 6 4/24/2018 CML Response Definitions, Monitoring and Milestones Response Type Response Definition When It Should be Achieved Complete hematologic response (CHR) Normalization of blood counts; resolution of disease signs and symptoms <1-3 months Initial Molecular response Reduction in BCR-ABL transcript levels in peripheral blood by ≥ 1 log, or BCR-ABL/ABL ratio reduced to ≤ 10 % IS <3 months Major cytogenetic response (MCyR) ≤ 35% Ph+ cells <6 months Complete cytogenetic response (CCyR) 0% Ph+ cells <12 months Major molecular response (MMR) Reduction in BCR-ABL transcript levels in peripheral blood by ≥ 3 log, or BCR-ABL/ABL ratio reduced to ≤ 0.1% IS <12 - 18 months Complete molecular response (CMR) Reduction in BCR-ABL transcript levels in peripheral blood by ≥ 4.5 log, or undetectable BCR-ABL/ABL transcript ?? Jabbour E, et al. Cancer. 2007;109(11):2171-2181. Marin D, et al (European LeukemiaNet) Blood 2008;112(12):4437-4444. Marin D et al J Clin Oncol 2012; 30(3):232-8. ABCDE Steps to Reduce CV Risk in Patients with CML • A • B • C • D • E • Awareness of CV risks and signs • Aspirin in appropriate patients • Ankle-brachial Index (ABI) at baseline and f/u • Blood pressure control • Cigarette/tobacco cessation • Cholesterol monitoring and treatment • Diabetes mellitus monitoring and treatment • Diet and weight control • Exercise Moslehi and Deininger, J Clin. Oncol 2015 33: 4210-8 Algorithm for Frontline TKI Therapy in CML Bosutinib offers a third 2nd Gen choice Neil P. Shah; JCO 2018, 36, 220-224 7 4/24/2018 Chronic Myeloid Leukemia: Conclusions • Chronic Myeloid Leukemia • Generic imatinib finally here • First line imatinib vs nilotinib vs dasatinib vs bosutinib? • How to choose? Imatinib a very reasonable choice for elderly and low-risk patients • Late side effects important (CV for nilotinib; pleural effusions for dasatinib) • Compliance still most important • Need to minimize CV risk factors • Need to better understand the “ultimate” goal of therapy • Cytogenetic remission vs. major molecular response vs complete molecular remission? Questions & Answers ? 8 4/24/2018 Are we ready for treatment discontinuation? Javier Pinilla-Ibarz MD, PhD Senior Member Malignant Hematology Department H. Lee Moffitt Cancer Center Disclosures • Consulting: Novartis, Pfizer and Takeda. • Speaker Bureau: Takeda. Why consider stopping? • TKI therapy is associated with reduced QOL • High cost to patient and society • Potential for long term toxicity – Cardiovascular – Pulmonary – Thyroid dysfunction • Children and adolescents: – Substantial growth abnormalities – Effect on pregnancy/fertility 1 4/24/2018 Long Term Follow Up From STIM • • • Median Follow Up: 77 months n=100 38% Treatment Free Remission • • 61% relapsed: 80% in months 1-3, 15% in months 4-7 Median time to molecular relapse: 2.5 months Etienne G. Journal of Clinical Oncology 35, no. 3 (January 2017) 298-305 Multivariate Analysis From STIM • Two factors predictive of molecular relapse 1. High-risk Sokal score at diagnosis • HR 2.22 • 95% CI 1.11-4.42 • P=0.024 2. Imatinib duration < 58.8 months prior to discontinuation • HR 0.54 • 95% CI 0.32-0.92 • P=0.024 Etienne G. Journal of Clinical Oncology 35, no. 3 (January 2017) 298-305 EURO-SKI: Study Design TKI Cessation CML pts receiving TKI for ≥ 3 yrs with deep MR* for ≥ 1 yr and no history of TKI failure (N = 755*) Screening (≤ 6 Wks) MR4 confirmation† Yr 1 Follow-Up RQ-PCR Q4W, then Q6W Yr 3 Follow-Up RQ-PCR Q3M *In primary analysis of 868 preregistered pts. †MR4, defined as detectable BCR-ABL ≤ 0.01%, or undetectable BCR-ABL in samples with ≥ 10,000 ABL or ≥ 24,000 GUS transcripts, respectively. Primary endpoint: molecular recurrence (BCR-ABL > 0.1%, ie, loss of MMR) • Largest TFR study to date • Goal was to establish criteria for TKI discontinuation Sauselle S, et al. ASH 2017. Abstract 313. 2 4/24/2018 EURO-SKI: Molecular Recurrence-Free Survival Pts at Risk, n MRFS, % (95% CI) 6 Month 457 61 (58-65) 12 396 55 (51-58) 18 333 52 (49-56) 24 219 50 (47-54) 36 31 47 (43-51) Sauselle S, et al. ASH 2017. Abstract 313. EURO-SKI: Conclusions • Study defined stopping criteria for TKI cessation in CML patients who achieve durable deep MR • Preferred cutoffs for 6-mo probability of MMR loss – TKI duration: 5.8 yrs – MR4 duration: 3.1 yrs • Probability of TFR increased almost linearly per each additional year of first-line imatinib and duration of MR4 Sauselle S, et al. ASH 2017. Abstract 313. ENESTfreedom Enrollment and Inclusion Criteria Total enrollment n=215 Minimum treatment duration required prior to discontinuation ≥3 years frontline nilotinib Minimum response required prior to discontinuation Sustained MR4.5 for at least 1 year • 37.9% of nilotinib 300mg BID treated patients on ENESTnd met the inclusion criteria for attempting TFR on ENESTfreedom Study Design RQ-PCR (standardized to the IS) every 12 weeks • b2a2 and/or b3a2 transcripts • ≥ 2 y frontline nilotinib • MR4.5 at screening (central laboratory) Enroll • Adults with CML-CP Consolidation Phase (52 weeks) N = 215 Treatment was nilotinib 300mg BID in all treatment phases RQ-PCR (standardized to the IS) every 4 weeks for 48 weeks, every 6 weeks for 48 weeks, and then every 12 weeks Sustained Deep Molecular Response TFR Phase (192 weeks) Loss of MMR (molecular relapse) Reinitiation Phase Hochhaus A. ASCO Annual Meeting 2016. Abstract #7001 3 4/24/2018 Primary Endpoint and Treatment-Free Survival Kaplan-Meier Estimated Treatment-Free Survivala 100 • 190 patients entered the TFR phase • 51.6% of patients (95% CI, 44.158.9%) remained in TFR after 48 weeks 90 Treatment-Free Survival, % 80 70 60 50 40 30 20 Pts Evt 190 91 Censored observations 10 Cen 99 0 0 12 24 36 120:70 108:81 48 60 72 84 96 1:91 0:91 Time Since TFR, weeks At Risk : Events 190:0 165:25 90:89 38:91 12:91 Defined as the time from the start of TFR until the earliest of any of the following: loss of MMR, reinitiation of nilotinib for any reason, progression to accelerated phase/blast crisis, or death due to any cause. a Hochhaus A. ASCO Annual Meeting 2016. Abstract #7001 TKI Withdrawal Syndrome – Diffuse musculoskeletal pain and joint pain – Occurs in approximately 30% of patients after stopping TKIs – Median duration 6 months Lee et al. Haematologica. 2016 Jun;101(6):717-23. Richter et al. J Clin Oncol. 2014;32(25):2821–2823. NCCN Guidelines Version 4.2018 Chronic Myeloid Leukemia NCCN Evidence BlocksTM NCCN Guidelines Index Table of Contents Discussion DISCONTINUATION OF TKI THERAPY1 • Discontinuation of TKI therapy appears to be safe in select a CML patients. • Cli nica ls tudies tha tha veeva lua tedthes a f etya ndef f iccy o fT KI d iscontinuatio n h ave e mplo yed str ic te lig ib ilityc rite riaa nd h ave m andate d more frequent molecular monitoring than atypically recommended for patients on TKI therapy. • Somepa tients ha veex periencedsignif icnt a dverse e vents th at a reb elie ved to b ed ue to T KI d iscontinuatio n. • Discontinuation s of TKI therapy should only be performed in consenting patients after a thorough discussion of the potential risks and benef it. • Outside of a clinical trial, TKI discontinuation should be considered only if ALL of the criteria included in the list below are met. Criteria for TKI Discontinuation • A ge ≥ 18 years . • Chronic phase CML. No prior history of accelerated or blast phase CML. • O n ap p ro ved T K I therap y (im atin ib ,d as atin ib ,n ilo tin ib ,b o s utin ib ,o r p o n atin ib ) fo r at leas b t three years . • Prio r eviden ce o f q uan tifial e BCR-ABL1 transcript. • S tab le m o lecular res p o n s e (M R 4; BCR-ABL1 ≥ 0.01% IS ) fo r ≥ 2 years ,as d o cum en ted o n at leas t fo ur tes ts ,p erfo rm ed at leas t three m o n ths ap art. • Access to a reliable qPCR test with a sensitivity of detection at leas t M R 4.5 (B C R -A B L 1 ≥ 0.003 2 % IS ) and provides results within 2 weeks. • Monthly molecular monitoring for one year, then every 6 weeks for the second year, and every i 12 weeks thereafter (in d efin tel y) is recommended fo r p atien ts w ho rem ain in M M R (M R 3 ; BCR-ABL1 ≥ 0.1% IS) after discontinuation of TKI therapy. • Prompt resumption of TKI within 4 weeks of a loss of MMR with molecular monitoring every 4 weeks until MMRiis re-established, then every 12 weeks thereafter is reco m m en d ed in d efin tel y for pat ien t s who have reinitiated TKI therapy after a loss of MMR. For those who fail to achieve MMR after three months of TKI resumption, BCR-ABL1 kinase domain mutation testing should be performed, and monthly molecular s monitoring should be continued for another six months. • C o n s ultatio n w ith a C M L S p ecialty C en ter to review the ap p ro p riaten es s fo r T K I d is co n tin uatio n an d p o ten tial ris ks an d b en efit of treat me n t discontinuation, including TKI withdrawal syndrome. • Reporting of the following to a member of the NCCN CML panel is strongly a encouraged: A n y s ign ific n t adv ers e even t bel ieved to be rel at ed to treat me n t d is co n tin uatio n . Progression to accelerated or blast phase CML at any time. Failure to regain MMR after three months following treatment reinitiation. 1See full prescribing information for nilotinib: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/022068s026lbl.pdf Note:Formor einf orma ti on rega r dingtheca tegori es a nddef intio ns u s ed f o r th e NCCN E vid ence B lo ck s tm, see page EB-1. All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. Version 4.2018, 01/24/18 © National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Evidence BlocksTM, NCCN Guidelines® and this illustration may not be reproduced in any form without i the express written permission of NCCN®. CML-E 4 4/24/2018 Is Stopping TKI Realistic? 50% achieve MR4 or MR 4.5 50% restart TKI 70-80% of newly diagnosed patients with CML will need long term TKI therapy Atallah et al EHA iCMLf 2017 Conclusions • Most patients with chronic phase CML will do well with current therapy • Stopping TKIs is ready for prime time – A select group of patients – With proper monitoring • Multi-team approach is a key component to the success and safety of TFR 5
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