DAVID S. SNYDER, M.D. - PDF Free Download

CML UPDATE 2019 DAVID S. SNYDER, M.D. MARCH 21,2019 Click to edit Master Presentation Date

Disclosures I do not have anything to disclose

2001 2016

Loss in expectation of life of patients with chronic myeloid leukemia in Sweden, over year of diagnosis, by age at diagnosis and sex. Hannah Bower et al. JCO 2016;34:2851-2857 2016 by American Society of Clinical Oncology

Number of Cases As Result of Treatment Success the Prevalence of CML Is Increasing Steadily 200000 180000 160000 140000 120000 100000 80000 60000 Incidence 4,700 per year Age-matched mortality ratio vs normal population = 1.50 10x greater steady state number of CML patients in US by 2050 40000 Accounts for increased US population to 410 million in 2050 20000 2000 2005 2010 2015 2020 2025 2030 2035 2040 2045 2050 CML = chronic myelogenous leukemia. Huang et al, 2012. Year

NCCN Guidelines Version 1.2019 Chronic Myeloid Leukemia NCCN Guidelines Index Table of Contents Discussion WORKUP CLINICAL PRESENTATION ADDITIONAL EVALUATION H&P, including spleen size by palpation (cm below costal margin) CBC with differential Chemistry profile Bone marrow a aspirate and biopsy for morphologic and cytogenetic evaluation Quantitative RT-PCR (qpcr) using International Scale (IS) for BCR- ABL1 (blood) Hepatitis panel (hepatitis B surface antigen [HBsAg], hepatitis B surface antibody [HBsAb], hepatitis B core antibody [anti-hbc], IgM anti-hbc, IgG anti-hbc) Ph positive or BCR- ABL1 positive Ph negative and BCR- ABL1 negative Chronic phase CML Advanced phase CML Accelerated phase b Blast phase b Evaluate for diseases other than CML (See NCCN Guidelines for Myeloproliferative Neoplasms) Determine risk score (See Risk Calculation Table CML-A) Additional testing Flow cytometry to determine cell lineage Mutational analysis HLA testing, if considering allogeneic HCT (See CML-6) See Primary Treatment (CML-2) See Primary Treatment (CML-4) a Bone marrow evaluation should be done for the initial workup, to provide morphologic review, and also to detect other chromosomal abnormalities in addition to Ph chromosome. Fluorescence in situ hybridization (FISH) can be used if cytogenetic evaluation is not possible. b See Definitions of Accelerated Phase and Blast Phase (CML-B). Version 1.2019, 08/01/18 National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. Note: 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. CML-6

NCCN Guidelines Version 1.2019 Chronic Myeloid Leukemia NCCN Guidelines Index Table of Contents Discussion CLINICAL PRESENTATION TREATMENT Advanced phase CML Treatment Considerations Disease progression to advanced phase while on TKI therapy has worse prognosis than presenting with advanced phase CML. Evaluate for allogeneic HCT Selection of TKI is based on prior therapy and/or BCR- ABL1 mutation profile. CNS involvement has been described in blast phase CML. Lumbar puncture and CNS prophylaxis is recommended for lymphoid blast phase. Accelerated phase b Blast phase b Lymphoid Clinical trial or TKI (CML-F) or k Omacetaxine (CML-F) Clinical trial or ALL-type induction chemotherapy + TKI (CML-F) (See NCCN Guidelines for Acute Lymphoblastic Leukemia) or TKI (CML-F) + steroids Allogeneic HCT l (CML-6) Allogeneic HCT (CML-6) Myeloid Clinical trial or AML-type induction chemotherapy + TKI (CML-F) (See NCCN Guidelines for Acute Myeloid Leukemia) or TKI (CML-F) Allogeneic HCT (CML-6) b See Definitions of Accelerated Phase and Blast Phase (CML-B). k Omacetaxine is a treatment option for patients with disease progression to accelerated phase CML. Omacetaxine is not a treatment option for patients who present with accelerated phase CML. l Patients who present with accelerated phase at diagnosis should be treated with a TKI, followed by evaluation for allogeneic HCT. Version 1.2019, 08/01/18 National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. Note: 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. CML-7

Why? Risk score calculation Predicts treatment response High and Intermediate Sokal risk NCCN guidelines suggest risk-based approach to TKI choice Predicts treatment free remission success Low Sokal risk Independent predictor of relapse with cessation Baseline Bcr-Abl transcript level @ 60 months 73% ( 95 %CI: 61-84) @ 60 months 47% ( 95 %CI: 34-62) Clarifies determination of early molecular response Patient-specific kinetics of transcript reduction P= 0.0076 Mahon et al, 2011.

EUTOS SCORE (7 X basophils %) + (4 X spleen size, cm below LCM) EUTOS score <=87 is low risk EUTOS score > 87 is high risk

PFS calculated for all 2010 patients with follow-up (log-rank test P =.0069). Joerg Hasford et al. Blood 2011;118:686-692 2011 by American Society of Hematology

Loss of CCyR (%) Value of MMR in Prolonging Remission 100 80 60 40 20 Response at 12 months n Loss of CCyR CCyR without MMR 95 24% CCyR plus MMR 32 3% P=0.04 Hughes et al, 2010; Cortes et al, 2005; Marin et al, 2008. 0 0 6 12 18 24 30 36 42 48 54 60 Months Since Start of Imatinib Therapy

% With MMR 13 3-Mo BCR-ABL Predicts MMR, PFS Similarly for Imatinib and Nilotinib Nilotinib (300 mg BID) Imatinib (400 mg QD) 100 90 80 70 60 1% > 1% 10% > 10% n = 120 n = 41 n = 89 n = 133 n = 24 n = 88 By 1 Year 76% 71% By 2 Years 89% 78% 67% 52% 3-y PFS 95.6% 95.3% 98.5% 96.5% 50 40 30 20 10 0 40% 31% 4% 2% 0 3 6 9 12 15 18 21 24 27 30 29% 20% 83.8% 82.9% 33 36 Time Since Randomization (Months) Note: greater numbers of early responders with frontline nilotinib Hochhaus A, et al. Haematologica. 2012;97(s1). Abstract 584.

Estimated 5-year (A, B) overall survival (OS) and (C, D) progression-free survival (PFS) by molecular response at 3 months for both treatment arms. Jorge E. Cortes et al. JCO 2016;34:2333-2340 2016 by American Society of Clinical Oncology

Summary >10% at 3 months is a poor risk category Not all patients with a BCR-ABL1 value >10% at 3 months have a high ongoing risk of treatment failure any reduction below 10% by 6 months may improve outcome the rate of reduction over the first 3 months is an important factor for outcome and could be considered in therapeutic decisions

NCCN Guidelines Version 1.2019 Chronic Myeloid Leukemia NCCN Guidelines Index Table of Contents Discussion EARLY TREATMENT RESPONSE MILESTONES c,f BCR-ABL1 (IS) 3 months 6 months 12 months g >15 months >10% h YELLOW RED >1% 10% GREEN YELLOW RED 1% GREEN COLOR CONCERN CLINICAL CONSIDERATIONS SECOND-LINE TREATMENT RED TKI-resistant disease Evaluate patient compliance and drug interactions Consider mutational analysis YELLOW Possible TKI resistance Evaluate patient compliance and drug interactions Consider mutational analysis Consider bone marrow cytogenetic analysis to assess for MCyR at 3 mo or CCyR at 12 mo Switch to alternate TKI (CML-5) and evaluate for allogeneic HCT (CML-6) Switch to alternate TKI (CML-5) or Continue same TKI (other than imatinib) (CML- F) i or Dose escalation of imatinib (to a max of 800 mg) and Consider evaluation for allogeneic HCT (CML-6) GREEN TKI-sensitive disease Monitor response (CML-F) and side effects Continue same TKI (CML-F) j csee Monitoring Response to TKI Therapy and Mutational Analysis (CML-C). f See Criteria for Hematologic, Cytogenetic, and Molecular Response and Relapse (CML-D). g BCR-ABL1 0.1% at 12 months is associated with a very low probability of subsequent disease progression and a high likelihood of achieving a subsequent MR4.0, which may facilitate discontinuation of TKI therapy. h Patients with BCR-ABL1 only slightly >10% at 3 months and/or with a steep decline from baseline may achieve <10% at 6 months and have generally favorable outcomes. Therefore, it is important to interpret the value at 3 months in this context before making drastic changes to the treatment strategy. i Achievement of response milestones must be interpreted within the clinical context. Patients with more than 50% reduction compared to baseline or minimally above the 10% cutoff can continue the same dose of dasatinib, nilotinib, or bosutinib for another 3 months. Continuation of imatinib 400 mg is not recommended. j Discontinuation of TKI with careful monitoring is feasible in selected patients. See Discontinuation of TKI Therapy (CML-E). Version 1.2019, 08/01/18 National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. Note: 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. CML-16

NCCN Guidelines Version 1.2019 Chronic Myeloid Leukemia NCCN Guidelines Index Table of Contents Discussion MONITORING RESPONSE TO TKI THERAPY AND MUTATIONAL ANALYSIS Test Bone marrow cytogeneti cs 1 qpcr using IS BCR-ABL kinase domain mutation analysis Recommendation At diagnosis Failure to reach response milestones Any sign of loss of response (defined as hematologic or cytogenetic relapse) At diagnosis Every 3 months after initiating treatment. After BCR-ABL1 (IS) 1% (>0.1% 1%) has been achieved, every 3 months for 2 years and every 3 6 months thereafter If there is 1-log increase in BCR-ABL1 transcript levels with MMR, qpcr should be repeated in 1 3 months Chronic phase Failure to reach response milestones Any sign of loss of response (defined as hematologic or cytogenetic relapse) 1-log increase in BCR-ABL1 transcript levels and loss of MMR Disease progression to accelerated or blast phase 1 FISH has been inadequately studied for monitoring response to treatment. Version 1.2019, 08/01/18 National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. Note: 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. CML-C

FIRST LINE THERAPY Click to edit Master Presentation Date

NCCN Guidelines Version 1.2019 Chronic Myeloid Leukemia NCCN Guidelines Index Table of Contents Discussion CLINICAL PRESENTATION PRIMARY TREATMENT Chronic phase CML Treatment Considerations: Patient comorbidities and drug toxicities Monitor response c Evaluate patient compliance and drug interactions Early toxicity monitoring Low-risk score (See Risk Calculation Table CML-A) Intermediate- or highrisk score (See Risk Calculation Table CML-A) First-generation TKI (Imatinib or generic imatinib 400 mg QD) (category 1) or Second-generation TKI (Bosutinib 400 mg QD [category 1] or Dasatinib 100 mg QD [category 1] or Nilotinib 300 mg BID [category 1]) or Clinical trial Second-generation TKI (Bosutinib 400 mg QD [category 1] d or Dasatinib 100 mg QD [category 1] d or Nilotinib 300 mg BID [category 1] d) or First-generation TKI (Imatinib or generic imatinib 400 mg QD) e or Clinical trial See Response Milestones and Treatment Options (CML-3) c See Response Milestones and Treatment Options (CML-3) c csee Monitoring Response to TKI Therapy and Mutational Analysis (CML-C). dbased on long-term follow-up data from the DASISION and ENESTnd trials and preliminary data from the BFORE trial, second-generation TKIs (dasatinib, nilotinib, or bosutinib) are preferred for patients with an intermediate- or high-risk Sokal or Hasford score, especially for young women whose goal is to achieve a deep and rapid molecular response and eventual drug discontinuation of TKI therapy for fertility purposes. e Imatinib may be preferred for older patients with comorbidities such as cardiovascular disease. Version 1.2019, 08/01/18 National Comprehensive Cancer Network, Inc. 2018, All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN. Note: 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. CML-20

What Is the Standard? Comparative Results: Imatinib 400/600,Nilotinib, Dasatinib IRIS (IM400) IM400 ENEST/D ASISION TIDEL I (IM600) TIDEL II (IM600) SPIRIT FRANCE (IM600) ENESTnd (NIL) DASISION (DAS) >10% at 3 mos --- 33%/36% 24% 12% --- 9% 16% CCyR at 12mos 69% 65%/73% 88% 87% a 65% 80% 85% MMR at 12mos 40% 27%/28% 47% 64% 49% 55% 46% MMR at 24 mos 55% 44%/46% 73% 73% 53% 71% 64% MR4.5 at 12mos --- 4%/--- 18% b 19% 22% b 11% 5% MR4.5 at 24mos --- 9%/8% --- 34% 26% b 25% 17% OS at 3 yrs 92% 94%/93% --- 96% --- 95% 94% a Inferred from MR2.0; b MR4.0 rather than MR4.5. Druker et al, 2006; Kantarjian et al, 2010; Kantarjian, Shah et al, 2012; Hughes et al, 2008; Yeung et al, 2015; Preudhomme et al, 2010.

Second Generation TKIs Have Improved Response But Not Changed Overall Survival Over Imatinib Response Landmarks Complete cytogenetic response at 12 mos Major molecular response at 12 mos Major molecular response at 60 mos Complete molecular response at 60 mos Overall survival at 60 mos ENESTnd DASISION Imatinib Nilotinib Gain Imatinib Dasatinib Gain 65% 80% +15% 73% 85% +12% 27% 55% +28% 28% 46% +18% 60% 77% +17% 64% 76% +12% 31% 54% +23% 33% 42% +9% 91.7% 93.7% +2% 90% 91% +1% Δ Green Indicates Statistically Significant Difference Red Indicates Nonsignificant Difference Saglio et al, 2010; Kantarjian et al, 2010; Kantarjian, Shah et al, 2012; Larson et al, 2013; Hochhaus et al, 2013.

BCR-ABL Mutations: 3-Year Exploratory Analysis Dasatinib 100 mg QD (n=259) DASISION 4-Year Fol Imatinib 400 mg QD (n=260) Patients with mutations detected 17 18 Clinically relevant on-treatment events, n a No MMR within 12 months 12 16 No cccyr within 12 months 8 12 Loss of CCyR 6 4 5-fold BCR-ABL increase with loss of MMR 2 1 Tested at discontinuation 12 months 3 2 Mutations detected (n) F317I/L (3) V299L (3) G250E (1) T315I (11) M244V (1) G250E (3) D276G (1) E355G (2) L387M (1) E450G (1) L248V (1) E255K/V (4) M351T (3) F359C/I/V (5) H396P (1) Y253H (1) Three additional patients in the imatinib arm (and no additional patients in the dasatinib arm) had mutations in the 4- year per-protocol analysis: G250E, M244V, and F317L/H396R Includes 7 patients with 2 mutations: 1 dasatinib patient (V299L/F317I) and 6 imatinib patients (M351T/F359V, E255V/E450G, L248V/E355G, E255K/M351T, E255V/Y253H, D276G/F359C) a Patients may have had multiple events.

RESISTANCE AND 2 ND /3 RD LINE THERAPY Click to edit Master Presentation Date

Second Generation TKIs, CML Chronic Phase, After Imatinib: Similar Benefits Months follow-up >24 Complete Hematologic Response Dasatinib Bosutinib Nilotinib Median of 24 >24 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, 2010; Kantarjian, Giles et al, 2011; Cortes et al, 2011.

Mutations: When to Look Both the European LeukemiaNet (ELN) and National Comprehensive Cancer Network recommend ABL kinase domain mutational analysis under certain circumstances: Soverini et al, 2011; NCCN, 2016. Recommendations on When to Perform Mutational Analysis ELN At diagnosis - Only in advanced phase or blast crisis patients During first-line imatinib therapy - In case of failure - In case of an increase in BCR-ABL transcript levels leading to loss of major molecular response - In any other case of suboptimal response During second-line dasatinib or nilotinib therapy - In case of hematologic or cytogenetic failure NCCN BCR-ABL transcript levels >10% by qpcr IS or less than partial cytogenetic response at 3 months Less than complete cytogenetic response at 12 or 18 months Any sign of loss of response - Defined as hematologic or cytogenetic relapse or 1 log increase in BCR-ABL transcript levels and loss of major molecular response Disease progression to advanced phase

Iceberg Analogy #2: Resistance May Be More Complex Than We Think Old sequencing (Sanger sequencing): lower detection limit, 20% Y253H F359V New sequencing techniques, like ultra deep sequencing: lower detection limit, 1% T315I + Y253H T315I L248R Soverini et al 2013.

BCR-ABL1 Kinase Domain (KD) Mutations Choice of TKI Tyrosine-kinase After Resistance inhibitors (TKIs) are the mainstay of the treatment of CML BCR-ABL1 KD mutations are the most frequently identified mechanism of acquired TKI resistance 1 BCR-ABL1 mutation testing by conventional Sanger sequencing is recommended for patients with progression, failure and warning 2 1 Clin Cancer Res. 2006; 12(24):7374-9. 2 Blood. 2013;121(3):489-498. 55 th American Society of Hematology Annual Meeting December 7-10, 2013 New Orleans, LA 1

Resistance to TKIs and Compound Mutations Hard to differentiate polyclonal mutations (2 different clones) From compound mutations (>1 mutation in the same clone) Zabriskie et al, 2014. That may be challenging to treat

Simona Soverini et al. Blood 2018;132:789 2018 by American Society of Hematology

CML BCR ABL1 Despite a common initiating genetic lesion, CML is a heterogeneous disease and a proportion of patients fail therapy We used next-generation sequencing to 1. Determine whether mutations in other genes are present at diagnosis in some patients that may cooperate with BCR-ABL1 to drive primary drug resistance or modify response 2. To assess additional genomic lesions at disease progression Susan Branford et al, ASH 2017

% Frequency of relevant SNVs/indels/fusions in genes recurrently mutated in patients with additional variants 80 60 40 58% 47% 35% Diagnosis Acquired at BC Missense Fs/Stop/Splice Fusion Exon deletion 20 0 24% 20% 14% 6% 6% 4% 4% 4% 4% Susan Branford et al, ASH 2017

Presence of mutation in genes associated with epigenetic regulation confer poor long-term TKI response. TaeHyung Kim et al. Blood 2017;129:38-47 2017 by American Society of Hematology

Ponatinib After Second Generation TKI Failure In a cross-study comparison, ponatinib consistently achieved higher complete cytogenetic response rates after 2nd generation TKI failure Lipton et al, 2013.

Jorge E. Cortes et al. Blood 2018;132:393-404 2018 by American Society of Hematology

Omacetaxine Conclusions Omacetaxine is a first-in-class protein synthesis inhibitor with modest activity in highly pretreated CP-CML and accelerated phase patients, including those with the BCR-ABL T315I mutation Response duration appears to be modest Grade 3/4 myelosuppression is common Non-hematologic grade 3/4 toxicities are uncommon Omacetaxine was approved by the US FDA in October 2012 for the treatment of imatinib-resistant chronic and accelerated phase CML

EARLY AND LATE COMPLICATIONS Click to edit Master Presentation Date

The Spectrum of CML TKI Toxicities Ponatinib Vascular adverse events Hypertension Pancreatic enzyme elevation Rash Nilotinib Vascular adverse events Hyperglycemia, Lipids Pancreatic enzyme elevation Indirect hyperbilirubinemia Imatinib Edema/fluid retention Myalgias Hypophosphatemia GI effects (diarrhea, nausea)?renal changes Myelosupression Transaminase Electrolyte Δ QT prolongation Dasatinib Bosutinib Diarrhea/nausea Transaminitis?Renal effects Pleural/pericardial effusion Pulmonary arterial hypertension Bleeding risk NCCN, 2016.

Exposure-adjusted yearly incidence rates for newly occurring arterial occlusive events and median dose intensity by year. Jorge E. Cortes et al. Blood 2018;132:393-404 2018 by American Society of Hematology

Estimated Probability Ponatinib Phase II Study (PACE) Multivariate Analysis: Arterial Thrombotic AEs 0.3 0.2 0.1 0.0 fit & 95% CI 15 30 45 Dose Intensity (mg/day) Factors significantly associated with arterial thrombotic AEs: Older age (P<0.0001) History of diabetes (P=0.0003) History of ischemia (P=0.0087) Higher dose intensity to time of first event (P=0.0009) Each 15 mg/d reduction in dose intensity results in a predicted reduction of ~40% in the risk of an arterial thrombotic event Cortes, Kim et al, 2013.

Risk Mitigation Strategies 1. ASA 81 mg a day; statins? 2. Dose reduction: at start? After MMR? 3. Control traditional risk factors

ATE with TKI in CML-CP Multivariate Analysis Variables IR 95% CI For IR P value Age 1.04 1.00 1.07 0.023 TKI Imatinib Nilotinib 2.77 1.20 6.42 0.017 Ponatinib 6.57 1.81 23.78 0.004 Dasatinib 3.58 1.40 9.16 0.008 Male 1.35 0.63 2.90 0.445 Race (white) 1.19 0.43 3.29 0.744 Diabetes 3.03 1.36 6.74 0.007 Coronary artery disease 2.09 0.88 5.09 0.104 Hypertension 1.19 0.54 2.62 0.658 Dyslipidemia 1.39 0.63 3.08 0.416

ATE with TKI in CML-CP Conclusion ATE occur relatively frequently during therapy with TKI Incidence increases with time of exposure Higher incidence with 2 nd and 3 rd generation TKI compared to imatinib (ponatinib > nilotinib/dasatinib > imatinib) Older age and history of diabetes increase risk Close monitoring and management of co-morbidities required during treatment Occurrence with all TKI suggests possible association with abl inhibition

Algorithm for determining the clinical management of low- and high-risk patients with CML treated with TKIs. Mary C. Barber et al. Hematology 2017;2017:110-114 2017 by American Society of Hematology

TKI DISCONTINUATION AND TREATMENT FREE REMISSION (TFR) Click to edit Master Presentation Date

REASONS TO DISCONTINUE: 1. ONGOING TOXICITY- FATIGUE, ARTHRALGIAS, GI UPSET, ETC. 2. FINANCIAL TOXICITY 3. FEMALE PATIENT AND PREGNANCY Click to edit Master Presentation Date

EURO-SKI: Adverse events musculoskeletal symptoms A TKI withdrawal syndrome consisting of new, mostly transient, musculoskeletal pain or discomfort has been described in EUROSKI patients and other cessation trials (Richter et al JCO 2014 Mori et al 2015, Am J Hematology 2015; Lee et al, Haematologica 2016). Grade 1-2 % Grade 3 % TOTAL % Musculoskeletal symptoms** 226 29.7 9 1.2 235 30.9 ** musculoskeletal pain, bone and/or joint pain, arthralgia, muscle pain, myalgia, joint stiffness, lumbalgia, articular pain, muscular pain, neck pain, arthromyalgia, pain both arms, pain legs.

Percent CMR 4.5 Paradise Lost, Regained? Cumulative incidence of regained MR4.5 in A-STIM retreated patients after loss of MMR 100 Percent MR 4.5 80 60 40 20 With >500 patients reported and very large numbers under investigation, single case of transformation resulting from TFR trial 0 0 12 24 36 Months Median time to regain deep molecular remission: 7.3 mo One patient with CML >15 yr experienced lymphoid blast crisis 8.5 mo from regained MMR after restarting imatinib Rousselot et al, 2014.

Molecular profile of 15 patients at our institution attempting and failing TFR. (A) Molecular relapse after TKI cessation. Naranie Shanmuganathan, and Timothy P. Hughes Blood 2018;132:2125-2133 2018 by American Society of Hematology

Cumulative incidence of molecular relapses At 60 months 61% ( 95% CI: 52-70) Cumulative incidence function, accounting for competing events (death in CMR without any relapse n = 1*) *1 case in CMR after 9 months of imatinib cessation (due to myocardial infarction)

Molecular Relapse-free Survival (%) Molecular Relapse-free Survival 100 80 Molecular Relapse-free Survival in All Enrolled Patients (N = 84) Estimated survival 95% confidence band MRFS, % (95% CI) 60 49% (38.0, 59.4) 40 20 0 0 4 8 12 16 20 24 28 32 36 Patients at risk Months Since Dasatinib Discontinuation 84 61 44 39 31 27 22 15 15 5 Patients on first-line dasatinib (n = 37) 54 (38.0, 70.1) Patients on subsequent lines of dasatinib (n = 47) Resistant (n = 25) Intolerant (n = 18) 45 (30.2, 58.7) 44 (24.5, 63.5) 50 (26.9, 73.1) No patients lost CCyR or CHR; no transformation events or deaths were observed CI = confidence interval; CCyR = complete cytogenetic response; CHR = complete hematologic response; MMR = major molecular response; MRFS = molecular relapse-free survival. 57

Conclusion EURO-SKI outlines important preconditions which can be employed as guidance for stopping criteria. Best cut-off was defined by 3.1 years for MR 4 duration and 5.8 years for total imatinib-treatment duration. Apart from the two cut-offs, an almost linear increase in TFR probability per additional year on treatment / in MR 4 for patients treated first-line with imatinib could be demonstrated and validated! MR 4 duration was most important (relative increase of probability of about 16% / year). Time on TKI without MR 4 was hardly important (relative increase of probability to stay in MMR about 0.86% / year).

Treatment free remission with first and second generation tyrosine kinase inhibitors Treatment free remission with first and second generation tyrosine kinase inhibitors, First published: 05 November 2018, DOI: (10.1002/ajh.25342)

Survival without MMR loss Cumulative incidence of MMR loss MMR stability after nilotinib dose reduction and once daily dosing 2 patients lost MMR 4 and 6 months after nilotinib dose reduction QD Cumulative incidence of MMR loss by 12 months was 9.7% (95% CI: 88.%-99.3) Survival without MMR loss was 97.2% at 12 months Survival without MMR loss Cumulative incidence of MMR loss 100% 100% 80% 80% 60% 60% 40% 40% 20% At 12 months: 97.2% (5% CI: 93.3%-100%) 20% By 12 months: 9.7% (95% CI: 88.%-99.3) 0% 0 12 24 36 48 60 Months since nilotinib dose reduction 0% 0 12 24 36 48 60 72 Months since nilotinib dose reduction

Conclusion (2) New CML management proposal for clinical practice Lower dose TKI Full dose TKI Lower dose TKI No DMR: Lifelong low-dose therapy CML Optimal response Induction Optimal response Consolidation Long-lasting DMR: TFR attempt Stop TKI

FUTURE AND CURRENT STATE Click to edit Master Presentation Date

4th Generation TKI ABL001 Allosterically Inhibits BCR-ABL1 Kinase Activity BCR SH3 SH3 t(9;22) SH2 Kinase SH2 BCR ABL001 Kinase 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 Ottman et al, 2015.

Mechanisms of persistence and approaches to targeting CML leukemia stem cells. Ravi Bhatia Hematology 2017;2017:115-120 2017 by American Society of Hematology

2018 by American Society of Hematology David T Yeung et al. Blood 2018;132:459