What is New in CML Jorge Cortes, MD Chief, CML and AML Sections Department of Leukemia MD Anderson Cancer Center Houston, Texas

What is New in CML 2018 Jorge Cortes, MD Chief, CML and AML Sections Department of Leukemia MD Anderson Cancer Center Houston, Texas

Final Results CML-IV Molecular Response with Imatinib 1538 pts newly diagnosed CML-CP randomized to imatinib 400, imatinib 800, imatinib + IFN, imatinib + ara-c, or imatinib after IFN Median age 53 yrs, 12% HR EURO score 62% still on imatinib at final evaluation 92% 89% 81% 72% 59% Patients at risk Kalmanti L, et al. Leukemia. 2015;29(5):1123-1132. Hehlmann R, et al. Blood. 2017;130(suppl): Abstract 897.

Final Results CML-IV Overall Survival By Treatment Arm By Response @ 6 mo Predictors of survival (MVA): EURO score (low v high), setting (academic v community or office-based), comorbidity score, smoking (non v any), ACA at diagnosis (no major route v major route) Hehlmann R, et al. Blood. 2017;130(suppl): Abstract 897.

BFORE: First-line Bosutinib vs Imatinib in CML Molecular Response at 12 and 18 Months Randomized frontline pivotal study of bosutinib 400 mg (n=268) v imatinib 400 mg (n=268) Stratified by Sokal and geographic area Molecular response (%) 60 50 40 30 20 10 0 P=0.01 46.6 36.2 P=0.02 56.7 46.6 P=0.02 47.2 36.9 P=0.04 56.9 47.7 P=0.01 Month: 12 18 12 18 12 18 12 18 20.7 12.0 P=0.11 24.4 Bosutinib ITT: n=268 mitt: n=246 12 months 18 months 18.3 P=0.02 MMR (ITT) MMR (mitt) MR 4 (mitt) MR 4.5 (mitt) MR 4 (ITT), % Bosutinib Imatinib P 12 mo 20.5 11.6 <0.01 18 mo 24.6 18.3 0.08 8.1 Imatinib ITT: n=268 mitt: n=241 12 months 18 months 3.3 P=0.11 11.4 7.1 MR 4.5 (ITT), % Bosutinib Imatinib P 12 mo 7.5 3.0 0.02 18 mo 11.9 8.2 0.16 Gambacorti-Passerini C, et al. Blood. 2017;130(suppl): Abstract 896.

BFORE: First-line Bosutinib vs Imatinib in CML EFS and OS at 18 Months (mitt Population) Bosutinib (n=246) Imatinib (n=241) Patients with on-treatment transformation to AP/BP, n (%)* 6 (2.4) 7 (2.9) Cumulative incidence of ontreatment progression or 4.5 death, % (95% CI) (2.4 7.6) 6.7 (4.0 10.3) Overall survival, % (95% CI) 99.6 (97.1 99.9) 96.6 (93.4 98.3) * 6 pts (n=3 each arm) met AP criteria within 2 wks based on basophils; all 6 continued on study drug with 4 achieving MMR and 1 CCyR. Includes death, transformation to AP/BP, doubling of WBC without CHR, loss of CCyR, or loss of CHR. Gambacorti-Passerini C, et al. Blood. 2017;130(suppl): Abstract 896.

BFORE: First-line Bosutinib vs Imatinib in CML Grade 3 TEAEs* (Safety Population) System organ class preferred term Blood and lymphatic system disorders, n (%) Thrombocytopenia Neutropenia Anemia Leukopenia Leukocytosis Bosutinib (n=268) 48 (17.9) 37 (13.8) 19 (7.1) 10 (3.7) 3 (1.1) 2 (0.7) Imatinib (n=265) 58 (21.9) 16 (6.0) 34 (12.8) 13 (4.9) 10 (3.8) 7 (2.6) Gastrointestinal disorders, n (%) Diarrhea Laboratory investigations, n (%) Alanine aminotransferase increased Lipase increased Aspartate aminotransferase increased Metabolism and nutrition disorders, n (%) Hypophosphatemia 31 (11.6) 22 (8.2) 91 (34.0) 56 (20.9) 28 (10.4) 27 (10.1) 14 (5.2) 3 (1.1) 9 (3.4) 2 (0.8) 35 (13.2) 4 (1.5) 12 (4.5) 5 (1.9) 12 (4.5) 9 (3.4) * Select all-causality adverse events occurring in 2% pts in either treatment arm. Medical Dictionary for Regulatory Activities (MEDRA) v20.0; pts may report >1 AE at the level of preferred term within each system organ class. Gambacorti-Passerini C, et al. Blood. 2017;130(suppl): Abstract 896.

Matched Cohort Study of Generic v Brand Imatinib 732 pts frontline imatinib since 2001 (prospective data 2009) Endpoints: Primary: switch to another TKI; secondary: discontinuation Probability of persistence 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 Switch Branded 88.2 (82.8-93.6) Generic 72.8 (63.9-81.6) Log-rank P = 0.03 Adjusted HR = 2.13 (1.18-3.86) Probability of persistence 1.00 0.98 0.96 0.94 0.92 0.90 0.88 0.86 Discontinuation Branded Generic Log-rank P = 0.12 Adjusted HR = 2.85 (0.88-9.23) 92.0 (83.1-100.0) 85.3 (77.2-93.5) 0.0 0 10 20 30 40 50 Duration of follow-up (months) 0.84 0 10 20 30 40 Duration of follow-up (months) Switched from generic: 36/167 (22%); toxicity 25 (15%), suboptimal response 12 (7%) To branded 64%, dasatinib 28%, nilotinib 8% Switched from branded: 17/167 (10%); toxicity 9 (5%), suboptimal response 9 (5%) To dasatinib 76%, nilotinib 18%, bosutinib 6% Discontinued generic: 13/167 (8%); 9 for susmr5 (4 re-treated) Discontinued branded: 4/167 (2%); 2 for susmr5 (1 re-treated) 7 Klil-Drori A, et al. Blood. 2017;130(suppl): abstract 315.

Generic Imatinib in US 27 pts switched to generic imatinib (19 frontline, 8 post-ifn) Median time on innovator 11.9 yrs (2.5-16.7); all MMR, 20 MR4.5 After switch: CBC, SMA every 1 mo, PCR every 3 mo BCR-ABL PCR (IS) on innovator imatinib before the switch. BCR-ABL PCR (IS) on generic imatinib at last follow-up. Sustained complete molecular response. Aboudalle I, et al. Blood. 2017;130(suppl): Abstract 2906.

Total N = 27 Generic Imatinib in US Number (Percent) Innovator Imatinib Generic Imatinib Non hematologic AE (any grade) Edema 17 (63) 7 (26) Muscle cramps 15 (56) 8 (30) Diarrhea 11 (41) 5 (19) Fatigue 9 (33) 5 (19) Nausea 9 (33) 7 (26) Rash 4 (15) 0 (0) Weight gain 3 (11) 0 (0) Increased Creatinine 2 (7) 3 (11) Increased Bilirubin 2 (7) 0 (0) Increased LDH 2 (7) 2 (7) Insomnia 1 (4) 2 (7) Pruritus 1 (4) 0 (0) Hematologic AE (any grade) Anemia 9 (33) 2 (7) Thrombocytopenia 2 (7) 0 (0) Neutropenia 1 (4) 2 (7) 5 pts discontinued: 2 elective, 2 due to diarrhea (back to innovator), 1 due to renal toxicity (pre-existing, changed to dasatinib) 1 dose reduction (fatigue, diarrhea), 1 interruption (edema) No deaths or transformations (median f/u 7 mo [3-28]) Aboudalle I, et al. Blood. 2017;130(suppl): Abstract 2906.

n= PETAL: Nilotinib ± PEG-IFN Overall molecular response rates 200 pts newly diagnosed CML randomized to nilotinib 300 mg BID ± PEG-IFN (lead in 30 mcg/wk x1 mo, then add nilotinib + PEG-IFN 30 mcg/wk x2, then 45 mcg/wk x 2yr) 68.5 78 87 72 p=0.019 p=0.91 p=0.49 35 52 33 37 17 12 30.5 34 91 91 72 63 63 Predictors MR4.5 at 12 mo: female, Sokal low + intermediate, PEG-IFN cumulative 540 mcg (by 9 mo) 47 49 37 27 29 36 24 8 Nicolini F, et al. Blood. 2017;130(suppl): Abstract 899.

Lower-Dose Dasatinib Newly Diagnosed CML-CP 56 pts, median age 46 y (range, 22-80 y) Dasatinib 50 mg/d Response, n/n (%) 3 mo 6 mo 9 mo 12 mo BCR-ABL/ABL <10% IS 40/43 (93) 26/27 (96) 19/20 (95) 9/9 (100) CCyR 23/43 (51) 25/27 (93) 18/20 (90) 9/9 (100) MMR 12/43 (28) 19/27 (70) 16/20 (80) 9/9/ (100) MR4 1/43 (2) 8/27 (30) 14/20 (70) 9/9 (100) MR4.5 0/43 (0) 2/27 (7) 4/20 (20) 3/9 (33) Treatment interruption 14 (25); no dose modifications Naqvi K, et al. Blood. 2017;130(suppl): Abstract 1611.

Radotinib v Imatinib in Frontline CML Molecular Response 2 nd generation TKI approved in Korea Active against BCR-ABL and most mutants (not T315I) MMR MR4.5 By 36 months Radotinib 300mg BID Patients with MMR, % By 12 months 52%, P =.0044 Δ 22% 30% By 24 months 66%, P =.0536 Δ 15% 51% 75%, P =.0076 Δ 21% 54% Patients with MR 4.5, % Imatinib 400mg QD By 24 months 33%, P =.1331 By 12 months Δ 11% 15%, P =.2012 22% By 36 months 43%, P =.0538 Δ 13% 28% Δ 6% 9% Months since randomization Months since randomization 3 mo EMR: radotinib 86%, imatinib 71% 6 mo EMR: radotinib 77%, imatinib 58% Do YR, et al. Blood. 2017;130(suppl): Abstract 317.

Radotinib v Imatinib in Frontline CML Cardiovascular Events (All Grades) Adverse Event, n (%) Radotinib 300mg BID (n=79) Imatinib 400mg QD (n=81) Ischemic Heart Disease 0 (0) 0 (0) Acute MI 1 (1) 0 (0) Unstable Angina 1 (1) 0 (0) Angina Pectoris 2 (3) 0 (0) PAOD a 0 (0) 0 (0) a PAOD: Peripheral Arterial Occlusive Disease Regardless of causalities Do YR, et al. Blood. 2017;130(suppl): Abstract 317.

Frontline Imatinib in Children and Adolescents with CML 148 pts, mean age 12.3 y (range, 1.25-17.9 y) Imatinib 300 mg/m 2 (max dose 400 mg) Response At time (mo) Percentage CCyR 12 63 MMR 18 59 MR4 18 22 MR4.5 18 16 Failure* 27 PFS 18 97 TFR 2/7 pts * Inadequate response 12%, relapse 6%, intolerance 6%, poor adherence 1%, unknown 2% Median growth impairment: ~-0.25 SD/y Suttorp M, et al. Blood. 2017;130(suppl): Abstract 898.

2 nd -line Bosutinib in CP CML: 8-Year Update Efficacy Summary Phase 1/2 bosutinib 500 mg/d 284 pts: imatinib resistant 195, intolerant 89 Median age 53 y (18-91 y), prior IFN 35%, SCT 3% n (%) Imatinibresistant Imatinibintolerant Total Cytogenetic responses Evaluable patients 182 80 262 MCyR 110 (60) 48 (60) 158 (60) CCyR 89 (49) 41 (51) 130 (50) Survival outcomes Cumulative incidence of progression or death 57 (29) 10 (11) 67 (24) Deaths 40 (21) 11 (12) 51 (18) New toxicities year 5-8: renal (14%), diarrhea 1 (0.8%), liver 7 (6%) Vascular events (per 100 pt/year): cardiovascular 0.008, cerebrovascular 0.005, peripheral vascular 0.001 Brümmendorf TH, et al. Blood. 2017;130(suppl): Abstract 900.

2 nd -line Bosutinib in CP CML: 8-Year Update MCyR Duration & Overall Survival MCyR Duration Overall Survival 1.0 1.0 0.9 0.9 Probability of retaining response 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Evaluable patients n (%) Sustained MCyR* at Year 8, % (95% CI) Imatinib-resistant (n=182) 110 (60.4) 60.4 (49.1 70.0) Imatinib-intolerant (n=80) 48 (60.0) 74.5 (55.5 86.3) Total (n=262) 158 (60.3) 64.5 (55.0 72.5) Probability of overall survival 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Patients Deaths n (%) OS at Year 8, % (95% CI) Imatinib-resistant (n=195) 40 (20.5) 74.5 (67.1 81.9) Imatinib-intolerant (n=89) 11 (12.4) 87.2 (78.6 95.8) Total (N=284) 51 (18.0) 78.5 (72.7 84.3) 0 24 48 72 96 120 144 168 192 216 240 264 288 312 336 360 384 408 432 456 480 504 528 552 576 600 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108 114 Duration of MCyR, weeks Months No deaths assessed as treatment-related; 6 new deaths after the 5-year F/U * Includes responses newly attained or maintained from baseline; 29.7% of patients had loss of response, PD, or death (imatinib-resistant: 34.5%; imatinib-intolerant: 18.8%). Received 1 dose of bosutinib and had a valid baseline cytogenetic assessment. 13 deaths occurred within 30 days of the last bosutinib dose (imatinib-resistant patients: n=11; imatinib-intolerant patients: n=2). Most deaths were due to progressive disease (n=29 [10.2%]; imatinib-resistant patients: n=23 [11.8%]; imatinib-intolerant patients: n=6 [6.7%]) or AEs unrelated to study drug (n=16 [5.6%]; imatinib-resistant patients: n=14 [7.2%]; imatinib-intolerant patients: n=2 [2.2%]). Brümmendorf TH, et al. Blood. 2017;130(suppl): Abstract 900.

2 nd Line TKI in CML CP 621 pts treated with 2 nd TKI: dasatinib 55%, nilotinib 31%, bosutinib 6%, other (7%) 1 st TKI: imatinib (85%), ponatinib (7%), nilotinib (5%), dasatinib (3%) or bosutinib (<1%) Reason to switch: resistance 55%, intolerance 45% Median F/U: 50 mo (0.1-139 mo) Response: CCyR 50%; Best molecular: MMR 13%, MR4.5 38% MVA: specific TKI no impact in OS or TFS; nilotinib or other inferior EFS and FFS Chamoun K, et al. Blood. 2017;130(suppl): Abstract 1594.

2 nd Line TKI in CML CP MR4.5 Overall Survival N Events 342 72 195 44 39 10 44 9 Transformation-Free Survival Event-Free Survival N Events 342 61 195 58 39 16 44 9 N Events 342 24 195 17 39 9 44 3 Chamoun K, et al. Blood. 2017;130(suppl): Abstract 1594.

5-Year Outcome with Ponatinib in CML-CP by Prior TKI 270 pts CML-CP treated with ponatinib 45 mg/d post- TKI failure Median F/U 56.8 mo (0.1-73.1 mo) Percent 5-yr Probability MCyR MMR MR4.5 MCyR MMR PFS OS 1 TKI 79 58 32 75 NA 62 89 2 TKI 71 45 25 88 65 68 78 3 TKI 50 37 24 84 54 45 73 4 TKI 58 8 8 NA NA NA Hochhaus A, et al. Blood. 2017;130(suppl): Abstract 1617.

3 rd Line TKI in CML 185 pts treated with 3 rd TKI: nilotinib 36%, dasatinib 35%, ponatinib 12%, imatinib 10%, bosutinib 7% Median time from Dx: 58 mo (3 199 mo) 1 st TKI: intolerance 44%, resistance 67%; 2 nd TKI: intolerance 60%, resistance 49% Response % CCyR 38 MMR 41 MR4 33 MR4.5 29 MVA predictors of CCyR: ponatinib, Hgb, intolerance (same + nilotinib for MMR) Khan M, et al. Blood. 2017;130(suppl): Abstract 2882.

3 rd Line TKI in CML OS TFS EFS MVA for survival: ponatinib, bosutinib; age; female; intolerance (v resistance) Khan M, et al. Blood. 2017;130(suppl): Abstract 2882.

PF-114 3 rd Generation Inhibitor of Bcr-Abl 3 rd generation Abl inhibitor, structural analog of ponatinib Rationally designed to avoid inhibition of off-target kinases Orthotopic murine BaF3 cell model of T315I+ CML Ponatinib NSG Mice iv xenograft of human T315I Ph+ALL Turkina AG, et al. Blood. 2017;130(suppl): Abstract 895.

Phase 1 of PF-114 in CML Structural analog of ponatinib modified to avoid inhibition of key kinases 24 pts with CML any phase with failure to 2 TKI or with T315I CML Phase Chronic Accelerated Mutation N CHR MCyR % n * /N ** % n * /N *** T315I 9 40 2/5 80 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 Blast T315I 1 100 1/1 0 0/1 No DLT at doses up to 500 mg Main AE rash: 13 grade 2, 4 grade 3 (1 DLT) No cardiac events (54% high- to fatal-riak per European SCORE) 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 Turkina AG, et al. Blood. 2017;130(suppl): Abstract 895.

New TKI Under Development TKI Features Current status ABL-001 Allosteric inhibitor Completed phase 1, single agent and combination Pivotal phase 3 3 rd line v bosutinib started Radotinib 2 nd generation Approved in South Korea 1 st and 2 nd line Pending studies elsewhere PF-114 Ponatinib analog, not binding VEGFR Nearing MTD Starting phase 2 K0706 3 rd generation Phase 1 started

EURO-Ski: The Effect of Duration of TKI Treatment and MR4 755 pts with sustained MR4 for 1 yr Molecular relapse = loss MMR Overall MRFS 47% at 36 months Predictors of outcome: Sokal, depth of response, history of resistance, prior IFN, treatment duration, molecular response duration Duration of TKI Therapy Duration of MR4 Saussele S, et al. Blood. 2017;130(suppl): Abstract 313.

EURO-Ski: Probability of Molecular Relapse by Duration of TKI Treatment and Duration of MR4 Duration of MR4 TKI Treatment Duration Before MR4 4 years MR 4 duration: Probability = 0.53 (95%-CI: 0.48-0.58) 6 years MR 4 duration: Probability = 0.59 (95%-CI: 0.54-0.64) 0.2 years duration: Probability = 0.54 10.2 years duration: Probability = 0.62 absolute increase of probability of about 3% / year MR 4 duration: Odds ratio: 1.13 (95%-CI 1.04-1.23) relative increase of probability to stay in MMR about 0.86% / year TKI before MR 4 : Odds ratio: 1.04 (95%-CI: 0.93-1.15) TFR is mostly dependent on duration of response Duration of TKI independent of duration of response has minimal benefit as time on TKI prior to MR4 has minimal benefit Saussele S, et al. Blood. 2017;130(suppl): Abstract 313.

Outcome of CML Patients After TKI Discontinuation - MDACC Initial Report Updated Report 1.00 CMR before TKI discontinuation 64 months 75% 75% 65% Cumulative survival 0.75 0.50 0.25 < 64 months Rate of relapse 6% 15% p = 0.02 0% 0.00 0 10 20 30 40 Month to molecular relapse <24 24-48 48-72 72-96 96-120 >120 MR4.5 duration before discontinuation (months) Benjamini O, et al. Leuk Lymphoma. 2014;55(12):2879-2886. Chamoun K, et al. Blood. 2016;128(suppl): Abstract 1923.

DASFREE - Molecular Relapse-Free Survival 84 pts with sustained MR4.5 for 1 yr (confirmed in central lab) Relapse = loss of MMR Frontline 44%, subsequent 56% (resistant 53%, intolerant 38%) 100 Estimated survival Molecular Relapse-free Survival (%) 80 60 40 20 49% (38.0, 59.4) 95% confidence band Pts on 1 st -line dasatinib (n = 37) Pts on subsequent lines of dasatinib (n = 47) Resistant (n = 25) Intolerant (n = 18) MRFS, % (95% CI) 54 (38.0, 70.1) 45 (30.2, 58.7) 44 (24.5, 63.5) 50 (26.9, 73.1) 0 Patients at risk 0 4 8 12 16 20 24 28 32 36 Months Since Dasatinib Discontinuation 84 61 44 39 31 27 22 15 15 5 No patients lost CCyR or CHR, transformed or died All evaluable pts regained MMR a median of 1.9 mo after restarting dasatinib Factors associated with RFS: age (p = 0.04), 1 st line (p = 0.07) 8 withdrawal events Shah N, et al. Blood. 2017;130(suppl): Abstract 314.

Nilotinib Schedule Change to QD Observational study of nilotinib schedule change to QD: 71 pts to 450 mg QD 89%, 400 mg QD 9%, 300 mg QD 2% Loss of MMR not observed in pts with DMR* before change 2 pts with MMR only lost MMR spontaneously re-gained Most patients improved response after schedule change Survival without MMR loss 100% 80% 60% 40% 20% Survival without MMR loss by molecular response at baseline Molecular response category: MR3 only (n=10) MR4 only (detectable) (n=19) At least MR4.5 (detectable+ undetectable) (n=42) Logrank: 0.0017 0% 0 12 24 36 48 60 *DMR: deep molecular response Months since nilotinib dose reduction Proportion of patients % Molecular response after change 80% 60% 40% 20% 0% 14.5% 8.8% MR3 only 27.5% 20.6% MR4 only Month 0 Month 12 58% 70.6% At least MR4.5 Rea D, et al. Blood. 2017;130(suppl): Abstract 318.

2 nd -line Bosutinib in CP CML: 8-Year Update Cytogenetic Responses After Dose Reduction Imatinibresistant (n=195) Imatinibintolerant (n=89) Total (N=284) Patients reducing bosutinib to 400 mg QD, n 81 56 137 MCyR, % 1 st response following dose reduction 48 36 43 Response maintained after dose reduction 15 23 18 Response lost after dose reduction 3 4 3 CCyR, % 1 st response following dose reduction 40 29 35 Response maintained after dose reduction 14 21 17 Response lost after dose reduction 1 5 3 Brümmendorf TH, et al. Blood. 2017;130(suppl): Abstract 900.

Significance of Dose Adjustments of 2 nd Generation TKI in Frontline Therapy 98 pts treated with nilotinib 400mg BID (n=50) or dasatinib 50 mg BID or 100 mg QD (n=48) as initial therapy fro CML CP Dose reductions in 50 (51%) (nilotinib 42%, dasatinib 60%) Percentage Dose reduction No dose reduction MCyR 94 88 CCyR 92 88 2-yr FFS 72 83 2-yr OS 100 100 Santos FP, et al. Br J Haematol. 2010;150(3):303-312.

Management of Pregnancy and CML Assi R, et al. Blood. 2017;130(suppl): Abstract 2881.

Management of Pregnancy and CML 20 unplanned pregnancies Status at pregnancy: CHR 2, CCyR 3, MMR 6, MR4.5 9 Treatment during pregnancy: observation 18, hydroxyurea 1, leukapheresis 1 Pregnancy outcome: live birth 11, miscarriage 5, elective termination 3, ongoing 1 Response last F/U: MR4.5 10, MMR 7, CCyR 3 14 CML diagnosis during pregnancy Treatment: None 5, hydorxyurea 5, IFN 2, leukapheresis 1, TKI 1 (@ 3 rd trimester) Pregnancy outcomes: live birth 5, miscarriage 2, elective termination 1 Response: MR4.5 = 6, MMR = 7, 1 NR (had received IFN, nor response to dasatinib BP) 9 planned pregnancies (6 CMR pre-conception) 2 transcripts observation, 1 lost CHR hydrea dasatinib after delivery (MR4) Assi R, et al. Blood. 2017;130(suppl): Abstract 2881.

NGS for Mutations Analysis in CML 214 pts with failure (n=132) or warning (n=82) to TKI sequenced by Sanger and NGS 4 labs: concordance 81% (discordant samples with mutations <3%) Sanger: 42 (20%) with mutations NGS: 74 (36%) new mutations: 52 negative by Sanger, 24 additional mutations T315I 8, resistant to TKI (non-t315i) 43, unknown profile 25 Median mutation burden 11% (3-19%) 1-4 low-burden mutation per patient Compound mutations 2 pts (CML-BP) Soverini S, et al. Blood. 2017;130(suppl): Abstract 248.

Genetic Complexity of CML Integrative genomics: multiple mutations and fusions at diagnosis and BP BP: ABL1 mutations usually with other mutations Mutations frequently associated with progression (most commonly RUNX1, ASXL1, TET2, BCOR) Also identified in pts with CCA/Ph- Novel gene mutations: SETD1B, PTPR; novel fusions: MLL, RUNX1, IKZF1, MECOM) Branford S, et al. Blood. 2017;130(suppl): Abstract 251. Awad SA, et al. Blood. 2017;130(suppl): Abstract 250. Jain P, et al. Blood. 2017;130(suppl): Abstract 4172.

CML in 2018 Frontline therapy is good (and getting better, safer and cheaper?) 2 nd line options grossly equivalent; 3 rd line ponatinib better (new ones safer?) Dose reductions safe in most instances Treatment discontinuation feasible if done right (better to wait for long MR4.5) Minimal intervention during pregnancy CML more molecularly complex than we thought

Questions? jcortes@mdanderson.org 713-794-5783