BMS Satellite Symposium

Transcription

1 ICKSH 2018 BMS Satellite Symposium Emerging Trends in CML Management

2 CHAIRMAN The Head of Catholic Hematology Hospital The Director of the Catholic Leukemia Research Institute at the Catholic University of Korea Prof. Kim's research interests focus on the biology and treatment of chronic myeloid leukemia. He is the author or co-author of more than 200 peer-reviewed publications in prestigious journals. His work has been carried out by grants from numerous governments and pharmaceutic Dong-Wook Kim MD Ph.D

3 SPEAKER Associate Professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center Section Chief, Acute Lymphocytic Leukemia, Department of Leukemia, The University of Texas MD Anderson Cancer Center Elias Jabbour MD Dr. Jabbour is actively involved in research in both acute and chronic forms of leukemia. He was actively involved in clinical trials that lead to the approval of several drugs in chronic myeloid leukemia (CML) and myelodysplastic syndromes. His research on resistance to imatinib and mutations of the protein kinase domain were presented in several international; meetings and published in peer-reviewed journals. He is also developing tailored therapies to CML.

4 Emerging Trends in CML Management Elias Jabbour, M.D. Seoul

5 CML. The Past and Today Parameter Before 2000 Today Course Fatal Indolent Prognosis Poor Excellent 10-yr survival 10% 84-90% Frontline Rx Allo SCT; IFN- Imatinib; dasatinib; nilotinib; bosutinib Second line Rx? Bosutinib, ponatinib ; allo SCT 5

6 CML Survival by Era Harrison s Principles of Internal Medicine. 2014

7 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 92% 89% 81% 72% 59% Patients at risk Kalmanti L, et al. Leukemia. 2015;29(5): Hehlmann R, et al. Blood. 2017;130(suppl): Abstract 897.

8 Number of Cases CML - Increasing Prevalence Over Time , , , , ,000 Incidence 4700 per year Age-matched mortality ratio vs normal population = 1.50 Accounts for increased US population to 410 million in Year Wang. Blood 127: 2742; 2016

9 Therapy of CML in 2018 Frontline - imatinib 400 mg daily - dasatinib 100 mg daily - nilotinib 300 mg BID - bosutinib 400mg daily Second / third line - nilotinib, dasatinib, bosutinib, ponatinib, omacetaxine - allogeneic SCT Other - decitabine, pegasys - hydrea, cytarabine, combos of TKIs and with TKIs

10 CML. Questions Best frontline TKI therapy Generic imatinib vs Gleevec and second generation TKIs Endpoint of Rx: CGCR vs CMR Aim of Rx: survival vs Rx-free remission Long-term side effects; costs Role and timing of allo SCT TKIs vs allo SCT cost considerations Optimal monitoring of CML TKI Rx discontinuation

11 Survival with Imatinib vs IFN + ara-c in Newly Dx CML (IRIS; 10 yr) 553 pts randomized to imatinib 10 yr survival 83.3% Cumulative CGCR rate 83% 10-Yr CGCR rate 22% 10-Yr MMR rate 93% 10-Yr MR 4.5 rate 23% 10 yr survival by Sokal: low 90%; intermediate 80%; high 69% Annual rate of transformation: 1.5%, 2.8%, 1.8%, 0.9%, 0.5%, 0%, 0%, & 0.4% Hochhaus. NEJM 2017; 376: 917

12 CML. Incidence of blast CML-BP Over Time Hehlmann et al, Leukemia 2017

13 Survival with Imatinib vs IFN + ara-c in Newly Dx CML (IRIS; 10 yr) Hochhaus. NEJM 2017; 376:

14 CML Frontline Therapy 8 main studies compared new generation TKIs to imatinib frontline: ENEST-nd (nilotinib), DASISION (dasatinib), BFORE (bosutinib), EPIC (ponatinib), others All showed higher rates of favorable early surrogate endpoints: CG CR, MMR, MR4.5, AP/BP Increased uncommon toxicities with newer TKIs: PAOD-MI-TIA, pancreatitis, pleural effusions; HT and pulmonary HT, BS, vasospastic reactions, non-cml deaths

15 CML. Long-term Results of TKIs at MDACC 478 pts Rx with imatinib 400 (n=71) or 800 mg/d (n=204), nilotinib (n=105), or dasatinib (n=98) as frontline Rx; median FU 106 mos % IM400 IM800 Nilo Dasa CGCR MR yr OS 93%, TFS 86%, EFS 81%, FFS 69% In pts in CGCR, no differences in outcomes if MR4.5 or not Falchi, Cortes-unpublished 2015.

16 Propensity Score-Matched Comparison of Dasatinib and Nilotinib as Frontline CML Therapy Pts treated with dasatinib (N=102) or nilotinib (N=104) matched by propensity score 3-year Survival Endpoints Percentage Dasatinib N=87 Nilotinib N=87 P value Overall Event-free Failure-free Transformation-free

17 DASISION The Final Report 519 pts randomized to dasatinib (n=259) or imatinib (n=260) Minimum follow-up 5 yrs Outcome (%) Dasatinib Imatinib P value or HR Discontinued m cccyr P= y MMR P= y MR P= m <10% y AP/BP y OS HR y PFS HR 1.06 Cortes. JCO. 34: 2333; 2016

18 % With MMR DASISION Cumulative MMR Rates Over Time 100 N Dasatinib 100 mg QD 259 Imatinib 400 mg QD By 4 years By 5 years P = By 1 year 46% By 2 years 64% 46% By 3 years 67% 55% 73% 60% 76% 64% % Months Since Randomization Cortes J, et al. Blood. 2014;124: Abstract 152.

19 ENESTnd The 6-Year Update 846 pts: nilotinib 600 (n=282), nilotinib 800 (n=281) or imatinib (n=283) Minimum follow-up 6 yrs Outcome (%) Nil 600 Nil 800 Imatinib P value or HR Discontinued* y MMR* P< y MR P< m <10% y AP/BP P=0.06/ y OS HR 0.9/0.46 * 5-yr data from Larson et al ASCO 2014; Abstract #7073 Hochhaus. Leukemia 30: 1044; 2016

20 ENEST-nd-CV Events. Hochhaus et al., Leukemia 2016

21 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 P=0.01 P=0.02 P=0.02 P=0.04 Bosutinib ITT: n=268 mitt: n= months 18 months Imatinib ITT: n=268 mitt: n= months 18 months P=0.01 P=0.11 P=0.02 P=0.11 Month: MMR (ITT) MMR (mitt) MR 4 (mitt) MR 4.5 (mitt) MR 4 (ITT), % Bosutinib Imatinib P 12 mo < mo MR 4.5 (ITT), % Bosutinib Imatinib P 12 mo mo Gambacorti-Passerini et al. ASH 2017; abstract #896

22 Patients with MMR, % Patients with MR 4.5, % Radotinib v Imatinib in Frontline CML Molecular Response 2 nd generation TKI approved in Korea Active against BCR-ABL and most mutants (not T315I) By 36 months Radotinib 300mg BID By 12 months 52%, P =.0044 Δ 22% 30% By 24 months 66%, P =.0536 Δ 15% 51% 75%, P =.0076 Δ 21% 54% Imatinib 400mg QD By 24 months 33%, P =.1331 By 12 months Δ 11% 15%, P = % 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 et al. ASH 2017; abstract #317

23 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 et al. ASH 2017; abstract #317

24 Generic Imatinib in India: Survival of the Cheapest 1367 pts newly diagnosed CML: 1193 innovator, 174 generic CP 90% & 83%; AP 7% & 10%; BP 4% & 7% Innovator Generic CCyR MMR MR AP/BP 8 7 AEs Edema, any grade 12 6 Myalgia, any grade Rash, grade 3 <1 3 Thrombocytopenia, any grade 6 9 Neutropenia, any grade 5 3 Anemia, any grade 9 6 Madhav et al. ASH 2016; abstract #630

25 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 CCyR yr FFS yr OS Santos et al. Br. J Haematol 2010; 150:

26 Lower-Dose Dasatinib Newly Diagnosed CML-CP 56 pts, median age 46 y (range, 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 et al. ASH 2017; abstract #1611

27 Frontline CML Therapy in Dasatinib 50mg* daily produces similar efficacy and significantly less toxicity than 100mg daily Current frontline: dasatinib 50mg daily+venetoclax 400mg daily. Aim to achieve high rates of durable CMRs and Rx discontinuation=molecular cures * Off-label use

28 CML. What Happens in 2018? Parameter Imatinib 2 nd TKIs Efficacy excellent even better Tolerance excellent even better Cost ($/yr) 2-10,000 > 120,000 %5 10 yr survival 80 90? > 90 EFS 50-60??? difference at 5-10 yrs in EFS and OS determines frontline Rx new long-term side-effects of 2 nd TKIs; Rx value

29 CML Therapy in 2018 Imatinib for low-risk Sokal and older pts ( yrs) Second TKIs for higher-risk Sokal until CGCR, then back to imatinib second TKI indefinitely Second TKIs for younger pts (< 50 yrs) in whom Rx DC important

30 Rx Endpoints When Comparing Second TKIs to Imatinib in Frontline Rx Lower incidence of early transformation to AP-BP Survival Molecular cure Long-term safety Cost; cost-effectiveness = Rx value

31 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

32 Cumulative survival Outcome of CML Patients After TKI Discontinuation - MDACC Initial Report Updated Report 1.00 CMR before TKI discontinuation 64 months < 64 months 0.25 p = Month to molecular relapse Benjamini et al. Leuk & Lymphoma 2014; 55(12): ; Chamoun et al. ASH 2016; abstract #1923

33 Molecular Relapse-free Survival (%) 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%) Estimated survival 95% confidence band MRFS, % (95% CI) 60 49% (38.0, 59.4) Pts on 1 st -line dasatinib (n = 37) 54 (38.0, 70.1) Pts 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) 0 Patients at risk Months Since Dasatinib Discontinuation No patients lost CCyR or CHR, transformed or died All evaluable pts regained MMR a median of 1.9 mo after restarting dasatinib Factprs associated with RFS: age (p = 0.04), 1 st line (p = 0.07) 8 withdrawal events Shah et al. ASH 2017; abstract #314

34 TKIs Rx DC in Clinical Practice-- Requirements Parameter Yes No Sokal risk low-intermediate high BCR-ABL transcripts quantifiable-b2a2, B3A2 (e13a2 or e14a2) not quantifiable CML past Hx chronic AP-BP Response to first TKI optimal failure Duration of all TKIs Rx > 8 yrs < 3 yrs Depth of molecular response Duration of molecular response Monitoring availability/center-pt CMR (MR 4.5) less than MR 4.0 > 2-3 yrs < 2 yrs ideal (q2 mo in yrs 1-2) poor; non-compliant

35 CML Rx Discontinuation Ready for community practice If CMR 2-3 yrs and Rx DC 50% molecular cures; monitor BCR-ABL transcript levels Q2 mos in Yr 1-2, then Q3-6 mos. If molecular relapse, then restart TKIs Accidental pregnancy DC TKIs; 1-2% risk of fetal malformations (ex. omphalos, kidneys, bone--- n =3/125) Males with CML no risk to female partners pregnancies Wilful pregnancy ideally DC TKI 2 weeks before pregnancy attempt and only if CMR; monitor until delivery then resume TKI

36 CML. Role and Timing of allo SCT Status TKIs Allo SCT AP-BP Interim Rx to MRD ASAP IM failure in CP, T315I IM failure in CP no CE, no mutations, good initial response IM failure in CP CE, bad mutations, no CG response Older post IM failure Ponatinib interim Rx to MRD Long-term second line TKIs Interim Rx to MRD Long-term; even if no CGCR? If no/loss response to ponatinib Third line post second TKI failure Second line May forgo allo SCT for many yrs of 36 QOL

37 Monitoring CML Course Cytogenetics Fluorescent in situ hybridization (FISH) Quantitative PCR (QPCR):real time, competitive Abl mutations Must do FISH and PCR pre-rx for FU 37

38 When to Look For Mutations? Mutation analysis in 1301 pts receiving imatinib or 2 nd generation TKI (GIMEMA) Clinical condition % Positive Failure 27 No CHR at 3 mo 19 No CyR at 6 mo 11 No PCyR at 12 mo 17 No CCyR at 18 mo 17 Loss CCyR 31 Loss CHR 50 Suboptimal 5 No CyR at 3 mo 7 No PCyR at 6 mo 5 No CCyR at 12 mo 8 No MMR at 18 mo 0 Loss MMR 4 Soverini. Blood 118:1208 and abst 112, 2011

39 Impact of Mutations and TKI choice Mutation on Health Care System. Percentage of Patients with Mutation Jabbour. D: mutation Am may J Clin not respond Oncol. to the 2G-TKI Nov therapy Mutation Class for 2 nd Generation Tyrosine Kinase Inhibitor (2G-TKI) Response* Dasatinib Nilotinib T315I 3.3% D D M351T 7.3% A A G250E 5.3% A A F359V 4.3% A C M244V 5.0% A A Y253H 3.0% A C E255K 3.1% B C H396R 3.3% A A F317L 2.7% C A E355G 2.3% A A Q252H 1.7% B B E255V 1.6% B C E459K 1.6% A A F486S 1.5% A A L248V 1.2% A A D276G 1.2% A A E279K 1.2% A A Y253F 0.7% A B F359C 0.7% A C F359I 0.7% A B *Class A: mutation may have same response as no mutation to 2G-TKI. Class B: mutation may confer intermediate insensitivity/resistance to the 2G-TKI. Class C: mutation may confer substantial insensitivity/resistance to the 2G-TKI. Class 39

40 Total Drug Cost ($) per Event Impact of Mutations and TKI choice on Health Care System. $300,000 $250,000 $200,000 $150,000 Δ vs. Open Access = 5% $126,753 $120,706 Δ vs. Open Access = 41% $169,990 Δ vs. Open Access = 6% Δ vs. Open Access = 22% $241,515 $209,259 $198,284 $100,000 $50,000 $0 Total Cost per CHR Total Cost per MCyR Open Access to Both 2G-TKIs Access to Only Dasatinib Access to Only Nilotinib Jabbour. Am J Clin Oncol. Nov

41 Analysis of Mutations in CML If CG or hematologic relapse, mutations studies help No role for mutation studies pre-rx or in imatinib responding patients T315I: no role for new TKIs; allo SCT or others (HU, ara-c, HHT, T315I inhibitors ) Y253H, E255K/V, F359V/C/I : dasatinib V299L,T315A, F317L/V/I/C : nilotinib Kantarjian. Blood 111:1774, Soverini. Blood 118 : 1208,

42 % Survival/TFS by Early Molecular Response Study QPCR < 10% QPCR > 10% Marin ( 8-yr) MD Anderson (10-yr) ENEST-nd DASISION BELA Marin JCO 30: 232; Jain. Blood 120: abst 70,2012; Hochhaus. Blood 120:abst 167; 2012; Saglio. Blood 120: abst 1675; 2012;Brummendorf. Blood 120: abst 69; 2012.

43 BCR-ABL Transcripts < 10% at 6 mos Associated with Better Outcome Response 3 Mo 6 Mo No. % Survival % PFS % FFS > > > > 10 > Brandford. Blood 122: abst 254; 213

44 CML. Survival by > or 1% BCR-ABL Transcript Levels at 6 Months Patients at risk 1% > 1% Hehlmann et al, Leukemia 2017

45 Criteria for Response/Failure and Change of Rx Time (mo) Imatinib Second TKIs 3-6 Major CG; QPCR 10% CG CR; QPCR 1% 12 CG CR CG CR Later CG CR CG CR CG 35% QPCR 10% CGCR QPCR 1%

46 CML. Criteria for Failure and Suboptimal Response to Imatinib ELN 2013 Time (mo) Any and beyond Response Failure Warning Optimal No CHR, And/or Ph+ >95% BCR-ABL >10% and/or Ph+ >35% BCR-ABL >1% and/or Ph+ >0% Loss of CHR Loss of CCyR Confirmed loss of MMR Mutations CCA/Ph+ BCR-ABL >10%, and/or Ph % BCR-ABL 1-10%, and/or Ph+ 1-35% BCR-ABL 10%, and/or Ph+ <35% BCR-ABL <1%, and/or Ph+ 35% BCR-ABL >0.1-1% BCR-ABL <0.1% CCA/Ph- (-7, or 7q-) BCR-ABL <0.1% Baccarani. Blood 2013; 122:

47 Important Response Categories in CML Response Translates into: BCR-ABL 10% at 6 mos; CCyR later MMR CMR Significantly improved survival Modest improvement in EFS; possible longer duration CCyR; no survival benefit Possibility of Rx discontinuation (clinical trials only)

48 Therapy of CML Post Frontline Failure

49 Dasatinib in CML CP After Imatinib Failure 670 pts randomized to 4 dasatinib schedules 6-year follow-up Outcome (100 mg/d) Percent MCyR / CCyR (within 2 yr) 63 / 50 MMR 46 IM Resistant 43 IM Intolerant 55 7-yr OS 65 7-yr PFS 42 Discontinued treatment 78 Reason for discontinuation: AE 30% (related 24%, unrelated 6%), progression 21%, other 47%. Pleural effusion 28%, pulmonary hypertension 2%. Shah. Am J Hematol 2016; 91:

50 OS by Dasatinib Dose After Imatinib Failure % Alive % 70% 68% 65% mg QD 140 mg QD 50 mg BID 70 mg BID Months Imatinib-resistant Imatinib-intolerant Overall OS, % (95% CI) 63 (53 71) 70 (52 82) 65 (56 72) PFS, % (95% CI) 39 (29 49) 51 (32 67) 42 (33 51) Shah. AJM 91: 896; 2016

51 Better Outcome on Dasatinib with Earlier Intervention Patients on dasatinib studies analyzed by failure status on imatinib: loss of MCyR vs loss of CHR Status at IM Failure No. Percentage CCyR MMR Loss of MCyR Loss of CHR & MCyR Loss of CHR (never MCyR) Quintás-Cardama. Cancer 115: , 2009

52 Dasatinib Early Intervention EFS & OS Event-Free Survival Overall Survival Time to intervene: Loss of MCyR Quintás-Cardama. Cancer 115: , 2009

53 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 ( 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 et al. ASH 2017; abstract #1594

54 2 nd Line TKI in CML CP MR4.5 Overall Survival N Events Transformation-Free Survival Event-Free Survival N Events N Events Chamoun et al. ASH 2017; abstract #1594

55 Predictors of Outcome to 2 nd Line TKI in CML 123 pts treated with dasatinib (n=78) or nilotinib (n=45) after imatinib failure Median follow-up 76 months (range, ) MCyR 63%, CCyR 59%, 3-yr EFS 53%, 3-yr OS 84% 3-mo CCyR33% MVA: 3-mo CCyR only factor independently associated with EFS (p<0.001) and OS (p=0.03) Jabbour et al. Blood. 2010;116: Abstract Jabbour et al. Clin Lymphoma Myeloma Leuk Jan 11. [Epub ahead of print]

56 How Do You Choose The Second Generation TKIs Disease characteristics - AP/BP: favor Dasatinib/ponatinib and combinations - chronic: see below Mutations -T315I ponatinib - nilotinib IC50 > 150nM avoid - dasatinib IC50 > 3nM avoid Patient Hx - Hypertension, CHF, lung problems, COPD avoid dasatinib - Severe diabetes, pancreatitis Hx, atherosclerosis avoid nilotinib - QTc problems Bosutinib

57 Ponatinib Phase 2 Study Responses to Therapy Ponatinib 45 mg daily 93% 2 prior TKI, 58% 3 prior TKI Median follow-up 38.4 mo ( mo) Percentage CP-CML AP BP Ph+ ALL MCyR CCyR MMR MR4.5 MaHR MaHR MaHR R/I T315I Total ** Median mo to response NR Cortes et al. ASH 2014; Abstract #3135; Kantarjian et al. ASCO 2014; Abstract #7081

58 5-Year Outcome with Ponatinib in CML-CP by Prior TKI 270 pts CML-CP Rx with ponatinib 45 mg/d post-tki failure Median F/U 56.8 mo ( mo) Percent 5-yr Probability MCyR MMR MR4.5 MCyR MMR PFS OS 1 TKI NA TKI TKI TKI NA NA NA Hochhaus A, et al. Blood. 2017;130(suppl): Abstract 1617.

59 3 rd Line TKI in CML 185 pts Rx 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% MVA predictors of CCyR and MMR: ponatinib, Hgb, Response % CCyR 38 MMR 41 MR4 33 MR intolerance Khan M, et al. Blood. 2017;130(suppl): Abstract 2882.

60 3 rd Line TKI in CML OS TFS MVA for survival: ponatinib, bosutinib; age; female; intolerance (v resistance) Khan M, et al. Blood. 2017;130(suppl): Abstract 2882.

61 Survival (%) Survival (%) Survival (%) Ponatinib or SCT for T315I CML Pts 18 yrs with CML T315I in any stage enrolled in PACE (n=449) or EBMT ( ; n=222) Median age (yr): CP 53 vs 48; AP 55 vs 46; BP 47 vs 44; Ph+ ALL 55 vs 36 Disease group Median survival (mo) PACE EBMT CP NR 103 AP NR 56 BP 7 11 Ph+ ALL % 80% 60% 40% 20% 0% 100% 80% 60% 40% 20% 0% 100% 80% 60% 40% 20% 0% CP Months from treatment initiation AP BP Ponatinib SCT Ponatinib SCT Months from treatment initiation SCT Ponatinib Months from treatment initiation Nicolini et al et al, Blood 2014: Abstract #480

62 Ponatinib Toxicities of Concern CML Therapy? Optimal dose: 30 vs. 45 mg daily? I use 30 mg daily Incidence of toxicities of concern Pancreatitis 7% Skin rashes 40%; severe 4-7% Vasoocclusive disorders (cardiac, CNS, PAOD) 12% Hypertension 67%; severe 20%

63 Therapy of CML Transformation Accelerated--TKI alone or combo with low intensity Rx (DAC, AZA, LD ara C, HU, etc) Lymphoid BP--TKI + ALL Rx (e.g. HCVAD) Non-lymphoid BP--TKI + AML Rx or DAC/AZA

64 Survival in Advanced Phase CML Accelerated Phase Blast Phase 4A 5A Kantarjian. Blood 2012; 119: 1981

65 CMLBP-MDACC Experience ( ) 477 pts Rx: lymphoid BP 28%; TKI alone 35%, TKI + ChemoRx 48%; allo SCT 22% MHR 50%; CGCR 21%; MHR with TKI alone 43%; TKI + chemo 64% Median OS 12 mos MVA for OS: TKI combo, allo SCT, lymphoid BP favorable

66 Hyper CVAD + TKIs in CML Lymphoid BP 42 pts; HCVAD and imatinib (n=27) or dasatinib (n=15) CR 90%, CGCR 58%, CMR 25%, FCM-MRD negative 42% Median remission 14 mos; median survival 17 mos; 18 (47%) had allo SCT. 66 Strati et al. Cancer 2014; 120: 373

67 Summary CML 2018 Excellent therapy for CML : imatinib, dasatinib, nilotinib, bosutinib, ponatinib, omacetaxine CGCR is endpoint of Rx = improves survival Early response (3-6 mos) predictive--do not change at 3 mos, monitor at 6 mos and decide Aim for PCR<10% by 6 mos, and for CG CR by 12+mos these are only indications to change Rx Deeper molecular responses (MMR) improve EFS; no impact on transformation or survival

68 Summary CML 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

69 Leukemia Questions? Cell: Office: