Elias Jabbour, MDUniversity of Texas M. D. AndersonCancer CenterCML and Imatinib Resistance: Which TKI and When?

CML and Imatinib Resistance: Which TKI and When?Marcos de Lima, MD

Stem Cell Transplantation ProgramCase Western Reserve UniversityUniversity Hospitals Seidman Cancer CenterCleveland - OH

Results with Imatinib in Early CP CML The IRIS Trial at 8-Years304 (55%) patients on imatinib on studyProjected results at 8 years:CCyR 83%82 (18%) lost CCyR, 15 (3%) progressed to AP/BPEvent-free survival 81%Transformation-free survival 92%If MMR at 12 mo: 100%Survival 85% (93% CML-related)Annual rate of transformation: 1.5%, 2.8%, 1.8%, 0.9%, 0.5%, 0%, 0%, & 0.4%Deininger et al; Blood 2009; 114: Abst# 1126

IRIS 8-Year UpdateDeininger et al; Blood 2009; 114: Abst# 1126

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No.(%)

No CCyR17

Safety5

Lost CCyR15

Lost-regained CCyR3

CCyR Other7

Sustained CCyR on study53

100

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*IRIS. Survival Without AP/BC Worse If No Major CG Response at 12 mosEstimated rate at 60 monthsn= 86 93%n= 73 81%n= 350 97% p

Criteria for Failure and Suboptimal Response to ImatinibBaccarani. JCO 2009; 27: 6041-51

Time (mo)ResponseFailureSuboptimalOptimal3No CHRNo CG Response< 65% Ph+6No CHR>95% Ph+35% Ph+35% Ph+1235% Ph+1-35% Ph+0% Ph+185% Ph+ No MMRMMRAnyLoss of CHRLoss of CCgRMutationCELoss of MMRMutationStable or improving MMR

NCCN Treatment Recommendations3-Month Follow-up Therapy

National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: chronic myelogenous leukemia. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Revised September 13, 2012.

Adherence Is the Most Important Factor Contributing to Molecular ResponsesMarin D et al. J Clin Oncol. 2010;28(14):2381-2388. Adherence monitored over a period of 3 months using a microelectronic monitoring device in the imatinib bottle cap. Patients were not aware of the device.0.112Time Since Start of Imatinib Therapy (months)1.00.90.80.70.60.50.40.30.20618243036424854606672Probability of MMRAdherence >90% (n = 64) Adherence 90% (n = 23) P

EFS by Response to IM at 6 and 12 Mos6 month response12 month response281 pts; imatinib frontline (400mg in 73, 800mg in 208)Suboptimal response at 6-12 months: 12-17% with 400mg, 1-4% with 800mg (p=0.002)Alvarado. Cancer. 2009;115:3709-18.

MDACC Retrospective Analysis: MCyR at 6 Months Associated With OSPatients with MCyR have better OS than patients that do notLandmark analysis at 6 mos01224364860720.850.010.621.00.80.60.40.20Proportion aliveMonthsKantarjian H. Cancer. 2008;112:837845.

Cytogenetic response at 6 mosTotalDeadP-valueComplete2015Partial 391Minor103Othersa93

MDACC Retrospective Analysis: CCyR at 12 Months Associated With PFSPatients with CCyR have better PFS than patients that do not. Similar results were observed in patients achieving CCyR at 18 and 24 mos.Landmark analysis at 12 mosProportion PFS1.00.80.60.40.200122436486072Months0.020.20.22Kantarjian H. Cancer. 2008;112:837845.

Cytogenetic response at 12 mosTotalFailureP-valueComplete2147Partial 193Minor52Others85

EFS and Survival by 12-month Response-CCyR with vs without MMR with TKI Frontline Rx Jabbour E et al. Blood. 2011.

Outcome by 12-Month Response in CML CPHehlman et al. JCO 2011;29:1634-42

848 pts randomized to IM 400mg, IM 800mg, or IM 400 + IFNMedian FU: 40 months12-month BCR-ABL/ABL (IS)NPercentagePFSOS1%2679493P value0.00230.0011Outcome independent of treatment arm

Probability of survivalTime from onset of imatinib therapy (years)BCR-ABL/ABL9.8% OS= 54%p

CML IV: Long-Term Impact of Response at 3 MonthsHanfstein et al. ASH 2011; Abstract #783

1223 pts randomized to imatinib 400, imatinib + IFN, imatinib + ara-C, imatinib 8003 month analysis: PCR in 692 pts, cytogenetics in 4603 mo transcript levels predictive of achievement of CCyR and MMR% 5-year outcomeCytogenetics (% Ph+)Molecular [BCR-ABL/ABL (IS)]35%>35%10%>10%PFS94879387OS95879587

OS by Response to TKI at 3 Months at MDACCNaqvi et al. ASH 2011; Abstract #3784

EFS by Response to TKI at 3 Months at MDACCNaqvi et al. ASH 2011; Abstract #3784

Failure On Imatinib And Strategies

Imatinib Failure ImatinibSecond Generation TKI Ph 100% at 6 mos_+ Ph 35% at 12 mos++ No CGCR in yr 2++ CG relapse++ Hematologic relapse_+

Imatinib Dose Escalations Similar results from IRIS 31Kantarjian Blood 101:473, 2003 2Jabbour Blood 113:2154, 2008 3Kantarjian Cancer 115:551, 2008

% 2-yrResistance1,2No.% CG CRTFSOSCytogenetic63528090Hematologic2155167

2nd Generation TKI in CML

ParameterDasatinibNilotinibBosutinibPotency (fold vs IM)3253020-50TargetSrc & AblAblSrc & ABLBCR-ABL bindingActive + InactiveInactiveIntermediateResistant mutationsT315IT315IT315IMutations with intermediate sensitivityE255K/V, V299L, F317LE255K/V, Y253F/H, Q252H, F359VE255V/K,V299L, F317L Standard dose (CP)100mg QD400mg BID500mg QDGrade 3-4 neutropenia & thrombocytopenia33% / 22%31% / 33%12% / 21%Other notable toxicitiesPleural effusion, bleedingBilirubin, lipase elevationDiarrhea, rashC-kit inhibition (vs imatinib)IncreasedSimilarNonePDGFR inhibition (vs imatinib)IncreasedSimilarNoneClinical activityHighly activeHighly activeHighly active

Phase II Studies of Dasatinib After Imatinib FailureBlood 110:abst 470 and 734, 2007.

ResponsePercent by Disease StageCPn=387APn=174MyBPn=109LyBPn=48ALLn=46Hematologic9164503949 CHR9150262935 NEL-14767Cytogenetic6240475862 Complete5333274654 Partial97762

Baccarani. Blood 112:abst 450, 2008

Optimal Dose and Schedule of Dasatinib IN CML CP after Imatinib FailureShah. Blood 112:abst 3225, 2008

% Parameter100mgQDN=16650mgBIDN=166140mgQDN=16370mgBIDN=167MCyR63616361CGCR5050505424-months PFS80767576Neutropenia, G3-435474445Thrombocytopenia, G3-423364138Pleural effusion, G3-42455Interruption58666971Reduction33455457

Phase II Studies of Nilotinib After Imatinib FailureBlood 112:abst 3229, 3238, 2008.

ResponsePercentageCPn =321APn =137MyBPn =106LyBPn =30HR77542420CHR76261213CytogeneticMajor59313850Complete44192833

Nilotinib in Chronic Phase CML Post Imatinib Failure321 pts; nilotinib 400 mg BID; median FU 19 mos; median nilotinib 788 mg/D; median days off 20Kantarjian. Blood 114:abst 1129; 2009

OutcomePercent- CGCR46- MMR28 (56% of CGCR)- 24-mos PFS64- 24-mos OS87

Nilotinib in CML Chronic Phase. Survival and PFSKantarjian. Blood 112:abst 3238, 2008% Progression-free survival

Summary of Bosutinib - Preclinical ActivityOrally bioavailablePotent dual Src/Abl inhibitorMinimal inhibitory activity against PDGFR and c-KITInhibits Bcr-Abl signaling in CML cellsActive against imatinib-resistant mutants of Bcr-Abl, except T315IBoschelli DH, et al. J Med Chem. 2005;48:3891-3902; Golas JM, et al. Cancer Res. 2003;63:375-381;Puttini M, et al. Cancer Res. 2006;66:11314-22.

Bosutinib in CML-CP post imatinib failure288 pts Rx with bosutinib 500 mg/D: Imatinib resistant 200; intolerant 88ParameterPercent -CHR86 -MCyR53 -CCyR41 -MMR if CCyR64 -2-yr PFS79 2-yr OS92

Side effects: diarrhea 9%, rash 9% Cortes. Blood 118: 4567;2012

Response to Bosutinib 3rd Line TherapyKhoury. Blood 119:3403;2012

Dual Src & Abl inhibitor, no effect over c-kit or PDGFR118 pts who failed imatinib (600mg) & dasatinib or nilotinibResponse, %IM + D resistant(n = 37)IM + D intolerant(n = 50)IM + NI resistant(n = 27)CHR508077MCyR313032CCyR142827PCyR1728MMR335112-yr PFS2261502-yr OS6685100IM, imatinib; D, dasatinib; NI, nilotinib.

2nd Generation TKI in CML CP Post-Imatinib ResistanceShah et al. Haematologica 2010; 95: 232-40Kantarjian et al. Blood 2011; 117: 1141-45Cortes et al. Blood 2011; 118; 4567-76

ResponsePercentageDasatinibNilotinibBosutinibFU (mo)>24>2424*CHR897786MCyR595654CCyR44414124 mo PFS**80%64%79%24 mo OS**91%87%92%* Median** All patients

2nd-Generation TKI in CML CP Post- Imatinib Failure

ToxicityDasatinibNilotinibBosutinibPleural effusion++--Liver+++Transaminases++++Bilirubin-++-Rash++++Diarrhea--++Lipase- (+)++-Glucose-++-Hypophosphatemia+++++Bleeding+--QTc++++-

2nd-Generation TKI in CML CP Post- Imatinib FailureShah et al. Haematologica 2010; 95: 232-40Kantarjian et al. Blood 2011; 117: 1141-45Cortes et al. Blood 2011; 118; 4567-76

ToxicityDasatinibNilotinibBosutinibAnemia131113Neutropenia353118Thrombocytopenia233024

Better Outcome on Dasatinib with Earlier InterventionPatients on dasatinib studies analyzed by failure status on imatinib: loss of MCyR vs loss of CHRQuints-Cardama. Cancer 115: 2912-21, 2009

Status at IM FailureNo.PercentageCCyRMMRLoss of MCyR1517260Loss of CHR & MCyR334229Loss of CHR (never MCyR)1092626

Dasatinib Early InterventionEFS & OSQuints-Cardama. Cancer 115: 2912-21, 2009Event-Free SurvivalOverall SurvivalTime to intervene: Loss of MCyR

Prognosis with 2nd TKIs. SurvivalAdverse factors: PS 1 and lack of CyR to imatinibJabbour. Blood 117: 1822-7, 2011

PFS and Response to 2nd TKI113 CML CP pts receiving nilotinib (n=43) or dasatinib (n=70) after imatinib failureTam. Blood 112: 516-8, 2008p = 0.003

Response @ 12 mo% AP/BP/Death/CHR loss Next YearMCyR3%No MCyR17%

Optimal Response to 2nd TKIs. Survival

% 3-month% 3-yearParameterCategoryNoCCyRp-valueEFSpOSp-valueClonal evolutionNo94300.35540.46870.22Yes28414871CML duration (year)0-327460.3410.56780.894-541325683655295587CHR at the start of 2nd TKINo39420.21530.63900.40yes84295281Best response to imatinibIntolerant875

0.00150

How Do You Choose The Second Generation TKIsDisease characteristics- AP/BP: favor dasatinib (?) and combinations- chronic: see belowMutations-T315I none- nilotinib IC50 > 150nM avoid- dasatinib IC50 > 3nM avoidPatient Hx- Hypertension, CHF, lung problems, COPD avoid dasatinib, consider bosutinib/nilotinib- Severe diabetes, pancreatitis Hx, atherosclerosis avoid nilotinib, consider bosutinib/dasatinib - QTc problems be cautious with all (?)

Ponatinib Phase 2 Study - PACE Response Characteristics CP-CMLCortes J, et al. Blood. 2012;120: Abstract 163.

93% failed 2 TKI, 58% failed 3 TKIResponse Rate, n (%)N=267Any Cytogenetic Response180 (67)MCyR149 (56) CCyR124 (46)MMR91 (34) MR4.539 (15)BCR-ABL 10% at 3 months, n/N(%)142/240 (59) 1 prior approved TKI14/16 (88)Median Time to Response*, months [range]MCyR2.8 [1.6 11.3]MMR5.5 [1.8 19.2]91% MCyR sustained at 12 months (K-M)

Ponatinib Phase 2 Study - PACE Response by Baseline Mutation CP-CMLCortes J, et al. Blood. 2012;120: Abstract 163.

MCyRCP-CMLN=267n/N (%)R/I, no mutation66/136 (49)R/I, any non-T315I mutation38/67 (57)T315I mutation45/64 (70)

Ponatinib Phase 2 Study - PACE Response in Advanced Phase*MaHR = primary endpoint; 14 AP-CML patients with baseline MaHR and 1 AP-CML patient with no baseline MaHR assessment counted as non-responders **CCyR + PCyR + minor CyR + minimal CyR#MMR was assessed on the International Scale using peripheral blood; Patients missing a valid baseline MMR assessment , or who met the criteria for MMR at baseline, were counted as non-responders Kantarjian HM, et al. Blood. 2012;120: Abstract 915.

n (%)AP-CML N=83BP-CML N=62Ph+ ALLN=32Myeloid N=52Lymphoid N=10MaHR*47 (57)15 (29)4 (40)13 (41)Any CyR**46 (55)19 (37)5 (50)15 (47) MCyR32 (39)10 (19)4 (40)15 (47)CCyR20 (24)8 (15)3 (30)12 (38)MMR#13 (16)N/AN/AN/A

Omacetaxine for CML CP After Failure to 2 TKIKantarjian HM, et al. Blood. 2012;120: Abstract 2767.

122 pts with CML CP (n=81) or AP (n=41) with 2 prior TKI Omacetaxine 1.25 mg/m2 BID x14d, then x7dResponse, %CPN=81APN=41Primary endpointMCyR 20%MaHR 27%CCyR 10%CHR 24%Median duration, mo17.79Median PFS, mo9.64.7Median OS, mo33.91611 pts (9 CP, 2 AP) ongoing responseMedian 35 cycles over median 39 monthsMedian response duration: 14 mo CP, 24 mo AP

Allo SCT. Second or Third Salvage?Imatinib failure in AP, BP: use new TKI as bridge to MRD, then alloSCT ASAPT315I mutation in any CML phase: use AP 24534, other T315I inhibitors, HHT, HU, others as bridge to MRD, then allo SCT ASAP Imatinib failure in CP: if IC50 , clonal evolution, or no major CG in 12 mos allo SCT (risk should also be reasonable: young, good match)If not TKI until failureAge 70 yrs or if poor match: may decide to forgo curative allo SCT option for several years of CML control; Young patient (?) Financial considerations

Monitoring Patients with CML While on TKI TherapyAdequate monitoring required to optimize outcome / Not too much, not too littleCCyR is associated with survival benefitMMR is associated with durable CCyR and may therefore decrease probability of relapseCMR offers hope for treatment discontinuation (clinical trials only) Results should be interpreted in the context of alternative optionsNot failure criterion / QPCR in CCyR

CML in 2013Imatinib,nilotinib,dasatinib are standard frontline Rx (except p190 CML)Dose optimization and adequate monitoringSub-optimal response dose imatinib (400mg 800mg)New TKIFailureDasatinib, nilotinib, bosutinibAllogeneic SCTT315I: ponatinib, omacetaxine

Questions?ejabbour@mdanderson.org

Marcos.delima@uhhospitals.org

****Overall survival by MCyR vs no MCyR at 3 months p=0.156*Event free survival by MCyR vs No MCyR at 3 months p=0******Introducing dasatinib in patients with CML CP failing imatinib after loss of MCyR was associated with improved CCyR rates as well as EFS, PFS, and OS, compared with introducing dasatinib after loss of CHR or loss of CHR and CCyR, thus supporting the notion that switching therapy from imatinib to dasatinib early during the course of failure increases the chances of a favorable long-term outcome.*These 2 factors, older age and lack of any CG respose to previous imatinib therapy had similar effect on the EFS

Patients with 0, 1, or 2 adverse factors had an estimated 18-month event-free survival with second generation TKI therapy of 81%, 54%, and 20%, respectively.

*Achieving a major cytogenetic response is a known major determinant of outcome in previous generations of therapy including interferon alpha and imatinib.

In a previous report from our institution, patients who achieved a major cytogenetic response after 12 months of therapy with second generation TKI had at least a better progression-free survival. *In the univariate analysis for event-free survival, factors associated with poor event-free survival were older age (> 55 years), lack of any cytogenetic response to previous imatinib therapy, an ECOG performance status 1 at the start of second generation TKI therapy, and more than 90% Philadelphia-positive metaphases at the start of second generation TKI therapy.

Kinase domain sequencing was performed in only 88 patients. When added to the analysis, the presence of KD mutations with intermediate IC50 at the start of second generation TKI was associated with poor event-free survival.

In the subsequent multivariate analysis, the lack of any cytogenetic response to previous imatinib therapy (p