Working Groups in Chronic Myelogenous Leukemia: Choice of Therapy After First-line Treatment Failure This program is supported by an educational grant from

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clinicaloptions.com/oncology Treatment of CML: State of the Art Faculty Elias Jabbour, MD Assistant Professor Department of Leukemia University of Texas M. D. Anderson Cancer Center Houston, Texas

clinicaloptions.com/oncology Treatment of CML: State of the Art Disclosure Elias Jabbour, MD, has disclosed that he has received fees for non-CME/CE services from Bristol-Myers Squibb and Novartis.

clinicaloptions.com/oncology Treatment of CML: State of the Art Choice of Therapy After First-line Treatment Failure  Considering the established treatment options in second- line therapy: second-generation TKIs and other novel agents  Treatment recommendations and guidelines  Criteria to determine appropriate dosing of second- generation TKIs  Recent clinical trial data on approved second-generation TKIs  Ongoing or planned studies and research directions

clinicaloptions.com/oncology Treatment of CML: State of the Art Mechanisms of Resistance to Imatinib  BCR-ABL dependent –Amplification/overexpression –Mutations in ABL –Remigration of BCR-ABL to cytoplasm  BCR-ABL independent –Increased MDR expression –Increased alpha-1 acid glycoprotein –Overexpression of Src-related kinases  Quiescent stem cells (persistence) le Coutre P, et al. Blood. 2000;95: Weisberg E, et al. Blood. 2000;95: Mahon FX, et al. Blood. 2000;96: Gambacorti-Passerini C, et al. J Natl Cancer Inst. 2000;92: Vigneri P, et al. Nat Med. 2001;7:

clinicaloptions.com/oncology Treatment of CML: State of the Art Spectrum and Frequency of BCR-ABL KD Mutations Recovered After TKI Therapy This research was originally published in Blood. Cortes J, et al. Blood. 2007;110: © the American Society of Hematology. BCR-ABL Mutation (%) G250E Nilotinib Dasatinib Imatinib Y253H/F E255K V299L F311I T315I F317L M351T E355G/A F359C/V H396R/P

clinicaloptions.com/oncology Treatment of CML: State of the Art Your Menu for BCR/ABL Mutants Redaelli S, et al, J Clin Oncol. 2009;27: BosutinibDasatinibImatinibNilotinib WT L248V G250E Q252H Y253F E255K E255V D276 G E279K V299L T315I F317L M351T F359V L384M H396P G398R F486S Resistant Moderately Resistant Sensitive Highly Resistant

clinicaloptions.com/oncology Treatment of CML: State of the Art Failure on Imatinib and My Recommended Strategies Imatinib FailureIncrease Imatinib Dose Second-Generation TKI Ph 100% at 6 mos–+ Ph ≥ 35% at 12 mos++ No CGCR in Yr 2++ CG relapse++ Hematologic relapse – +

clinicaloptions.com/oncology Treatment of CML: State of the Art When Does Imatinib Dose Escalation Work?  Imatinib dose escalation in 84 patients with imatinib failure –CG failure (n = 63):  imatinib associated with CGCR in 52% –MCyR durable at 2 yrs in 88% of patients –Hematologic failure (n = 21): only transient responses; CGCR in 5%  However, results of new TKIs better in CG relapse vs hematologic relapse Jabbour E, et al. Blood. 2009;113:

clinicaloptions.com/oncology Treatment of CML: State of the Art Phase II Studies of Dasatinib After Imatinib Failure *At least major. 1. Stone RM, et al. ASH Abstract Apperley JF, et al. J Clin Oncol. 2009;27: Cortes J, et al. Leukemia. 2008;22: Porkka K, et al. ASH Abstract Response, %CP [1] (n = 387) AP [2] (n = 174) MyBP [3] (n = 109) LyBP [3] (n = 48) ALL [4] (n = 46) Hematologic*  CHR  NEL Cytogenetic*  Complete  Partial97762

clinicaloptions.com/oncology Treatment of CML: State of the Art Dasatinib in Chronic-Phase CML After Imatinib Failure (START-C and START-R)  Pooled analysis of pts receiving 70 mg BID dasatinib in START-C (n = 387) and START-R (n = 101) –IM resistance: 80%; minimum follow-up: 24 mos Baccarani M, et al. ASH Abstract 450. OutcomePatients, % MCyR/CCyR at Mo 2460/51  IM resistant55/44  IM intolerant82/78 24-mo MMR40 24-mo duration of MCyR88 24-mo PFS81  MCyR at 12 mos94  No MCyR at 12 mos79

clinicaloptions.com/oncology Treatment of CML: State of the Art PFS and OS With Dasatinib in Chronic- Phase CML by Imatinib Failure Progression defined as increasing WBC count, loss of CHR/MCyR, AP/BP, or death. Imatinib Resistance Imatinib Intolerance Stone RM, et al. ASH Abstract 734. Reprinted with permission Mos PFS OS Mos PFS OS 96% 92% 88% 75% 100% 98% 100% 94%

clinicaloptions.com/oncology Treatment of CML: State of the Art Optimal Dose and Schedule of Dasatinib in CP CML After Imatinib Failure Shah NP, et al. ASH Abstract Reprinted with permission. Parameter, % 100 mg QD (n = 166) 50 mg BID (n = 166) 140 mg QD (n = 163) 70 mg BID (n = 167) MCyR CGCR mo PFS Neutropenia, grade 3/ Thrombocytopenia, grade 3/ Pleural effusion, grade 3/ Interruption Reduction

clinicaloptions.com/oncology Treatment of CML: State of the Art Nilotinib in Chronic-Phase CML Post- Imatinib Failure  N = 321 –Median duration of exposure to nilotinib: 18.4 mos –Patients on therapy for ≥ 12 months: 62% and ≥ 24 months: 42% –Patients requiring a dose interruption: 58% –median cumulative duration of interruption: 20 days Kantarjian HM, et al. Blood. 2011;117: OutcomePatients, % CGCR44 MMR28 (56% of CGCR) 24-mo PFS64 24-mo OS87

clinicaloptions.com/oncology Treatment of CML: State of the Art Nilotinib in Chronic-Phase CML: Major Cytogenetic Responses  MCyR –Overall: 59% –Imatinib-resistant patients: 56% –Imatinib-intolerant patients: 66% –Proportion of patients with baseline CHR significantly higher vs those who did not (73% vs 52%, respectively; P =.0002) Kantarjian HM, et al. Blood. 2011;117:

clinicaloptions.com/oncology Treatment of CML: State of the Art Nilotinib in Chronic-Phase CML: Complete Cytogenetic Responses  CGCR –Overall: 44% –Imatinib-resistant patients: 41% –Imatinib-intolerant patients: 51% –Proportion of patients with baseline CHR significantly higher vs those who did not (58% vs 36%, respectively; P =.0002) Kantarjian HM, et al. Blood. 2011;117:

clinicaloptions.com/oncology Treatment of CML: State of the Art Nilotinib Adverse Events Adverse Event, %All GradesGrade 3/4 Peripheral Edema60 Pericardial effusion< 1 Pleural effusion1< 1 Hematologic Anemia5311 Neutropenia5331 Thrombocytopenia5830 Kantarjian HM, et al. Blood. 2011;117:

clinicaloptions.com/oncology Treatment of CML: State of the Art Phase II Studies of Nilotinib After Imatinib Failure Kantarjian HM, et al. ASH Abstract le Coutre PD, et al. ASH Abstract Response, %CP (n = 321) AP (n = 137) MyBP (n = 106) LyBP (n = 30) HR  CHR Cytogenetic  Major  Complete

clinicaloptions.com/oncology Treatment of CML: State of the Art Bosutinib (SKI–606) in CP CML: Phase I/II  Src-Abl inhibitor 30 x more potent than IM; minimal inhibition of PDGFR, c-kit  Bosutinib mg/day (phase II: 500 mg/day) in 294 patients with chronic- phase CML and imatinib resistance/intolerance (no other previous TKIs); median follow-up: 23.8 mos  Grade 3/4 toxicity: thrombocytopenia 24%, neutropenia 16%, anemia 12%, diarrhea 9%, rash 9% Cortes J, et al. ASCO Abstract Response, %ResistantIntolerant Hematologic(n = 75)(n = 34)  CHR8897 Cytogenetic(n = 158)(n = 56)  MCyR6073  CCyR4659 Molecular(n = 108)(n = 43)  MMR5449  CMR3040

clinicaloptions.com/oncology Treatment of CML: State of the Art Survival by Response to Second TKI  113 CML patients (CP = 87; AP = 26) receiving nilotinib (n = 43) or dasatinib (n = 70) after imatinib failure This research was originally published in Blood. Tam CS, et al. Blood. 2008;112: © the American Society of Hematology Proportion Alive Mos From 12-Mo Landmark PCyR or CCyR miCyR or CHR Hematologic failure PCyR/CCyR vs rest: P =.01 nDeaths PCyR/CCyR642 miCyR/CHR346 Hematologic failure92

clinicaloptions.com/oncology Treatment of CML: State of the Art EFS, OS, McyR With Second TKIs in CML  Adverse factors: EGOC PS ≥ 1 and lack of CG to imatinib Jabbour E, et al. Blood. 2011;117: Risk Factor, n P =.001 P =.002 P = Month EFS 24 Month OS 12 Month MCyR 0 1 2

clinicaloptions.com/oncology Treatment of CML: State of the Art Prognosis With Second TKIs in CML: Application of EFS Model  Data suggest feasibility of a simple scoring system model –Easily applicable in the clinic  Outcome of patients after imatinib failure treated with second-generation TKIs, dependent on: –Cytogenetic response to imatinib –ECOG performance status at start of second therapy  Patients at high risk (ie, poor performance status and no previous CG response) have a low probability of responding to second-generation TKI Jabbour E, et al. Blood. 2011;117:

clinicaloptions.com/oncology Treatment of CML: State of the Art Allo SCT: Second or Third Salvage?  Imatinib failure in AP, BP: use new TKI as bridge to MRD, then allo SCT ASAP  T315I 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 chronic phase –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 failure –70 yrs of age or older or if poor match: may decide to forgo curative allo SCT option for several years of CML control

clinicaloptions.com/oncology Treatment of CML: State of the Art Ponatinib (AP24534) in CML  Oral TKI designed by computational drug design  IC 50 (nm): WT: 0.5; T315I: 11; F317V: 10; others: 1-35  Phase I: 2  60 mg daily; 74 pts  DLT: fatigue, QT , GI,  lipase/amylase  CP: CHR 95%; CGCR 53, CG major 66%, MMR 42%  T315I: CGCR 89%, CG major 100%, 2/2 AP Cortes. Blood 114: abst 643, 2009

clinicaloptions.com/oncology Treatment of CML: State of the Art Omacetaxine (HHT) in CML and T315I Post Imatinib Failure  90 pts, 66 evaluable: 40 CP, 16 AP, 10 BP  Median age 58 yrs; median CML 54 mos; 79% failed  2 TKIs  CP: T315I clones  57% in CP; 2-yr surv 88% Cortes. Blood 114:abst 644, 2009 CML phaseNo.%CHR/HR% CG response CP %; 15% major (2 CR, 2 PR) AP16371 CGCR BP1030

clinicaloptions.com/oncology Treatment of CML: State of the Art How Do You Choose the Second- Generation TKIs  Disease characteristics –AP/BP: favor dasatinib (?) and combinations –Chronic: see below  Mutations –T315I → none –Nilotinib IC50 > 150nM → avoid –Dasatinib IC50 > 3nM → avoid  Patient history –Hypertension, CHF, lung problems, COPD → avoid dasatinib –Severe diabetes, pancreatitis history → avoid nilotinib –QTc problems → be cautious with all (?)

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