EUROPEAN LEUKEMIANET RECOMMENDATIONS FOR CHRONIC MYELOID LEUKEMIA

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1 EUROPEAN LEUKEMIANET RECOMMENDATIONS FOR CHRONIC MYELOID LEUKEMIA SAN DIEGO, 11 DECEMBER 2011 AMSTERDAM, 14 JUNE 2012 BALTIMORE, 20 SEPTEMBER 2012 ATLANTA, 6 DECEMBER 2012 ELN, CML Panel Jane Apperley Michele Baccarani Francisco Cervantes Richard Clark Jorge Cortes Michael Deininger John Goldman François Guilhot Rüdiger Hehlmann Henrik Hjorth-Hansen Andreas Hochhaus Timothy Hughes Hagop Kantarjian Dong-Wook Kim Richard Larson Jeff Lipton François Xavier Mahon Giovanni Martinelli Jiri Mayer Martin Mueller Fabrizio Pane Jerald Radich Gianantonio Rosti Philippe Rousselot Giuseppe Saglio Susanne Saussele Charles Schiffer Richard Silver Bengt Simonsson Juan Luis Steegmann,

2 ELN Recommendations 2013 Recommendations and not guidelines International panel of experts, not only European The recommendations report the opinion of the majority of the experts and not necessarily the uniform opinion of all of them on all the aspects Consensus is reached by elaborating the answers to a series of questions and subsequent discussions.

3 Evolution of CML Treatment and Milestones 2013

4 2013: NewerFactsConsidered Recent data support the relevance of early molecular assessment to predict the outcome of TKI therapy. Withfrontline2 nd generationtki therapy,response is faster and deeper than with imatinib. This faster and deeper responses translate into less evolution to Accelerated & Blastic Phase of thediseaseandintohigher%ofmr 4.5

5 Parameters to evaluate response in CML Degreeof leukemicburdenreduction Time to achieveit

6 Monitoring Response in CML: Hierarchic Order Of Responses Leukemic Burden BCR-ABL% Hematologic 10 remission Optimal timing of response 11 is now2 logs changing CCyR Overall survival More stable response Low risk of progression Possibility to discontinue therapy MMR MR 4.5 CMR log 2/3 logs 100% 1% 0,1% % 10 5

7 ELN, OPTIMAL RESPONSE 2009* months -CHR, and -At least minor CgR (Ph + 65%) 6 months -At leastpcgr (Ph+ < 35%) -CHR, and -At least PCgR (Ph + < 35%) and / or -BCR-ABL < 10% -CCgR (Ph + 0), and / or -BCR-ABL < 1% 12 months -CCgR (Ph + 0) -MMR (BCR-ABL 0.1%) THEN -MMR (MR 3.0) or better -MMR (MR 3.0) or better Baccarani M et al., JClinOncol., 2009; 27: Baccarani em et al, submitted

8 Cumulative Incidence of MMR BCR-ABL IS at3 months<1% vs. 1-10% vs. >10% <1% 1-10% >10% BCR-ABL IS n <1% % 279 >10% 189 p<0.001 Hanfstein B et al.leukemia 1012

9 Overall Survival(OS) BCR-ABL IS at3 months 10% vs. >10% 10% >10% BCR-ABL IS n 5Y-OS p-value 10% % >10% % <0.001 Hanfstein B et al.leukemia 2012

10 Overall survival (OS) Ph+ at 3 months 35% vs. >35% 35% >35% Ph+ n 5Y-OS p-value 35% % >35% % Hanfstein B, et al. Leukemia Sep;26(9):

11 Importance of Molecular Response at 3 Months Survival with imatinib first line according to molecular response at 3 months. Hammersmith series (n= 282) BCR-ABL/ABL<9.8% OS= 93.3% Probability of survival BCR-ABL/ABL>9.8% OS= 54% p< Time from onset of imatinib therapy (years) Marin et al., JCO 2012; 30:232-38

12 6 months CCyR 12 months CCyR EFS EFS OS OS Jabbour E et al, Blood 2011

13 PFS according to BCR-ABL level at 3 months 100 dasatinib 100 mg QD 84% had 10% BCR-ABL 100 imatinib 400 mg QD 64% had 10% BCR-ABL Patients not progressed (%) BCR-ABL level at 3 months 3-Year PFS 1% 92.3% }P=.9639 >1-10% 94.0% }P=.0135 >10% 68.2% 10% vs >10% P= BCR-ABL level at 3 months 3-Year PFS 1% 100% }P=.3459 >1-10% 94.9% }P=.0002 >10% 75.2% 10% vs >10% P< Months Subjects at risk 1% >1-10% >10% Months Subjects at risk 1% >1-10% >10% Saglio G, et al. Blood. 2012;120(21):[abstract 1675].

14 Overall Survival according to BCR-ABL level at 3 months 100 dasatinib 100 mg QD 84% had 10% BCR-ABL 100 imatinib 400 mg QD 64% had 10% BCR-ABL Patients alive (%) BCR-ABL level at 3 months 3-Year OS 1% 95.5% }P=.7342 >1-10% 96.5% }P=.0525 >10% 85.9% 10% vs >10% P= BCR-ABL level at 3 months 3-Year OS 1% 100% }P=.3453 >1-10% 95.0% }P=.0110 >10% 87.8% 10% vs >10% P= Months 42 Subjects at risk 1% >1-10% >10% Months Subjects at risk 1% >1-10% >10% Saglio G, et al. Blood. 2012;120(21):[abstract 1675].

15 ENESTnd 5-Year Update Overall Survival by BCR-ABL Levels at 3 Months Nilotinib 300 mg BID Imatinib 400 mg QD EMR Failure: 9% of pts EMR Failure: 33% of pts Patients Alive, % BCR-ABL Level 1% > 1% to 10% > 10% Censored Observations Pts Evt Cen OS by 5 Years a 97.6% 95.7% Time Since Randomization, Calendar Years 81.9% P =.4871 P =.0007 Patients Alive, % BCR-ABL Level 1% > 1% to 10% > 10% Censored Observations Pts Evt Cen Time Since Randomization, Calendar Years OS by 5 Years a 99.2% 95.3% 79.5% P =.0873 P <.0001 Patients with EMR failure (BCR-ABL > 10% at 3 months) have significantly worse 5-year OS Rates of EMR failure are lower on nilotinib 300 mg BID vs imatinib Cen, censored; EMR, early molecular response; Evt, events; Pts, patients. a OS rates reported consider each year to consist of twelve 28-day cycles. 15 Saglio et al., ASH 2013 Data cutoff: May 22, 2013

16 BCR-ABL1 transcript levels at 3 months are the only requirement for predicting outcome for CML patients treated with TKIs Marin et al. J Clin Oncol Jan 20;30(3):232-8.

17 Proportion of Patients With MR 4.5 by BCR-ABL Levels at 3 Months Nilotinib 300 mg BID BCR-ABL IS 1%: 56% of pts Imatinib 400 mg QD BCR-ABL IS 1%: 16% of pts Patients With MR 4.5, % BCR-ABL Level 1% > 1% to 10% > 10% Pts % P =.0001 MR 4.5 by 4 Years a 28% P = % MR 4.5 by 5 Years a 70% 52% 8% P =.0046 P = Time Since Randomization, Calendar Years Patients With MR 4.5, % BCR-ABL Level 1% > 1% to 10% > 10% Pts MR 4.5 by 4 Years a 65% P < % 5% MR 4.5 by 5 Years a 67% 34% P =.0001 P =.0016 P = 15% Time Since Randomization, Calendar Years Patients with BCR-ABL 1% at 3 months have significantly higher rates of MR 4.5 by 5 years More patients achieve BCR-ABL 1% at 3 months on nilotinib 300 mg BID vs imatinib a Cumulative response rates reported consider each year to consist of twelve 28-day cycles. 17

18 Background for the Update of the ELN Recommendations No recommendation of a specific TKI as front-line therapy, but strong emphasis on the achievement of specific therapeutic goals. Shorter time frame and more stringent criteria for the evaluation of the response. The response to TKI therapy should be simplified as optimal and failure, eliminating the suboptimal category. Early molecular assessment can be used to guide TKI treatment.

19 3 registered drugs 3 options to be chosen according to the the patient s characteristics EUROPEAN LEUKEMIANET 2013 TREATMENT RECOMMENDATIONS, CHRONIC PHASE, FIRST LINE IMATINIB 400 mg or NILOTINIB 300 mg x 2 or DASATINIB 100 mg, Still investigational FOR ALL PATIENTS Contrasting data in the literature A higherdose of imatinib (600 to 800 mg) and the combination of a standard, 400 mg, dose of imatinib with different formulations of interferon-alfa have been shown to be highly effective (or to be competitive ), in some but not in all studies.

20 FROM RECOMMENDATIONS TO PRACTICE THE CHOICE OF THE TREATMENT DEPENDS ON MANY FACTORS EFFICACY SAFETY - (EARLY) SURROGATE MARKERS OF THE OUTCOMES (RATE, DEPTH, AND TIME OF CgR AND MolR) - CLINICAL OUTCOMES, PFS and OS SIDE EFFECTS -LONG TERM, OFF TARGET COMPLICATIONS PATIENT - ACUTE, SEVERE - CHRONIC, MILD 1.AGE 2. COMORBIDITIES 3. LIFESTYLE 4. EDUCATION 5. COMPLIANCE AND ALSO ON DRUG AVAILABILITY (NOT ALL DRUGS ARE AVAILABLE WORLDWIDE) AND COST (NOT ALL COUNTRIES HAVE THE SAME FINANCIAL POSSIBILITIES; THE COST OF THE DRUGS IS NOT THE SAME IN ALL COUNTRIES)

21 Efficacy: OS MR4.5 Risk: Long term toxicity

22 ENESTnd 5-Year Update Selected cardiovascular events by 5 years (all cause*, all grade) Patients With an Event, n Imatinib 400 mg QD n = 280 Nilotinib 300 mg BID n = 279 Nilotinib 400 mg BID n = 277 Total, n Y1-4, n Y5, n Total, n Y1-4, n Y5, n Total, n Y1-4, n Y5, n Ischemic Heart Disease(ICH) Ischemic cerebrovascular events (ICVE) Peripheral arterial disease (PAD) Due to the discontinuation rate, patients had longer exposure to nilotinib than imatinib Approximately 85% of patients with a cardiovascular event had at least 1 risk factor and were not optimally managed for hyperglycemia and hypercholesterolemia *All cause indicates all events, not only those deemed study drug-related by the investigator. Data cutoff: May 22, 2013 Saglio G, et al. Blood. 2013:[abstract 92].

23 Monitoringof TKI Treatmentof CP-CML Response Hematologic Monitoring Initial, every 2 weeks until CHR achieved and confirmed; then every 3 months Cytogenetic Molecular Mutation study Initial, at 3 and 6 months, then every 6 months until CCyR confirmed; then every 12 months if regular molecular monitoring not possible and in case of unexplained cytopenias. FISH of blood can substitute for conventional cytogenetics if marrow cells cannot be obtained and only for the definition of CCyR Every 3 months until MMolR achieved and confirmed; then at least every 6 months If failure or increase in transcript levels Baccarani et al., Blood 2013; 122:872-84

24 WHEN THE RESULTS OF HEMATOLOGIC, CYTOGENETIC, OR MOLECULAR TESTS ARE BORDERLINE OR ARE NOT CONGRUENT, BOTH METHODS OR A SECOND CHECK ARE ALWAYS RECOMMENDED.

25 ELN Treatment Policy 1st LINE Imatinib 400, Nilotinib 300 BID, Dasatinib 100 2nd LINE -Intolerance Switch to one of the other TKIs, taking into account comorbidities and side effects -Failure - Switch Imatinib to other TKI, considering mutations, comorbidities and side effects - Switch Nilo to Dasa, Bosu or Pona - Switch Dasa to Nilo, Bosu or Pona - Allogeneic Stem Cell Transplant 3rd LINE - Switch to another TKI (Pona) - Allogeneic Stem Cell Transplant - Experimental treatment Anyline, T315I mutation - Ponatinib, search for donor and consider allo Stem Cell Transplant

26 For those who are not optimal responders to first-line therapy, when to change therapy?

27 EUROPEAN LEUKEMIANET 2013 RESPONSE TO TREATMENT FIRSTLINE, IMATINIB, NILOTINIB, and DASATINIB Wait& Youcan monitor also wait& more closely! monitor more closely! OPTIMAL WARNING FAILURE Switch! BASELINE NA -HIGH RISK, -CCA/Ph+ (Major route) 3 mo Ph+ 35% and/or BCR-ABL 10% 6 mo Ph+ 0 and/or BCR-ABL < 1% Efficacy of switching is not Ph % and/or BCR-ABL 10% Ph % and/or BCR-ABL 1-10% NA No CHR and/or Ph+ > 95% yet demonstrated Ph + > 35% and/or BCR-ABL > 10% 12 mo BCR-ABL 0.1% BCR-ABL % Ph + 1%, and/or BCR-ABL >1% 24 mo BCR-ABL 0.1% BCR-ABL 0.1-1% BCR-ABL > 1% Yellow = cytogenetic response Baccarani M et al., submitted comm.

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31 Thank you for your attention!