Chronic Myeloid Leukemia - Hematology Highlights -

1. Neil Shah, MD PhD Edward S. Ageno Distinguished Professor in Hematology/Oncology UCSF School of Medicine San Francisco, California Chronic Myeloid Leukemia - Hematology Highlights -

2. Chronic Phase CML Treatment Landscape Evolution

3. Chronic Phase CML Treatment Landscape Evolution Imatinibapproved by FDA 2000 2002 2004 2006 2008 2010 2012

4. Chronic Phase CML Treatment Landscape Evolution Imatinibapproved by FDA Dasatinib approved for resistant or intolerant CML 2000 2002 2004 2006 2008 2010 2012

5. Chronic Phase CML Treatment Landscape Evolution Imatinibapproved by FDA Dasatinib approved for resistant or intolerant CML 2000 2002 2004 2006 2008 2010 2012 Nilotinib approved for resistant or intolerant CP Ph+ CML

6. Chronic Phase CML Treatment Landscape Evolution Imatinibapproved by FDA Nilotinib approved for frontline treatment of CML Dasatinib approved for resistant or intolerant CML 2000 2002 2004 2006 2008 2010 2012 Nilotinib approved for resistant or intolerant CP Ph+ CML

7. Chronic Phase CML Treatment Landscape Evolution Dasatinib approved for frontline treatment of CML Imatinibapproved by FDA Nilotinib approved for frontline treatment of CML Dasatinib approved for resistant or intolerant CML 2000 2002 2004 2006 2008 2010 2012 Nilotinib approved for resistant or intolerant CP Ph+ CML

8. Chronic Phase CML Treatment Landscape Evolution Dasatinib approved for frontline treatment of CML Imatinibapproved by FDA Nilotinib approved for frontline treatment of CML Dasatinib approved for resistant or intolerant CML Omacetaxineapproved for CML resistant/intolerant to ≥2 TKIs 2000 2002 2004 2006 2008 2010 2012 Nilotinib approved for resistant or intolerant CP Ph+ CML

9. Chronic Phase CML Treatment Landscape Evolution Dasatinib approved for frontline treatment of CML Imatinibapproved by FDA Nilotinib approved for frontline treatment of CML Dasatinib approved for resistant or intolerant CML Omacetaxineapproved for CML resistant/intolerant to ≥2 TKIs 2000 2002 2004 2006 2008 2010 2012 Nilotinib approved for resistant or intolerant CP Ph+ CML Bosutinib approved for resistant or intolerant CML

10. Chronic Phase CML Treatment Landscape Evolution Dasatinib approved for frontline treatment of CML Imatinibapproved by FDA Nilotinib approved for frontline treatment of CML Dasatinib approved for resistant or intolerant CML Omacetaxineapproved for CML resistant/intolerant to ≥2 TKIs 2000 2002 2004 2006 2008 2010 2012 Nilotinib approved for resistant or intolerant CP Ph+ CML Bosutinib approved for resistant or intolerant CML Ponatinib approved for resistant or intolerant CML

11. Chronic Phase CML - Goals of Therapy

12. Chronic Phase CML - Goals of Therapy • Prevention of disease transformation to blast phase • Chronic phase CML is not immediately life-threatening, so if blast phase can be prevented indefinitely, patients will be “functionally” cured • May require lifelong therapy • Chronically administered therapies should ideally be well-tolerated and minimally intrusive to everyday life

13. Chronic Phase CML - Goals of Therapy • Prevention of disease transformation to blast phase • Chronic phase CML is not immediately life-threatening, so if blast phase can be prevented indefinitely, patients will be “functionally” cured • May require lifelong therapy • Chronically administered therapies should ideally be well-tolerated and minimally intrusive to everyday life • True disease cure - enabling patients to be off all therapies • Allogeneic stem cell transplantation – best established curative therapy (~70% cure rate) • ~20% risk of short-term death (1-2 years) • ~50-60% risk of chronic graft vs host disease • “trading one disease for another”

14. MONITORING DISEASE IN PATIENTS WITH CML

15. Treatment Response Level of Response Definition Complete hematologic response (CHR) Normal CBC and differential, no extramedullary disease Minor cytogenetic response 36%–90% Ph-positive metaphases* Partial cytogenetic response (PCyR)† 1%–35% Ph-positive metaphases* Complete cytogenetic response (CCyR)† 0% Ph-positive metaphases* Major molecular response (MMR) ≥3-log reduction of BCR-ABL Complete molecular response Negativity by RT-PCR (≥4.5 log reduction of BCR-ABL) *Cytogenetic response is based on analysis of at least 20 metaphases. †PCyR + CCyR = major cytogenetic response (MCyR). Adapted from NCCN Clinical Practice Guidelines in Oncology: chronic myelogenous leukemia. V.3.2008. http://www.nccn.org. Accessed 02/04/2008; Deininger MW. Hematology Am SocHematolEduc Program. 2005;174-182.

16. Monitoring Disease Burden in CML Cytogenetics FISH 1-2 log reduction RT-PCR CML (log10) MMR = 3 log ~ 5-6 log reduction Dx Treatment Time

17. IMATINIB AS FRONTLINE THERAPY FOR CML

18. IMATINIB AS FRONTLINE THERAPY FOR CML 7-8 year update of newly-diagnosed Chronic Phase CML patients treated with 400 mg daily imatinib O’Brien et al. ASH 2008, Abstract 186

19. Overall Survival (ITT Principle): Imatinib Arm 100 90 80 70 Estimated overall survival at 8 years is 85% (93% considering only CML-related deaths) 60 % Without Event 50 40 30 Survival: deaths associated with CML 20 Overall Survival 10 0 0 12 24 36 48 60 72 84 96 Months Since Randomization Deininger et al. ASH 2009, Abstract 1126

20. ImatinibHas Revolutionized the Therapeutic Landscape for Patients With CML Best Available Therapy 5-Yr OS, % Imatinib* 93 IFN- or SCT plus 2nd-line imatinib† 71 IFN- or SCT‡ 63 IFN- 53 Hydroxyurea 46 Busulfan 38 2010 1.0 0.9 2002-2008, imatinib* 0.8 2000 0.7 1997-2008, IFN- or SCT plus 2nd-line imatinib† 0.6 1990 Survival Probability (All Ph+ CML Disease Phases) 0.5 1995-2008, IFN- or SCT‡ 0.4 1980 0.3 1986-2003, IFN- 0.2 1983-1994, hydroxyurea 0.1 1970 1983-1994, busulfan 0 0 2 4 6 8 10 12 14 16 18 20 22 1960 Yrs After Diagnosis *CML IV. †CML IIIA. ‡CML III. Leitner AA, et al. Internist (Berl). 2011;52:209-217.

21. IMATINIB DISCONTINUATION STUDIES Can imatinib be safely stopped in patients with deep molecular responses?

22. STIM study design N=100 Q- RT-PCR from peripheral blood every month in the first year and every 2 months thereafter STOP Start Imatinib CMR Sustained CMR for ≥ 2 years Molecular recurrence: positivity of BCR–ABL transcript in Q-RT-PCR confirmed by a second analysis point indicating the increase of one log in relation to the first analysis point, at two successive assessments, or loss of MMR at one point. Five BCR–ABL analyses by Q- RT-PCR during these 2 years Sixth datapoint checked in centralized laboratory Mahon FX et al. The Lancet Oncology, 2010;11(11): 1029-1035.

23. Treatment-free survival At 60 months 40% ( 95% CI: 30-49)

24. Follow-up of the molecular-relapse patients (n=61) Among the 57 patients alive another attempt of TKI discontinuation was proposed for 16 patients in sustained CMR

25. Conclusions • With longer follow-up: • Approximately 40 percent of patients in CMR are able to discontinue imatinib without suffering molecular relapse • Second and third attempts at treatment discontinuation in patients who have suffered molecular relapse are ongoing • Discontinuation should only be performed in the context of a clinical trial with strict molecular monitoring and plans for careful long-term follow up. • Many ongoing trials are assessing TKI cessation in patients with sustained CMR. • A very long-term follow-up of various cessation studies necessary to affirm CML cure.

26. Imatinib: the gold medal winner?

27. Imatinib: IRIS 8-Yr Update Shows 37% Have Unacceptable Outcome *Unacceptable outcome. Deininger M, et al. ASH 2009. Abstract 1126.

28. Annual Event Rates: Imatinib Arm EventLoss of CHR,Loss of MCR, AP/BC,Death during treatment AP/BC • KM estimated EFS at 8 years = 81% • KM estimated rate without AP/BC at 8 years = 92% 7.5 4.8 % With Event 3.3 2.8 2.0 1.7 1.6 1.5 * 1.2 0.9 0.8 0.5 0.4 0.3 0.4 0 Year *Total events (n=3) including two CML-unrelated deaths (n=2), and one patient with progression to AP/BC Deininger et al. ASH 2009, Abstract 1126

29. Most Frequently Reported AEs: First-Line Imatinib • Only Serious Adverse Events (SAEs) were collected after 2005 • Grade 3/4 adverse events decreased in incidence after years 1-2 O’Brien et al. ASH 2008, Abstract 186

30. Imatinib - Conclusions • Imatinib (400 mg daily) remainsthestandard dose forchronicphase CML patients • 85% overall survival with imatinib exceeds that of all other CML therapies, with 7% patients dying from CML after eight years • 82% ofpatientstreatedwithimatinibachieved a CCyR • 55% of all imatinibrandomizedpatientsare still on studytreatment, andnearly all oftheseare in CCyR • Responses are typically durable, and the annual risk of progression generally decreases with time • Some patients appear to be able to have prolonged treatment-free molecular remissions • No new safety findings seen with long term follow-up

31. Imatinib: maybe the silver medal winner?

32. IMATINIB-RESISTANT DISEASE How is it defined?

33. Imatinib Resistance in Chronic Phase CML Definitions • Primary resistance: lack of an acceptable initial response • Primary hematologic resistance – rare • Primary cytogenetic resistance – ~35% of patients • lack of PCyR (≤35% Ph) by 3 months • lack of CCyR (0% Ph) by 12 - 18 months

34. Imatinib Resistance in Chronic Phase CML Definitions • Primary resistance: lack of an acceptable initial response • Primary hematologic resistance – rare • Primary cytogenetic resistance – ~35% of patients • lack of PCyR (≤35% Ph) by 3 months • lack of CCyR (0% Ph) by 12 - 18 months • Secondary resistance: loss of an established initial response (relapse despite tx) • Hematologic Relapse – WBC >nl and increasing) • Cytogenetic Relapse – ≥30% increase in Ph+ metaphases • Molecular Relapse – confirmed 1-log increase in BCR-ABL transcript level with lack/loss of MMR

35. Imatinib Resistance in Chronic Phase CML Definitions • Primary resistance: lack of an acceptable initial response • Primary hematologic resistance – rare • Primary cytogenetic resistance – ~35% of patients • lack of PCyR (≤35% Ph) by 3 months • lack of CCyR (0% Ph) by 12 - 18 months • Secondary resistance: loss of an established initial response (relapse despite tx) • Hematologic Relapse – WBC >nl and increasing) • Cytogenetic Relapse – ≥30% increase in Ph+ metaphases • Molecular Relapse – confirmed 1-log increase in BCR-ABL transcript level with lack/loss of MMR Primary resistance is a risk factor for the development of secondary resistance

36. 100 90 80 70 60 Patients without AP/BC (%) 50 Estimated rate at 60 months Response at 18 months 40 CCyR with ≥3 log reduction n=139 100% 30 P=.11 P<.001 CCyR with <3 log reduction n=54 98% 20 No CCyR n=88 87% 10 0 0 6 12 18 24 30 36 42 48 54 60 66 Imatinib Survival Without Accelerated Phase/Blast Crisis by Molecular Response: IRIS Study Time (months since randomization) Druker B et al. N Engl J Med. 2006;355:2408-2417.

37. IMATINIB-RESISTANT DISEASE Can it be identified earlier than six months, ideally by less invasive methods than bone marrow aspiration?

38. BCR-ABL/ABL after 3 Months of Imatinib Predicts OS Outcomes 1.0 BCR-ABL/ABL< 9.84% 8-yr OS: 93.3% 0.8 BCR-ABL/ABL > 9.84% 8-yr OS: 56.9% 0.6 Probability of Survival P < .001 0.4 0.2 0 0 1 2 3 4 5 6 7 8 Time From Onset of Imatinib Therapy (Yrs) Marin D, et al. J Clin Oncol. 2012;30:232-238.

39. Individual 3-month decline of BCR-ABL transcriptlevelsasan optimizedpredictorofsurvival in CML B. Hanfstein, V. Shlyakhto, R. Hehlmann, M. Lauseker, S. Saussele, P. Erben, A. Fabarius, U. Proetel, S. Schnittger, H.J. Kolb, S.W. Krause, J.E.A. Schubert, H. Einsele, M. Hänel, J. Dengler, C. Falge, L. Kanz, A. Neubauer, M. Kneba, F. Stegelmann, M. Pfreundschuh, C.F. Waller, K. Spiekermann, G.M. Baerlocher, M. Pfirrmann, J. Hasford, W.-K. Hofmann, A. Hochhaus and M.C. Müller for the SAKK and the German CML Study Group

40. Absolute 3-month transcriptlevelsgive an estimateofBCR-ABL slope 3 months diagnosis 100% BCR-ABLIS (%) ? 10% Time since imatinib onset

41. BCR-ABL slopeisdefinedby3-month reductionratiooftranscripts diagnosis 3 months reductionratio= BCR-ABLIS(%) BCR-ABL at 3 months BCR-ABL atdiagnosis Time since imatinib onset

42. Wide variability in BCR-ABL transcriptlevels in untreatedpatients • Median 33% • Range 1-230 BCR-ABLIS (%) using GUS (CF=2.18) Patient #

43. Progression-freesurvival (PFS) accordingto BCR-ABL reductionto0.35-fold at3 months BCR-ABL reductionton5Y-PFSp-value ≤ 0.35-fold 25396% >0.35-fold 48 77% <0.001

44. Progression-freesurvival (PFS) accordingto10% BCR-ABLIS at 3 months • BCR-ABLISat 3 monthsn5Y-PFS p-value • ≤ 10% 234 95% • > 10% 67 87% n.s.

45. Overall survival (OS) accordingtoBCR-ABL reductionto0.35-fold at3 months • BCR-ABL reductionton5Y-OS p-value • ≤ 0.35-fold 253 98% • >0.35-fold 4883% 0.001

46. Overall survival (OS) accordingto10% BCR-ABLISat 3 months • BCR-ABLISat 3 monthsn5Y-OS p-value • ≤ 10% 234 97% • > 10% 67 90% n.s.

47. Conclusions • BCR-ABLIS ratiosatdiagnosisvary in a widerange (1-230%). • The assumptionof 100% BCR-ABLISatdiagnosisdoes not reflectthe real-lifesituation. • Individual baselinelevelshavetobetakenintoaccount, when3-month levelsareinterpreted. • Noprognosticimpactcanbederivedfrombaseline BCR-ABL. • The individual declinetothe 0.35-fold ofbaselinelevelswithin 3 monthsyieldeda betterdiscriminationwithregardtoPFS and OS thanthe 10% BCR-ABLIScut-off. • High-riskpatients in needoftreatmentescalationmightbeidentifiedmorepreciselybythe individual declineof BCR-ABL transcriptsat 3 monthsoftreatment.

48. FRONTLINE THERAPY FOR CML How active are newer agents in the frontline management of CP-CML?

49. ENESTnd 5-Year Update ENESTnd Update: Nilotinib vs Imatinib in Patients With Newly Diagnosed CML-CP and the Impact of Early Molecular Response and Sokal Risk at Diagnosis on Long-Term Outcomes G. Saglio, A. Hochhaus, T. P. Hughes, R. E. Clark, H. Nakamae, D.-W. Kim, S. Jootar, G. Etienne, I. W. Flinn, J. H. Lipton, R. Pasquini, B. Moiraghi, C. Kemp, X. Fan, H. D. Menssen, H. M. Kantarjian, and R. A. Larson, on behalf of the ENESTnd Investigators 49

50. ENESTnd Study Design • Patients were stratified according to Sokal risk score at diagnosis R A N DO M I Z E Nilotinib 300 mg BID (n = 282) N = 846 217 centers 35 countries Nilotinib 400 mg BID (n = 281) Imatinib 400 mg QD (n = 283) Follow-up: 5 years; extended to 10 years after protocol amendment 50 BID, twice daily; QD, once daily.