Chronic Myeloid Leukemia 2010

1. Chronic Myeloid Leukemia 2010

2. Summary of CML therapy • TKI therapy is remarkably effective for CML-CP. • Some patients become resistant and progress. • Imatinib resistance can be treated by “second generation” TKIs (dasatinib or nilotinib), although CCyR can only be achieved in 50% of CP patients with IM resistance. • Monitoring endpoints correlate with long-term outcomes have been established using cytogenetic, PCR and mutation testing.

4. Have We “Optimized” First-line Therapy?

5. 1 0 0 9 0 8 0 7 0 E s t i m a t e d o v e r a l l s u r v i v a l 6 0 a t 8 y e a r s w a s 8 5 % (93%, considering onlyCML related deaths) % 5 0 , e v i l 4 0 A 3 0 2 0 S u r v i v a l : d e a t h s a s s o c i a t e d w i t h C M L 1 0 O v e r a l l S u r v i v a l 0 0 1 2 2 4 3 6 4 8 6 0 7 2 8 4 9 6 1 0 8 M o n t h s S i n c e R a n d o m i z a t i o n IRIS 8-Year UpdateResults: Overall Survival (Intent-to-Treat) – Imatinib Arm % Alive

6. ELN recommendations (2006 and 2009)

7. Using the ELN criteria, 25% of early CP cases would be declared a “failure” or “suboptimal response” of imatinib. • Another small proportion of cases will be intolerant to imatinib therapy.

8. The first approach is to just give more imatinib. (1) TOPS and other study showed that those patients who can tolerate higher doses of IM, without interruptions for side effects, have a better response. (2) It is not clear whether this will translate into long-term survival differences and how this strategy will compete with second-generation TKIs. • Dasatinib and nilotinib are second-generation TKIs approved for the treatment of patients with CML resistant or intolerant to imatinib. (1) CCyR: Resistant 50%; Intolerant 70% (2) Both drugs have been tried as first-line therapy in newly diagnosed CML-CP.

9. ENESTnd 24-Month Update: Continued Superiority of Nilotinib Versus Imatinib In Patients with Newly Diagnosed CML-CP Hughes TP, et al. Blood. 2010;116(21):94-95 [abstract 207] ENESTnd: Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Patients

10. Study Design and Endpoints R A N DO M I Z ED * 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 • Primary endpoint: MMR at 12 months • Key secondary endpoint: Durable MMR at 24 months • Other endpoints: CCyR, time to MMR and CCyR, EFS, PFS, time to AP/BC, OS Hughes TP, et al. Blood. 2010;116(21):94-95 [abstract 207]

11. MMR AT 12 and 24 Months* Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD P < . 0001 P < . 0001 P < .0001 P < .0001 % With MMR n = 282 n = 281 n = 282 n = 281 n = 283 n = 283 MMR at 24 months MMR at 12 months1 Durable MMR at 24 months:Less than 2% of patients in each treatment arm lost MMR between 12 and 24 months *ITT population 1. Saglio G, et al. NEJM. 2010;362:2251-2259. Data cut-off: 20Aug2010

12. Cumulative Incidence of MMR* n 100 Nilotinib 300 mg bid 282 By 24 months 90 Nilotinib 400 mg bid 281 Imatinib 400 mg qd 283 80 71%, P < .0001 By 12 months 70 55%, P < .0001 67%, P < .0001 60 Δ 23%-27% % with MMR 50 51%, P < .0001 44% Δ 24%-28% 40 30 27% 20 10 0 0 3 6 9 12 15 18 21 24 27 30 33 Time since randomization (Months) *ITT population Data cut-off: 20Aug2010

13. CCyR Rates by 24 Months* P = .0018 P = .016 % With CCyR n = 282 n = 281 n = 283 *ITT population Data cut-off: 20Aug2010

14. Suboptimal Response and Treatment Failure by 18 Months* % of Patients n = 282 n = 281 n = 283 n = 282 n = 281 n = 283 *ITT population Suboptimal response: < PCyR at 6 months; < CCyR at 12 months; < MMR at 18 months Treatment failure: No CyR at 6 months; < PCyR at 12 months; < CCyR at 18 months; at any time within 18 months loss of CHR, loss of CCyR, progression to AP/BC, or clonal evolution Patients satisfying criteria for both suboptimal response and treatment failure were counted as treatment failure Data cut-off: 20Aug2010

15. Progression to AP/BC onCore Treatment*† Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD P = .0059 P = .0003 P = .0196 P = .0089 Number of Patients 0.7% 1.1% 4.2% 0.7% 1.8% 6.0% Including Clonal Evolution *ITT population †Progression to AP/BC or death due to CML while on core treatment Data cut-off: 20Aug2010

16. PFS on Core Treatment*† *ITT population †Progression to AP/BC or death due to any cause while on core treatment Data cut-off: 20Aug2010

17. Overall Survival*† *ITT population †Including deaths after discontinuation of core treatment Data cut-off: 20Aug2010

18. Grade 3/4 Myelosuppression 21 12 % of Patients 12 11 10 9 5 4 4 Anemia Neutropenia Thrombocytopenia Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD Data cut-off: 20Aug2010

19. Selected Grade 3/4 Biochemical Abnormalities 9 8 8 7 6 5 % of Patients 4 4 3 3 < 1 0 Lipase ↑ ALT ↑ Total bilirubin ↑ Glucose ↑ Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD Data cut-off: 20Aug2010

20. Nilotinib continues to demonstrate: Superior CCyR, MMR, and CMR. Significantly fewer progressions to AP/BC. Lower rates of suboptimal response and treatment failure. Nilotinib at both doses was generally well-tolerated, and fewer adverse events lead to discontinuation in the nilotinib 300 mg BID arm. Longer follow-up supports the superiority of nilotinib for the treatment of patients with newly diagnosed CML-CP. ENESTnd 24-Month Update

21. The strategy for the treatment of newly diagnosed CML may change.

22. Debating Points • Whether or not a small benefit in early cytogenetic response with the second-generation TKIs will translate to a long-lasting survival benefit. • The wisdom of switching to second-generation drugs without long-term safety data. • Cost issues.

23. Is Resistance Forever?

24. One of the unifying features of the biology of CML is the genetic instability caused by Bcr-Abl. • The interval from the acquisition of Bcr-Abl and diagnosis allows Bcr-Abl signaling, and thus the genetic instability causing either resistance or progression. (1) Resistance is lowest in early-phase CP, higher in late CP, and higher yet in AP and BC. (2) Progression to CML-AP is associated with the consequences of instability. (3) Abl point mutations can be found in late-phase CP and AP CML even prior to initiation of TKI therapy.

25. At the time of resistance, selective pressure facilitates the outgrowth of multiple-resistant clonal populations. • Treatment with second generation TKI caused new natural selection forcing resistant clones to outcompete sensitive ones. • With sequential clonal selection, the proportion of patients carrying the T315I, which is resistant to both nilotinib and dasatinib, increases.

27. Implications of these observations • Once a patient fails primary TKI therapy, one cannot just expect treatment with a second-generation drug. ----- Allogeneic transplantation; Clinical trial (1) It is important to proceed to transplant before progression occurs. (2) Two studies have suggested measures of response to guide second-line TKI therapy, allowing physicians to declare failure early and expeditiously proceed to transplant.

28. Genetic instability is the rationale for more vigorous suppression of Bcr-Abl activity at the beginning of treatment. (1) A more complete suppression of Bcr-Abl could curtail genetic instability and thus delay or eliminate the disease progression and the creation of competing clones. (2) The contrarian point of view is that there will always be a significant proportion of CML that had the disease for years before diagnosis; and add whatever TKI you will, clonal selection will still proceed. • We need ways to predict response to therapy.

29. Can We Predict Response?

30. Functional Studies • TKIs are among the class of drugs potentially imported and exported by drug influx and efflux pumps. • Imatinib can be imported by OCT-1. OCT-1 activity and mRNA OCT-1 levels correlate well with response rate (OS, EFS, molecular response, and mutation rate) . • Intracellular levels of nilotinib and dasatinib are influenced by ABC efflux pumps activity.

31. Early BCR-ABL Response • Perhaps the best predictor of long term response is short-term response. • The Australian group have demonstrated BCR-ABL PCR response after 3 months of therapy is strongly associated with treatment outcomes (CCyR, MMR, and PFS).

32. Mutation Testing • Testing for the ABL mutations is not useful in newly diagnosed CP patients. • Both ELN and NCCN suggest mutation testing at the time of increasing Bcr-Abl levels, or at loss of response. • Rationale for this approach: (1) Identify patients to have a T315I mutation. (2) Identify patients has a mutation that is sensitive to one second-generation TKI, but not to the other. • Recent study concluded that, although T315I mutation testing was important, there was no clear data that testing of other mutations mattered, because the outcomes of patients with any mutation versus those without mutations were similar.

33. Problems with mutation test • How the in vitro sensitivity of mutations are performed and calculated. • As methods of detecting mutations vary, the significance of mutation detection may potentially vary from study to study. • Selection of patients entering studies, as well as definition of outcomes. • Follow-up is not standard across studies.

34. What Do We Mean When We Talk About “Cure”?

35. One routinely hears arguments that TKI therapy is not “curative,” as opposed to transplantation, which supposedly is “curative.” • Some TKI patients become PCR-. Some patients are able to come off therapy, and roughly 40% will remain in CMR. • Following allogeneic transplantation, roughly 10% of cases will be BCR-ABL+ by PCR after 5 years of follow-up. Long-term relapses occur, at a rate of approximately 1% per year. The longest relapse took place 18 years post transplant. • Given that it is likely mathematically improbable that all leukemia stem cells can be destroyed, perhaps we should use “cure” as relieving symptoms without detectable disease, freeing patients and doctors from the impossible expectation of eliminating all disease.

36. Conclusions—What Else to Do?

37. We need to determine to best use of second-generation TKIs. (1) Upfront with imatinib, then switch to more active agents if aggressive milestones are not reached? (2) Give more potent second-generation drugs first and then switch optimal responders to maintenance therapy with a cheap imatinib? • We need to conduct trials on how reacting to specific Abl mutations makes a difference, as well as determine if treatment of a molecular relapse is useful. • We need to determine if complete molecular response is a relative and useful endpoint. • Lastly, we await effective therapy of the T315I mutation, lest it be the final destination of all resistance.

38. Thanks!