1. Practical management of CML Andreas Hochhaus Universitätsklinikum Jena, Germany

2. Improvement of survival of CML by therapy 1983 – 2011 German CML Study Group Year after diagnosis Survival probability n = 3615 Imatinib, 2002 – 2011 (CML IV) 5-year survival 90% 8-year survival 88% IFN or SCT, 1997 – 2003 (CML IIIA) 5-year survival 71% IFN or SCT, 1995 – 2001 (CML III) 5-year survival 63% IFN, 1986 – 1994 5-year survival 53% Hydroxyurea, 1983 – 1994, 5 yr surv. 44% Busulfan, 1983 – 1994 5-year survival 38% (CML I, II)

3. Estimated Prevalence of CML in Europe until 2050 Assumptions: Population 500 million, mortality 2% per year, incidence constant. Courtesy to Hasford and Pfirrmann. 1:2000

4. Overall survival on imatinib therapy: Impact of major route aberrations Fabarius et al., Blood. 2011 Oct 28. [Epub ahead of print] (+8, +Ph, iso(17))

5. Prediction of prognosis Sokal EUROEUTOS 198419982011 ParametersAgeAge SpleenSpleenSpleenBlastsPlatelets EosinophilsBasophils Treatment ChemotherapyIFNImatinib EndpointSurvivalSurvivalCCyR

6. EUTOS Score Hasford et al., Blood 2011 Time to CCyR PFS Spleen (cm below costal margin) % Basophils in PB

7. BCR-ABL IS n 5Y-OS ≤1% 21897% 1-10% 28394% >10% 19187% Overall Survival (OS) BCR-ABL IS at 3 months ≤1% vs. 1-10% vs. >10% n.s. 0.012 p-value ≤1% 1-10% >10% Hanfstein et al., ASH 2011

8. www.cellsignal.com TKI off-target effects?

9. Growth retardation of children on imatinib therapy Mariani S et al. Lancet, 2008 Schmid H et al. Haematologica, 2009 Kimoto T et al. Int J Haematol, 2009

10. Cytopenias and BCR-ABL Inhibitors These data are from separate studies. (1) Rosti G, et al. Blood. 2009 (2) Cortes JE, et al. JCO. 2010 (3) Hochhaus A, et al. Haematologica. 2011;96(s2):203-4 [abs 484, oral]. (4) Druker BJ, et al. NEJM. 2006 (5) Cortes JE, et al. JCO. 2010 (6) Hochhaus A, et al. Haematologica. 2011;96(s2):422 [abs 1011, oral]. (7) Gambacorti-Passerini C, et al. Blood 2010;116 [abs 208, oral]. 17.3 mo follow up (2) 24 mo follow up (5) 24 mo follow up (6) 24 mo follow up (3) 24 mo follow up (4) 12 mo follow up (7) 15 mo follow up (1) SRC Kinases: key signaling role in normal hematopoiesis 0

11. BCR-ABL Inhibitors and Infections Imatinib No increase in the rate of infections in registration studies (<1%). Nilotinib No increase in the rate of infections in registration or expanded access studies. Dasatinib In 55 pts: 56% had infections: 5.5% Neutrophils < 1/nL; Most: Localized. Opportunistic infections: In 1150 pts: 5%, 1% grade 3/4 including herpes simplex (2), herpes zoster (2), mycobacterial infection(1), cytomegalovirus infection (1), pneumocystis (2), unspecified fungal infection(1). Hochhaus et al. Leukemia 2009 Le Coutre et al. Blood 2009; 114 [abs 3286]. Al-Ameri et al. Blood 2009; 114 [abs 1120].

12. All gradesNilotinib ENESTnd* Imatinib ENESTnd* Dasatinib DASISION* Imatinib DASISION* Peripheral edema11%56%11%36% Pleural effusion<1%0%14%0% These data are from separate studies. Hughes TP, et al. Blood. 2010;116(21):94-95 [abstract 207]. Larson R. A. et al. JCO 28:7s ASCO 2010 [suppl; abs 6501, Oral]. Hochhaus A, et al. Haematologica. 2011;96(s2):422 [abstract 1011]. Pathogenesis and Incidence of Fluid Retention *24 months follow up

13. Hyperglycemia and Nilotinib n Imatinib and dasatinib can lower glucose levels n Nilotinib may induce hyperglycemia in patients at risk Incidence: All grades: 38-42% (Grade 3-4: 4-6%) In non-diabetic patients Median variation: +0.4 mmol/L In diabetic patients Median variation: +0.8 mmol/L 69% did not change diabetes therapy CML response not affected Mariani S, et al. Leuk Res 2010 Breccia et al. Leuk Res 2008 Breccia et al. Leuk Res 2007 Saglio G, et al. Blood 2010;116 [abs 3430]. Saglio G, et al. NEJM 2010;362(24):2251-2259.

14. TKI drug interactions Drugs inhibiting CYP3A4 may increase TKI exposure ketoconazole, itraconazole, voriconazole erythromycin, clarithromycin, telithromycin ritonavir, atazanavir, indinavir, nelfinavir, saquinavir, nefazodon, CYP3A4 inducers may decrease TKI exposure dexamethasone, rifampicin, rifabutin, phenytoin, carbamazepin, phenobarbital Concomitant use of TKI and CYP3A4 substrates may increase substrate exposure (narrow therapeutic index!) fentanyl, alfentanil astemizole, terfenadine cyclosporine, sirolimus, tacrolimus quinidin, ergot alkaloids, pimozide, cisapride simvastatin Grapefruit juice may increase TKI plasma concentration

15. Relative toxicities of TKIs in independent second-line trials after imatinib failure % Severe toxicity Imatinib* (Druker et al. 2006) Nilotinib (Nicolini et al. 2009; Dasatinib (Shah et al., 2008) Bosutinib (Cortes et al., 2010) Myelosuppression +++++++ Fluid retention ++-+++- Diarrhea ++++++  Glucose /  Lipase -+-- Druker et al. N Engl J Med. 2006 Nicolini et al. Haematologica (EHA Meeting Abstracts) 2009; 94(s2): Abstract 0630 Shah et al. Blood (ASH Annual Meeting Abstracts), Nov 2008; 112: 3225. Cortes et al. JCO. 2010; ASCO Ann. Meeting Proc. 28, 15S: 6502 * first line

16. Imatinib 800 mg vs. imtinib 400 mg +/- IFN Time to MMR by therapy n = 970 Hehlmann et al., J Clin Oncol 2011

17. CML-Study IV: Tolerability adapted dosage Hehlmann et al., J Clin Oncol 2011

18. Apperley, Lancet 2007

19. Predicting responses to second line TKI 21% 100% poor >2.5 intermediate≥1.5 <2.5 good <1.5 RiskScore Milojkovic et al, Haematologica 2010  Cytogenetic response to imatinib  Sokal score  Recurrent neutropenia

20. Transplantations for CML in Europe 2009 (3% of all indications) Gratwohl et al. Bone Marrow Transplant, 2011

21. Role of patients‘ advocates The CML community is an outstanding example for global patient advocacy – not to be seen in many other cancers Patients advocates have become an independent, strong community, supporting patients across the globe credible partner of clinicians (iCMLf, ELN), industry and authorities advisors of clinicians, research projects, industry A political voice: Access to diagnostics and therapies TKI reimbursement decisions "Information to patients" policy.

22.  Mission: to improve the outcomes for patients with CML globally  Aims: Foster and coordinate global clinical and research collaborations and to improve clinical practice and disease monitoring in CML  Advisors: 34 countries from all continents including patient group representation  Established by a group of leading hematologists  Founded & registered in 2009 as a charitable foundation PROJECTS: Emerging Regions Support and Partnership Preceptorship Program iCMLf Virtual Education Program Diagnosis and Testing Program Increasing access to equipment and facilities to enhance the diagnosis and monitoring of CML patients thus improving potential outcomes. The iCMLf Online

23. Prevalence increasing First line therapy improving Tailoring treatment according to molecular milestones feasible Selection of second line therapies based on patient history and molecular parameters Option for discontinuation after stopping TKI Life long surveillance needed Long term management of CML patients: Response consolidation >1 year Targeting detectable or undetectable residual disease with acceptable toxicity profile. TKI discontinuation Continuous MR Follow up IFN ? MR 4-4.5 Response induction Most active BCR-ABL inhibitor Combinations >2 years Diagnosis

24. Jane Apperley Nick Cross Ekkehard Eigendorff Thomas Ernst Alice Fabarius Jan Geissler Benjamin Hanfstein Jörg Hasford Rüdiger Hehlmann Tim Hughes Elias Jabbour Paul La Rosée David Marin Martin C. Müller Markus Pfirrmann Jerry Radich Giuseppe Saglio Susanne Saussele Giora Sharf Juan Luis Steegmann Meinolf Suttorp