Evolving CML Treatment Landscape

Evolving CML Treatment LandscapeGLEEVEC (imatinib)approved by FDA1TASIGNA (nilotinib) for resistant or intolerant CP Ph+ CML approved by FDA31st-Line CP Ph+ CML approval of TASIGNA3SPRYCEL (dasatinib) for resistant or intolerant CP Ph+ CML approved by FDA21st-Line CP Ph+ CML approval of SPRYCEL22000201020122008200620042002Ponatinib approved for resistant or intolerant CML Bosutinib approved for resistant or intolerant CML #You may not show or distribute this item outside BMS.You may NOT discuss the information in this item with customers.Speaker NotesSince initial discovery of the Philadelphia chromosome in 19601 and FDA approval of GLEEVEC (imatinib) in 2001,2 the treatment landscape of CML continues to evolveRead as stated

References1. Wong S, Witte O. Annu Rev Immunol. 2004;22:247306.2. GLEEVEC (imatinib) Full Prescribing Information. Novartis.

1Nilotinib and Dasatinib in Previously Untreated Chronic Phase CML PatientsConcluding ThoughtsNilotinib and dasatinib are superior to imatinib at achieving deep responses and are associated with a lower likelihood of transformation to accelerated/blast phase diseaseThe tolerability of nilotinib and dasatinib appears generally comparable to or slightly better than imatinibPatients and physicians have three approved TKI treatment options for newly diagnosed chronic phase CMLOf these, imatinib has the longest and most convincing safety record2Most Frequently Reported AEs: First-Line ImatinibMost Common Adverse Events (by 5 Years)All Grade AEs Patients, %Grade 3/4 AEs Patients %Superficial Edema602Nausea501Muscle cramps492Musculoskeletal pain475Diarrhea453Rash/skin problems403Fatigue392Headache37 0.1% (loss of MMR) on the IS at one time pointDR

EURO-SKI: Molecular Relapse Free Survival200 interim patients overtime, loss MMR=89

At 6 months : 63 % (95% CI : 55% - 69%)At 12 months: 56 % (95% CI : 49 % - 63 %)At 18 months : 55 % (95% CI : 47 % - 61 %)Relapses within 6 months , n=77

Mahon FX et al, Blood 2014 124:151PatientsGrade 1-4nPatientsGrade 3nAEsGrade 1-4nAEsGrade 3nMusculoskeletal pain, joint pain, arthralgia233396Other (sweating, skin disorders, folliculitis, depressive episodes, fatigueurticaria, weight loss)80183Do Adverse Events Occur With TKI Withdrawal?n=200

Musculoskeletal pain in CML patients after discontinuation of imatinib: a tyrosine kinase inhibitor withdrawal syndrome?J. Richter et al. J Clin Oncol. 2014 Sep 1;32(25):2821-3.

Tyrosine kinase inhibitor withdrawal syndrome: a matter of c-kit ?Response to Richter et al. Ph. Rousselot et al. 222 AEs in 98 patients were reported57 AEs in 31 patients were related to treatment stop, no grade 4Mahon FX et al, Blood 2014 124:151N auf dieser Folie um 4 hher, da hier auch die bercksichtigt werden, die ihr Einverstndnis zurckgezogen haben42With longer follow-up:Approximately 40 percent of patients in CMR are able to discontinue imatinib without suffering molecular relapseSecond 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 duration of follow-up of patients on TKI cessation studies is necessary to determine whether any of these patients are cured.TKI Discontinuation: Conclusions

CML is more than ever a model for raising awareness of curability

43BCR-ABL TKIs have transformed chronic phase CML to a manageable chronic condition in the vast majority of casesExcessive delays in diagnosis/treatment of chronic phase CML can be highly detrimental to long-term outcomesEffective monitoring is required to maximize therapeutic outcomesAdherence to treatment is critical to maximize the likelihood of a favorable outcome

Timely recognition and treatment of TKI resistance is necessary to maximize therapeutic outcomesCertain BCR-ABL kinase domain mutants may respond preferentially to a particular TKI

Many TKI manufacturers offer copayment assistance to minimize the cost to patients

Conclusions

CML is more than ever a model for raising awareness of curability

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