Safety and Efficacy of Nilotinib in Newly Diagnosed Chronic Myeloid Leukemia Patients

• Nilotinib (Drug), also known as AMN107: This was an open-label, single-arm, prospective, multi-center, Phase IIIb clinical study with nilotinib 300 mg bid treatment in newly diagnosed CML-CP patients not previously treated with imatinib therapy and diagnosed within 6 months of study entry. For patients insufficiently responding to nilotinib 300 mg bid, the dose may have been increased to 400 mg bid. Among patients with adverse events who had dose reduction, this study also allowed a possible re-escalation to 300 mg bid.

Primary outcomes

• The Percentage of Patients Achieving MMR by 12 Months [12 months]: MMR is defined as BCR-ABL ratio (%) on IS <= 0.1% (corresponds to >=3 log reduction of BCR-ABL transcripts from standardized baseline value). Clopper-Pearson method

Secondary outcomes

• Time to Molecular Response at 24 Months [24 months]: Estimated median time to first MMR by Kaplan-Meier method
• Duration of Major Molecular Response [3, 6, 9, 12, 15, 18, 21, 24 Months after MMR was detected]: Kaplan-Meier estimates of duration of first MMR among patients who achieved MMR (FAS) Duration of first MMR (months) = (Minimum date of (loss of first MMR , CML-related death, progression to AP/BC during study treatment, censoring) - date of first MMR + 1) / 30.4375
• Complete Cytogenetic Response [6 months]: Complete cytogenetic response (CCyR) is defined as a value of 0% Ph+ metaphases in bone marrow.
• Percentage of Participants Estimated to Maintain Their First CCyR for 6, 12, 18, and 24 Months After the First CCyR Was Achieved as Determined by Kaplan Meier Estimatation. [6,12,18 and 24 months]: * CCyR = 0% Ph+ metaphases based on at least 20 metaphases from bone marrow cytogenetics. Duration of first CCyR (months) = (date of CCyR loss or censoring - date of first CCyR +1) / 30.4375
• Overall Survival [3, 6, 9, 12, 15, 18, 21, 24 Months]: OS was defined as the time between date of study entry and date of death due to any cause at any time during the study, including the follow-up period after discontinuation of treatment.
• Kaplan-Meier Estimates of Progression-free Survival [3,6,9,12,15,18,21,and 24 months]: PFS was defined as the time from the date of study entry to the date of event defined as the first documented disease progression to AP/BC or the date of death from any cause occurring on treatment.
• Kaplan-Meier Estimates of Failure-free Survival [3,6,9,12,15,18,21,and 24 months]: Time to event (months) = (date of event or censoring - date of study entry + 1) / 30.4375. Date of event is the earliest date of the following events during treatment : discontinuation of nilotinib for nilotinib-related adverse events, death due to any cause, progression to AP or BC, loss of PCyR, loss of CCyR, loss of CHR. Time is censored at the date of last assessment in the trial for patients without event.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

-Patients with chronic myeloid leukemia in the chronic phase diagnosed within 6 months of study entry

Exclusion Criteria:

* Treatment with tyrosine kinase inhibitor or other antileukemic agents or treatments (including HSCT) for longer than 2 weeks, with exception of hydroxyurea and/or anagrelide
* Uncontrolled congestive heart failure or hypertension
* Myocardial infarction or unstable angina pectoris within past 12 months
* Known T315I mutations
* QTcF >450 msec
* Significant arrhythmias

Other protocol-defined inclusion/exclusion criteria may apply

Participant flow

Outcome results

• The Percentage of Patients Achieving MMR by 12 Months (Primary), Number, percentage of participants: Nilotinib 70.8 (66.1 to 75.2)
• Time to Molecular Response at 24 Months (Secondary), Median, Months: Nilotinib 6.0 (5.9 to 6.1)
• Duration of Major Molecular Response (Secondary), Number, percentage of participants: Nilotinib 100 (100 to 100)
• Complete Cytogenetic Response (Secondary), Number, percentage of participants: Nilotinib 58.7 (53.8 to 63.4)
• Percentage of Participants Estimated to Maintain Their First CCyR for 6, 12, 18, and 24 Months After the First CCyR Was Achieved as Determined by Kaplan Meier Estimatation. (Secondary), Number, percentage of participants: Nilotinib 100 (100 to 100)
• Overall Survival (Secondary), Number, percentage probability: Nilotinib 99.8 (99.3 to 100)
• Kaplan-Meier Estimates of Progression-free Survival (Secondary), Number, percentage probability: Nilotinib 99.7 (99.3 to 100)
• Kaplan-Meier Estimates of Failure-free Survival (Secondary), Number, percentage probability: Nilotinib 97.4 (95.8 to 98.9)

Adverse events

Serious adverse events by term

36 more terms not shown.

Other adverse events by term

• Results publication: Hughes TP, Munhoz E, Aurelio Salvino M, Ong TC, Elhaddad A, Shortt J, Quach H, Pavlovsky C, Louw VJ, Shih LY, Turkina AG, Meillon L, Jin Y, Acharya S, Dalal D, Lipton JH. Nilotinib dose-optimization in newly diagnosed chronic myeloid leukaemia in chronic phase: final results from ENESTxtnd. Br J Haematol. 2017 Oct;179(2):219-228. doi: 10.1111/bjh.14829. Epub 2017 Jul 12. PMID 28699641

• Novartis Pharmaceuticals, Study director, Novartis Pharmaceuticals