Trial Outcomes & Findings for Ponatinib in Participants With Resistant Chronic Phase Chronic Myeloid Leukemia (CP-CML) to Characterize the Efficacy and Safety of a Range of Doses (NCT NCT02467270)

Participants took part in the study at 61 investigative sites globally from 13 July 2015 to 23 April 2025.

Participants with chronic phase-chronic myelogenous leukemia(CP-CML) who received at least 2 prior tyrosine kinase inhibitor(TKI) therapies were enrolled in 1:1:1 ratio in 3 cohorts:ponatinib:45 milligrams(mg)(Cohort A);30mg(Cohort B);or 15mg(Cohort C). Participants who started at 45/30mg received mandatory dose reduction of their daily dose to 15mg upon achievement of less than equal to (≤)1% breakpoint cluster region-Abelson 1 transcript level as measured by International Scale (BCR-ABL1IS).

Number analyzed is the number of participants with data available for height at Baseline.

MR2 was defined as a ratio of reverse transcribed transcript of BCR-ABL to ABL \<=1% Breakpoint Cluster Region-Abelson Transcript Level as measured by the International Scale (BCR-ABL1IS), equivalent to a 2-log reduction in transcript.

MMR/MR3 was defined as a ratio of reverse transcribed transcript of BCR-ABL to ABL ≤0.1% on the international scale (equivalent to a 3-log reduction in transcript).

MCyR was defined as percentage of participants with complete cytogenetic response (CCyR) or partial cytogenetic response (PCyR). Cytogenetic response is the percentage of Philadelphia chromosome positive (Ph+) metaphases in bone marrow (BM). Response is further defined as MCyR: CCyR or PCyR, where CCyR: 0% Ph + metaphases; PCyR: \>0 to 35% Ph + metaphases.

Duration of MMR/MR3 was defined as the interval between the first assessment at which the criteria for \<=0.1% MMR were met until the earliest date at which loss of \<=0.1% MMR occurred, or the criteria for progression were met. Progression to accelerated phase (AP) was defined as: \>= 15% and \<30% blasts in peripheral blood or bone marrow or \>=20% basophils in peripheral blood or bone marrow or \>=30% blasts + promyelocytes in peripheral blood or bone marrow (but \<30% blasts) or \<100\*109 platelets per liter (/L) in peripheral blood unrelated to therapy or cytogenetic, genetic evidence of clonal evolution, and no extramedullary disease. Progression to blast phase (BP) was defined as: \>=30% blasts in peripheral blood or bone marrow or extramedullary disease other than hepatosplenomegaly.

Percentage of participants with adjusted incidence rates who developed AOEs and VTEs were categorized according to arterial occlusive events and venous thrombotic events. AE is any untoward medical occurrence in participant administered medicinal investigational drug. Untoward medical occurrence does not necessarily have to have causal relationship with treatment. SAE is any untoward medical occurrence that results in death; is life-threatening; requires inpatient hospitalization or prolongation of present hospitalization; results in persistent or significant disability/incapacity; is congenital anomaly/birth defect/is medically important event that may not be immediately life-threatening/result in death or hospitalization, but may jeopardize participant/may require intervention to prevent one of other outcomes listed in definition above, or involves suspected transmission via a medicinal product of an infectious agent.

Cytogenetic response was defined as the percentage of Ph+ metaphases in bone marrow (peripheral blood may not be used), with a review of a minimum of 20 metaphases. CCyR was defined as 0% Ph+ metaphases.

MR4 was defined as \<=0.01% BCR-ABL1IS. MR 4.5was defined as \<=0.0032% BCR-ALB1IS. MR4 and MR4.5 by each time point means the best outcome up to each time point after randomization.

MR1 was defined as percentage of participants achieving a ratio of \<=10% Breakpoint Cluster Region-Abelson (BCR-ABL1) transcripts on the international scale. MR1 is molecular response with 1-log reduction in transcript.

CHR was defined as achieving all of the following measurements: white blood cells (WBC) \<= institutional upper limit of normal (ULN), platelets less than (\<)450,000 per cubic millimeter (/mm\^3), no blasts or promyelocytes in peripheral blood, \<5% myelocytes plus metamyelocytes in peripheral blood, basophils in peripheral blood \<5%, and no extramedullary involvement (including no hepatomegaly or splenomegaly).

An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug.

DOR (≤1% BCR-ABL1IS) is defined as interval between first assessment at which criteria for ≤1% BCR-ABL1IS are met until earliest date at which loss of ≤1% BCR-ABL1IS occurs, or criteria for progression accelerated phase (AP) or blast Phase (BP) of chronic myeloid leukemia (CML) are met. Loss of ≤1% BCR-ABL1IS is an increase to \>1% of BCR-ABL1IS. Progression to AP: ≥15% and \<30% blasts in peripheral blood or bone marrow or ≥20% basophils in peripheral blood or bone marrow or ≥30% blasts + promyelocytes in peripheral blood or bone marrow (but \<30% blasts) or \<100\*109 platelets per liter in peripheral blood unrelated to therapy or cytogenetic, genetic evidence of clonal evolution, and no extramedullary disease. Progression to BP: ≥30% blasts in peripheral blood or bone marrow or extramedullary disease other than hepatosplenomegaly. Kaplan-Meier method was used for analysis of percentage of participants who achieved DOR of 12 and 24 months.

Duration of MMR/MR3 is defined as interval between first assessment at which criteria for MMR are met until earliest date at which loss of MMR occurs, or criteria for progression (progression to AP or BP of CML) are met. Participants remaining in MMR will be censored at last date at which criteria for MMR are met. Loss of MMR is an increase to \>0.1% of BCR-ABL1IS. Progression to AP: \>= 15% and \<30% blasts in peripheral blood or bone marrow or \>=20% basophils in peripheral blood or bone marrow or \>=30% blasts+promyelocytes in peripheral blood or bone marrow (but \<30% blasts) or \<100\*109 platelets/L in peripheral blood unrelated to therapy or cytogenetic, genetic evidence of clonal evolution, and no extramedullary disease. Progression to BP: \>=30% blasts in peripheral blood or bone marrow or extramedullary disease other than hepatosplenomegaly. Kaplan-Meier method was used for analysis of percentage of participants who achieved DOR of 12 and 24 months.

Duration of response in "responders" was defined as any participants who achieved ≤1% BCR-ABL1IS (MR2) at any time during the study. Responders were defined as those participants who met all of the following: were randomized and treated, responded at 12 months after the initiation of study treatment, and underwent baseline polymerase chain reaction (PCR) assessment.

Time to response was defined as the time interval from the date of the first dose of the study drug until the initial observation of CR or PR for participants with confirmed CR/PR. Response was defined as any participants who achieved ≤1% BCR-ABL1IS (MR2) at any time during the study. CR for target lesion: disappearance of all extranodal lesions and all pathological lymph nodes must have decreased to \<10 mm in short axis. CR for non-target lesion: Disappearance of all extranodal non-target lesions, all lymph nodes must be non-pathological in size (\<10mm short axis) and normalization of tumor marker level. PR: at least a 30% decrease in the SLD of target lesions, taking as reference the Baseline sum diameters.

Progression to AP is defined as: \>=15% and \<30% blasts in peripheral blood or bone marrow or \>=20% basophils in peripheral blood or bone marrow or \>=30% blasts + promyelocytes in peripheral blood or bone marrow (but \<30% blasts) or \<100\*109 platelets/L in peripheral blood unrelated to therapy or cytogenetic, genetic evidence of clonal evolution, and no extramedullary disease. Progression to BP is defined as: \>=30% blasts in peripheral blood or bone marrow or extramedullary disease other than hepatosplenomegaly.

PFS was defined as the interval between the first dose date of study treatment and the first date at which the criteria for progression were met (progression to the AP or BP of CML), or death due to any cause, censored at the last response assessment. Progression to AP was defined as: \>=15% and \<30% blasts in peripheral blood or bone marrow or \>=20% basophils in peripheral blood or bone marrow or \>=30% blasts + promyelocytes in peripheral blood or bone marrow (but \<30% blasts) or \<100\*109 platelets/L in peripheral blood unrelated to therapy or cytogenetic, genetic evidence of clonal evolution, and no extramedullary disease. Progression to BP was defined as: \>=30% blasts in peripheral blood or bone marrow or extramedullary disease other than hepatosplenomegaly.

OS was defined as the interval between the first dose of study treatment and death due to any cause, censored at the last contact date when the participant was alive.