Bosutinib for pretreated patients with chronic phase chronic myeloid leukemia: primary results of the phase 4 BYOND study

Bosutinib is approved for newly diagnosed Philadelphia chromosome-positive (Ph+) chronic phase (CP) chronic myeloid leukemia (CML) and for Ph+ CP, accelerated (AP), or blast (BP) phase CML after prior treatment with tyrosine kinase inhibitors (TKIs). In the ongoing phase 4 BYOND study (NCT02228382), 163 CML patients resistant/intolerant to prior TKIs (n = 156 Ph+ CP CML, n = 4 Ph+ AP CML, n = 3 Ph-negative/BCR-ABL1+ CML) received bosutinib 500 mg once daily (starting dose). As of ≥1 year after last enrolled patient (median treatment duration 23.7 months), 56.4% of Ph+ CP CML patients remained on bosutinib. Primary endpoint of cumulative confirmed major cytogenetic response (MCyR) rate by 1 year was 75.8% in Ph+ CP CML patients after one or two prior TKIs and 62.2% after three prior TKIs. Cumulative complete cytogenetic response (CCyR) and major molecular response (MMR) rates by 1 year were 80.6% and 70.5%, respectively, in Ph+ CP CML patients overall. No patient progressed to AP/BP on treatment. Across all patients, the most common treatment-emergent adverse events were diarrhea (87.7%), nausea (39.9%), and vomiting (32.5%). The majority of patients had confirmed MCyR by 1 year and MMR by 1 year, further supporting bosutinib use for Ph+ CP CML patients resistant/intolerant to prior TKIs.


Study design and patients
Patients had to have adequate bone marrow function, defined as absolute neutrophil count (ANC) >1 x 10 9 /L and platelets ≥75 x 10 9 /L for patients with chronic phase chronic myeloid leukemia (CP CML) after one or two prior tyrosine kinase inhibitors (TKIs), and ANC >0.5 x 10 9 /L and platelets ≥50 x 10 9 /L for patients with accelerated/blast phase (AP/BP) CML or CP CML after three prior TKIs.Patients also had to have adequate hepatic and renal function, defined as: aspartate (AST) and alanine (ALT) aminotransferase ≤2.5 x the upper limit of normal (ULN) or ALT/AST ≤5 x ULN if attributable to liver involvement of leukemia; total bilirubin ≤1.5 x ULN (unless the bilirubin was principally unconjugated and there was a strong suspicion of subclinical hemolysis, or the patient had documented Gilbert's Disease); alkaline phosphatase ≤2.5 x ULN; and creatinine ≤1.5 x ULN or estimated creatinine clearance ≥60 mL/min.
For non-hematologic adverse events (AEs), the following dose adjustments were permitted.Patients who experienced a grade 1 AE were to remain on the current dose level.For grade 2 AEs, bosutinib treatment was to be interrupted, and reintroduced at the same dose or the dose reduced by one level upon recovery to grade ≤1 within 4 weeks of stopping treatment.For grade 3 AEs, bosutinib treatment was to be interrupted, the dose reduced by one level upon recovery to grade ≤1 within 4 weeks of stopping treatment.If recovery was >4 weeks, the patient was to be evaluated to determine if bosutinib treatment should continue.Bosutinib treatment was to be discontinued in the event of a grade 4 AE, and the patient was to be evaluated to determine if bosutinib treatment should continue with an appropriate dose reduction.For grade 3/4 diarrhea, bosutinib treatment was to be interrupted and then resumed at 400 mg once daily upon recovery to grade ≤1.
For hematologic AEs, the following dose adjustments were permitted.Patients who experienced a grade 1 or grade 2 AE were to remain on the current dose level.For grade 3 AEs, bosutinib was to be interrupted.If recovered to grade ≤2 within 2 weeks, bosutinib was to be re-introduced at the same dose.If recovered within 4 weeks, bosutinib was to be reduced by one dose level.In the case of recurrent grade 3 toxicity, the dose was to be reduced upon recovery to grade ≤2.If recovery was >4 weeks, the patient was to be evaluated to determine if bosutinib treatment should continue.Bosutinib treatment was to be discontinued in the event of a grade 4 AE, and the patient was to be evaluated to determine if bosutinib treatment should continue with an appropriate dose reduction.

Molecular, cytogenetic, and hematologic response
Analyses of hematologic and cytogenetic response were based on data from local laboratory assessments.Real-time quantitative polymerase chain reaction for molecular response assessment (BCR-ABL1 transcript levels international scale [IS]) and mutational analysis of the BCR-ABL1 kinase domain were performed by a central laboratory.Hematologic assessments were performed at baseline and every week until week 4, at week 8, every 3 months until week 52, then at 6-month intervals during years 2, 3 and 4, and at end of treatment.Cytogenetic and molecular response assessments were performed at baseline and every 3 months until week 52, then at 6-month intervals during years 2, 3 and 4, and at end of treatment.All assessments were performed in the event of treatment failure and/or disease progression.Mutational analyses were performed from the peripheral blood or bone marrow samples that were used for molecular response assessment.

Resistance and intolerance
Patients were categorized as resistant or intolerant to prior TKIs by the investigator.Resistance was defined in accordance with European LeukemiaNet (ELN) 2013 recommendations [1] or National Comprehensive Cancer Network (NCCN) guidelines [2].Intolerance to prior TKIs was defined as ≥1 of the following criteria: any life-threatening grade 4 non-hematologic toxicity; any grade 3/4 nonhematologic toxicity that persisted despite dose reduction and optimal symptomatic measures; grade 3/4 hematologic toxicity that was unresponsive to supportive measures and required dose reduction below the accepted minimal effective dose; or any combination of non-hematologic toxicities of any grade that persisted despite supportive measures and necessitated a change of therapy.

Treatment-emergent adverse events
Medical Dictionary for Regulatory Activities (MedDRA) preferred terms included in treatmentemergent AE (TEAE) clusters of special interest: The following MedDRA preferred terms were clustered for cytopenias:  Anemia: PT in anemia, hemoglobin decreased  Neutropenia: PT in neutropenia, neutrophil count decreased  Leukopenia: PT in leukopenia, white blood cell count decreased  Thrombocytopenia: PT in thrombocytopenia, platelet count decreased.

Patient-reported outcomes
Patient-reported outcomes were assessed using the Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu) quality-of-life (QoL) questionnaire at baseline, every 3 months for the first year, and every 6 months during years 2, 3 and 4 of treatment [3,4].Higher scores reflected better QoL.Minimal important differences (MID) were defined as the smallest change in a PRO measure that was perceived by patients as beneficial or would result in a clinician considering change in treatment.MID domain scores included: 2-3 in physical well-being), 2 for emotional well-being, 2-3 in functional wellbeing, 3-7 for FACT-General (FACT-G), 4-7 in leukemia-specific subscale, 6-12 for FACT-Leu total, and 5-6 for trial outcome index (TOI) FACT-Leu [5].The MID has not been defined for social wellbeing.
Full analysis set for Ph+ CP CML.† MID, i.e., the change identified as being clinically meaningful to a patient, has not been defined for social well-being.‡ n=38 for leukemia-specific and n=37 for FACT-Leu total and TOI FACT-Leu scores; § n=23 for social well-being, FACT-G total, and TOI FACT-Leu and n=22 for FACT-Leu total scores; || n=95 for social well-being, leukemia-specific, and FACT-G total, n=93 for TOI FACT-Leu, and n=92 for FACT-Leu total scores.CI confidence interval, CP CML chronic phase chronic myeloid leukemia, FACT-G Functional Assessment of Cancer Therapy-General, FACT-Leu Functional Assessment of Cancer Therapy-Leukemia, MID minimum important difference, Ph Philadelphia chromosome, TOI trial outcome index.

Line of Treatment
Full analysis set for Ph+ CP CML.CP CML chronic phase chronic myeloid leukemia, CP2L second-line, CP3L third-line, CP4L fourth-line, FACT-G Functional Assessment of Cancer Therapy-General, FACT-Leu Functional Assessment of Cancer Therapy-Leukemia, Ph Philadelphia chromosome, SD standard deviation, TOI trial outcome index.