Table S1. Study inclusion and exclusion criteria Inclusion criteria Aged 18 years Signed and dated informed consent form prior to protocol-specific screening procedures Cytogenetic- or PCR-based diagnosis of any phase of Ph+ CML or Ph+ ALL Disease resistant to full-dose imatinib ( 600 mg/day) or intolerant to any dose of imatinib Adequate duration of prior imatinib therapy ECOG Performance Status of 0 or 1 for chronic phase patients No antiproliferative or antileukemia treatment within 7 days of the first dose of bosutinib (except hydroxyurea and anagrelide) At least 3 months post-allogeneic stem cell transplantation Recovery to grade 0/1, or to baseline, from any toxicities from prior anticancer treatment (excluding alopecia) Able to take daily oral capsules or tablets reliably Adequate bone marrow function for imatinib-resistant patients in chronic phase only (ANC >1000 10 9 /L, platelets 100,000 10 9 /L, and absence of any platelet transfusions during the preceding 14 days) Adequate hepatic function (AST/ALT 2.5 ULN or 5 ULN if attributable to liver involvement of leukemia; total bilirubin 1.5
ULN) Adequate renal function (creatinine 1.5 ULN) QTc interval <470 msec at screening Willingness to use reliable birth control (if applicable) throughout the study and 30 days after the last dose Documented normal INR if not on oral anticoagulant therapy, or if on anticoagulants, consistent target INR 3 Exclusion criteria Ph chromosome negative or Bcr-Abl negative CML Overt leptomeningeal leukemia (free of CNS involvement for <2 months) Extramedullary disease only GVHD (for part 1, no prior GVHD allowed; for part 2, no treated or untreated GVHD within 60 days of study initiation) Documented history of T315I Bcr-Abl mutation Pregnant or breastfeeding Prior history of imatinib intolerance or exposure to Src, Abl, or Src/Abl kinase inhibitors (part 1 only) PCR, polymerase chain reaction; Ph+, Philadelphia chromosome positive; CML, chronic myeloid leukemia; ALL indicates acute lymphocytic leukemia; ECOG, Eastern Cooperative Oncology Group; ANC, absolute neutrophil count; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ULN, upper limit of normal; INR, international normalized ratio; CNS, central nervous system; GVHD, graft versus host disease.
Table S2. Definition of complete hematologic in patients with chronic phase CML Hematologic Definition Complete hematologic No peripheral blasts or promyelocytes Myelocytes + metamyelocytes <5% in blood WBC institutional ULN Platelets <450 10 9 /L Basophils <20% in blood* No extramedullary involvement (including hepato- or splenomegaly) CML, chronic myeloid leukemia; WBC, white blood cell; ULN, upper limit of normal. *Per study protocol.
Table S3. Complete hematologic and major cytogenetic s by Bcr-Abl mutation status at baseline Bcr-Abl Complete hematologic Major cytogenetic * mutation status at baseline (n = 61) (n = 94) All patients with 34 33 97 59 41 69 1 or more mutations More than 1 3 3 100 3 2 67 mutation No mutations 27 27 100 35 19 54 P-loop 9 9 100 10 7 70 mutations L248V 3 3 100 3 2 67 G250E 1 1 100 2 2 100 Y253F 1 1 100 1 0 0 Y253H 1 1 100 1 1 100 E255K 2 2 100 2 1 50 E255V 1 1 100 1 1 100 Non P-loop 23 22 96 39 26 67 mutations M244V 2 2 100 3 2 67
Bcr-Abl Complete hematologic Major cytogenetic * mutation status at baseline (n = 61) (n = 94) D276G 1 1 100 1 0 0 L298V 1 1 100 1 0 0 F311I 1 1 100 1 1 100 F311L 1 1 100 1 1 100 T315I 2 1 50 3 0 0 F317L 0 3 3 100 N331S 0 1 1 100 M351T 3 3 100 6 6 100 E355G 2 2 100 2 1 50 F359I 1 1 100 1 1 100 F359V 6 6 100 7 4 57 L364P 0 1 1 100 L387F 0 1 0 0 H396P 1 1 100 2 2 100 H396R 1 1 100 0 D421G 1 1 100 1 0 0 I432T 0 1 0 0 E450V 1 1 100 1 1 100 E453K 0 1 1 100
Bcr-Abl Complete hematologic Major cytogenetic * mutation status at baseline (n = 61) (n = 94) E453Q 1 1 100 1 1 100 E459K 0 1 0 0 P480A 0 1 1 100 Unknown 3 3 100 11 9 82 *Major cytogenetic = complete + partial cytogenetic. Abnormalities not associated with known mutations (eg, nucleotide insertions or deletions, alternate splicing).