screening procedures Disease resistant to full-dose imatinib ( 600 mg/day) or intolerant to any dose of imatinib

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Miles Golden
5 years ago
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1 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 > /L, platelets 100, /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

2 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.

3 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 < /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.

4 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 or more mutations More than mutation No mutations P-loop mutations L248V G250E Y253F Y253H E255K E255V Non P-loop mutations M244V

5 Bcr-Abl Complete hematologic Major cytogenetic * mutation status at baseline (n = 61) (n = 94) D276G L298V F311I F311L T315I F317L N331S M351T E355G F359I F359V L364P L387F H396P H396R D421G I432T E450V E453K

6 Bcr-Abl Complete hematologic Major cytogenetic * mutation status at baseline (n = 61) (n = 94) E453Q E459K P480A Unknown *Major cytogenetic = complete + partial cytogenetic. Abnormalities not associated with known mutations (eg, nucleotide insertions or deletions, alternate splicing).

Form 2012 R3.0: Chronic Myelogenous Leukemia (CML) Pre-Infusion Data

Form 2012 R3.0: Chronic Myelogeus Leukemia (CML) Pre-Infusion Data Key Fields Sequence Number: Date Received: - - CIBMTR Center Number: CIBMTR Research ID: Event date: - - HCT type: (check all that apply)