Berlin-Frankfurt-Munster plus Tyrosine Kinase Inhibitor for the Treatment of Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

Inclusion Criteria

• Patients >= 18 years of age
• Baseline Eastern Cooperative Oncology Group (ECOG) Performance Status =< 2, and patient is a candidate for intensive chemotherapy
• Newly diagnosed Ph+ ALL
• Written informed consent prior to any screening procedures. Permitted exceptions are that the diagnostic marrow exam/peripheral blood/nodal biopsy tests confirming Ph+ B-Cell ALL, as well as pre-induction cardiac workup (electrocardiogram [EKG]/transthoracic echocardiography [TTE]/radionuclide ventriculogram scan [MUGA]), may be performed prior to the patient providing written informed consent if these tests are within 14 days of enrollment
• Patient able to give informed consent
• B-cell acute lymphoblastic leukemia with BCR-ABL1, i.e., Philadelphia chromosome-positive (Ph+) ALL * B-cell lineage determined by standard flow cytometry/Immunohistochemistry (IHC) * Ph+ by cytogenetics (karyotype/fluorescence in situ hybridization [FISH]) and/or molecular (BCR-ABL1 transcripts) * Determined in Clinical Laboratory Improvement Act (CLIA)-certified laboratory
• Previously untreated, except for the below therapy allowances in a recent diagnosis and up until 48 hours after starting trial therapy: * Corticosteroids * Hydroxyurea * Leukapheresis

Exclusion Criteria

• Any of the following subtypes of ALL: * Ph-negative B-Cell ALL * T-Cell ALL *. Relapsed Ph+ ALL * Lymphoid Blast Crisis of Chronic Myeloid Leukemia (CML) * Mature B-Cell (Burkitt’s) ALL
• Clinical signs of central nervous system (CNS) disease
• Active ALL in CNS or testes
• Estimated glomerular filtration rate (eGFR) by modification of diet in renal disease (MDRD) formula and calculated creatinine clearance (CrCl), based on a 24-hour urine collection, < 30 mL/min — unless related to ALL/tumor lysis syndrome and able to be corrected
• Total bilirubin > 2 x upper limit of normal (ULN), unless related to ALL liver infiltration
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) > 10 x ULN, unless related to ALL liver infiltration
• Patients with known history of human immunodeficiency virus (HIV), Hepatitis B, or Hepatitis C
• Pre-treatment Fridericia's correction formula (QTcF) > 480 msec
• Left ventricular ejection fraction < 45%. If an initial TTE demonstrates left ventricular ejection fraction (LVEF) < 45%, a confirmatory MUGA should be performed to confirm LVEF is < 45% prior to excluding the patient. Both a TTE and a MUGA with LVEF < 45% are needed to exclude a patient. Either a TTE or MUGA alone, if LVEF is >= 45%, is sufficient to include a patient
• Have significant or active cardiovascular disease, specifically including but not restricted to: * Known prior type 1 (thrombotic) myocardial infarction (type 2 myocardial infarction/demand ischemia is not necessarily excluded) * History of clinically significant atrial arrhythmia or any ventricular arrhythmia * Unstable angina within the last 12 months * Congestive heart failure within the last 12 months * Currently uncontrolled hypertension (> grade 3; or systolic blood pressure > 160 mm Hg and/or diastolic blood pressure > 100 mm Hg)
• Acute pancreatitis within the last year or a history of chronic pancreatitis
• Have malabsorption syndrome or other gastrointestinal illness that could affect the absorption of orally administered chemotherapy
• Ongoing uncontrolled severe nausea or vomiting
• History of a significant bleeding disorder unrelated to ALL, including: * Diagnosed congenital bleeding disorders (e.g., von Willebrand’s disease) * Diagnosed acquired bleeding disorder within one year (e.g., acquired antifactor VIII antibodies)
• Taking any medications or herbal supplements that are known to be strong inhibitors or inducers of CYP3A4 within at least 7 days or 5 half-lives (whichever is longer) before the first dose of study chemotherapy on day 1 of Remission Induction Phase I (RIP1)
• Active malignancy requiring treatment, other than ALL, within two years prior to the start of treatment, with the exception of basal cell carcinoma or squamous cell carcinoma of the skin, colon polyp, carcinoma in situ of the cervix, or breast ductal carcinoma in situ (DCIS)/breast lobular carcinoma in situ (LCIS) of the breast
• Active uncontrolled infection, any other concurrent disease, or medical condition that is deemed to interfere with the conduct of the study as judged by the investigator
• Pregnant women or women who are breastfeeding
• Women of childbearing potential who are unable or unwilling to adhere to the below effective contraception strategy
• Women must be willing to not breast feed up until 30 days following the end of trial therapy
• Women must agree not to donate egg(s) during the course of trial therapy or within 90 days following the end of trial therapy
• Women of childbearing potential are defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception defined as: * Total abstinence (when this is in line with the preferred and usual lifestyle of the patient). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception * Female sterilization (surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment * Male sterilization (at least six months prior to enrolling). For female patients on the study, the vasectomized male partner should be the sole partner for that patient * Use of a combination of any two of the following: ** Use of oral, injected, or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate < 1%), for example hormonal vaginal ring or transdermal hormone contraception ** Placement of an intrauterine device (IUD) or intrauterine system (IUS) ** Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/cream/vaginal suppository
• Women are considered post-menopausal and not of childbearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks prior to enrolling. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment is she considered not of childbearing potential
• If a study patient becomes pregnant or suspects being pregnant during the study or within 30 days after the final dose of trial therapy, the Study Doctor needs to be informed immediately
• Male patients who are unable or unwilling to adhere to the above effective contraception strategy
• Male patients must agree to not donate sperm during the course of trial therapy or within 120 days following the end of trial therapy