Low-Intensity Chemotherapy, Ponatinib and Blinatumomab in Treating Patients With Philadelphia Chromosome-Positive and/or BCR-ABL Positive Acute Lymphoblastic Leukemia

Inclusion Criteria:

• Patients >= 18 years of age with previously untreated Ph-positive ALL (eithert(9;22) and/or BCR-ABL positive) (includes patients initiated on first cycle ofhyper-CVAD before cytogenetics known. These patients could have received one or twocycles of chemotherapy with or without other TKIs and still eligible.

• If they achieved CR, they are assessable only for event-free and overallsurvival, or

• If they failed to achieve CR, they are assessable for CR, event-free, andoverall survival.

Patients >= 18 years of age with relapsed/refractory Ph-positive ALL or lymphoid accelerated or blast phase chronic myelogenous leukemia (CML)

• Performance status =< 2 (Eastern Cooperative Oncology Group [ECOG] scale)

• Total serum bilirubin =< 2 x upper limit of normal (ULN), unless due to Gilbert'ssyndrome

• Alanine aminotransferase (ALT) =< 3 x ULN

• Aspartate aminotransferase (AST) =< 3 x ULN

• Serum lipase and amylase =< 1.5 x ULN

• Creatinine =< 2.0 mg/dl

• Female patients who: are postmenopausal for at least 1 year before the screeningvisit, OR are surgically sterile, OR if they are of childbearing potential, agree topractice 2 effective methods of contraception, at the same time, from the time ofsigning the informed consent through 4 months after the last dose of study drug, oragree to completely abstain from heterosexual intercourse

• Male patients, even if surgically sterilized (i.e., status post-vasectomy), who:agree to practice effective barrier contraception during the entire study treatmentperiod and through 4 months after the last dose of study drug, or agree tocompletely abstain from heterosexual intercourse

• Adequate cardiac function as assessed clinically by history and physical examination

• Signed informed consent

Exclusion Criteria:

• Active serious infection not controlled by oral or intravenous antibiotics

• Known active hepatitis B. Patients with chronic hepatitis B who are on appropriateviral suppressive therapy may be allowed after discussion with the principalinvestigator (PI)

• History of acute pancreatitis within 1 year of study or history of chronicpancreatitis

• History of alcohol abuse

• Uncontrolled hypertriglyceridemia

• Active secondary malignancy other than skin cancer (e.g., basal cell carcinoma orsquamous cell carcinoma) that in the investigator's opinion will shorten survival toless than 1 year

• Active grade III-V cardiac failure as defined by the New York Heart Associationcriteria

• Uncontrolled, or active cardiovascular disease, specifically including, but notrestricted to: myocardial infarction (MI), stroke, or revascularization within 3months; unstable angina or transient ischemic attack; congestive heart failure priorto enrollment, or left ventricular ejection fraction (LVEF) less than lower limit ofnormal per local institutional standards prior to enrollment; diagnosed or suspectedcongenital long QT syndrome; clinically significant atrial or ventriculararrhythmias as determined by the treating physician; prolonged corrected QT (QTc)interval on pre-entry electrocardiogram (> 470 msec) unless corrected afterelectrolyte replacement. or approved by cardiologist; Significant venous or arterialthromboembolism including deep venous thrombosis or pulmonary embolism. Patientswith a history of treated prior superficial or catheter associated phlebitis willnot be considered as significant embolism and after discussion with principalinvestigator (PI) will not be excluded from eligibility. Uncontrolled hypertension (diastolic blood pressure > 90 mmHg; systolic > 140mmHg). Patients with hypertensionshould be under treatment on study entry to effect blood pressure control

• Taking any medications or herbal supplements that are known to be strong inhibitorsof CYP3A4 within at least 14 days or 5 half-lives before the first dose of ponatinibin patients with newly diagnosed only

• History or presence of clinically relevant central nervous system (CNS) pathologysuch as epilepsy, childhood or adult seizure, paresis, aphasia, stroke, severe braininjuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome,or psychosis. Patients with active CNS leukemia will NOT be excluded

• Current autoimmune disease or history of autoimmune disease with potential CNSinvolvement

• Treatment with any investigational antileukemic agents or chemotherapy agents in thelast 7 days before study entry, unless full recovery from side effects has occurredor patient has rapidly progressive disease judged to be life-threatening by theinvestigator

• Pregnant and lactating women will not be eligible; women of childbearing potentialshould have a negative pregnancy test prior to entering on the study and be willingto practice methods of contraception. Women do not have childbearing potential ifthey have had a hysterectomy or are postmenopausal without menses for 12 months. Inaddition, men enrolled on this study should understand the risks to any sexualpartner of childbearing potential and should practice an effective method of birthcontrol

• History of significant bleeding disorder unrelated to cancer, including: diagnosedcongenital bleeding disorders (e.g., von Willebrand's disease); and diagnosedacquired bleeding disorder within one year (e.g., acquired anti-factor VIIIantibodies)

• Patients with documented significant pleural or pericardial effusions unless theyare thought to be secondary to their leukemia