Dose‑adjusted EPOCH chemotherapy with or without rituximab plus ponatinib for newly diagnosed Philadelphia chromosome–positive B‑cell ALL/lymphoblastic lymphoma

Inclusion Criteria:

* Adults (age 18 years and older) with newly-diagnosed Ph+ B-ALL. Ph status will be determined by routine cytogenetics, fluorescence in situ hybridization (FISH), and/or reverse transcriptase-polymerase chain reaction (RT-PCR) for the BCR::ABL1 translocation
* Marrow or blood involvement by abnormal lymphoblasts detectable by multiparameter flow cytometry (MFC)
* Total bilirubin (TBili) ≤ 1.5 x upper limit of normal (ULN) (unless attributed to Gilbert's disease or other causes of inherited indirect hyperbilirubinemia, at which point TBili must be ≤ 4 x ULN)

  * (Note: Patients with liver test abnormalities attributable to hepatic involvement by ALL will be permitted if the TBili is ≤ 5 x ULN)
* Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase \[SGPT\]) ≤ 2.5 x institutional ULN

  * (Note: Patients with liver test abnormalities attributable to hepatic involvement by ALL will be permitted if the ALT/AST are ≤ 8 x ULN)
* Calculated creatinine clearance of \> 30 ml/min/1.73m\^2, as measured by the Modification of Diet in Renal Disease (MDRD) equation, will be eligible
* As patients with ALL frequently have cytopenias, no hematologic parameters will be required for enrollment or to receive the first cycle of treatment. However, adequate recovery of blood counts will be required to receive subsequent cycles
* Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2. (Performance status of 3 will be allowed if poor performance status is thought to be directly secondary to ALL)
* Ability to give informed consent and comply with the protocol
* Anticipated survival of at least 3 months, independent of ALL
* Female subjects of reproductive potential must agree to use an effective method of birth control from the time of signing the consent form until one of the following:

  * For subjects not expected to receive rituximab (i.e., CD20-negative): at least 3 weeks after the last dose of ponatinib, or
  * For subjects expected to receive rituximab (i.e., CD20-positive): at least 12 months after the last dose of rituximab
  * A subject does not have reproductive potential if they are (1) surgically sterilized, or (2) postmenopausal (i.e., a female who is \> 50 years old or who has not had menses for ≥ 1 year), or (3) not heterosexually active
* Male subjects must agree to use an effective method of birth control and to not donate sperm from the time of signing the consent form until at least 3 weeks after the last dose of ponatinib

Exclusion Criteria:

* Burkitt lymphoma/leukemia
* No prior systemic therapy for ALL except to control acute symptoms and/or hyperleukocytosis (e.g., corticosteroids, cytarabine, etc.)
* No isolated extramedullary or known parenchymal central nervous system (CNS) disease
* History of acute pancreatitis within 1 year of enrollment or known chronic pancreatitis
* Symptomatic atherosclerotic cardiovascular disease (e.g., myocardial infarction, cerebrovascular accident, peripheral arterial disease, etc.) within 1 year of enrollment
* Active resistant hypertension, defined as having an ambulatory blood pressure above goal despite use of 3 antihypertensive medications from different classes
* Venous thromboembolic event (e.g., deep venous thrombosis, pulmonary embolism) within 6 months of enrollment
* Known hypersensitivity or intolerance to any of the agents under investigation
* Other medical or psychiatric conditions that in the opinion of the investigator would preclude safe participation in the protocol
* May not be pregnant or nursing. Pregnancy test is only required in females, unless they do not have reproductive potential. For subjects not expected to receive rituximab (i.e., CD20-negative), nursing can occur 1 week after the last dose of ponatinib. For subjects expected to receive rituximab (i.e., CD20-positive), nursing can occur 6 months after the last dose of rituximab