• Newly diagnosed de novo B-precursor acute lymphoblastic leukemia (ALL) as determined by World Health Organization (WHO) criteria. Patients must have unequivocal diagnosis of precursor B ALL. This includes an institutional immunophenotyping report that is to assign B-lineage or T-lineage.

• Ph-like signature, as determined by low density micro-array (LDA) card

• Jak-targetable genetic signature as defined by any of the following:

‣ Cytokine receptor-like factor 2 (CRLF2) rearranged (JAK2 mutant or wild-type)

⁃ JAK2 or erythropoietin receptor (EPOR) fusions.

⁃ Other JAK pathway alterations at the discretion of the principle investigator including, but not limited to:

• SH2B adaptor protein 3 (SH2B3) deletions

• Interleukin-7 receptor subunit alpha (IL7RA) mutations

• Prior therapy

‣ Prior to starting ruxolitinib, patients must have completed a 4-drug induction regimen with intrathecal chemotherapy (modified aBFM regimen or equivalent) as per the institutional standard of care. Recommended induction treatment is outlined in Section 5.1.2.

⁃ No additional prior therapy for acute leukemia except emergency therapy (corticosteroids or hydroxyurea) for blast cell crisis, superior vena cava syndrome, or renal failure due to leukemic infiltration of the kidneys. When indicated, leukapheresis or exchange transfusion is recommended to reduce the white blood cell count (WBC).

⁃ Screening may occur at any point prior to or during induction therapy

• Age ≥ 18 years and \< 40 years. Because this is specifically a study of the adolescent and young adult population and no adverse event data are currently available on the use of this pediatric-based chemotherapy regimen in patients ≥ 40 years of age, older adults are excluded from this study, but may be eligible for future trials.

• Eastern Cooperative Oncology Group (ECOG) performance status ≤2 (Karnofsky ≥ 60%)

• Platelet count \> 25,000/uL.

• Patients must have normal organ function as defined below:

‣ total bilirubin ≤ 2 mg/dL

⁃ aspartate aminotransferase (AST) / alanine aminotransferase (ALT) ≤ 2.5 × institutional upper limit of normal

⁃ creatinine within normal institutional limits OR creatinine clearance ≥ 60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal.

• Because the therapeutic agents used in this study are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation.

• Ability to understand and the willingness to sign a written informed consent document.