Ruxolitinib and Chemotherapy in Adolescents and Young Adults With Ph-like Acute Lymphoblastic Leukemia

Inclusion Criteria:

• Newly diagnosed de novo B-precursor acute lymphoblastic leukemia (ALL) as determinedby World Health Organization (WHO) criteria. Patients must have unequivocaldiagnosis of precursor B ALL. This includes an institutional immunophenotypingreport 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 investigatorincluding, 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 inductionregimen with intrathecal chemotherapy (modified aBFM regimen or equivalent) asper the institutional standard of care. Recommended induction treatment isoutlined in Section 5.1.2.

• No additional prior therapy for acute leukemia except emergency therapy (corticosteroids or hydroxyurea) for blast cell crisis, superior vena cavasyndrome, or renal failure due to leukemic infiltration of the kidneys. Whenindicated, leukapheresis or exchange transfusion is recommended to reduce thewhite 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 theadolescent and young adult population and no adverse event data are currentlyavailable on the use of this pediatric-based chemotherapy regimen in patients ≥ 40years of age, older adults are excluded from this study, but may be eligible forfuture 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 ≥ 60mL/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, womenof child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry andfor the duration of study participation. Should a woman become pregnant or suspectshe is pregnant while she or her partner is participating in this study, she shouldinform her treating physician immediately. Men treated or enrolled on this protocolmust also agree to use adequate contraception prior to the study, for the durationof study participation.

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

Exclusion Criteria:

• Patients who are receiving any other investigational agent.

• Patients with a "currently active" second malignancy other than non-melanoma skincancers. Patients are not considered to have a "currently active" malignancy if theyhave completed therapy and are free of disease for ≥ 3 years.

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to ruxolitinib or other agents used in study.

• Use of any potent cytochrome P450 (CYP) 3A4 inhibitor or inducer within 5 half-livesbefore the first dose of the study drug. Potent inhibitors of CYP3A4 includesystemic ketoconazole, posaconazole, voriconazole, clarithromycin, itraconazole,nefazodone, and telithromycin. At the fluconazole dose of 200mg daily used thisregimen, there is minimal inhibition of CYP3A4 [36] and therefore fluconazole is notprohibited on this trial and no dose modifications should be made in the presence offluconazole.

Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated list such as http://medicine.iupui.edu/clinpharm/ddis/table.aspx; medical reference texts such as the Physicians' Desk Reference may also provide this information. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product.

• Uncontrolled intercurrent illness including, but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, unstable angina pectoris, cardiacarrhythmia, or psychiatric illness/social situations that would limit compliancewith study requirements.

• Pregnant women are excluded from this study because ruxolitinib is a class C agentwith the potential for teratogenic or abortifacient effects. Because there is anunknown but potential risk for adverse events in nursing infants secondary totreatment of the mother with ruxolitinib breastfeeding should be discontinued if themother is treated with ruxolitinib. These potential risks may also apply to otheragents used in this study.

• Down Syndrome due to the likelihood of excessive toxicity resulting. These patientsshould be treated in consultation with a pediatric oncologist.

• Burkitt type leukemia

• Ph+ ALL at time of diagnosis