Inclusion Criteria:

• Be in first relapse with >25% blasts in the bone marrow with a duration of first remission of ≥6 months and no longer in the intensive phase(s) of initial ALL therapy (e.g., patients who are in the maintenance or continuation phases of therapy [or beyond] and who have completed the induction or intensification phases).
• Have received no more than 2 prior induction regimens prior to the date of first relapse. Patients who are in first relapse but have failed a re-induction attempt (i.e., 1 cycle of re-induction therapy) are not eligible for inclusion in this study.
• Be ≥1 and ≤30 years old and have a body weight of >10 kg at study entry. (Note: no more than 3 patients aged >21 ≤30 are to be enrolled.)
• Be able to receive all study drugs with no known contra-indications.
• Be able to provide adequate venous access.
• Have a Karnofsky Performance Status (KPS) of ≥50 for patients >10 years of age or a Lansky Performance Status (LPS) of ≥50 for patients ≤10 years of age.
• Patients (≥18 years of age) or the parent or legal guardian(s) (for patients <18 years of age) must provide signed, written informed consent according to local institutional review board (IRB) and institutional requirements. For patients <18 years of age, signed assent should be obtained according to local IRB and institutional requirements.
• Be able to comply with study procedures and follow-up examinations.
• Have adequate liver, renal, pancreatic, and cardiac function considered acceptable by laboratory values and cardiac assessments
• Have no active central nervous system (CNS) leukemia, as evidenced by negative cytology on lumbar puncture and absence of clinical central neurologic symptoms. Diagnostic lumbar puncture should be performed only after all other eligibility assessments have been completed and reviewed, except for bone marrow aspirate and/or biopsy. Patients with CNS1 or CNS2 leukemia may be enrolled in the study.
• Have recovered to baseline from all toxicities from prior chemotherapy regimens prior to enrollment in the study.

Exclusion Criteria:

• Have received previous treatment with clofarabine.
• Have a history of clinical allergy (Grade 3 or 4) to PEG-asparaginase.
• Have a history of severe pancreatitis (Grade 3 or 4) attributed to asparaginase therapy.
• Have Burkitt's leukemia.
• Have overt testicular relapse.
• Adequate time has not elapsed since patient's last therapy. Patients who relapse while receiving standard ALL maintenance chemotherapy will not be required to have a washout period before entry onto this study. Note that patients may receive intrathecal (IT) ara-C, methotrexate, or hydrocortisone immediately prior to the administration of study drugs. Patients may also receive hydroxyurea up to 24 hours prior to the start of study therapy. Patients who relapse when they are not receiving standard ALL maintenance therapy must have fully recovered from the acute toxic effects of all prior therapy (excluding hematologic toxicity), immunotherapy or radiotherapy.
• Have an uncontrolled systemic fungal, bacterial, viral, or other infection. For patients with a history of fever within the preceding 3 days at the time of enrollment, documentation of negative blood cultures for at least 48 hours is required.
• Are pregnant or lactating.
• Male and female patients who are fertile must agree to use an effective means of birth control (i.e., latex condom, diaphragm, cervical cap, etc.) while on study therapy, and for a minimum of 1 month following final study visit.
• Have psychiatric disorders that would interfere with consent, study participation, or follow-up.
• Have any other severe concurrent disease, or have a history of serious organ dysfunction or disease involving the heart, kidney, liver, or pancreas.
• Have received any stem cell transplantation or high-dose chemotherapy with stem cell rescue regimen.
• Have a history of cirrhosis or known human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS).
• Have a history of at least 1 positive test for hepatitis B or hepatitis C infection.
• Have Down syndrome.
• Are currently participating in another concurrent investigational treatment protocol.