Everolimus and Combination Chemotherapy in Treating Younger Patients with Relapsed Acute Lymphoblastic Leukemia

Inclusion Criteria

• ALL in first bone marrow relapse occurring > 18 months (> 540 days) from initial diagnosis; marrow must have >= 25% blasts (M3 marrow), either on an aspirate or biopsy sample, as assessed by morphology, flow cytometry, and/or immunohistochemistry; individuals with CNS, testicular or other extramedullary involvement are eligible as long as they also meet marrow involvement criteria
• No prior therapy for recurrent ALL is allowed prior to study entry with the exception of intrathecal (IT) chemotherapy; participants who have relapsed while receiving up-front therapy are eligible, but must have recovered from adverse effects from any previously administered agents
• Patients who underwent stem cell transplant (SCT) in first complete remission are eligible, as long as all of the following criteria are met: * At least 100 days have elapsed since stem cell infusion * At least 14 days off of all medications for graft-versus-host-disease (GVHD) prophylaxis or treatment * No evidence of acute GVHD
• Performance status: Lansky >= 50 for individuals 18 months to < 10 years old; Karnofsky > 50% for individuals 10-21 years old
• Direct bilirubin =< 1.5 X institutional upper limit of normal (ULN)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 5 X institutional upper limit of normal
• Creatinine less than the institutional upper limit of normal or creatinine clearance >= 60 mL/min/1.73 m^2 for subjects with creatinine levels above institutional normal
• Serum lipase < 3 X institutional upper limit of normal
• Shortening fraction >= 28% on screening echocardiogram
• Fasting serum cholesterol =< 300 mg/dL or =< 7.75 mmol/L AND fasting triglycerides =< 300 mg/dL or 3.42 mmol/L * NOTE: non-fasting cholesterol/triglyceride levels that meet these criteria are acceptable; if these thresholds are exceeded in non-fasting samples, then fasting samples should be obtained * NOTE: if one or both of these thresholds are exceeded in fasting samples, the patient can only be included after initiation of appropriate lipid lowering medication
• International normalized ratio (INR) =< 1.5
• Maximum prior cumulative doxorubicin dose of =< 360 mg/m^2 or equivalent
• 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 participating in this study, she should inform her treating physician immediately
• Ability of participant (or parent/guardian for participants who are minors) to understand and the willingness to sign the written informed consent document

Exclusion Criteria

• Individuals with a known t(9;22)/breakpoint cluster region-Abelson (BCR-ABL) fusion based on testing at either initial diagnosis or at relapse
• Individuals whose lymphoblasts have surface immunoglobulin by flow cytometry and/or known t(8;14), t(2;8), or t(8;22); absence of surface immunoglobulin by flow cytometry at time of initial diagnosis or relapse is sufficient to rule out mature B-cell leukemia; karyotype or fluorescent in situ hybridization (FISH) results documenting absence of t(8;14), t(2;8), or t(8;22) are not necessary prior to enrollment if absence of surface of immunoglobulin is documented by flow cytometry
• Individuals with Down syndrome
• Prior therapy with mammalian target of rapamycin (mTOR) inhibitors (e.g. sirolimus, temsirolimus)
• Individuals who have had a stem cell transplant and are still receiving treatment for GVHD or GVHD prophylaxis, or who have evidence of acute GVHD, or who are less than 100 days from stem cell infusion
• Individuals who have received any investigational drug within 4 weeks
• Individuals with a history of asparaginase-associated pancreatitis
• Individuals with a history of allergic reactions to any of the agents being used in this trial, with the exception of PEG asparaginase; participants with a history of allergy to PEG asparaginase are allowed on study but should receive Erwinia asparaginase instead of PEG asparaginase; individuals with a history of allergy to both PEG and Erwinia asparaginase are excluded from the study
• Individuals receiving any medications or substances that are strong inhibitors or inducers of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) enzyme(s) are eligible only if principal investigator approves subject enrollment prior to registration; participants who have received a medication or substance listed may be enrolled on study as long as they have discontinued its use at least 48 hours prior to registration
• Individuals with active lung disease as defined by presence of pulmonary infiltrates on screening chest x-ray or baseline room air oxygen saturation of < 92%
• Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of everolimus (e.g. ulcerative colitis, uncontrolled nausea, vomiting, diarrhea, malabsorption or small bowel resection)
• Individuals with severe and/or uncontrolled intercurrent illness including, but not limited to: * Active (acute or chronic) or uncontrolled severe infections * Liver disease such as cirrhosis or severe hepatic impairment (Child-Pugh class C) * Unstable angina pectoris, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia or other clinically significant cardiac disease * Uncontrolled diabetes as defined by fasting serum glucose >= 200 mg/dL (note: participants with history of hyperglycemia receiving medical management whose fasting serum glucose is < 200 mg/dL with that management are eligible for enrollment) * Psychiatric illness/social situations that would limit compliance with study requirements
• Individuals with a documented history of previous or current hepatitis B or C infection; hepatitis B or C serologic screening is not required prior to enrollment, except in participants with any of the following high-risk features: * Suspected (but not documented) previous hepatitis B or C infection * Blood transfusion(s) prior to 1990 * Current or prior IV drug use * Current or prior dialysis * Household contact with hepatitis B or C infected individual * Mother with known hepatitis B or C infection * Current or prior high-risk sexual activity For participants with any of the above high risk features: study enrollment will only be allowed if hepatitis B virus (HBV)-deoxyribonucleic acid (DNA) or hepatitis B surface antigen (HBsAg) and hepatitis C virus (HCV)-ribonucleic acid (RNA) polymerase chain reaction (PCR) are negative within 14 days prior to study enrollment; any patient with a positive result on any of these screening tests is ineligible
• Pregnant women are excluded from this study; breastfeeding is not allowed during study treatment
• Individuals with a history of a different malignancy (other than ALL) are ineligible except for the following circumstances: individuals with a history of other malignancies are eligible if they have been disease-free for at least 5 years and are deemed by the investigator to be at low risk for recurrence of that malignancy; individuals with the following cancers are eligible if diagnosed and treated within the past 5 years: cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin
• Human immunodeficiency virus (HIV)-positive individuals on combination antiretroviral therapy are ineligible
• Participants who have received immunizations with attenuated live vaccines within one week of study entry are not eligible; examples of live vaccines include intranasal influenza, measles, mumps, rubella, oral polio, bacillus Calmette-Guerin (BCG), yellow fever, varicella and TY21a typhoid vaccines