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This phase III trial compares the effect of adding levocarnitine to standard chemotherapy versus (vs.) standard chemotherapy alone in protecting the liver in patients with leukemia or lymphoma. Asparaginase is part of the standard of care chemotherapy for the treatment of acute lymphoblastic leukemia (ALL), lymphoblastic lymphoma (LL), and mixed phenotype acute leukemia (MPAL). However, in adolescent and young adults (AYA) ages 15-39 years, liver toxicity from asparaginase is common and often prevents delivery of planned chemotherapy, thereby potentially compromising outcomes. Some groups of people may also be at higher risk for liver damage due to the presence of fat in the liver even before starting chemotherapy. Patients who are of Japanese descent, Native Hawaiian, Hispanic or Latinx may be at greater risk for liver damage from chemotherapy for this reason. Carnitine is a naturally occurring nutrient that is part of a typical diet and is also made by the body. Carnitine is necessary for metabolism and its deficiency or absence is associated with liver and other organ damage. Levocarnitine is a drug used to provide extra carnitine. Laboratory and real-world usage of the dietary supplement levocarnitine suggests its potential to prevent or reduce liver toxicity from asparaginase. The overall goal of this study is to determine whether adding levocarnitine to standard of care chemotherapy will reduce the chance of developing severe liver damage from asparaginase chemotherapy in ALL, LL and/or MPAL patients.

Primary Objective:

1. To determine in a randomized manner whether the addition of levocarnitine prophylaxis to asparaginase-containing regimens will decrease the incidence of conjugated hyperbilirubinemia (> 3 mg/dL) during ALL induction therapy for adolescents and young adults (adolescents and young adults [AYAs], age 15-39 years).

Secondary Objectives:

1. To examine the impact of levocarnitine prophylaxis on differences in the incidence of grade >= 3 alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevations during ALL Induction.

2. To compare rates of minimal residual disease (MRD) positivity at end of Induction and describe MRD+ by end of consolidation (EOC) in those receiving ALL induction chemotherapy with and without levocarnitine.

Exploratory Objectives:

1. To compare rates of toxicity and associated dose reductions for chemotherapy administered with and without concomitant levocarnitine supplementation.

2. To compare across study arms the peak levels during Induction of conjugated and total bilirubin, AST, ALT, and duration of conjugated hyperbilirubinemia from onset > 3 mg/dL to =< 3 mg/dL.

3. To describe the efficacy of levocarnitine prophylaxis to reduce the incidence and/or severity of early patient-reported chemotherapy-induced peripheral neuropathy.

4. To describe the three-year event-free and overall survival (EFS/OS) in those treated with and without levocarnitine prophylaxis.

5. To examine the association of age with asparaginase activity and asparaginase-associated hepatotoxicity during induction.

6. To examine the association of body-mass-index (BMI) percentile (or absolute BMI for young adults) with asparaginase activity and asparaginase-associated hepatotoxicity during induction.

7. To describe adherence by self-report and pill-count to oral levocarnitine in patients randomized to the intervention arm.

8. To examine the association of plasma levels of carnitine and related markers with the efficacy of levocarnitine supplementation.

9. To determine the impact of inherited genetic variation on hepatoxicity and levocarnitine efficacy.

Outline: Patients are randomized to 1 of 2 arms (arm A vs. B).

Arm A: Patients receive levocarnitine orally (Po) or intravenously (IV) as a bolus over 2 to 3 minutes or by infusion (over 10 to 30 minutes or per institutional standard) starting prior to standard of care induction chemotherapy with pegaspargase or calaspargase pegol and continued through the earlier of the last day of Induction phase (i.e., day prior to start of next phase) or Induction day 35. Patients may also undergo blood sample collection during screening and on study.

Arm B: Patients receive standard of care induction chemotherapy with pegaspargase or calaspargase pegol on study. Patients may also undergo blood sample collection during screening and on study.

ARM C (RESCUE): Patients in Arms A and B who develop conjugated hyperbilirubinemia > 3 mg/dL during induction may receive levocarnitine rescue PO or IV as a bolus dose over 2 to 3 minutes or by infusion (over 10 to 30 minutes or per institutional standard) until resolution of conjugated hyperbilirubinemia =< 3 mg/dL (or start of consolidation or the next treatment phase, whichever occurs first).

Inclusion Criteria:

• >= 15 and < 40 years at time of diagnosis

• Newly diagnosed B-ALL, T-ALL, lymphoblastic lymphoma (LLy), or mixed-phenotype acute leukemia/lymphoma (MPAL)

  • Note: Philadelphia chromosome (PH)+ and PH-like acute leukemia are eligible (use of tyrosine kinase inhibitors [TKI] or CRLF2* targeted concomitant medication must be documented, if used)

• Conjugated bilirubin =< 1.5 x upper limit of normal (ULN) for age, regardless of baseline bilirubin (within 7 days prior to enrollment), and

• Serum glutamate pyruvate transaminase (SGPT) (ALT) =< 225 U/L (=< 5x ULN) (within 7 days prior to enrollment), and

  • Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the value of 45 U/L and serum glutamic oxaloacetic transaminase (SGOT) (AST) to 50 U/L regardless of baseline

• SGOT (AST) =< 250 U/L (=< 5x ULN) (within 7 days prior to enrollment)

  • Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the value of 45 U/L and SGOT (AST) to 50 U/L regardless of baseline

• For patients receiving ursodiol prior to enrollment, laboratory values must meet above criteria off ursodiol for 7 days

• PEDIATRIC PATIENTS (AGE 15-17 years):

  • A 24-hour urine creatinine clearance >= 30 mL/min/1.73 m^2 (within 7 days prior to enrollment) OR

  • A glomerular filtration rate (GFR) >= 30 mL/min/1.73 m^2. GFR must be performed using one of the following methods (within 7 days prior to enrollment):

    • 1. Estimated GFR (eGFR) >= 30 mL/min/1. 73 m^2.
      • An online calculator is available through the National Kidney Foundation at https://www.kidney.org/professionals/kdoqi/gfr_calculatorped
    • 1. Measured GFR >= 30 mL/min/1. 73 m^2 (any age). If measured GFR is used, it must be performed using direct measurement with a nuclear blood sampling method or small molecule clearance method (iothalamate or other molecule per institutional standard).

• ADULT PATIENTS (AGE 18 YEARS OR OLDER): Creatinine clearance >= 30 mL/min, as estimated by the Cockcroft and Gault formula or a 24-hour urine collection (within 7 days prior to enrollment). Estimated creatinine clearance is based on actual body weight

  • An online calculator is available through the National Kidney Foundation at https://www.kidney.org/professionals/kdoqi/gfr_calculatorcoc

• Berlin-Frankfurt-Munich (BFM), Children's Oncology Group (COG), or C10403-based Induction regimen and must be inclusive of >= 1 dose of pegaspargase or calaspargase pegol, and

• First dose of asparaginase must be planned within the first week of induction therapy, and

• Dose of pegaspargase or calaspargase pegol must be >= 1,000 IU/ m^2 (dose-capping permitted per primary regimen)

  • Note: Co-enrollment on a therapeutic consortia trial is not required

• All patients and/or their parents or legal guardians must sign a written informed consent

• All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Exclusion Criteria:

• Down syndrome

• Known inherited or autoimmune liver disease impacting conjugated bilirubin (e.g., Alagille syndrome, primary sclerosing cholangitis, other)

• Known biopsy (or imaging) proven severe liver fibrosis (Batts-Ludwig >= stage 3)

• Unable to tolerate oral formulation of study drug at enrollment

• Patients who received chemotherapy or treatment for a prior malignancy are not eligible

  • The following are permitted: steroid prophase, hydroxyurea, or other cytoreduction prior to initiation of Induction chemotherapy (must be documented) and chemotherapy for current diagnosis (i.e. initiation of Induction therapy within enrollment window). Chemotherapy prior to enrollment for treatment of a non-malignancy (e.g., steroid or methotrexate for autoimmune disease) is also permitted and must be documented

• Female patients who are pregnant since fetal toxicities and teratogenic effects in humans are unknown for study drug. A pregnancy test is required for female patients of childbearing potential

• Lactating females who plan to breastfeed their infants

• Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation