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Inotuzumab Ozogamicin

Pegaspargase

Folic Acid

Vitamin B Complex

Asparaginase

Trace Elements

Folate

Vitamin B9

Carnitine

Folinic Acid

Patients receive levocarnitine IV over 2-3 minutes every 6 hours up to 4 times a day (inpatient) or PO TID (outpatient). Patients also receive vitamin B complex PO BID. Treatment continues for up to 30 days after the last dose of either PEG-asparaginase or inotuzumab, or until Tbili of ≤ 1.5 x ULN or at least a 50% reduction in peak Tbili is achieved.

Levocarnitine

Elias Jabbour, MD

Elias Jabbour

This phase II trial studies how well levocarnitine and vitamin B complex works in treating abnormal high liver enzyme levels (hyperbilirubinemia) caused by treatment with PEG-asparaginase or inotuzumab ozogamicin in patients with acute lymphoblastic leukemia. Amino acids, such as levocarnitine, may work in normalizing liver enzyme levels due to treatment. Vitamin B complex is a dietary supplement that may be used for patients with nutritional deficiencies. Giving levocarnitine and vitamin B complex may work better in treating hyperbilirubinemia in patients with acute lymphoblastic leukemia.

PRIMARY OBJECTIVES:

I. To evaluate the efficacy of levocarnitine in combination with vitamin B complex in treating PEG-asparaginase (PEG) or inotuzumab ozogamicin (INO) induced hyperbilirubinemia (total bilirubin \[Tbili\] \> 3 x upper limit of normal \[ULN\]) in patients (pts) with acute lymphoblastic leukemia (ALL).

SECONDARY OBJECTIVES:

I. To evaluate chemotherapy dose intensity in patients treated with PEG-asparaginase or inotuzumab ozogamicin.

II. To characterize the safety, tolerability, and adverse event profile of levocarnitine and vitamin B for the treatment of hyperbilirubinemia.

OUTLINE: Patients are assigned to 1 of 2 cohorts.

Patients receive levocarnitine intravenously (IV) over 2-3 minutes every 6 hours up to 4 times a day (inpatient) or orally (PO) three times a day (TID) (outpatient). Patients also receive vitamin B complex PO twice daily (BID). Treatment continues for up to 30 days after the last dose of either PEG-asparaginase or inotuzumab, or until Tbili of ≤ 1.5 x ULN or at least a 50% reduction in peak Tbili is achieved.

After completion of study treatment, patients are followed up at 30 days.

Levocarnitine and Vitamin B Complex in Treating PEG-Asparaginase or Inotuzumab Ozogamicin-Induced Hyperbilirubinemia in Patients With Acute Lymphoblastic Leukemia

Mitochondrial Cofactors for the Treatment of Hyperbilirubinemia Due to PEG-Asparaginase and or Inotuzumab Ozogamicin in Patients With Acute Lymphoblastic Leukemia (ALL)

The time to hyperbilirubinemia normalization or achieving at least a 50% reduction in peak total bilirubin will be compared to historical controls using the Log rank test. Competing risk analysis will be considered in the case that patients died before bilirubin normalization or at least a 50% reduction in peak total bilirubin is achieved.

Will be defined by normalization of hyperbilirubinemia. Response rates will be estimated along with the 95% confidence interval. The duration of time to hyperbilirubinemia normalization of at least 50% reduction in peak total bilirubin will be estimated using the Kaplan-Meier method.

Descriptive statistics will be used to summarize secondary endpoints. The incidence rates of binary secondary endpoints will be estimated, along with the 95% confidence intervals.

Will be graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Descriptive statistics will be used to summarize secondary endpoints. The incidence rates of binary secondary endpoints will be estimated, along with the 95% confidence intervals. Safety data will be summarized by adverse event (AE) category, severity and frequency. The proportion of patients with AEs will be estimated.

National Cancer Institute (NCI)

M.D. Anderson Cancer Center

Adults, or patients ≥ 50 kg: 990 mg PO (by mouth) bis in die (BID, twice a day) Children, or patients \< 50 kg: 50 mg/kg/day PO divided BID (maximum daily dose of 2,000 mg)

Van T. Huynh, M.D.

Deepa Jeyakumar, MD

Acute lymphoblastic leukemia (ALL) is the most common cancer seen in pediatric oncology. The necessary chemotherapy for pediatric and adolescent and young adult (AYA) patients with ALL includes steroids, anthracyclines, asparaginase, and vincristine. One of the most hepatotoxic chemotherapy agents is asparaginase, with treatment-associated hepatotoxicity (TAH) observed in up to 60% of patients. The frequency of TAH is increased in overweight or obese patients of Latino heritage. Carnitine is a naturally-derived compound that is produced in the liver and kidneys; it is found in certain foods, such as meat, poultry, fish, and some dairy products. Endogenous carnitine transports long-chain fatty acids into the mitochondria, where they are oxidized to produce energy, and acts as scavengers of oxygen free radicals. Thus, carnitine can reduce oxidative stress and modulate inflammatory response. Levocarnitine is a supplement form of carnitine used typically in the care and management of patients with carnitine deficiency. Pediatric and AYAs with ALL will be given oral levocarnitine as a supplement during their initial phases of treatment, when the most hepatotoxic agents are administered, to determine if the incidence of liver toxicity can be reduced or eliminated.

Primary Aims

1. Prospectively evaluate whether the prophylactic use of levocarnitine during Induction and Consolidation (phases with asparaginase therapy) in ALL patients receiving treatment according to a Children's Oncology Group (COG) treatment protocol reduces hepatotoxicity.
2. Demonstrate an association between ethnicity and liver function test abnormalities in children and AYAs with ALL. Specifically, that Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grade ≥ 3 elevated liver function tests is more prevalent in self-identified Latinos as compared to other ethnicities in a retrospective control group.

Secondary Aims

1. Determine whether obesity or overweight status, as measured by body mass index, at diagnosis increases the risk of hepatic dysfunction.
2. Quantify the disease response, based on the end of Induction minimal residual disease (MRD) in the bone marrow of patients receiving levocarnitine, compared to historical controls to determine that levocarnitine does not have a negative impact on MRD.
3. Assess incidence of nonalcoholic fatty liver disease (NAFLD), via non-invasive ultrasound elastography, in pediatric and AYA patients newly diagnosed with ALL.
4. Assess incidence of other known toxicities of asparaginase treatment, including hyper/hypoglycemia, hypertriglyceridemia, pancreatitis, and thrombosis that are CTCAE version 5.0 grade ≥ 3 with onset ≤ 30 days (or next dose if sooner) of asparaginase.

Study Design:

The proposal is a non-randomized case-control pilot study that will use retrospective case-control data as comparison (i.e., control group).

Participants:

A sample of 20 pediatric and AYA patients, ages 5 to \< 30 years, newly diagnosed with ALL will be enrolled to study. Participants who withdraw or who are withdrawn from study, who have taken less than 50% of planned levocarnitine supplementation, and who did not have a post-levocarnitine supplementation laboratory testing will be replaced. An additional 20 retrospective cases -- matched by age at diagnosis, biological sex, and risk classification at initial diagnosis -- will be included to provide control data.

Study Intervention:

Levocarnitine will be administered by mouth twice daily during Induction and Consolidation phases of treatment for patients with ALL who are treated as per a COG treatment plan (either on study or treated according to the protocol). The duration of intervention is expected to be approximately three months.

Use of Levocarnitine to Reduce Asparaginase Hepatotoxicity in Patients With Acute Lymphoblastic Leukemia

Calculate proportion of patients who experience hepatotoxicity, as measured by the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grade ≥ 3 elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total and direct bilirubin.

Calculate prevalence of hepatotoxicity in patients who self-identify as Latino or non-Latino, using laboratory assessments and self-reported measures of ethnicity and/or race.

Calculate body mass index (BMI), from recorded height and weight obtained at time of initial diagnosis and determine if there is increased risk of hepatotoxicity in patients who are overweight or obese at diagnosis as determined by Centers for Disease Control and Prevention (CDC) clinical growth charts for study participants 5 to \< 20 years of age and by a BMI of ≥ 25.0 for study participants 20 to \< 30 years of age.

Quantify disease response, using end of Induction minimal residual disease (MRD) results, where an MRD value \< 0.01 is considered "negative."

Calculate incidence of nonalcoholic fatty liver disease (NAFLD), using ultrasound elastography, in pediatric and AYA patients newly diagnosed with ALL.

Calculate proportion of patients who experience other known toxicities of asparaginase treatment, as measured by CTCAE version 5.0 grade ≥ 3 hyper/hypoglycemia, hypertriglyceridemia, pancreatitis, and thrombosis.

University of California, Irvine

Children's Hospital of Orange County

Precursor T-Cell Lymphoblastic Leukemia-Lymphoma

Acute Leukemia of Ambiguous Lineage

Liver Extracts

Patients receive levocarnitine PO or IV prior to standard of care induction chemotherapy with pegaspargase or calaspargase pegol on study. Patients may also undergo blood sample collection during screening and on study.

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.

Patients in Arms A and B who develop conjugated hyperbilirubinemia \> 3 mg/dL during induction may receive levocarnitine rescue PO or IV supplementation until resolution of conjugated hyperbilirubinemia =\< 3 mg/dL (or start of consolidation or the next treatment phase, whichever occurs first).

Biospecimen Collection

Given standard of care calaspargase pegol

Calaspargase Pegol

Quality-of-Life Assessment

Site Public Contact

Aman Wadhwa

Holly E. Pariury

David L. Becton

Robert M. Cooper

Lindsey Murphy

Jacqueline N. Casillas

Etan Orgel

Karen S. Fernandez

Jennifer G. Michlitsch

Michaela Liedtke

Maria I. Castellanos

Scott M. Bradfield

Emad K. Salman

William B. Slayton

Iftikhar Hanif

Maggie E. Fader

Fouad M. Hajjar

Jeffrey H. Schwartz

Andrew J. Galligan

Don E. Eslin

Andrew L. Pendleton

Shira N. Dinner

Mary L. Schmidt

Wendy Stock

Rebecca E. McFall

Gregory P. Brandt

Rachael R. Schulte

Bassem I. Razzouk

Samantha L. Mallory

David S. Dickens

Kenneth Byrd

James T. Badgett

Ashok B. Raj

Craig Lotterman

Sei-Gyung K. Sze

Jason M. Fixler

Stacy L. Cooper

Joshua W. Goldman

Kathleen J. Yost

Laura E. Agresta

Keith J. August

Robin D. Hanson

Jill C. Beck

Jing Chen

Alissa Kahn

Jessica M. Valdez

Lauren R. Weintraub

Alice Lee

Chana L. Glasser

Michal Bar-Natan

Jessica C. Hochberg

Thomas B. Alexander

Samuel J. Milanovich

Erin Wright

Erin H. Breese

Duncan S. Stearns

Rabi Hanna

Mark A. Ranalli

Mukund G. Dole

Jamie L. Dargart

Rene Y. McNall-Knapp

Susan J. Lindemulder

Jagadeesh Ramdas

Susan R. Rheingold

Colleen Mathews

Howland E. Crosswell

Aniket Saha

Kayelyn J. Wagner

Susan E. Spiller

This phase III trial compares the effect of adding levocarnitine to standard chemotherapy 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:

I. 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:

I. 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.

II. 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:

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

II. 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.

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

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

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

VI. 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.

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

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

IX. 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) prior to 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 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 supplementation until resolution of conjugated hyperbilirubinemia =\< 3 mg/dL (or start of consolidation or the next treatment phase, whichever occurs first).

Studying the Effect of Levocarnitine in Protecting the Liver From Chemotherapy for Leukemia or Lymphoma

A Randomized Trial of Levocarnitine Prophylaxis to Prevent Asparaginase-Associated Hepatotoxicity in Adolescents and Young Adults Receiving Acute Lymphoblastic Leukemia Therapy

For patients assigned to arms A and B, the proportion experiencing CTCAE grade \>=4 adverse events by the end of induction chemotherapy will be estimated along with 95% confidence intervals.

For patients assigned to arms A and B, the proportion receiving a dose reduction during induction chemotherapy relative to planned doses at the beginning of induction chemotherapy for daunorubicin, vincristine, and/or asparaginase will be estimated along with 95% confidence intervals

For patients assigned to arms A and b, the median percent planned dose given during induction will also be calculated as well as 95% confidence intervals.

For patients assigned to arms A and B, the investigators will calculate median peak conjugated bilirubin as well as corresponding 95% confidence intervals.

For patients assigned to arms A and B, the investigators will calculate median peak ALT as well as corresponding 95% confidence intervals.

For patients assigned to arms A, B, and C, the investigators will calculate the median days from onset of conjugated hyperbilirubinemia as well as 95% confidence intervals.

The 11-question FACT/GOG-NTX survey will be used to assess patient reported CIPN, where a higher score indicates more severe CIPN. For patients on arms A and B, a median and corresponding 95% confidence interval will be estimated and reported.

For EFS analysis, 3-year EFS probabilities and corresponding 95% CI will be estimated for Arms A and B, separately, using the Kaplan Meier method. A log-rank test will be used to compare EFS between Arm A versus Arm B (Arm C patients will not contribute to this analysis after they start levocarnitine rescue). Additional EFS analyses comparing Arms A versus B will also be performed using Cox regression models adjusted for "levocarnitine rescue" (i.e., Arm C patients/time) as a time-varying covariate. Hazard ratio and the corresponding 95%CI will be reported for each arm.

For OS analysis, 3-year OS probabilities and corresponding 95% CI will be estimated for Arms A and B, separately, using the Kaplan Meier method.

Spearman's correlation coefficients and corresponding 95% confidence intervals will be reported comparing asparaginase activity to age and BMI.

The association of BMI percentile with asparaginase activity will be assessed using Spearman's correlation. Logistic regression will be used to separately assess the relationship of BMI (considered as a continuous variable and an ordinal variable) and asparaginase activity with hepatotoxicity (conjugated hyperbilirubinemia, ALT) dichotomized as conjugated hyperbilirubinemia \>3 versus =\< 3 mg/dl and CTCAE grade \>= 3 versus \< 3 AST or ALT, respectively. Analyses will be performed separately for asparaginase activity measured on Days \~8, 15, and 22 and for Arms A and B.

Descriptive statistics (mean (sd) or median (range) as appropriate) will be used to summarize adherence to levocarnitine tablets during induction in AYA patients randomized to the intervention Arm A as assessed by self-report (% doses compliant) and pill-counts (% pills returned). The percentage of doses compliant will be calculated as: the number of reported missed doses / total prescribed doses for the entire induction period. And the percentage of pills returned will be calculated as the number of pills returned / (number of pills dispensed - number of pills prescribed not taken \[i.e., for prescribed dose reductions for toxicity for the entire induction period\]).

The investigators will report the median percentage dose compliance across patients assigned to arm A as well as a 95% confidence interval.

The Investigators will calculate mean plasma levels of carnitine at baseline and at steady state for patients in arms A and B who do and do not experience conjugated hyperbilirubinemia \>3 mg/dL and will calculate corresponding 95% confidence intervals.

This aim will use specimens banked for future research to describe the association of candidate genes (PNPLA3, SOD2, GST family, other) with conjugated hyperbilirubinemia \>3 mg/dL and CTCAE Grade ≥3 AST or ALT elevations between treatment arms. Analyses will include ethnic and racial differences, with ancestry determined by self-report and complementary admixture mapping. The association of observed genetic differences with oxidant stress markers (e.g., protein oxidation, lipid peroxidation, total oxidant capacity) pre- and post-asparaginase will be assessed. In general, a multivariable logistic regression model will be used to examine the association between the occurrence of the primary endpoint and the genetic variant of interest, inclusive of covariates: age, obesity, and treatment versus control arm (1:1).

For patients assigned to arms A and B, the investigators will separately estimate the proportion of patients who experience conjugated hyperbilirubinemia \> 3mg/dL during induction chemotherapy by arm along with corresponding 95% confidence intervals.

For patients assigned to arms A and B, the investigators will separately estimate the proportion of patients who experience grade \>= 3 alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevations during induction chemotherapy by arm along with corresponding 95% confidence intervals.

For patients assigned to arms A and B, the proportion having MRD positivity at the end of induction chemotherapy will be estimated separately by arm along with corresponding 95% confidence intervals. For patients assigned to arms A and B, the proportion having MRD positivity at the end of consolidation chemotherapy will be estimated separately by arm along with corresponding 95% confidence intervals (only patients with end of consolidation MRD evaluated and who did not get placed on the rescue arm C will be included).

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Levocarnitine and Vitamin B Complex in Treating PEG-Asparaginase or Inotuzumab Ozogamicin-Induced Hyperbilirubinemia in Patients With Acute Lymphoblastic Leukemia	NCT03564678	Acute Lymphobla... Hyperbilirubine...	Levocarnitine Vitamin B Compl...	18 Years -	M.D. Anderson Cancer Center
Use of Levocarnitine to Reduce Asparaginase Hepatotoxicity in Patients With Acute Lymphoblastic Leukemia	NCT05501899	Acute Lymphobla... Hepatotoxicity	Levocarnitine	5 Years - 29 Years	Children's Hospital of Orange County
Use of Levocarnitine to Reduce Asparaginase Hepatotoxicity in Patients With Acute Lymphoblastic Leukemia	NCT05501899	Acute Lymphobla... Hepatotoxicity	Levocarnitine	5 Years - 29 Years	Children's Hospital of Orange County
Studying the Effect of Levocarnitine in Protecting the Liver From Chemotherapy for Leukemia or Lymphoma	NCT05602194	B Acute Lymphob... B Acute Lymphob... B Acute Lymphob... Lymphoblastic L... Mixed Phenotype... T Acute Lymphob...	Biospecimen Col... Calaspargase Pe... Levocarnitine Pegaspargase Quality-of-Life...	15 Years - 40 Years	Children's Oncology Group

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