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

Lymphoblastic Lymphoma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05602194
• Other study ID #: ACCL1931
• Secondary ID: NCI-2022-08058AC
• Status: Recruiting
• Phase: Phase 3
• Start date: August 24, 2023
• Est. completion date: December 31, 2027

Study information

• Verified date: May 2024
• Source: Children's Oncology Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 440
• Est. completion date: December 31, 2027
• Est. primary completion date: December 31, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 15 Years to 40 Years

Eligibility

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

• 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)

• 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

Related Conditions & MeSH terms

• B Acute Lymphoblastic Leukemia
• B Acute Lymphoblastic Leukemia With t(9;22)(q34.1;q11.2); BCR-ABL1
• Leukemia
• Leukemia, Lymphoid
• Lymphoblastic Lymphoma
• Lymphoma
• Mixed Phenotype Acute Leukemia
• Precursor Cell Lymphoblastic Leukemia-Lymphoma
• Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
• T Acute Lymphoblastic Leukemia

Intervention

Procedure:
• Biospecimen Collection
Undergo blood sample collection

Drug:
• Calaspargase Pegol
Given standard of care calaspargase pegol

Dietary Supplement:
• Levocarnitine
Given PO or IV

Drug:
• Pegaspargase
Given standard of care pegaspargase

Other:
• Quality-of-Life Assessment
Ancillary studies

Locations

Country	Name	City	State
Canada	IWK Health Centre	Halifax	Nova Scotia
United States	Children's Hospital Medical Center of Akron	Akron	Ohio
United States	Albany Medical Center	Albany	New York
United States	University of New Mexico Cancer Center	Albuquerque	New Mexico
United States	Kaiser Permanente-Anaheim	Anaheim	California
United States	C S Mott Children's Hospital	Ann Arbor	Michigan
United States	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan
United States	Dell Children's Medical Center of Central Texas	Austin	Texas
United States	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland
United States	Sinai Hospital of Baltimore	Baltimore	Maryland
United States	Bronson Battle Creek	Battle Creek	Michigan
United States	Kaiser Permanente-Bellflower	Bellflower	California
United States	Children's Hospital of Alabama	Birmingham	Alabama
United States	Children's Hospital at Montefiore	Bronx	New York
United States	Montefiore Medical Center - Moses Campus	Bronx	New York
United States	Montefiore Medical Center-Einstein Campus	Bronx	New York
United States	Montefiore Medical Center-Weiler Hospital	Bronx	New York
United States	UNC Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina
United States	University of Virginia Cancer Center	Charlottesville	Virginia
United States	Northwestern University	Chicago	Illinois
United States	University of Chicago Comprehensive Cancer Center	Chicago	Illinois
United States	University of Illinois	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	Rainbow Babies and Childrens Hospital	Cleveland	Ohio
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	Geisinger Medical Center	Danville	Pennsylvania
United States	Dayton Children's Hospital	Dayton	Ohio
United States	Blank Children's Hospital	Des Moines	Iowa
United States	Kaiser Permanente Downey Medical Center	Downey	California
United States	City of Hope Comprehensive Cancer Center	Duarte	California
United States	Michigan State University Clinical Center	East Lansing	Michigan
United States	Sanford Broadway Medical Center	Fargo	North Dakota
United States	Kaiser Permanente-Fontana	Fontana	California
United States	Golisano Children's Hospital of Southwest Florida	Fort Myers	Florida
United States	Cook Children's Medical Center	Fort Worth	Texas
United States	University of Florida Health Science Center - Gainesville	Gainesville	Florida
United States	Helen DeVos Children's Hospital at Spectrum Health	Grand Rapids	Michigan
United States	Spectrum Health at Butterworth Campus	Grand Rapids	Michigan
United States	Trinity Health Grand Rapids Hospital	Grand Rapids	Michigan
United States	BI-LO Charities Children's Cancer Center	Greenville	South Carolina
United States	Saint Francis Cancer Center	Greenville	South Carolina
United States	Saint Francis Hospital	Greenville	South Carolina
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	Memorial Regional Hospital/Joe DiMaggio Children's Hospital	Hollywood	Florida
United States	Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center	Houston	Texas
United States	M D Anderson Cancer Center	Houston	Texas
United States	Ascension Saint Vincent Indianapolis Hospital	Indianapolis	Indiana
United States	Riley Hospital for Children	Indianapolis	Indiana
United States	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa
United States	Nemours Children's Clinic-Jacksonville	Jacksonville	Florida
United States	Ascension Borgess Cancer Center	Kalamazoo	Michigan
United States	Borgess Medical Center	Kalamazoo	Michigan
United States	Bronson Methodist Hospital	Kalamazoo	Michigan
United States	West Michigan Cancer Center	Kalamazoo	Michigan
United States	Children's Mercy Hospitals and Clinics	Kansas City	Missouri
United States	University of Kansas Cancer Center	Kansas City	Kansas
United States	East Tennessee Childrens Hospital	Knoxville	Tennessee
United States	University of Kentucky/Markey Cancer Center	Lexington	Kentucky
United States	Arkansas Children's Hospital	Little Rock	Arkansas
United States	Miller Children's and Women's Hospital Long Beach	Long Beach	California
United States	Children's Hospital Los Angeles	Los Angeles	California
United States	Kaiser Permanente Los Angeles Medical Center	Los Angeles	California
United States	Norton Children's Hospital	Louisville	Kentucky
United States	Covenant Children's Hospital	Lubbock	Texas
United States	UMC Cancer Center / UMC Health System	Lubbock	Texas
United States	Valley Children's Hospital	Madera	California
United States	Marshfield Medical Center-Marshfield	Marshfield	Wisconsin
United States	Nicklaus Children's Hospital	Miami	Florida
United States	Children's Hospital of Wisconsin	Milwaukee	Wisconsin
United States	NYU Winthrop Hospital	Mineola	New York
United States	Trinity Health Muskegon Hospital	Muskegon	Michigan
United States	The Children's Hospital at TriStar Centennial	Nashville	Tennessee
United States	Vanderbilt University/Ingram Cancer Center	Nashville	Tennessee
United States	Ochsner Medical Center Jefferson	New Orleans	Louisiana
United States	NYP/Weill Cornell Medical Center	New York	New York
United States	Corewell Health Lakeland Hospitals - Niles Hospital	Niles	Michigan
United States	Children's Hospital of The King's Daughters	Norfolk	Virginia
United States	Cancer and Hematology Centers of Western Michigan - Norton Shores	Norton Shores	Michigan
United States	Advocate Children's Hospital-Oak Lawn	Oak Lawn	Illinois
United States	UCSF Benioff Children's Hospital Oakland	Oakland	California
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Children's Hospital and Medical Center of Omaha	Omaha	Nebraska
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	AdventHealth Orlando	Orlando	Florida
United States	Nemours Children's Hospital	Orlando	Florida
United States	Stanford Cancer Institute Palo Alto	Palo Alto	California
United States	Advocate Children's Hospital-Park Ridge	Park Ridge	Illinois
United States	Saint Joseph's Regional Medical Center	Paterson	New Jersey
United States	Sacred Heart Hospital	Pensacola	Florida
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania
United States	Oregon Health and Science University	Portland	Oregon
United States	Corewell Health Reed City Hospital	Reed City	Michigan
United States	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia
United States	Carilion Children's	Roanoke	Virginia
United States	Corewell Health Lakeland Hospitals - Marie Yeager Cancer Center	Saint Joseph	Michigan
United States	Lakeland Medical Center Saint Joseph	Saint Joseph	Michigan
United States	Mercy Hospital Saint Louis	Saint Louis	Missouri
United States	Children's Hospital of San Antonio	San Antonio	Texas
United States	Methodist Children's Hospital of South Texas	San Antonio	Texas
United States	University of Texas Health Science Center at San Antonio	San Antonio	Texas
United States	Kaiser Permanente-San Diego Mission	San Diego	California
United States	Kaiser Permanente-San Diego Zion	San Diego	California
United States	UCSF Medical Center-Mission Bay	San Francisco	California
United States	Memorial Health University Medical Center	Savannah	Georgia
United States	Maine Children's Cancer Program	Scarborough	Maine
United States	Seattle Children's Hospital	Seattle	Washington
United States	Sanford USD Medical Center - Sioux Falls	Sioux Falls	South Dakota
United States	Providence Sacred Heart Medical Center and Children's Hospital	Spokane	Washington
United States	Southern Illinois University School of Medicine	Springfield	Illinois
United States	Mary Bridge Children's Hospital and Health Center	Tacoma	Washington
United States	Saint Joseph's Hospital/Children's Hospital-Tampa	Tampa	Florida
United States	Tampa General Hospital	Tampa	Florida
United States	ProMedica Toledo Hospital/Russell J Ebeid Children's Hospital	Toledo	Ohio
United States	Munson Medical Center	Traverse City	Michigan
United States	Banner University Medical Center - Tucson	Tucson	Arizona
United States	New York Medical College	Valhalla	New York
United States	University of Kansas Hospital-Westwood Cancer Center	Westwood	Kansas
United States	Alfred I duPont Hospital for Children	Wilmington	Delaware
United States	University of Michigan Health - West	Wyoming	Michigan

Sponsors (1)

Lead Sponsor	Collaborator
Children's Oncology Group

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Incidence of CTCAE grade >= 4 adverse events during induction chemotherapy	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.	Up to 35 days (induction phase)
Other	Incidence of daunorubicin, vincristine, and/or asparaginase chemotherapy dose reductions during induction chemotherapy	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	Up to 35 days (induction phase)
Other	Percentage of planned dose given for daunorubicin, vincristine, and/or asparaginase during induction chemotherapy	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.	Up to 35 days (induction phase)
Other	Peak levels during induction of conjugated bilirubin	For patients assigned to arms A and B, the investigators will calculate median peak conjugated bilirubin as well as corresponding 95% confidence intervals.	Up to 35 days (induction phase)
Other	Peak levels during induction of total bilirubin	For patients assigned to arms A and B, the investigators will calculate median peak ALT as well as corresponding 95% confidence intervals.	Up to 35 days (induction phase)
Other	Peak levels of AST during induction chemotherapy	For patients assigned to arms A and B, the investigators will calculate median peak ALT as well as corresponding 95% confidence intervals.	Up to 35 days (induction phase)
Other	Peak levels of ALT during induction chemotherapy	For patients assigned to arms A and B, the investigators will calculate median peak ALT as well as corresponding 95% confidence intervals.	Up to 35 days (induction phase)
Other	Days of conjugated hyperbilirubinemia (> 3 mg/dL) to <=3 mg/dL during induction	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.	Up to 35 days (induction phase)
Other	Severity of patient-reported chemotherapy induced peripheral neuropathy (CIPN) as measured by the 11-question Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-NTX) survey	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.	Up to 35 days (induction phase)
Other	Event free survival (EFS)	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.	The time from randomization to first event (relapse, second malignant neoplasm, remission or death) or date of last contact for those who are disease-free, assessed up to 3 years
Other	Overall survival (OS)	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.	Time from study entry to death or date of last contact for those alive at last contact, assessed up to 3 years
Other	Asparaginase activity	Spearman's correlation coefficients and corresponding 95% confidence intervals will be reported comparing asparaginase activity to age and BMI.	Days 8, 15, and 22
Other	Association of body-mass-index (BMI) percentile (or absolute BMI for young adults) with asparaginase activity and asparaginase-associated hepatotoxicity during induction therapy	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.	Days 8, 15, and 22
Other	Adherence to oral levocarnitine during induction chemotherapy measured by percentage of pills returned relative to those prescribed	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]).	Up to 35 days (induction phase)
Other	Adherence to oral levocarnitine measured by percentage dose compliance (% doses reported taken relative to prescribed)	The investigators will report the median percentage dose compliance across patients assigned to arm A as well as a 95% confidence interval.	Up to 35 days (induction phase)
Other	Mean plasma levels of carnitine	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.	Up to 3 years
Other	Impact inherited genetic variation on hepatoxicity and levocarnitine efficacy	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).	Up to 3 years
Primary	Incidence of conjugated hyperbilirubinemia >3 mg/dL during induction therapy	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.	During induction therapy (up-to 35-days after initiating induction chemotherapy)
Secondary	Incidence of grade >= 3 alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevations during induction therapy	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.	During induction therapy (up-to 35-days after initiating induction chemotherapy)
Secondary	Incidence of minimal residual disease (MRD) positivity (MRD >= 0.01%)	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).	At end of induction chemotherapy (up-to 35-days after initiating induction chemotherapy), and at end of consolidation chemotherapy (up-to day 56 days after initiating induction chemotherapy)