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Published results

TOTXVI: TOTAL Therapy Study XVI for Newly Diagnosed Patients with Acute Lymphoblastic Leukemia

Why was this study done?

TOTXVI is the 16th in a series of studies for children with acute lymphoblastic leukemia (ALL). The Total studies began in 1962 at St. Jude. Each study has built on what we have learned from past Total studies, discoveries at St. Jude, and work from other groups treating childhood leukemia worldwide.

Earlier studies showed that most children with ALL can have long-term remission (no evidence of disease) if they get strong chemotherapy (chemo) with several drugs. Past treatments also included radiation to the brain.

The study’s main goals were to:

  • Improve the survival rates of children with ALL
  • Find out if a higher dose of a drug called PEG-asparaginase (PEG-ASP) would give better results than a standard dose, without more side effects
  • Learn if giving more intense treatment to high-risk patients would increase their survival rates over past studies
  • Find out if stronger chemo, into the fluid around the brain and spinal cord (CSF) for high-risk patients would prevent the leukemia from coming back (relapse) in the CSF
  • Learn more about how the drugs are handled by the body, how the drugs affect the body, and how they are eliminated
  • Test new ways to measure any remaining disease (MRD) and adjust treatments to reduce the risk of relapse
  • Examine stool samples to learn more about preventing and treating infections in ALL patients
  • Learn more about how drugs affect the brain’s structure and function, and how the drugs are influenced by genetic factors

When was this study done?

The study opened in October 2007 and closed in March 2017.

What did the study consist of?

There are 3 main stages of treatment:

  • Remission induction uses several strong drugs to kill leukemia cells in the bone marrow and allow normal blood cells to grow back. The goal is remission (no evidence of leukemia).
  • Consolidation tries to deliver a “knock-out punch” to any remaining leukemia cells.
  • Continuation (or maintenance) tries to keep leukemia from coming back.

Patients got different treatments according to their risk group: low, standard, or high risk.

What did we learn from this study?

We learned that leukemia in the brain could be controlled without using radiation on the brain. This was true even for patients with high-risk subtypes. Optimal chemo, including 3 drugs given in the fluid around the brain and spinal cord, can prevent relapses in the brain without extra harm (toxicity).

We learned the importance of giving antibiotics to prevent infections. Infection is one of the most common causes of death in children treated for ALL. Most life-threatening infections occur during the induction stage. Giving antibiotic treatment before an infection takes hold has been debated. Some doubt the value of this practice. Others worry that bacteria might survive antibiotic treatment and resist it in the future (known as antibiotic resistance).

In the largest study of its kind, some patients in TOTXVI got no preventive antibiotics during induction. A second group got an antibiotic called levofloxacin. A third group got other antibiotics. Scientists learned that preventive antibiotics reduced the chance of serious infections by more than 70%. Levofloxacin reduced the chance of a Clostridium difficile bacterial infection by more than 95%.

We learned more about how to improve the effect of PEG-asparaginase (PEG-ASP) in the fluid of the brain and spinal cord. To grow and spread, leukemia cells need an amino acid called asparagine. The drug PEG-ASP can reduce asparagine levels in the blood and spinal fluid. We learned that the timing and number of doses given are more important to lower asparagine levels than the amount of the dose. Also, PEG-ASP lowers asparagine levels longer than another type of asparaginase called erwinase.

We learned more about PEG-ASP allergies and reactions. Many children develop allergies to PEG-ASP. When this happens, they need to switch to another drug they take more often. Scientists wanted to find out what increases the risk for PEG-ASP allergies.

The scientists found antibodies (substances made by the immune system) that can predict a reaction to PEG-ASP. Children who had more chemotherapy injections (IT-MHA), more often, into their spinal fluid had fewer reactions to PEG-ASP. This may be due to of the immune suppression of the IT-MHA. Children given PEG-ASP had fewer allergies than those given L-ASP, a similar drug used in the previous TOTXV clinical trial.

We learned how to predict infection risk through stool samples. Scientists know that microbes living in our gut can affect our overall health. If chemo gets these microbes out of balance, life-threatening infections can occur. Researchers collected stool samples from patients from the time of diagnosis and after each phase of chemo. The researchers studied the stool samples to better understand what the microbes do. They collected information about the role of microbes in problems as diarrhea, bloodstream infections, fever, or low numbers of white blood cells.

Before chemo, children who have a lot of a specific type of bacteria in their gut (proteobacteria) may have more fever and lower white blood cell numbers. White blood cells help prevent infection. Researchers also found that higher numbers of some bacteria during chemo predicts future infections and diarrhea.

What are the next research steps as a result of this study?

  • As a result of research on preventive antibiotics, scientists now suggest using levofloxacin to prevent infection in children who have induction therapy for ALL. These children should receive close long-term monitoring for antibiotic resistance.
  • The research on PEG-ASP gave us a better understanding of allergic reactions to that drug. This will help predict which patients cannot take it. More research will help us see if lower doses of PEG-ASP will reduce asparagine levels in the spinal fluid as needed.
  • The study on the gut microbiome showed us ways to predict which patients have a high risk of infections. We can design customized treatments to lessen this risk.

How does this study affect my child?

Every childhood cancer survivor should have long-term follow-up care. In the St. Jude After Completion of Care clinic, we will give your child information and guidance for care after treatment. Please speak with your St. Jude doctor about specific guidelines for your child.

For more information

Please talk with your child’s St. Jude doctor about questions or concerns you have as a result of this study.

Publications generated from this study:

Levofloxacin Prophylaxis During Induction Therapy for Pediatric Acute Lymphoblastic Leukemia. Wolf J, Tang L, Flynn PM, Pui CH, Gaur AH, Sun Y, Inaba H, Stewart T, Hayden RT, Hakim H, Jeha S. Clin Infect Dis. 2017 Nov 13;65(11):1790-1798.

Antibodies Predict Pegaspargase Allergic Reactions and Failure of Rechallenge. Liu Y, Smith CA, Panetta JC, Yang W, Thompson LE, Counts JP, Molinelli AR, Pei D, Kornegay NM, Crews KR, Swanson H, Cheng C, Karol SE, Evans WE, Inaba H, Pui CH, Jeha S, Relling, MV. J Clin Oncol. 2019 Aug 10;37(23):2051-2061.

Gut Microbiome Composition Predicts Infection Risk During Chemotherapy in Children With Acute Lymphoblastic Leukemia. Hakim H, Dallas R, Wolf J, Tang L, Schultz-Cherry S, Darling V, Johnson C, Karlsson EA, Chang TC, Jeha S, Pui CH, Sun Y, Pounds S, Hayden RT, Tuomanen E, Rosch JW. Clin Infect Dis. 2018 Aug 1;67(4):541-548.

Improved CNS Control of Childhood Acute Lymphoblastic Leukemia Without Cranial Irradiation: St Jude Total Therapy Study 16. Jeha S, Pei D, Choi J, Cheng C, Sandlund JT, Coustan-Smith E, Campana D, Inaba H, Rubnitz JE, Ribeiro RC, Gruber TA, Raimondi SC, Khan RB, Yang JJ, Mullighan CG, Downing JR, Evans WE, Relling MV, Pui CH. J Clin Oncol. 2019 Oct 28:JCO1901692. [Epub ahead of print]

Pharmacodynamics of Cerebrospinal Fluid Asparagine after Asparaginase. Panetta JC, Liu Y, Bottiglieri T, Arning E, Cheng C, Karol SE, Yang JJ, Zhou Y, Inaba H, Pui CH, Jeha S, Relling MV. Cancer Chemother Pharmacol. 2021 Oct;88(4):655-664. Epub 2021 Jun 25.

The above information is intended to provide only a basic description about a research protocol that may be currently active at St. Jude. The details made available here may not be the most up-to-date information on protocols used by St. Jude. To receive full details about a protocol and its status and or use at St. Jude, a physician must contact St. Jude directly.


Full title:

TOTAL Therapy Study XVI for Newly Diagnosed Patients with Acute Lymphoblastic Leukemia (TOTXVI)

Study goal:

Find out if a higher dose of a drug called PEG-asparaginase (PEG-ASP) would give better results than a standard dose, without more side effects


Acute Lymphoblastic Leukemia (ALL)

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