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Results summary of St. Jude clinical trial: 



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

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 has been learned from past TOTAL studies, new discoveries at St. Jude, and advances from other groups treating childhood leukemia around the world.

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

The study’s main goals were to:

  • improve the survival rates of children with acute lymphoblastic leukemia.
  • find out if a higher dose of a drug called PEG-asparaginase (PEG-ASP) would yield better results than a standard dose without more side effects
  • learn if giving more intense treatment to high-risk patients increases survival rates over past studies
  • find out if giving more intensive 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 processed, eliminated and affect the body
  • test new methods to measure minimal residual disease (MRD) to help adjust the intensity of treatment to the risk of relapse
  • use stool samples to learn more about preventing and treating infections in children and young adults with ALL
  • learn more about how drugs affect the brain’s structure and function, and how they are influenced by genetic factors

When was this study done?

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

What did the study consist of?

There are three main stages of treatment (remission induction, consolidation and continuation):

  • Remission induction therapy uses several strong drugs to kill leukemia cells in the bone marrow and to allow normal blood cells to begin to grow again. The goal is remission, in which there is no evidence of leukemia.
  • The next stage, called consolidation, tries to deliver a “knock-out punch” to any remaining leukemia cells.
  • In the final stage, called maintenance, we try to keep the leukemia from coming back.
  • Patients received different treatments according to their risk group: low risk, standard risk or high risk

What did we learn from this study?

  • We learned that excellent control of leukemia in the brain can be achieved without using cranial irradiation. That finding applies even to patients with high-risk subtypes. Optimal chemo, including three drugs given in the cerebrospinal fluid, can prevent relapses in the brain without excessive toxicity.
  • We learned the importance of giving antibiotics to prevent infections. Infection is one of the most common causes of death in children being treatment for ALL. Most life-threatening infections occur during the induction phase. Preventive antibiotic treatment has been controversial because of worries about whether it’s needed or if it may cause antibiotic resistance.

    In the largest study of its kind, some patients in TOTXVI received 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 Clostridium difficile infections by more than 95%.

    Many children develop allergies to PEG-ASP, an important drug used to treat leukemia. When that happens, they need to switch to another drug that must be given more often. Scientists wanted to find out what puts children at risk for PEG-ASP allergies.

    The scientists found antibodies that predict reactions to PEG-ASP. They also learned that children who had more intrathecal therapy (when the drug is infused into the fluid-filled area in the spinal cord) had fewer reactions to PEG-ASP. PEG-ASP resulted in fewer allergies than L-ASP, a similar drug that had been used in the previous TOTXV clinical trial.
  • We learned how to predict infection risk through stool samples. Scientists know that the 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 at diagnosis and after each phase of chemo. They used those samples to study the role of the microbes in the gut. The scientists’ aim was to find characteristics that predict such problems as diarrhea, bloodstream infections, fever or low numbers of white blood cells.

    The scientists discovered that children who have a lot of proteobacteria (a certain type of bacteria) in the gut before chemo are at a high risk of getting fever and low numbers of white blood cells. Researchers also found that high numbers of Enterococcaceae or Streptococcaceae bacteria at any time 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 as a preventive measure in children who undergo induction therapy for ALL. The researchers suggest close long-term monitoring of antibiotic resistance in these children.

As a result of the research into PEG-ASP, clinicians now have a better understanding of allergic reactions to this drug, which will help predict which patients cannot take this drug.

From the study on the gut microbiome, we learned better ways to predict which patients have a high risk of infections. Customized treatments can now be designed to lessen this risk.

 How does this study affect my child?

Every childhood cancer survivor should receive long-term follow-up care. Through the St. Jude After Completion of Care clinic, your child will receive information and guidance for care after treatment. Please speak with your St. Jude doctor about specific guidelines that apply to 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]