Why was this study done?
TOTXV is the 15th 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 results from past Total studies and new discoveries by St. Jude and other groups worldwide.
Earlier studies showed that most children with ALL can have long-term remissions (no evidence of disease) if they get optimal doses and combinations of several chemotherapy (chemo) drugs. Some treatments in the past also included brain radiation.
The study’s main goals were to:
- Pioneer the use of response to the first 6 weeks of chemo as determined by minimal residual disease (MRD). MRD measures how much leukemia is left in the body. We used those details to adjust the chemo and dosages that came after that point. This is how we can know who needs more intense treatment for cure and who can be successfully treated with less chemo to reduce acute and long-term side effects.
- Pioneer the use of chemo given into the cerebrospinal fluid and blood to replace radiation to the brain. We did this to prevent and treat leukemia in the central nervous system.
- Learn if the amount of the drug methotrexate that gets into leukemia cells is related to the child’s leukemia subtype, genetic makeup, or length of methotrexate infusion.
We also studied the side effects of treatment.
When was this study done?
The study opened in June 2000 and closed in August 2008.
What did the study consist of?
- First, children got 4 days of methotrexate to find out if the infusion length affects how well the drug works.
- Next came remission induction therapy. We used several strong drugs to kill leukemia cells in the bone marrow and to allow normal blood cells to grow again. The goal was to have no sign of leukemia in the blood or bone marrow (remission).
- For the next phases of treatment, we treated patients according to their risk group: low risk, standard risk, or high risk.
- Children in TOTXV got many drugs. These included glucocorticoids (also known as steroids) during remission induction and maintenance therapy. Glucocorticoids are a crucial part of therapy. They are man-made versions of steroids that occur naturally in the body. Glucocorticoids in TOTXV included prednisone, dexamethasone, and hydrocortisone.
What did we learn from this study?
One side effect of glucocorticoids is osteonecrosis. In this condition, the bone tissue of the joint tissue dies from a lack of blood supply. It is a common side effect of ALL treatment.
St. Jude scientists wanted to know if some children in TOTXV genetic changes (variations) had passed down through their families that increased their risk for osteonecrosis. By studying the complete DNA sets, or genomes, of patients, we found that:
- Patients of European origin, especially girls, were at higher risk of osteonecrosis.
- It happens most often in children over 10 years old.
- It usually occurs within the first 2 years of treatment.
- Certain inherited variations cause its development.
Patients in TOTXV took part in studies to learn more about neurocognitive outcomes, such as:
- The ability to concentrate
- Remember things
- Process information
- Learn
- Understand
When we did not give some patients radiation therapy, it helped preserve some of these functions. But treatment with chemo alone can also have risks.
We learned that survivors of ALL have a higher risk for learning and memory problems. They are more likely to have problems with attention, processing speed, memory span, mental flexibility, using language (fluency), and planning. These problems can appear during therapy and continue long after treatment. Survivors with these issues are more likely to have problems in school. The most common risk factors include younger age at diagnosis and stronger treatments. Patients with severe infections, seizures, or other issues during treatment may also be at risk. All survivors need monitoring for learning and memory problems during and after therapy.
Pain can also affect a child’s ability to learn, pay attention, remember, and complete tasks. We found that patients who had nerve pain or those treated with opioids had more learning and memory problems at the end of therapy. It is important to monitor patients and treat their pain as soon as possible. It is also important to find ways to relieve pain without using opioids, when possible.
What are the next research steps as a result of this study?
Because of this study, scientists know the genes involved in osteonecrosis and their variations. Researchers are studying how these genes affect this problem. The scientists hope to develop ways to decrease osteonecrosis in children with these issues.
Scientists will study other childhood cancer groups to see if they have learning and memory problems due to pain or its treatment. Researchers will also study the long-term effects of pain on children with cancer.
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 Therapy 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:
Treating childhood acute lymphoblastic leukemia without cranial irradiation. Pui CH, Campana D, Pei D, Bowman WP, Sandlund JT, Kaste SC, Ribeiro RC, Rubnitz JE, Raimondi SC, Onciu M, Coustan-Smith E, Kun LE, Jeha S, Cheng C, Howard SC, Simmons V, Bayles A, Metzger ML, Boyett JM, Leung W, Handgretinger R, Downing JR, Evans WE, Relling MV. New England Journal of Medicine. 2009 Jun 25;360(26):2730-41.
https://www.ncbi.nlm.nih.gov/pubmed/19553647
Pharmacokinetic, pharmacodynamic, and pharmacogenetic determinants of osteonecrosis in children with acute lymphoblastic leukemia. Kawedia JD, Kaste SC, Pei D, Panetta JC, Cai X, Cheng C, Neale G, Howard SC, Evans WE, Pui CH, Relling MV. Blood. 2011 Feb 24;117(8):2340-7.
https://www.ncbi.nlm.nih.gov/pubmed/21148812
Cognitive outcomes following contemporary treatment without cranial irradiation for childhood acute lymphoblastic leukemia. Conklin HM, Krull KR, Reddick WE, Pei D, Cheng C, Pui CH. J Natl Cancer Inst. 2012 Sep 19; 104(18):1386-95.
https://pubmed.ncbi.nlm.nih.gov/22927505/
Genetics of glucocorticoid-associated osteonecrosis in children with acute lymphoblastic leukemia. Karol SE, Yang W, Van Driest SL, Chang TY, Kaste S, Bowton E, Basford M, Bastarache L, Roden DM, Denny JC, Larsen E, Winick N, Carroll WL, Cheng C, Pei D, Fernandez CA, Liu C, Smith C, Loh ML, Raetz EA, Hunger SP, Scheet P, Jeha S, Pui CH, Evans WE, Devidas M, Mattano LA Jr, Relling MV. Blood. 2015 Oct 8;126(15):1770-6.
https://www.ncbi.nlm.nih.gov/pubmed/26265699
Longitudinal assessment of neurocognitive outcomes in survivors of childhood acute lymphoblastic leukemia treated on a contemporary chemotherapy protocol. Jacola LM, Krull KR, Pui C-H, Pei D, Cheng C, Reddick WE, Conklin HM. J Clin Oncol. 2016 Apr; 34: 1239-47.
https://pubmed.ncbi.nlm.nih.gov/26858334/
Neurocognitive outcomes among children who experienced seizures during treatment for acute lymphoblastic leukemia. Nassar SL, Conklin HM, Zhou Y, Ashford JM, Reddick WE, Glass JO, Laningham FH, Jeha S, Cheng C, Pui CH. Pediatr Blood Cancer. 2017 Aug; 64(8).
https://pubmed.ncbi.nlm.nih.gov/28130818/
Longitudinal trajectories of neurocognitive functioning in childhood acute lymphoblastic leukemia. Partanen M, Phipps S, Russell K, Anghelescu DL, Wolf J, Conklin HM, Krull KR, Inaba H, Pui CH, Jacola LM. J Pediatr Psychol. 2021 Feb 19; 46(2):168-178.
https://pubmed.ncbi.nlm.nih.gov/33011782/
Neuropathic pain and neurocognitive functioning in children treated for acute lymphoblastic leukemia. Partanen M, Alberts NM, Conklin HM, Krull KR, Pui CH, Anghelescu DA, Jacola LM. Pain. 2022 Jun 1;163(6):1070-1077. Epub 2021 Sep 25. https://pubmed.ncbi.nlm.nih.gov/34813516/