TOTAL Therapy Study XV for Newly Diagnosed Patients with Acute Lymphoblastic Leukemia (TOTXV)
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 as well as new discoveries by our doctors and researchers 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 six 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 make-up 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 to accrual in August 2008.
What did the study consist of?
- Children first got four days of methotrexate to find out if the length of infusion affects how well the drug works.
- Next came remission induction therapy. Several strong drugs were used to kill leukemia cells in the bone marrow and to allow normal blood cells to begin to grow again. The goal was to have no evidence of leukemia in the blood or bone marrow (remission).
- For the next phases of treatment, patients were treated 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, joint bone tissue dies from lack of blood supply. It is one of the more common side effects of ALL treatment.
St. Jude scientists wanted to know if some children in TOTXV had genetic variations passed down through their families that increased their risk of osteonecrosis. By studying the complete DNA sets, or genomes, of patients, we found that:
- Patients of European ancestry, especially girls, were at higher risk of osteonecrosis.
- It happens most often in children over 10 years old.
- It usually occurs within the first two years of treatment.
- Certain inherited variations are involved in its development.
Patients in TOTXV took part in studies to learn more about neurocognitive outcomes. These are the ability to concentrate, remember things, process information, learn and understand. Removing brain radiation from therapy helped preserve cognitive abilities. But, treatment with chemo alone is not without risk.
We learned that survivors of ALL are at higher risk for neurocognitive problems than the general population. They are more likely to have problems with attention, processing speed, memory span and executive function (mental flexibility, fluency and planning). Such problems can be seen during therapy and continue into survivorship. Survivors with these issues are more likely to have difficulties in school. The most common risk factors include younger age at diagnosis and greater treatment intensity. Patients with severe infections, seizures or other such issues during treatment may also be at risk. All survivors should be monitored for neurocognitive problems during and after therapy.
What are the next research steps as a result of this study?
Because of this study, scientists now know where the variations are located and the genes that are involved in osteonecrosis. Researchers are studying in the lab how these genes contribute to this complication. The scientists hope to develop ways to decrease osteonecrosis in children with these genetic variations.
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:
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.
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.
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.
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.
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.
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).
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.