Thiopurine Enhanced ALL Maintenance (TEAM): study protocol for a randomized study to evaluate the improvement in disease-free survival by adding very low dose 6-thioguanine to 6-mercaptopurine/methotrexate-based maintenance therapy in pediatric and adult patients (0–45 years) with newly diagnosed B-cell precursor or T-cell acute lymphoblastic leukemia treated according to the intermediate risk-high group of the ALLTogether1 protocol

Abstract

Background A critical challenge in current acute lymphoblastic leukemia (ALL) therapy is treatment intensification in order to reduce the relapse rate in the subset of patients at the highest risk of relapse. The year-long maintenance phase is essential in relapse prevention. The Thiopurine Enhanced ALL Maintenance (TEAM) trial investigates a novel strategy for ALL maintenance. Methods TEAM is a randomized phase 3 sub-protocol to the ALLTogether1 trial, which includes patients 0–45 years of age with newly diagnosed B-cell precursor or T-cell ALL, and stratified to the intermediate risk-high (IR-high) group, in 13 European countries. In the TEAM trial, the traditional methotrexate (MTX)/6-mercaptopurine (6MP) maintenance backbone (control arm) is supplemented with low dose (2.5–12.5 mg/m2/day) oral 6-thioguanine (6TG) (experimental arm), while the starting dose of 6MP is reduced from 75 to 50 mg/m2/day. A total of 778 patients will be included in TEAM during ~ 5 years. The study will close when the last included patient has been followed for 5 years from the end of induction therapy. The primary objective of the study is to significantly improve the disease-free survival (DFS) of IR-high ALL patients by adding 6TG to 6MP/MTX-based maintenance therapy. TEAM has 80% power to detect a 7% increase in 5-year DFS through a 50% reduction in relapse rate. DFS will be evaluated by intention-to-treat analysis. In addition to reducing relapse, TEAM may also reduce hepatotoxicity and hypoglycemia caused by high levels of methylated 6MP metabolites. Methotrexate/6MP metabolites will be monitored and low levels will be reported back to clinicians to identify potentially non-adherent patients. Discussion TEAM provides a novel strategy for maintenance therapy in ALL with the potential of improving DFS through reducing relapse rate. Potential risk factors that have been considered include hepatic sinusoidal obstruction syndrome/nodular regenerative hyperplasia, second cancer, infection, and osteonecrosis. Metabolite monitoring can potentially increase treatment adherence in both treatment arms. Trial registration EudraCT, 2018–001795-38. Registered 2020-05-15, Clinicaltrials.gov, NCT04307576. Registered 2020-03-13, https://clinicaltrials.gov/ct2/show/NCT04307576

Thiopurine 6TG treatment increases tumor immunogenicity and response to immune checkpoint blockade

“… 20 Higher 6TG treatment doses induced higher DNA-TG levels and the 0.01 µg/ml dose induced DNA-TG levels between 300 and 1200 fmol/µg DNA ( Figure 1h ), which is comparable with the DNA-TG levels obtained in ALL patients on thiopurine-based maintenance therapy. 15 , 31 , 32 …”

“… 16 This strategy is called Thiopurine Enhanced ALL Maintenance (TEAM) and was tested in a pilot study including 34 patients. 15 Our hypothesis is that increased DNA-TG levels in the tumor cells likely result in an increasing number of mutations, which can be translated into neoantigens that can stimulate antitumor immune responses. Naturally, our next goal is to use the TEAM strategy to improve ICI outcomes in patients, but before proceeding with the clinical trial, we first wanted to confirm the rationale behind the study design in a preclinical mouse model.…”

“… 13 Random methylation of DNA-TG favors fraudulent G·T mismatching which leads to either apoptosis after futile mismatch repair (MMR) attempts or novel mutations. In a clinical trial, higher DNA-TG levels during 6MP maintenance therapy of acute lymphoblastic leukemia (ALL) patients were correlated with reduced relapse risks, 14 , 15 which could reflect higher burden of random mutations and explain the necessity of more than 18 months of continuous thiopurine therapy. We recently showed that addition of low dose of 6TG to 6MP therapy (TEAM strategy) markedly increases DNA-TG levels, 16 and this strategy is approved for clinical testing (clinicaltrials.gov: NCT04307576).…”

Trending Drugs Combination to Target Leukemia associated Proteins/Genes: using Graph Neural Networks under the RAIN Protocol

“…The study focuses on both pediatric and adult patients, ranging from 0 to 45 years of age, who have recently been diagnosed with B-cell precursor or T-cell acute lymphoblastic leukemia. These patients are being treated in accordance with the intermediate risk-high group of the ALLTogether1 protocol [86], [112]- [114].…”