Maintenance therapy for acute lymphoblastic leukemia: basic science and clinical translations

Abstract

Maintenance therapy (MT) with oral methotrexate (MTX) and 6-mercaptopurine (6-MP) is essential for the cure of acute lymphoblastic leukemia (ALL). MTX and 6-MP interfere with nucleotide synthesis and salvage pathways. The primary cytotoxic mechanism involves the incorporation of thioguanine nucleotides (TGNs) into DNA (as DNA-TG), which may be enhanced by the inhibition of de novo purine synthesis by other MTX/6-MP metabolites. Co-medication during MT is common. Although Pneumocystis jirovecii prophylaxis appears safe, the benefit of glucocorticosteroid/vincristine pulses in improving survival and of allopurinol to moderate 6-MP pharmacokinetics remains uncertain. Numerous genetic polymorphisms influence the pharmacology, efficacy, and toxicity (mainly myelosuppression and hepatotoxicity) of MTX and thiopurines. Thiopurine S-methyltransferase (encoded by TPMT) decreases TGNs but increases methylated 6-MP metabolites (MeMPs); similarly, nudix hydrolase 15 (encoded by NUDT15) also decreases TGNs available for DNA incorporation. Loss-of-function variants in both genes are currently used to guide MT, but do not fully explain the inter-patient variability in thiopurine toxicity. Because of the large inter-individual variations in MTX/6-MP bioavailability and metabolism, dose adjustments are traditionally guided by the degree of myelosuppression, but this does not accurately reflect treatment intensity. DNA-TG is a common downstream metabolite of MTX/6-MP combination chemotherapy, and a higher level of DNA-TG has been associated with a lower relapse hazard, leading to the development of the Thiopurine Enhanced ALL Maintenance (TEAM) strategy—the addition of low-dose (2.5–12.5 mg/m2/day) 6-thioguanine to the 6-MP/MTX backbone—that is currently being tested in a randomized ALLTogether1 trial (EudraCT: 2018-001795-38). Mutations in the thiopurine and MTX metabolism pathways, and in the mismatch repair genes have been identified in early ALL relapses, providing valuable insights to assist the development of strategies to detect imminent relapse, to facilitate relapse salvage therapy, and even to bring about changes in frontline ALL therapy to mitigate this relapse risk.

FH variant pathogenicity promotes purine salvage pathway dependence in kidney cancer

“…Importantly, 6-MP is also metabolized to thioinosinate and 6-methylthioinosinate, which inhibit other aspects of purine biosynthesis including glutamine-5-phosphoribosylpyrophosphate amidotransferase, adenylosuccinate synthase, and IMP dehydrogenase (Extended Data Fig. 11c) 35 . It is likely that fumarate accumulation renders cells more sensitive to 6-MP due to: 1) a necessary reliance on the purine salvage pathway resulting from the fumarate-driven reversal of ADSL enzymatic activity, and/or 2) increased nucleoside uptake and metabolism, including 6-MP.…”

A Retrospective Cohort Study of the Efficacy, Safety, and Clinical Value of 6-TG versus 6-MP Maintenance Therapy in Children with Acute Lymphoblastic Leukemia

“…Doppler ultrasound is also helpful for the diagnosis of HSOS, including hepatomegaly, splenomegaly, ascites, thickening of gallbladder wall, elevated resistance index of hepatic artery, and blood reflux signal in portal vein. In recent years, the clinical use of multislice spiral CT combined with MPR and liver CTA imaging is helpful to the differential diagnosis and clinical evaluation of HSOS [ 43 ]. Most of the reversible HVOD patients in the American CCG-1952 test have only HSOS manifestations and do not have mature clinical manifestations of HVOD or meet the pathological diagnostic criteria [ 44 ].…”

Hyperdiploidy: the longest known, most prevalent, and most enigmatic form of acute lymphoblastic leukemia in children

“…The daunting challenge is now to reduce treatment intensity to diminish side effects and avoid ensuing long-term sequelae without endangering the hitherto achieved excellent overall treatment outcome. Some of the trials that have addressed this issue so far have been quite successful (even without utilizing any genetic risk score), whereas those trials which reduced the duration of maintenance therapy to 6 months were not, at least as regards HD ALL [55,117,[122][123][124][125]. Although Kato et al found that one year of maintenance therapy is probably sufficient for TCF3::PBX1-and ETV6::RUNX1-positive cases, it is definitely not adequate for all HD leukemias.…”