Acute Lymphoblastic Leukaemia (ALL) is the most frequent cancer in children. The survival
rate has improved significantly during the last decades, but the treatment still fails to
cure 15 % of the patients. Within the Nordic/Baltic countries, children are treated according
to the same protocol, i.e. NOPHO ALL-2008 protocol. Children and adolescents with
Lymphoblastic Non-Hodgkin's Lymphoma (LBL) are treated in accordance with the EURO-LB 02
protocol, whereas adults with Lymphoblastic Non-Hodgkin's Lymphoma in Denmark are commonly
treated in accordance with the NOPHO ALL-2008 protocol.
The longest treatment phase in both protocols is maintenance therapy, which is composed of
6-Mercaptopurine (6MP) and Methotrexate (MTX).
The cytotoxic property of 6MP relies upon conversion of 6MP into thioguanine nucleotides
(TGN), which can be incorporated into DNA instead of guanine or adenine. This incorporation
can cause nucleotide mismatching and cause cell death second to repetitive activation of the
mismatch repair system. At Rigshospitalet investigators have developed pharmacological
methods able to measure the incorporation of TGN into DNA (DNA-TGN). In a Nordic/Baltic study
the investigators have demonstrated higher levels of DNA-TGN during maintenance therapy in
children with ALL that do not develop relapse (Nielsen et al. Lancet Oncol. 2017 Apr;18(4)).
Preliminary studies indicate that the best approach to obtain DNA-TGN within a target range
could be a combination of 6MP, MTX and 6-thioguanine (6TG), as 6TG more readily can be
converted into TGN.
This study aims to explore if individual dose titration of 6TG added to 6MP/MTX therapy can
achieve DNA-TGN levels above a set target above 500 fmol/µg DNA, and thus can be integrated
into future ALL and LBL treatment strategies to reduce relapse rates in ALL and LBL.
The investigators plan to include 30 patients, and A) give incremental doses of 6TG until a
mean DNA-TGN level above 500 fmol/µg DNA is obtained; and B) analyze the changes in DNA-TGN
as well as cytosol levels of TGN and methylated 6MP metabolites (the latter inhibits purine
de novo synthesis and thus enhance DNA-TGN incorporation), and C) occurrence of bone-marrow
and liver toxicities during 6TG/6MP/MTX therapy.
Phase:
Phase 1/Phase 2
Details
Lead Sponsor:
Kjeld Schmiegelow
Collaborators:
Danish Child Cancer Foundation Nordic Society for Pediatric Hematology and Oncology