Thiopurine EnhAnced Maintenance Therapy

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.

Sex

All

Minimum age

6 Months

Maximum age

45 Years

Male and female patients of all ethnicities meeting all of the following criteria will be considered eligible for study participation:

1. Meet just one of the following:

   1. Confirmed diagnosis with non-HR-ALL and in first remission at inclusion into this investigation. Patients aged 1-45 years at diagnosis are eligible or
   2. Confirmed diagnosis with T-LBL or pB-LBL, and in first remission at inclusion into this investigation. Patients aged 0.6-45 years at the time of inclusion are eligible.
2. Have reached maintenance II therapy phase at inclusion.
3. Scheduled to receive 6MP/MTX maintenance therapy without any other concomitant myelosuppressive agents.
4. Patients must have a minimum of 3 months of 6MP/MTX maintenance therapy remaining at the time of inclusion.
5. Bilirubin \< UNL according to age, factor 2-7-10 \> 0.5 or INR \< 1.5 within 1 week prior to inclusion.
6. WBC \> 1.5 x109/L, ANC \> 0.5 x109/L and TBC \> 50 x109/L within 1 week prior to inclusion.
7. Subject, if female of child-bearing potential (defined as postmenarche), must present with a negative pregnancy test and must be nonlactating.
8. Sexually active females and males must use accepted safe contraception (OCPs, IUD, transdermal hormonal patch, vaginal hormonal ring or subdermal hormonal implants for women and condom for men) during therapy and until three months after study exit/early termination.
9. No live vaccines given within 2 months prior to inclusion.
10. Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.
11. Whenever appropriate, the child should participate in the oral and written informed consent process together with the parents. Involving the child in discussions and the decision-making process respects their emerging maturity. This process will be conducted with enough time and at the same time as obtaining the consent from the parents or the legal representative, so that the informed consent reflects the presumed will of the minor, in accordance with Article 4(a) of the Clinical Trial Directive.
12. If the study participant is unable to provide legally binding consent subject's legally authorized representative (e.g., both parent, legal guardian) must voluntarily sign and date a parental permission/ Informed Consent that is approved by the Danish Ethical Committee(EC), and the subject must sign an EC approved assent, before undergoing any protocol specific procedures or assessments according to Ethical considerations for clinical trials on medicinal products conducted with the paediatric population Directive 2001/20/EC1, ICH/GCP guidelines, and the Helsinki II Declaration.

Exclusion Criteria

1. Patients with ALL and a minimal residual disease (MRD)-negative bone-marrow at treatment day 29 (counted from diagnosis)-since these patients have an excellent prognosis on current therapy, and DNA-TG has not been associated with risk of relapse for these patients
2. 2\. DNA-TG \> 1,500 fmol/μg DNA due to (i) a potential association with toxicity (although not shown so far), and (ii) the lack of evidence regarding an association between reduced relapse rates and such high DNA-TG levels. If DNA-TG subsequently fell below 1,500 fmol/μg DNA, the patient would be eligible for TEAM.
3. Any clinical suspicion of relapse or disease progression on routine imaging or in laboratory results.
4. Previous sinusoidal obstruction syndrome (SOS) / veno-occlusive disease (VOD).
5. Allergic hypersensitivity towards any ingredients in the three medicinal products used in the study.

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