Thiopurine EnhAnced Maintenance Therapy
Condition: Acute Lymphoblastic Leukemia; Lymphoblastic Lymphoma
MeSH terms: Lymphoma; Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      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.
    

Detailed description: 
      Acute Lymphoblastic Leukaemia (ALL) is the most frequent cancer in children. Each year
      approximately 220 children are diagnosed with ALL within the Nordic and Baltic countries.

      The survival rate has improved significantly during the last decades, but the treatment still
      fails to cure approximately 15 % of the patients. A significant proportion of these relapses
      are likely to reflect adverse drug disposition rather than resistence to antileukemic agents.
      This emphazises the importance of developing new dosing strategies for reduction of relapse
      rates.

      Most ALL relapses occur during or after maintenance therapy, and recent studies have
      indicated that almost 50% of these relapses are caused by insuffient exposure of DNA to the
      cytotoxic metabolites of 6MP.

      Childhood Non-Hodgkin's Lymphoma (NHL) constitutes approximately 5% of all childhood
      malignancies in the Nordic countries and one out of four children with NHL has lymphoblastic
      lymphoma (LBL), the majority being T cell lymphoblastic lymphoma (T-LBL). Nordic children are
      treated in accordance with the EURO-LB 02 protocol, and every year 12-15 children are
      diagnosed with T-LBL within the Nordic countries. During the last 25 years, the cure rate for
      childhood T-LBL has increased from 25% to 75%, however, among patients failing first line
      therapy almost none survive.

      The treatment of childhood and adolescent T-LBL and pre B cell lymphoblastic lymphoma
      (pB-LBL) resembles that of ALL and consists of an induction phase, a re-induction phase and a
      maintenance phase with oral 6MP/MTX, which is continued until 2 years from diagnosis to
      eliminate residual disease.

      Adult LBL accounts for approximately 2% of all NHL, the majority being T-LBL (85-90%). LBL
      occurs more commonly in children than in adults, mostly in males, and has a highly aggressive
      nature. The prognosis in adults has dramatically improved with the introduction of pediatric
      intensive chemotherapy regimens for ALL, in concert with the prognosis of childhood NHL, with
      a disease-free survival reaching 45-72% in adults. However, a broadly accepted standard
      treatment for adult T- and pB-LBL has not yet been defined. Patients with T-LBL and pB-LBL,
      classified as non-HR, and in first remission will be eligible for inclusion into this study.

      The cytotoxic property of 6MP relies upon conversion of 6MP into thioguanine nucleotides
      (TGN). TGN is a substrate for the DNA polymerase, and can be incorporated into DNA instead of
      guanosine or adenine (DNA-TGN). Incorporated TGN is hereafter occasionally mismatched to
      thymidine, which causes cell death second to activation of the mismatch repair system. During
      thiopurine-based therapy patients vary widely in their DNA-TGN levels and patients with low
      DNA-TGN levels may have an increased risk of relapse.

      The investigators will explore

        1. If individualized addition of 6TG to maintenance therapy can obtain a stable mean
           DNA-TGN level > 500 fmol/microgram DNA after addition of 6TG. DNA-TGN calculated as a 4
           weeks mean.

        2. The toxicities encountered during 6TG/6MP/MTX therapy.

      The investigators hypothesize that 6TG/6MP/MTX combination therapy will achieve significantly
      higher DNA-TGN levels, and they will describe toxicities and thiopurine metabolite levels
      during MTX/6MP/6TG combination therapy.

      The TEAM Study is designed as a prospective, multicentre, non-randomised, phase 1-2 clinical
      trial. This trial is a "proof of principle" and feasibility study planned with a modified
      crossover design, where participants serve as their own (historical) controls.

      Additionally, data from the maintenance therapy substudy by Nielsen et. al (Lancet Oncol.
      2017 Apr;18(4)) will be used in order to compare DNA-TG levels in patients receiving MTX/6MP
      based maintenance therapy, and DNA-TG levels in patients treated according to TEAM strategy
      (i.e. maintenance therapy with MTX/6MP/6TG).

      Pharmacological target:

      The investigators will include 30 participants. Upon inclusion in the TEAM study; 6MP dose is
      reduced to 2/3rd, if the current 6MP dose is > 50 mg/m2/day. However, if 6MP dose reduction
      is indicated, 6MP dose is not reduced below 50 mg/m2/day. If the current 6MP dose is < 50
      mg/m2/day, the patient continues on this 6MP dose without dose reduction. 6TG treatment is
      initiated concomitantly. MTX dose is not changed. The investigators give A) incremental doses
      of 6TG (steps of 2.5 mg/meter square, max 12.5 mg/meter square) until a mean DNA-TGN of at
      least 500 fmol/µg DNA is obtained; and B) analyze the changes in DNA-TGN as well as Ery-TGN
      and MeMP. The dose increments of 6TG in steps of 2.5 mg/square metre will be spaced by
      intervals of at least two weeks, and DNA-TGN measurements will be measured weekly during 6TG
      dose increments. 6TG dose increments will continue until a mean DNA-TGN level > 500 fmol/µg
      or a maximum dose of 6TG of 12.5 mg/square metre is reached. If tolerated, the participant
      can then continue on that 6TG dose until the end of ALL/LBL therapy. Participants can at any
      time point drop out of TEAM by their own decision or by that of the treating physician. 6TG
      is provided as a liquid formulation to ease precise dose titration.
    

Intervention name(s): Thioguanine (oral)
Intervention type(s): Drug
Intervention description(s): Addition of incremental doses of oral Thioguanine to oral daily 6-mercaptopurine and oral weekly methotrexate maintenance therapy of Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma. Oral 6-thioguanine is added at a starting dose of 2.5 mg/m.sq. with dose increments of 2.5 mg/m.sq. at two weeks intervals until a maximum dose of 12.5 mg/m.sq. of 6-thioguanine is given or dose-limiting toxicity occurs.
Other intervention name(s): 6-mercaptopurine (oral); Methotrexate (oral)
Intervention MeSH terms: Methotrexate; Mercaptopurine; Thioguanine
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Cancer; Thioguanine; Acute Lymphoblastic Leukemia; 6 Mercaptopurine; Maintenance Therapy of Leukemia; Denmark; Lymphoblastic Lymphoma