Pharmacokinetics and Immunogenicity of the First Doses of PEG-Asparaginase -An ALLTogether Pilot Study
Condition: Acute Lymphoblastic Leukemia
MeSH terms: Precursor Cell Lymphoblastic Leukemia-Lymphoma
Study type: Observational

Summary: 
      Acute lymphoblastic leukemia (ALL) is the most common malignant disease in childhood.
      Survival rates exceed 90% in children and 75% in adults (aged 18-45 years). During the
      induction period Asparaginase is an indispensable part of the multiagent treatment, but is
      often associated with hypersensitivity, either with clinical allergy or silent inactivation.
      In both cases, Asparaginase is inactivated. It is well known that truncation of Asparaginase
      treatment due to inactivation reduces survival. To approach understanding Asparaginase
      dynamics and hypersensitivity in ALL patients it is important to examine the pharmacokinetics
      of Asparaginase.

      The aim of this study is to identify serological parameters for prediction of
      hypersensitivity reaction after the first doses of PEG-Asparaginase given intravenously on
      the ALLTogether protocol.
    

Detailed description: 
      Asp enzyme activity is measurable in plasma, and trough levels above 100 IU/l secure effect.
      Patients, who have their treatment truncated, have inferior outcome. For many years prolonged
      Asp treatment for 30 weeks has been part of most protocols worldwide, but a recent Nordic
      randomized study showed that less asparaginase (8 doses vs 15 doses intramuscularly (IM))
      results in the same disease-free survival and significant less toxicity in the less intensive
      treatment arm (6).

      Accordingly, in the current Western European protocol (ALLTogether) less Asp is now given.
      The Nordic Countries participate in this protocol.

      Unlike in the previous Nordic protocol, NOPHO ALL2008, in ALLTogether Asp will be initiated
      early during induction (day 4 compared to day 30) and given intravenously (IV) and not IM. In
      February 2017 it was approved by the NOPHO Board to do more extensive pharmacokinetic studies
      of IM administered PEG-asparaginase, as it has not been shown if IM or IV is preferably in
      respect to minimizing the incidence of hypersensitivity. Most study groups in the world use
      IV administration, thus NOPHO has a unique chance to illuminate inactivation after IM
      administration, also in adult patients. Other groups have not published this.

      For >50% of the patients in ALLTogether, the induction therapy has been reduced from 4 drugs
      to 3 drugs. This emphasizes the importance of optimal treatment from the beginning.
      Therapeutic Drug Monitoring (TDM) will identify patients without activity in order to change
      Asp preparation. Additional sampling close after the first dose of PEG-Asp is expected to
      identify these patients earlier, providing an opportunity to optimize their treatment for
      better disease-free survival.

      The aim of this study is to identify serological parameters for prediction of
      hypersensitivity reaction after the first dose of PEG-Asp given IV on the ALLTogether
      protocol.
    

Observational model: Cohort
Time perspective: Other
Sampling method: Non-Probability Sample
Study population: 
        All patients with ALL 1-45 years of age treated on the ALLTOGETHER pilot protocol in the
        Nordic and Baltic countries.