Towards optimal therapy intensity in pediatric acute lymphoblastic leukemia: The right dose for the right patient

B-cell acute lymphoblastic leukemia (ALL) accounts for 25% of childhood cancer cases. Risk adapted treatment strategies have increased the 5-year survival rates from 0% in the 1960s to over 90% on recent trials. With the current high survival rates, possibilities for therapy reduction become an increasingly important topic. Although current trials do test de-escalation of several drugs, unconscious undertreatment might also be present. For further safe reduction of therapy, more knowledge is needed on how much therapy is needed to cure the disease and on biological factors associated with relapse. The aim of this thesis is to contribute to this knowledge by looking into several subgroup-specific challenges.

The research presented in this thesis shows that besides response to the first chemotherapy courses, the biology of leukemic and germline cytogenetic aberrations can affect treatment outcome. The survival rate of children with ALL with an ETV6::RUNX1 translocation is around 97%. This high survival rate asks for studies how to reduce therapy in this group of patients. We show that in ETV6::RUNX1 ALL different dosage schemes and dose intensities can lead to similar outcomes suggesting possibilities for treatment de-escalation. However, for safe treatment reduction more knowledge on relapse in ETV6::RUNX1 ALL specifically is needed. Therefore, we investigated the effect of IKZF1 deletions, a known poor prognostic factor in B-ALL, and found that they do not affect prognosis in ETV6::RUNX1 ALL. To explore the genetic landscape of relapse in ETV6::RUNX1 ALL further, we generated single cell genome wide copy number data to make an overview of the spectrum of (sub)clonal and co-occurring copy number alterations in ETV6:RUNX1 ALL experiencing relapse. This was of value in detecting (sub)clonal gains and losses larger than 1Mb in size, as well as genomic duplication thereby elucidating heterogeneity in copy number aberrant clones and patterns of relapse evolution in ETV6::RUNX1 ALL.

In contrast to ETV6::RUNX1 ALL, we found that when treating non-high risk ALL in patients with Down syndrome, due to differences in drug metabolism and resulting prescription behavior, unintentional treatment reduction might occur in this patient group. Differences in prescription behavior were also found in our study exploring the effect of socio-economic position on maintenance therapy. Although adherence to maintenance drugs did not differ, children in families with short parental education or unemployed parents were prescribed lower doses of maintenance therapy drugs by their physicians. Therefore, one should be cautious when reducing treatment intensity in these specific patient groups to maintain an effective therapy.

The great puzzle of safely reducing treatment to reduce side effects without endangering leukemia cure rates is unfortunately not yet solved. However, this thesis adds new insights needed to ultimately give all pediatric patients with B-ALL optimal treatment and an optimal quality of life.