Pieters group

Aims of the Pieters group

Studies

• ALLTogether1

  This large international study includes 1400 newly diagnosed ALL patients from many European countries per year. Patients are stratified according to the molecular genetic abnormalities of the ALL cells and the MRD response to induction. Several questions will be answered:

  • In the low-risk and intermediate-low risk groups, a randomized study is done to study the safety and efficacy of reducing the use of anthracyclines.

  • In intermediate-high risk patients, it is tested whether intensification with the CD22 targeted compound inotuzumab reduces the risk of relapse and whether the addition of low dose 6-thioguanine (6TG) to maintenance therapy reduces relapse risk.

  • For ALL patients with ABL-class abnormalities, it is studied whether adding the targeted tyrosine kinase inhibitor imatinib to chemotherapy improves outcome.

  • For B-cell precursor (BCP) ALL patients in the high risk group are eligible for innovative immunologic therapy with genetically engineered autologous T-cells (CAR-T cells) instead of very intensive chemotherapy and stem cell transplantation.

  • Children with Down syndrome and ALL receive the bispecific antibody blinatumomoab instead of intensive chemotherapy courses to reduce the high toxicity in this specific group.

  • The prognostic relevance of serum asparaginase activity is studied

  Study questions b, c, d and f are led by investigators from our group. The ALLtogether2 study is under development and will be co-led by our group.

• Interfant-21

  This very large international study for infants with newly diagnosed KMT2A-rearranged ALL in the first year of life is led by our group and includes the addition of two courses of blinatumomab to improve the event-free survival. This based upon our pilot study which had very favorubale results. Also, based upon MRD, patients are now stratified to receive either ALL-or AML-based consolidation chemotherapy or AML which was shown to in fluence outcome in the Interfant-06 study. Patients with insufficient MRD responses to chemotherapy are eligible for an experimental agent followed by stem cell transplantation. Several long-term side effects are analyzed as well as the concordance of MRD assessments by IG-TR PCR and KMT2A PCR, flow cytometry, and Next Generation Sequencing (NGS).

• EsPhALL2017

  This is an international study in children with BCR-ABL positive ALL in which our group participates. The primary aim of the study is

  • To compare disease-free survival of Standard Risk (SR) pediatric Ph+ ALL treated with continuous imatinib combined with either a high-risk COG ALL chemotherapy backbone or the more intensive EsPhALL chemotherapy backbone.

  Secondary aims are to determine:

  • the feasibility of administration of imatinib after allogeneic HSCT in High Risk (HR) Ph+ ALL patients.

  • event-free-survival (EFS) of HR pediatric Ph+ ALL patients treated with EsPhALL chemotherapy, HSCT in first complete remission and post-HSCT imatinib.

  • To compare rates of Grade 3 or higher infections in SR Ph+ ALL patients between the two randomized arms.

• Relapse ALL studies

  IntReALL2010-SR international study in children with standard-risk relapsed ALL. The primary aims of the study are:

  • Overall Improvement of event-free survival (EFS) probabilities in childhood relapsed ALL

  • Compare EFS of ALL-REZ BFM 2002 (Arm A) versus ALLR3 (Arm B).

  • Study the influence of Epratuzumab on EFS in consolidation of SR patients

  IntReALL2010-HR international study in children with high-risk relapsed ALL. The aims of the study are:

  • Improvement of complete remission rates, EFS and OS in HR relapsed ALL patients

  • Improvement of MRD reduction after induction with versus without bortezomib

  • Toxicity of induction with versus without bortezomib

  • Efficacy of consolidation by Blinatumomab to reduce MRD load until allo-HSCT

  • Study to efficacy and toxicity of CAR-T cell therapy in patients with refractory ALL or with ≥2nd relapse of ALL.

• Asparaginase studies

  • Therapeutic drug monitoring (TDM) of asparaginase:

  To evaluate the feasibility and efficacy of TDM

  a. Does TDM of asparaginase reduce the number and severity of asparaginase associated toxicities?

  b. To study the costs of the TDM program and compare these costs with the costs of a fixed dosing schedule.

  • To gain more insight in PEGasparaginase and Erwinia asparaginase pharmacokinetics and factors influencing the asparaginase clearance with a non-linear mixed models analysis.

  • To study the influence of asparaginase on methotrexate toxicity and efficacy. For the methotrexate efficacy, intracellular red blood cell methotrexate polyglutamates are measured.

  • To develop an assay measuring anti-PEG antibodies and anti-linker antibodies and study the different antibody profiles in patients with a hypersensitivity reaction to PEGasparaginase.

  • To perform a cost-effectiveness analysis of Erwinia asparaginase, the expensive second line asparaginase formulation.

• Blinatumomab in infant ALL

  A pilot study to test the feasibility, safety and efficacy of the addition of the BiTE antibody Blinatumomab to the Interfant-06 backbone in infants (< 1 year) with MLL-rearranged acute lymphoblastic leukemia. A collaborative study of the Interfant network.

• Optimizing maintenance therapy

  Children with acute lymphoblastic leukaemia (ALL) receive chemotherapy until two years after initial diagnosis. Setting a correct dose of the maintenance chemotherapy is important for toxicity and outcome. In clinical practice the dose levels are continuously adjusted according to their effect on the blood cell counts and on the occurrence of clinical side effects, especially infections. The novelty of the research project is to consider the interplay between patients’ toxicity and dose modifications. The final objective is to determine optimal dose levels for personalized care, and practical guidelines for ALL maintenance treatment.

• Inotuzumab phase III study

  A randomized study to evaluate the efficacy of inotuzumab ozogamicin (anti-CD22) in pediatric patients and adults (1- 45 yrs) with newly diagnosed BCP-ALL treated according to the intermediate risk high group of the ALLTogether-1 protocol.

• Inotuzumab phase I/II study

  A phase I/II study of Inotuzumab ozogamicin as a single agent and in combination with chemotherapy for pediatric CD22-positive relapsed/refractory Acute Lymphoblastic (see phase I/II studies of the Zwaan group).

• Seludex phase I/II study

  International phase I/II expansion trial of the MEK inhibitor selumetinib in combination with dexamethasone for the treatment of relapsed/refractory RAS-pathway mutated paediatric and adult Acute Lymphoblastic Leukaemia

Grants and awards

• Grants

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• Awards

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