Group leader: Prof.dr. Rob Pieters
Specific goals of the Pieters group
- Increasing cure rates and quality of life by implementation of immunotherapies including antibody based strategies and cellular therapies in treatment protocols for frontline and relapsed ALL
- Reduction of therapy and thereby improving quality of life for specific patient groups selected by genetic features and MRD
- Improving cure rates by development of more effective and more specific therapies for molecular-genetic and immunophenotypic subclasses of ALL
- More rational and specific use of chemotherapeutic agents by therapeutic drug monitoring
Patients are stratified by minimal residual disease status after induction and consolidation courses and by genetic abnormalities.
Primary aims of the study:
- To improve the overall outcome as compared to the previous protocols of the DCOG, especially ALL-9 and ALL-10.
This is aimed for by decreasing therapy for part of the patients (TEL/AML1, Down syndrome, PPR only), increasing therapy for IKZF1 mutated cases, decreasing the cumulative dose of anthracyclines, omitting cranial irradiation and total body irradiation and individualizing asparaginase therapy for all patients. - Does a continuous schedule of Asparaginase lead to less allergic reaction/inactivation of Asparaginase than the standard non continuous schedule of Asparaginase?
Patients are randomized to receive non-continuous PEGasparaginase in IA (induction) and intensification of the Medium Risk group (standard arm A) or to receive continuous PEGasparaginase in IA, IB, M and intensification (continuous arm B) with the same cumulative number of doses of PEGasparaginase. - Does prophylactic administration of intravenous immunoglobulins reduce the number of infections during the intensive treatment phases?
Patients are randomized in the induction and MR treatment group to receive or not receive prophylactic immunoglobulins. - Individualize the dose schedule of asparaginase by therapeutic drug monitoring in order to detect silent inactivation of asparaginase, to prevent allergic/anaphylactic reactions, to switch Asparaginase preparation in time and to prevent too high levels with possible toxicity.
- To assess the role of an early intensification of two "AML" induction blocks versus protocol Ib directly after induction, in a randomized way in MLL rearranged ALL
- the overall outcome of the Interfant-06 protocol compared to the historical control series, especially the Interfant-99.
- which factors have independent prognostic value
- the role of SCT in HR patients and MR patients with high MRD levels at the start of OCTADAD
- 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.
- 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.
- 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
- 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.
Key publications
Van der Sluis IM, de Lorenzo P, Kotecha RS, Attarbaschi A, Escherich G, Nysom K, Stary J, Ferster A, Brethon B, Locatelli L, Schrappe M, Scholte-van Houtem PE, Valsecchi MG, Pieters R. Blinatumomab added to chemotherapy in infant lymphoblastic leukemia. N Engl J Med 2023; 388: 1572-1581. Pubmed PMID: 37099340
Pieters R, de Groot-Kruseman HA, Fiocco M, Verwer F, van Overveld M, Sonneveld E, van der Velden V, Beverloo HB, Bierings M, Dors N, de Haas V, Hoogerbrugge P, van der Sluis IM, Tissing W, Veening M, Boer J, den Boer ML. Improved outcome for ALL by prolonging therapy for IKZF1 deletion and decreasing therapy for other risk groups. J Clin Oncol 2023; 41: 4130-4142. Pubmed PMID: 37459571
Pieters R, Mullighan CG, Hunger SP. Advancing diagnostics and therapy to reach universal cure in childhood ALL. J Clin Oncol 2023; 41:5579-5591. Pubmed PMID: 37820294
Van Kalsbeek RJ, Hudson MM, Mulder RL, Ehrhardt M, Green DM, Mulrooney DA, Hakkert J, den Hartogh J, Nijenhuis A, van Santen HM, Schouten-van Meeteren AYN, van Tinteren H, Verbruggen LC, Conklin HM, Jacola LM, Webster RT, Partanen M, Kollen WJW, Grootenhuis MA, Pieters R, Kremer LC. A joint international consensus statement for measuring quality of survival for patients with childhood cancer. Nature Med 2023; 29: 1340-1348. Pubmed PMID: 37322119
Stutterheim J, Van der Sluis IM, de Lorenzo P, Alten J, Ancliffe P, Attarbaschi A, Brethon B, Biondi A, Campbell M, Cazzaniga G, Escherich G, Ferster A, Kotecha RS, Lausen B, Li CK, Lo Nigro L, Locatelli F, Marschalek R, Meyer C, Schrappe M, Stary J, Vora A, Zuna J, van der Velden VHJ, Szczepanski T, Valsecchi MG, Pieters R. Clinical implications of minimal residual disease detection in infants with KMT2A rearranged acute lymphoblastic leukemia treated on the Interfant-06 protocol. J Clin Oncol 2021:39:652-662. Pubmed PMID: 33405950
Pieters R, de Lorenzo P, Ancliff P, Aversa LA, Brethon B, Biondi A, Campbell M, Escherich G, Ferster A, Gardner RA, Kotecha RS, Lausen B, Li CK, Locatelli F, Attarbashi A, Peters C, Rubnitz JE, Silverman LB, Stary J, Szczepanski T, Vora A, Schrappe M, Valsecchi MG. Outcome of infants younger than 1 year with acute lymphoblastic leukemia treated with the Interfant-06 protocol: results from an international phase III randomized study. J Clin Oncol 2019: 37:2246-2256. Pubmed PMID: 31283407