Group leader: Prof.dr. Rob Pieters
Treatment study protocol of the Dutch Childhood Oncology Group for children and adolescents (1-19 year) with newly diagnosed acute lymphoblastic leukemia
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.
"If cure rates for ALL can go from 0% to 85% in 40 years we can reach 100% in the next 15 years" Prof.dr. Rob Pieters - Group leader
This is an international study in infant ALL in 25 countries. Led by our group. The primary aim of the study is:
- 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
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.
- 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
- 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
Pieters R, Schrappe M, de Lorenzo P, Hann I, de Rossi G, Felice M, Hovi L, Leblance T, Szczepanski T, Ferster A, Janka G, Rubnitz J, Silverman L, Stary J, Campbell M, Li CH, Mann G, Suppiah R, Biondi A, Vora A, Valsecchi MG. A treatment protocol for infants younger than 1 year with acute lymphoblastic leukaemia (Interfant-99) : an observational study and a multicentre randomised trial. Lancet 2007; 370:240-250. PubMed PMID:17658395
Boer den ML, van Slegtenhorst M, De Menezes RX, Cheok MH, Buijs-Gladdines JGCAM, Peters STCJM, van Zutven LJCM, Beverloo HB, van der Spek PJ, Escherich G, Horstmann MA, Janka/Schaub GE, Kamps WA, Evans WE, Pieters R. A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome± a genome-wide classification study. Lancet Oncol 2009;10:125-134. PubMed PMID:19138562
Holleman A/Cheok MH*, den Boer ML, Yang W, Veerman AJ, Kazemier KM, Pei D, Cheng C, Pui CH, Relling MV, Janka-Schaub GE, Pieters R/Evans WE*. Gene-expression patterns in drug-resistant acute lymphoblastic leukemia cells and response to treatment. N Engl J Med 2004;351:533-42. (* shared 1st and last authorship) PubMed PMID:15295046
Pieters R, de Groot-Kruseman HA, van der Velden VHJ, Fiocco M, van den Berg H, de Bont ESJM, Egeler RM, Hoogerbrugge PM, Kaspers GJL, van der Schoot CE, de Haas V, van Dongen JJM. Successful therapy reduction and intensification for childhood acute lymphoblastic leukemia based on minimal residual disease monitoring: study ALL10 from the DCOG. J Clin Oncol 2016: 34:2591-2601. PubMed PMID:27269950