Publications by authors named "Christian Michel Zwaan"

26 Publications

  • Page 1 of 1

Paediatric Strategy Forum for medicinal product development of chimeric antigen receptor T-cells in children and adolescents with cancer: ACCELERATE in collaboration with the European Medicines Agency with participation of the Food and Drug Administration.

Eur J Cancer 2022 01 25;160:112-133. Epub 2021 Nov 25.

The Royal Marsden Hospital and the Institute of Cancer Research, London, UK.

The seventh multi-stakeholder Paediatric Strategy Forum focused on chimeric antigen receptor (CAR) T-cells for children and adolescents with cancer. The development of CAR T-cells for patients with haematological malignancies, especially B-cell precursor acute lymphoblastic leukaemia (BCP-ALL), has been spectacular. However, currently, there are scientific, clinical and logistical challenges for use of CAR T-cells in BCP-ALL and other paediatric malignancies, particularly in acute myeloid leukaemia (AML), lymphomas and solid tumours. The aims of the Forum were to summarise the current landscape of CAR T-cell therapy development in paediatrics, too identify current challenges and future directions, with consideration of other immune effector modalities and ascertain the best strategies to accelerate their development and availability to children. Although the effect is of limited duration in about half of the patients, anti-CD19 CAR T-cells produce high response rates in relapsed/refractory BCP-ALL and this has highlighted previously unknown mechanisms of relapse. CAR T-cell treatment as first- or second-line therapy could also potentially benefit patients whose disease has high-risk features associated with relapse and failure of conventional therapies. Identifying patients with very early and early relapse in whom CAR T-cell therapy may replace haematopoietic stem cell transplantation and be definitive therapy versus those in whom it provides a more effective bridge to haematopoietic stem cell transplantation is a very high priority. Development of approaches to improve persistence, either by improving T cell fitness or using more humanised/fully humanised products and co-targeting of multiple antigens to prevent antigen escape, could potentially further optimise therapy. Many differences exist between paediatric B-cell non-Hodgkin lymphomas (B-NHL) and BCP-ALL. In view of the very small patient numbers with relapsed lymphoma, careful prioritisation is needed to evaluate CAR T-cells in children with Burkitt lymphoma, primary mediastinal B cell lymphoma and other NHL subtypes. Combination trials of alternative targets to CD19 (CD20 or CD22) should also be explored as a priority to improve efficacy in this population. Development of CD30 CAR T-cell immunotherapy strategies in patients with relapsed/refractory Hodgkin lymphoma will likely be most efficiently accomplished by joint paediatric and adult trials. CAR T-cell approaches are early in development for AML and T-ALL, given the unique challenges of successful immunotherapy actualisation in these diseases. At this time, CD33 and CD123 appear to be the most universal targets in AML and CD7 in T-ALL. The results of ongoing or planned first-in-human studies are required to facilitate further understanding. There are promising early results in solid tumours, particularly with GD2 targeting cell therapies in neuroblastoma and central nervous system gliomas that represent significant unmet clinical needs. Further understanding of biology is critical to success. The comparative benefits of autologous versus allogeneic CAR T-cells, T-cells engineered with T cell receptors T-cells engineered with T cell receptor fusion constructs, CAR Natural Killer (NK)-cell products, bispecific T-cell engager antibodies and antibody-drug conjugates require evaluation in paediatric malignancies. Early and proactive academia and multi-company engagement are mandatory to advance cellular immunotherapies in paediatric oncology. Regulatory advice should be sought very early in the design and preparation of clinical trials of innovative medicines, for which regulatory approval may ultimately be sought. Aligning strategic, scientific, regulatory, health technology and funding requirements from the inception of a clinical trial is especially important as these are very expensive therapies. The model for drug development for cell therapy in paediatric oncology could also involve a 'later stage handoff' to industry after early development in academic hands. Finally, and very importantly, strategies must evolve to ensure appropriate ease of access for children who need and could potentially benefit from these therapies.
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http://dx.doi.org/10.1016/j.ejca.2021.10.016DOI Listing
January 2022

Paving the Way for Immunotherapy in Pediatric Acute Myeloid Leukemia: Current Knowledge and the Way Forward.

Cancers (Basel) 2021 Aug 28;13(17). Epub 2021 Aug 28.

Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands.

Immunotherapeutic agents may be an attractive option to further improve outcomes and to reduce treatment-related toxicity for pediatric AML. While improvements in outcome have been observed with immunotherapy in many cancer types, immunotherapy development and implementation into patient care for both adult and pediatric AML has been hampered by an incomplete understanding of the bone marrow environment and a paucity of tumor-specific antigens. Since only a minority of patients respond in most immunotherapy trials across different cancer types, it will be crucial to understand which children with AML are likely to respond to or may benefit from immunotherapies. Immune cell profiling efforts hold promise to answer this question, as illustrated by the development of predictive scores in solid cancers. Such information on the number and phenotype of immune cells during current treatment regimens will be pivotal to generate hypotheses on how and when to intervene with immunotherapy in pediatric AML. In this review, we discuss the current understanding of the number and phenotype of immune cells in the bone marrow in pediatric AML, ongoing immunotherapy trials and how comprehensive immune profiling efforts may pave the way for successful clinical trials (and, ultimately, implementation into patient care).
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http://dx.doi.org/10.3390/cancers13174364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8431730PMC
August 2021

Significant improvement in survival of advanced stage childhood and young adolescent cancer in the Netherlands since the 1990s.

Eur J Cancer 2021 11 4;157:81-93. Epub 2021 Sep 4.

Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands; Department of Research and Development, Netherlands Comprehensive Cancer Organisation (IKNL), Utrecht, The Netherlands. Electronic address:

Background: This is the first national study on trends in cancer survival and mortality for children and young adolescents in the Netherlands including unique information on stage at diagnosis.

Methods: All neoplasms in patients <18 years, diagnosed between 1990 and 2015 (N = 14,060), were derived from the Netherlands Cancer Registry. Cohort and period survival analyses were used to estimate observed survival (OS). Time trends in OS and mortality rates were evaluated by parametric survival models and average annual percentage change, respectively.

Results: Between 1990 and 2015, 5-year OS and 10-year OS of childhood and young adolescent cancer have improved significantly by 9 percent points, reaching 81% and 78%, respectively. Favourable trends in survival were observed for all age groups and most diagnostic (sub)groups, being particularly pronounced for advanced disease. Non-Hodgkin lymphomas Ann Arbor stage III, metastatic neuroblastomas (age ≥18 months) and Ewing bone sarcomas showed significant improvements in 5-year OS. Compared with 1990-99, the risk of dying within five years of diagnosis was decreased significantly during 2000-09 (hazard ratio [HR] = 0.8) and 2010-15 (HR = 0.6), after adjustment for age, gender and follow-up time. Nonetheless, the prognosis of young patients suffering from central nervous system tumours, neuroblastoma and osteosarcomas remained modest, with 5-year OS <70% and 10-year OS <65%. Childhood and young adolescent cancer mortality decreased by an average of 2.0% annually between 1990 and 2018.

Conclusions: Significant progress has been realised in the prognosis of childhood and young adolescent cancer in the Netherlands since the 1990s. Survival improvements were especially evident for patients with advanced stages and were also reflected in the declining mortality rates.
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http://dx.doi.org/10.1016/j.ejca.2021.08.001DOI Listing
November 2021

A phase 2 study of nilotinib in pediatric patients with CML: long-term update on growth retardation and safety.

Blood Adv 2021 07;5(14):2925-2934

Clinical Research for Holistic Management in Pediatric Hematology and Oncology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.

The phase 2, open-label study (DIALOG) of nilotinib in pediatric patients with Philadelphia chromosome-positive chronic myelogenous leukemia (CML) met its coprimary end points, showing sustained nilotinib efficacy in patients with newly diagnosed (ND) or imatinib/dasatinib resistant/intolerant (R/I) CML. This update assessed growth and safety profiles in patients who had completed ≥48, 28-day treatment cycles of nilotinib 230 mg/m2 twice daily, or previously discontinued the study. Height was assessed regularly and reported using standard deviation scores (SDSs) based on World Health Organization growth charts. All data were summarized descriptively (cutoff, 6 March 2019). Overall, 33 patients in the R/I cohort and 25 patients in the ND cohort received nilotinib. Each cohort showed a negative slope in height SDS over the course of the study, indicating attenuated growth rates during nilotinib treatment: overall median change from baseline in height SDS after 48 cycles was -0.54 SDS (range, - 1.6 to 0.4) and -0.91 SDS (-1.4 to -0.1) in R/I and ND cohorts, respectively. Patients in the R/I cohort were shorter at baseline than those in the ND cohort, and remained so throughout the study. The most common all-cause adverse events were increased blood bilirubin (53.4%), headache (46.6%), pyrexia (37.9%), and increased alanine transferase (36.2%). Apart from the impact on growth, the safety profile of nilotinib was generally consistent with previous reports. This study was registered on www.clinicaltrials.gov at #NCT01844765.
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http://dx.doi.org/10.1182/bloodadvances.2020003759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8341357PMC
July 2021

Inotuzumab ozogamicin in infants and young children with relapsed or refractory acute lymphoblastic leukaemia: a case series.

Br J Haematol 2021 06 2;193(6):1172-1177. Epub 2021 Feb 2.

Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.

No data on inotuzumab ozogamicin (InO) in infant acute lymphoblastic leukaemia (ALL) have been published to date. We collected data internationally on infants/young children (<3 years) with ALL treated with InO. Fifteen patients (median 4.4 months at diagnosis) received InO due to relapsed or refractory (R/R) disease. Median percentage of CD22 blasts was 72% (range 40-100%, n = 9). The median dose in the first course was 1.74 mg/m (fractionated). Seven patients (47%) achieved complete remission; one additional minimal residual disease (MRD)-positive patient became MRD-negative. Six-month overall survival was 47% (95% confidence interval [CI] 27-80%). Two patients developed veno-occlusive disease after transplant. Further evaluation of InO in this subgroup of ALL is justified.
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http://dx.doi.org/10.1111/bjh.17333DOI Listing
June 2021

A phase 1 study of inotuzumab ozogamicin in pediatric relapsed/refractory acute lymphoblastic leukemia (ITCC-059 study).

Blood 2021 03;137(12):1582-1590

Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.

This phase 1 study investigated the recommended phase 2 dose (RP2D) of inotuzumab ozogamicin (InO), a CD22-directed antibody-drug conjugate, in pediatric patients with multiple relapsed/refractory (R/R) CD22+ acute lymphoblastic leukemia (ALL). Patients (age ≥1 year or <18 years) received 3 doses of InO (days 1, 8, and 15) per course. Dose escalation was based on dose-limiting toxicities (DLTs) during course 1. Dose level 1 (DL1) was 1.4 mg/m2 (0.6, 0.4, 0.4 mg/m2) and DL2 was 1.8 mg/m2 (0.8, 0.5, 0.5 mg/m2). Secondary end points included safety, antileukemic activity, and pharmacokinetics. Twenty-five patients (23 evaluable for DLTs) were enrolled. In course 1, the first cohort had 1 of 6 (DL1) and 2 of 5 (DL2) patients who experienced DLTs; subsequent review considered DL2 DLTs to be non-dose-limiting. Dose was de-escalated to DL1 while awaiting protocol amendment to re-evaluate DL2 in a second cohort, in which 0 of 6 (DL1) and 1 of 6 (DL2) patients had a DLT. Twenty-three patients experienced grade 3 to 4 adverse events; hepatic sinusoidal obstruction syndrome was reported in 2 patients after subsequent chemotherapy. Overall response rate after course 1 was 80% (95% confidence interval [CI], 59% to 93%) (20 of 25 patients; DL1: 75% [95% CI, 43% to 95%], DL2: 85% [95% CI, 55% to 98%]). Of the responders, 84% (95% CI, 60% to 97%) achieved minimal residual disease (MRD)-negative complete response, and 12-month overall survival was 40% (95% CI, 25% to 66%). Nine patients received hematopoietic stem cell transplantation or chimeric antigen receptor T cells after InO. InO median maximum concentrations were comparable to simulated adult concentrations. InO was well tolerated, demonstrating antileukemic activity in heavily pretreated children with CD22+ R/R ALL. RP2D was established as 1.8 mg/m2 per course, as in adults. This trial was registered at https://www.clinicaltrialsregister.eu as EUDRA-CT 2016-000227-71.
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http://dx.doi.org/10.1182/blood.2020007848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7995290PMC
March 2021

Phase 2 study of nilotinib in pediatric patients with Philadelphia chromosome-positive chronic myeloid leukemia.

Blood 2019 12;134(23):2036-2045

Department of Pediatrics, Hematology and Oncology Division, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.

Chronic myeloid leukemia (CML) is rare in children and accounts for ≤15% of all myeloid leukemia cases. When we initiated this study with nilotinib, imatinib was the only tyrosine kinase inhibitor indicated for pediatric patients with Philadelphia chromosome-positive (Ph+) CML in chronic phase (CP); alternative treatment options were needed, particularly for patients who developed resistance or intolerance (R/I) to imatinib. This phase 2 study enrolled pediatric patients with either Ph+ CML-CP R/I to imatinib or dasatinib or newly diagnosed Ph+ CML-CP. Data presented are from analyses with minimum follow-up of up to 24 cycles (1 cycle is 28 days). Fifty-nine patients with Ph+ CML-CP were enrolled, and 58 were treated (R/I, n = 33; newly diagnosed, n = 25). Major molecular response (MMR) rate at cycle 6 in the R/I cohort was 39.4% (primary end point); 57.6% of patients achieved or maintained MMR and 81.8% achieved or maintained complete cytogenetic response (CCyR) by 24 cycles. In patients with newly diagnosed disease, rates of MMR by cycle 12 and CCyR at cycle 12 were 64.0% each (primary end points); by cycle 24, cumulative MMR and CCyR rates were 68.0% and 84.0%, respectively. The safety profile of nilotinib in pediatric patients was generally comparable with the known safety profile in adults, although cardiovascular events were not observed in this study, and hepatic laboratory abnormalities were more frequent; no new safety signals were identified. In summary, nilotinib demonstrated efficacy and a manageable safety profile in pediatric patients with Ph+ CML-CP. This trial was registered at www.clinicaltrials.gov as #NCT01844765.
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http://dx.doi.org/10.1182/blood.2019000069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6923664PMC
December 2019

Publisher Correction: The molecular landscape of pediatric acute myeloid leukemia reveals recurrent structural alterations and age-specific mutational interactions.

Nat Med 2019 Mar;25(3):530

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

In the version of this article originally published, the color key in Fig. 1a was wrong. In the Cytogenetics key, the box over t(8;21) originally was green. It should have been red, matching the color of the sections of the pie graphs below the key that were labeled with 15% and 19%.
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http://dx.doi.org/10.1038/s41591-019-0369-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7747938PMC
March 2019

Aprepitant for the prevention of chemotherapy-induced nausea and vomiting in paediatric subjects: An analysis by age group.

Pediatr Blood Cancer 2018 10 12;65(10):e27273. Epub 2018 Jun 12.

Department of Pediatric Oncology/Hematology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands.

Background: This was a subgroup analysis of age group, dexamethasone use, and very highly emetogenic chemotherapy (VHEC) use from a randomised, multicentre, double-blind, Phase 3 study of oral aprepitant in paediatric subjects.

Methods: Subjects aged 6 months to 17 years scheduled to receive chemotherapeutic agents associated with at least moderate risk for emesis were randomly assigned to receive either aprepitant plus ondansetron (aprepitant regimen) or placebo plus ondansetron (control regimen); both could be administered with or without dexamethasone. This secondary analysis evaluated subjects stratified by pre-specified age groups, dexamethasone use, and VHEC use. The primary endpoint of this analysis was the proportion of subjects who experienced complete response (CR) during the delayed phase.

Results: CR rates in the delayed phase were numerically higher with the aprepitant than the control regimen across all age categories, and reached significance for subjects aged 12-17 years (51% vs. 10%; P < 0.0001). In subjects receiving dexamethasone, CR was twice as high for the aprepitant versus control regimen in the 6 months to <2 year group (50% vs. 25%) and significantly higher in the 12-17 year group (40% vs. 7%, P < 0.05). CR was also significantly higher with aprepitant in the 6 months to <2 year and 12-17 year age groups who received VHEC. Similar proportions of subjects experiencing at least one adverse event were seen in both regimens across age categories.

Conclusion: A 3 day aprepitant regimen seemed effective and safe for prevention of chemotherapy-induced nausea and vomiting in paediatric subjects across subgroups (ClinicalTrials.gov NCT01362530).
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http://dx.doi.org/10.1002/pbc.27273DOI Listing
October 2018

An effective modestly intensive re-induction regimen with bortezomib in relapsed or refractory paediatric acute lymphoblastic leukaemia.

Br J Haematol 2018 05 20;181(4):523-527. Epub 2018 Apr 20.

Paediatric Oncology, Erasmus MC, Rotterdam, the Netherlands.

This trial explored the efficacy of re-induction chemotherapy including bortezomib in paediatric relapsed/refractory acute lymphoblastic leukaemia. Patients were randomized 1:1 to bortezomib (1.3 mg/m /dose) administered early or late to a dexamethasone and vincristine backbone. Both groups did not differ regarding peripheral blast count on day 8, the primary endpoint. After cycle 1, 8 of 25 (32%) patients achieved complete remission with incomplete blood count recovery, 7 (28%) a partial remission and 10 had treatment failure. Most common grade 3-4 toxicities were febrile neutropenia (31%) and pain (17%). Bortezomib was safely combined with vincristine. Bortezomib rarely penetrated the cerebrospinal fluid.
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http://dx.doi.org/10.1111/bjh.15233DOI Listing
May 2018

Pediatric oncology as a Learning Health System: Ethical implications for best available treatment protocols.

Learn Health Syst 2018 Apr 16;2(2):e10052. Epub 2018 Apr 16.

Department of Medical Humanities University Medical Center Utrecht Julius Center Utrecht The Netherlands.

Introduction: Pediatric oncology is often considered as a field in which research and care are highly integrated. We believe that this integration can be seen as a so-called Learning Health System, a system in which research is considered an important means to continuously improve the practice of care. In order to substantiate our assumption of pediatric oncology as an LHS, we will analyze so-called "best available treatment protocols." These protocols always contain research elements, even if themain goal of these protocols is to treat children diagnosed with cancer.

Methods: We will analyze the implications for ethical review and informed consent if these protocols had to function as exponents of pediatric oncology an LHS.

Results: An analysis of best available treatment protocols teaches us how these protocols integrate care and research and how these protocols can be seen as exponents of a system where care and research need no longer be sharply distinct practices.

Discussion: Further intervention in the field of pediatric oncology is essential to also meet the requirements for an ethically responsible LHS.

Conclusion: Best available treatment protocols, which combine research and care, can be seen as examples of pediatric oncology as an LHS. However, in order to prevent that research elements in these protocols will be overlooked, we will have to find new ways to accommodate for the oversight of these protocols, such as multifaceted review and risk-adapted approaches. Moreover, informed consent process must be changed in order for patients to understand how care and research are integrated in these protocols.
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http://dx.doi.org/10.1002/lrh2.10052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6508761PMC
April 2018

The molecular landscape of pediatric acute myeloid leukemia reveals recurrent structural alterations and age-specific mutational interactions.

Nat Med 2018 01 11;24(1):103-112. Epub 2017 Dec 11.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

We present the molecular landscape of pediatric acute myeloid leukemia (AML) and characterize nearly 1,000 participants in Children's Oncology Group (COG) AML trials. The COG-National Cancer Institute (NCI) TARGET AML initiative assessed cases by whole-genome, targeted DNA, mRNA and microRNA sequencing and CpG methylation profiling. Validated DNA variants corresponded to diverse, infrequent mutations, with fewer than 40 genes mutated in >2% of cases. In contrast, somatic structural variants, including new gene fusions and focal deletions of MBNL1, ZEB2 and ELF1, were disproportionately prevalent in young individuals as compared to adults. Conversely, mutations in DNMT3A and TP53, which were common in adults, were conspicuously absent from virtually all pediatric cases. New mutations in GATA2, FLT3 and CBL and recurrent mutations in MYC-ITD, NRAS, KRAS and WT1 were frequent in pediatric AML. Deletions, mutations and promoter DNA hypermethylation convergently impacted Wnt signaling, Polycomb repression, innate immune cell interactions and a cluster of zinc finger-encoding genes associated with KMT2A rearrangements. These results highlight the need for and facilitate the development of age-tailored targeted therapies for the treatment of pediatric AML.
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http://dx.doi.org/10.1038/nm.4439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5907936PMC
January 2018

aberrations in childhood B-cell precursor acute lymphoblastic leukemia.

Oncotarget 2017 Oct 16;8(52):89923-89938. Epub 2017 Sep 16.

Department of Pediatric Oncology/Hematology, Erasmus Medical Centre - Sophia Children's Hospital, Rotterdam, The Netherlands.

abnormalities may serve as target for precision medicines in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL). In the current study we performed a screening for mutations and translocations, analyzed the clinical outcome and studied the efficacy of two JAK inhibitors in primary BCP-ALL cells. Importantly, we identify a number of limitations of JAK inhibitor therapy. mutations mainly occurred in the poor prognostic subtypes -like and non- -like B-other (negative for sentinel cytogenetic lesions). translocations were restricted to -like cases. Momelotinib and ruxolitinib were cytotoxic in both translocated and mutated cells, although efficacy in mutated cells highly depended on cytokine receptor activation by TSLP. However, our data also suggest that the effect of JAK inhibition may be compromised by mutations in alternative survival pathways and microenvironment-induced resistance. Furthermore, inhibitors induced accumulation of phosphorylated JAK2, which resulted in a profound re-activation of JAK2 signaling upon release of the inhibitors. This preclinical evidence implies that further optimization and evaluation of JAK inhibitor treatment is necessary prior to its clinical integration in pediatric BCP-ALL.
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http://dx.doi.org/10.18632/oncotarget.21027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5685720PMC
October 2017

Safety and efficacy of nelarabine in children and young adults with relapsed or refractory T-lineage acute lymphoblastic leukaemia or T-lineage lymphoblastic lymphoma: results of a phase 4 study.

Br J Haematol 2017 10 2;179(2):284-293. Epub 2017 Aug 2.

Department of Paediatric Onco-Haematology, APHP, Armand Trousseau Hospital, Paris, France.

Nelarabine is an antineoplastic agent approved for the treatment of relapsed/refractory T-lineage acute lymphoblastic leukaemia (T-ALL) or T-lineage acute lymphoblastic lymphoma (T-LBL). The purpose of this phase 4, multicentre, single-arm, observational, open-label trial was to provide additional data on the safety and efficacy of nelarabine under licensed conditions of use in children and young adults ≤21 years of age. Patients (N = 28) had a mean ± standard deviation age of 11·5 ± 4·6 years; 71% were male and 61% had a diagnosis of T-ALL. Adverse events (AEs) and treatment-related AEs were experienced by 46% and 21%, respectively, and included few haematological AEs and no haematological serious AEs. Neurological AEs from one of four predefined categories (peripheral and central nervous systems, mental status change and uncategorized) were reported in four patients. There were no AE-related treatment discontinuations/withdrawals. The overall response rate was 39.3%: complete response (CR), 35.7%; CR without full haematological recovery (CR*), 3.6%. Post-treatment stem cell transplantation was performed for 46% of the cohort. Median overall survival (OS) was 3·35 months for non-responders and not reached for responders (CR + CR*). The response rate, median OS, and safety profile of nelarabine in this disease setting and population were consistent with those reported previously.
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http://dx.doi.org/10.1111/bjh.14874DOI Listing
October 2017

PHF6 mutations in paediatric acute myeloid leukaemia.

Br J Haematol 2016 12 21;175(5):967-971. Epub 2015 Dec 21.

Paediatric Oncology/Haematology, Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands.

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http://dx.doi.org/10.1111/bjh.13891DOI Listing
December 2016

MicroRNA-106b~25 cluster is upregulated in relapsed MLL-rearranged pediatric acute myeloid leukemia.

Oncotarget 2016 Jul;7(30):48412-48422

Department of Pediatric Oncology, Erasmus MC-Sophia Children's Hospital Rotterdam, Rotterdam, The Netherlands.

The most important reason for therapy failure in pediatric acute myeloid leukemia (AML) is relapse. In order to identify miRNAs that contribute to the clonal evolution towards relapse in pediatric AML, miRNA expression profiling of 127 de novo pediatric AML cases were used. In the diagnostic phase, no miRNA signatures could be identified that were predictive for relapse occurrence, in a large pediatric cohort, nor in a nested mixed lineage leukemia (MLL)-rearranged pediatric cohort. AML with MLL- rearrangements are found in 15-20% of all pediatric AML samples, and reveal a relapse rate up to 50% for certain translocation partner subgroups. Therefore, microRNA expression profiling of six paired initial diagnosis-relapse MLL-rearranged pediatric AML samples (test cohort) and additional eight paired initial diagnosis-relapse samples with MLL-rearrangements (validation cohort) was performed. A list of 53 differentially expressed miRNAs was identified of which the miR-106b~25 cluster, located in intron 13 of MCM7, was the most prominent. These differentially expressed miRNAs however could not predict a relapse in de novo AML samples with MLL-rearrangements at diagnosis. Furthermore, higher mRNA expression of both MCM7 and its upstream regulator E2F1 was found in relapse samples with MLL-rearrangements. In conclusion, we identified the miR-106b~25 cluster to be upregulated in relapse pediatric AML with MLL-rearrangements.
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http://dx.doi.org/10.18632/oncotarget.10270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5217027PMC
July 2016

Aprepitant for paediatric chemotherapy-induced nausea and vomiting - Authors' reply.

Lancet Oncol 2015 Jun 27;16(6):e260-1. Epub 2015 May 27.

Department of Pediatrics, Cancer Research Institute, Seoul National University College of Medicine, Seoul National University Children's Hospital, Seoul, South Korea.

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http://dx.doi.org/10.1016/S1470-2045(15)70235-4DOI Listing
June 2015

Aprepitant for the prevention of chemotherapy-induced nausea and vomiting in children: a randomised, double-blind, phase 3 trial.

Lancet Oncol 2015 Apr 12;16(4):385-94. Epub 2015 Mar 12.

Department of Pediatric Oncology/Hematology, Erasmus MC-Sophia Children's Hospital, Rotterdam, Netherlands.

Background: Oral aprepitant, a neurokinin-1 receptor antagonist, is recommended in combination with other anti-emetic agents for the prevention of nausea and vomiting associated with moderately or highly emetogenic chemotherapy in adults, but its efficacy and safety in paediatric patients are unknown. We did this phase 3 trial to examine the safety and efficacy of such treatment in children.

Methods: In this final analysis of a phase 3, randomised, multicentre, double-blind study, patients aged 6 months to 17 years with a documented malignancy who were scheduled to receive either moderately or highly emetogenic chemotherapy were randomly assigned with an interactive voice response system to an age-based and weight-based blinded regimen of aprepitant (125 mg for ages 12-17 years; 3·0 mg/kg up to 125 mg for ages 6 months to <12 years) plus ondansetron on day 1, followed by aprepitant (80 mg for ages 12-17 years; 2·0 mg/kg up to 80 mg for ages 6 months to <12 years) on days 2 and 3, or placebo plus ondansetron on day 1 followed by placebo on days 2 and 3; addition of dexamethasone was allowed. Randomisation was stratified according to patient age, planned use of chemotherapy associated with very high risk of emetogenicity, and planned use of dexamethasone as an anti-emetic. Ondansetron was dosed per the product label for paediatric use or local standard of care. The primary efficacy endpoint was the proportion of patients who achieved complete response (defined as no vomiting, no retching, and no use of rescue medication) during the 25-120 h (delayed phase) after initiation of emetogenic chemotherapy. Efficacy and safety analyses were done with all randomly assigned patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, number NCT01362530.

Findings: Between Sept 22, 2011, and Aug 16, 2013, 307 patients were randomly assigned at 49 sites in 24 countries to either the aprepitant group (155 patients) or to the control group (152 patients). Three patients in the aprepitant group and two in the control group did not receive study medication, and thus were excluded from analyses. 77 (51%) of 152 patients in the aprepitant group and 39 (26%) of 150 in the control group achieved a complete response in the delayed phase (p<0·0001). The most common grade 3-4 adverse events were febrile neutropenia (23 [15%] of 152 in the aprepitant group vs 21 [14%] of 150 in the control group), anaemia (14 [9%] vs 26 [17%]), and decreased neutrophil count (11 [7%] vs 17 [11%]). The most common serious adverse event was febrile neutropenia (23 [15%] patients in the aprepitant group vs 22 [15%] in the control group).

Interpretation: Addition of aprepitant to ondansetron with or without dexamethasone is effective for the prevention of chemotherapy-induced nausea and vomiting in paediatric patients being treated with moderately or highly emetogenic chemotherapy.

Funding: Merck & Co., Inc.
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http://dx.doi.org/10.1016/S1470-2045(15)70061-6DOI Listing
April 2015

Kinase pathway dependence in primary human leukemias determined by rapid inhibitor screening.

Cancer Res 2013 Jan 18;73(1):285-96. Epub 2012 Oct 18.

Department of Cell and Developmental Biology, Oregon Health & Science University, Portland, OR 97239, USA.

Kinases are dysregulated in most cancers, but the frequency of specific kinase mutations is low, indicating a complex etiology in kinase dysregulation. Here, we report a strategy to rapidly identify functionally important kinase targets, irrespective of the etiology of kinase pathway dysregulation, ultimately enabling a correlation of patient genetic profiles to clinically effective kinase inhibitors. Our methodology assessed the sensitivity of primary leukemia patient samples to a panel of 66 small-molecule kinase inhibitors over 3 days. Screening of 151 leukemia patient samples revealed a wide diversity of drug sensitivities, with 70% of the clinical specimens exhibiting hypersensitivity to one or more drugs. From this data set, we developed an algorithm to predict kinase pathway dependence based on analysis of inhibitor sensitivity patterns. Applying this algorithm correctly identified pathway dependence in proof-of-principle specimens with known oncogenes, including a rare FLT3 mutation outside regions covered by standard molecular diagnostic tests. Interrogation of all 151 patient specimens with this algorithm identified a diversity of kinase targets and signaling pathways that could aid prioritization of deep sequencing data sets, permitting a cumulative analysis to understand kinase pathway dependence within leukemia subsets. In a proof-of-principle case, we showed that in vitro drug sensitivity could predict both a clinical response and the development of drug resistance. Taken together, our results suggested that drug target scores derived from a comprehensive kinase inhibitor panel could predict pathway dependence in cancer cells while simultaneously identifying potential therapeutic options.
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http://dx.doi.org/10.1158/0008-5472.CAN-12-1906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3537897PMC
January 2013

Multimodal treatment, including interferon beta, of nasopharyngeal carcinoma in children and young adults: preliminary results from the prospective, multicenter study NPC-2003-GPOH/DCOG.

Cancer 2012 Oct 22;118(19):4892-900. Epub 2012 Feb 22.

Department of Pediatric and Adolescent Medicine, University Hospital Aachen, Aachen, Germany.

Background: The authors report preliminary results from a prospective multicenter study (Nasopharyngeal Carcinoma [NPC] 2003 German Society of Pediatric Oncology and Hematology/German Children's Oncology Group [NPC-2003-GPOH/DCOG]).

Methods: From 2003 to 2010, 45 patients (ages 8-20 years), including 1 patient with stage II NPC and 44 patients with stage III/IV NPC, were recruited to the study. The patient with stage II disease received radiotherapy (59.4 grays [Gy]). The patients with stage III/IV disease received 3 courses of neoadjuvant chemotherapy with cisplatin, 5-fluorouracil, and folinic acid. The cumulative irradiation dose was 54 Gy in 5 patients, who achieved complete remission after neoadjuvant chemotherapy, and 59.4 Gy in the remaining 40 patients. All patients received concomitant cisplatin during the first week and last week of irradiation. After irradiation, all patients received interferon beta for 6 months. Tumor response was evaluated by magnetic resonance imaging studies and positron emission tomography scans.

Results: After the completion of treatment, 43 of 45 patients were in complete remission. In 2 patients, only a partial response was achieved, followed by distant metastases (1 patient) or local progression and distant metastases (1 patient), 6 months and 10 months after diagnosis, respectively. Another patient developed a solitary pelvic bone metastasis 21 months after diagnosis. After a median follow-up of 30 months (range, 6-95 months), the event-free survival rate was 92.4%, and the overall survival was 97.1%. Acute toxicity consisted mainly of leucopenia, mucositis, and nausea; and late toxicity consisted of hearing loss and hypothyroidism.

Conclusions: Combined therapy with neoadjuvant chemotherapy, radiochemotherapy, and interferon beta was well tolerated and resulted in a very good outcome that was superior to the outcomes of published results from all other pediatric NPC study groups.
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http://dx.doi.org/10.1002/cncr.27395DOI Listing
October 2012

Phase II study of gemcitabine combined with oxaliplatin in relapsed or refractory paediatric solid malignancies: An innovative therapy for children with Cancer European Consortium Study.

Eur J Cancer 2011 Jan 11;47(2):230-8. Epub 2010 Oct 11.

Institut Gustave Roussy, Université Paris-Sud, 39 rue Camille Desmoulins, 94805 Villejuif, France.

Aim: To assess objective response rates after 4 cycles of gemcitabine in combination with oxaliplatin in children and adolescents with relapsed or refractory solid tumours.

Methods: This multicentre, non-randomised Phase II study included five strata: neuroblastoma, osteosarcoma, medulloblastoma and other CNS tumours strata with two-stage Simon designs and a miscellaneous, extra-cranial solid tumour stratum with descriptive design. Eligibility criteria included: age 6 months to 21 years; measurable, relapsed or refractory solid malignancy; no more than one previous salvage therapy. Gemcitabine was administered intravenously at 1000 mg/m(2) over 100 min followed by oxaliplatin at 100mg/m(2) over 120 min on Day 1 of a 14-d cycle. Tumour response was assessed every 4 cycles according to WHO criteria.

Results: Ninety-three out of 95 patients enrolled in 25 centres received treatment: 12 neuroblastoma; 12 osteosarcoma; 14 medulloblastoma; 13 other CNS tumours and 42 miscellaneous non-CNS solid tumours. Median age was 11.7 years (range, 1.3-20.8 years). Tumour control (CR+PR+SD) at 4 cycles was obtained in 30/93 evaluable patients (32.3%; 95% confidence interval (CI), 22.9-42.7%), including four PR: 1/12 patients with osteosarcoma, 1/12 with medulloblastoma, 1/12 with rhabdomyosarcoma and 1/4 with other sarcoma. Five out of 12 eligible patients with neuroblastoma experienced stable disease. During a total of 481 treatment cycles (median 4, range 1-24 per patient), the most common treatment-related toxicities were haematologic (leukopenia, neutropenia, thrombocytopenia) and neurological (dysesthesia, paresthesia).

Concluding Statement: The gemcitabine-oxaliplatin combination administered in a bi-weekly schedule has acceptable safety profile with limited activity in children with relapsed or refractory solid tumours.
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http://dx.doi.org/10.1016/j.ejca.2010.09.015DOI Listing
January 2011

Granulocyte colony-stimulating factor (G-CSF) treatment of childhood acute myeloid leukemias that overexpress the differentiation-defective G-CSF receptor isoform IV is associated with a higher incidence of relapse.

J Clin Oncol 2010 May 20;28(15):2591-7. Epub 2010 Apr 20.

Department of Pediatric Hematology and Oncology, Medical School Hannover, Hannover, Germany.

Purpose: This prospective, multicenter Acute Myeloid Leukemia Berlin-Frankfurt-Muenster (AML-BFM) 98 study randomly tested the ability of granulocyte colony-stimulating factor (G-CSF) to reduce infectious complications and to improve outcomes in children and adolescents with acute myeloid leukemia (AML). However, a trend toward an increased incidence of relapses in the standard-risk (SR) group after G-CSF treatment was observed.

Patients And Methods: Of 154 SR patients in the AML-BFM 98 cohort, 50 patients were tested for G-CSF receptor (G-CSFR) RNA isoform I and IV expression, G-CSFR cell surface expression, and acquired mutations in the G-CSFR gene.

Results: In patients randomly assigned to receive G-CSF after induction, 16 patients overexpressing the G-CSFR isoform IV showed an increased 5-year cumulative incidence of relapse (50% +/- 13%) compared with 14 patients with low-level isoform IV expression (14% +/- 10%; log-rank P = .04). The level of G-CSFR isoform IV had no significant effect in patients not receiving G-CSF (P = .19). Multivariate analyses of the G-CSF-treated subgroup, including the parameters G-CSFR isoform IV overexpression, sex, and favorable cytogenetics as covariables, revealed the prognostic relevance of G-CSFR isoform IV overexpression for 5-year event-free survival (P = .031) and the 5-year cumulative incidence of relapse (P = .049).

Conclusion: Our results demonstrate that children and adolescents with AMLs that overexpress the differentiation-defective G-CSFR isoform IV respond to G-CSF administration after induction, but with a significantly higher incidence of relapse.
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http://dx.doi.org/10.1200/JCO.2009.25.9010DOI Listing
May 2010

CEBPA resembles Roman god Janus.

Blood 2009 Jun;113(26):6501-2

Erasmus MC-Sophia Children's Hospital.

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http://dx.doi.org/10.1182/blood-2009-04-214296DOI Listing
June 2009
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