This report provides highlights of the recent 45th Congress of the International Society of Paediatric Oncology (SIOP)
Tiene Bauters PharmD PhD
Clinical Pharmacist, Paediatric Haematology, Oncology and Stem Cell Transplantation, Ghent University Hospital Pharmacy, Belgium
The 45th Congress of the International Society of Paediatric Oncology (SIOP) took place on 25–28 September 2013 in Hong Kong SAR, China. More than 1500 participants from over 84 countries attended this international event. SIOP is one of the largest international, professional organisations dedicated to paediatric oncology and is an important partner in advancing knowledge in all aspects of childhood cancer. It provides many educational opportunities and serves as a platform for international exchange for physicians, pharmacists, nurses, psychologists, parents, patients, survivors and volunteers.
Therapeutic drug monitoring
The importance of therapeutic drug monitoring of L-asparaginase was discussed by Rob Pieters (Rotterdam, The Netherlands). He concluded that pegylated (PEG) asparaginase (2500 IU/m²) leads to very high blood levels of asparaginase. However, they were more associated with toxicity (triglycerides, cholesterol). There was a high incidence of hypersensitivity reactions (after native Escherichia coli (E. coli) asparaginase in induction phase) but allergy was almost exclusively at second infusion in intensification. There was complete asparaginase depletion in patients without allergy inactivation. Switching from E. coli asparaginase to Erwinia asparaginase in case of silent inactivation to E. coli asparaginase influences outcome by increasing the event-free survival.
Erwinia asparaginase has lower asparaginase activity levels (20,000IU/m²) compared with PEG-asparaginase, without increased triglycerides or cholesterol levels and with a low incidence of hypersensitivity reactions and no silent inactivation, but not always complete asparagine depletion. Hypersensitivity reactions lead to inactivation of asparaginase and usually occur after an asparaginase-free interval.
It is advisable to switch preparation early (even if there is only mild allergy). In case of inactivation, the outcome is worse. Therapeutic drug monitoring improves adequate asparaginase therapy due to the detection of silent inactivation (low asparaginase levels) or detection of unnecessary high asparaginase levels. These findings have lead to changes in DCOG-ALL-11 protocol by using PEG-asparaginase instead of native E. coli asparaginase in induction and intensification. In addition, the starting dose of PEG-asparaginase has been reduced to 1500 IU/m². Therapeutic drug monitoring will be performed in all patients to individualise asparaginase dose to target activity and in cases of silent inactivation, a switch to Erwinia asparaginase is performed with individualisation of dose to target activity.
An overview of the limitations and potential of targeted therapies for paediatric cancer was presented by Peter Houghton (Nationwide Children’s Hospital, Ohio, USA). Targeted therapies are defined as therapies that ‘target’ oncogenic ‘drivers’, usually activated oncogenes, therapies that ‘target’ signaing pathways activated in cancer owing to loss of negative regulators or over-expression of growth factor receptors (HER2), and therapies that target products of genes amplified in cancer. Some examples of successful targeting include imatinib and dasatinib in Philadelphia-positive B-precursor acute lymphoblastic leukaemia (ALL).
Multi-targeted and selective kinase inhibitors are being advanced for clinical evaluation against childhood cancers. The molecular basis for drug activity is known for some cancers (for example, BCR-Abl, FTL3, JAK1-2, ALK, BRAF) but for other agents the rationale is less clear. Kinase inhibitor combinations (temsirolimus/IGF-1 inhibitors) are being studied in Phase II clinical trials while evaluation of combinations with chemotherapy is ongoing in Phase I/II clinical trials (for example, temsirolimus + irinotecan; Phase I for solid tumours) although scientific rationale may be lacking. Finally, kinase inhibitors targeted angiogenesis have generally had modest activity. In future, additional ‘driver mutations’ that may be targeted should be identified, just as biomarkers for accurate patient selection (ALK mutations or BRAF-activating mutations that predict response to targeted agents).
A standardised approach to ‘omically’ characterise tumours at resistance needs to be developed, just as to characterise a patient’s tumour at diagnosis, which might predict the mechanism of relapse. A strong scientific rationale for developing a kinase inhibitor for treatment of paediatric cancer, before initiating clinical trials is necessary. Major challenges are to identify combinations of (kinase) inhibitors that are synthetically lethal in the context of an oncogenic-driver mutation and to develop novel screening strategies that will encompass the genetic diversity of cancer subsets allowing identification of drug sensitivities. This would finally get out of the ‘cytotoxic drug mentality’.
The perspective of the Innovative Therapies for Children with Cancer (ITCC) on targeted therapies for paediatric malignancies was highlighted by Gilles Vassal (Villejuif, France). Goals for the next decade are to increase the cure rate for diseases with a poor prognosis and the quality of cure for patients with a curable disease (long-term sequelae). This needs to be performed with equal access to standard treatments and care across Europe, with adequate long-term follow-up and by the introduction of safe and effective new drugs in standard care. Biology-driven drug development using tumour molecular profiling in clinical development might be accelerated through innovative designs and professionalised European (international) networks. In addition, access to drugs needs to be increased and parents and patients are seen as partners of research.
Attention should be paid on training health professionals. Examples of ongoing ITCC early clinical trials (September 2013) include Phase I studies with azacitidine in leukaemia (ITCC-015); dabrafenib (ITCC-037) and ridaforolimus (ITCC-014 MK-056) in solid tumours; Phase II studies with bortezomib and chemotherapy for leukaemia/lymphoma (ITCC-021) and ipilimumab for melanoma (ITCC-034). The four challenges for the future are to improve access to innovative therapies across Europe, to prioritise compounds, to accelerate new drug development and to provide efficient partnering with all stakeholders.
The European Network for Cancer Research in Children and Adolescents’ (ENCCA) approach for targeted therapies for neuroblastoma was highlighted by Angelika Eggert (Berlin, Germany). New anticancer drugs for children need to be developed and prioritised by a biology-driven new drug development strategy by disease, integrated into current therapeutic strategies and ongoing or planned clinical trials towards personalised medicine and providing a frame for partnership with pharmaceutical companies and for Paediatric Investigation Plan evaluation and by facilitating co-funding at the European and national levels. Current targets or drugs for neuroblastoma with highest priority are ALK, MDM2, mTOR 1+2, AURKA, survivin and CHK1.
Advances in ALL
Recent advances in ALL were highlighted by Ching-Hon Pui (St Jude Children’s Research Hospital, Memphis, USA), who provided an overview of specific genetic abnormalities in ALL with molecular target therapy (for example, Aurora kinase inhibitors, DNA methylation inhibitors, tyrosine kinase inhibitors). In addition, new immunological approaches to treat ALL were discussed. It was concluded that driving somatic mutations could be identified in all cases of ALL. Genome-wide analysis disclosed increasing number of somatic mutations that can be treated with target therapy. Pharmacogenetic variants can influence treatment response and outcome, and the development of ALL.
Future of immunotherapy
The future of immunotherapy for childhood cancer was discussed by Nai-Kong Cheung (New York, USA). These treatment strategies have improved the survival for patients with metastatic neuroblastoma dramatically. Immunotherapy has now become the standard of care for these patients. Moreover, localised neuroblastoma is curable today and many of these patients can be treated with surgery alone. Results of randomised trials with CH14.18/CHO (anti-GD2, a chimeric monoclonal antibody that recognises the ganglioside D2 on neuroblastoma cells) showed a higher overall survival for patients treated with standard therapy of CH14.18/CHO + Il-2 + GM-CSF compared with standard therapy (induction stem cell transplantation, accutane).
An overview of ongoing active studies with CH14.18/CHO in High-Risk Neuroblastoma protocol (HR-NBL 5.1); Phase II feasibility study using CH14.18/CHO antibody + subcutaneous Il-2 after haploidentical hematopoietic stem cell transplantation in children with relapsed neuroblastoma and finally, long-term continuous infusion of CH14.18/CHO plus aldesleukin (reduced toxicity profile) were presented.
Down syndrome and AML
T Tran (Toronto, Canada) presented on infections in children with Down syndrome and acute myeloid leukaemia (AML). He concluded that there was no excessive infectious toxicity during AML treatment for children with Down syndrome compared with the general paediatric population. However, treatment with a Down syndrome-specific AML protocol gives a much more favourable infectious profile.
An overview on haplo-identical stem cell transplantation (pros and cons) was highlighted by R Maarten Egeler (Toronto, Canada). Possible ‘cons’ included graft failure, slow immunosuppression, increased rate of infection and relapse of malignant disease. ‘Pros’ of haplo-identical transplantation include the availability of a donor for almost every patient and limited frequency of graft-versus-host disease. In addition, it provides the perfect platform for cell therapy.
Advantages, challenges and future directions of cord blood transplantation in children were provided by Michael Pulsipher (Utah, USA). Advantages and challenges of cord blood include the rapidly availability and broadly compatibility with limited chronic graft-versus-host disease. Challenges include the slow engraftment and the high risk of late rejection. Improvements are achieved by improved supportive care (EBV reactivation) and dose enhancement.
After the closing ceremony at the end of the Congress, participants were invited to tour local Hong Kong Hospitals (Children’s Cancer Centre at the Prince of Wales Hospital, Shatin and the Children’s Cancer Centre at Queen Mary Hospital, Pokfulam). The first tour also included a visit to the McDonald House, provided by a charity funding. As many families travel far from home and spend several weeks or months to get treatment for their seriously ill or injured, the Ronald McDonald House is that ‘home away from home’ for families. In this way, they can stay close to their hospitalised child at little or no cost. The tour to the Queen Mary Hospital was followed by a visit to the Laboratory for Medical Translational Immunology (University of Hong Kong).
Save the date
The next SIOP meeting will take place in October 2014 in Toronto, Canada.