SY Ha, DKL Cheuk

Abstract

The practice of Paediatric Haematology and Oncology has advanced substantially over recent quarter century. The developments in biotechnology and molecular technology have enabled innovations in diagnostic tools and improved treatment, resulting in better patient outcome. Although they are uncommon conditions, acute leukaemia, thalasssaemia and haemophilia are the important haematological / oncological diseases affecting Hong Kong children who will need considerable health care resources. Patients with transfusion-dependent thalassaemia can now enjoy better quality of life with regular transfusion and appropriate iron chelation therapy. Haematopoietic stem cell transplantation can render patient transfusion independent and there are alternative donors other than HLA matched siblings. New patients with haemophilia are spared of the risk of transfusion-transmitted infection with enhanced transfusion safety. The prevalence of chronic arthropathy has dramatically reduced as a result of prophylactic factor replacement. The treatment outcome in children with cancer including leukaemia has improved over last 25 years. In addition to the conventional treatment modalities, targeted therapy and immunotherapy show promise in combatting refractory or relapsed leukaemia.

Introduction

Paediatric Haematology and Oncology are the clinical specialties which focus on blood disorders and cancers in childhood respectively. These 2 specialties are often put together by tradition as there are many overlaps in clinical practice and they are often organised as integral parts of a comprehensive service program. With more refined developments in subspecialised areas, clinicians and scientists can now focus in a designated area under these specialties. Over the past quarter century, we are very lucky to work in the field of Paediatric Haematology and Oncology and able to witness the innovations with many discoveries impacting patient outcome. Advances in molecular biology and genomic discovery have enhanced our understanding of the pathogenesis of blood diseases and cancers and have contributed to development of new diagnostic tests and treatment approaches.¹ Promising new immune-based and cellular-based therapies have been developed for some of the most challenging disorders. The previous era of dismal outcome for many childhood cancers has been replaced by an era in which most childhood cancers are cured. This has been made possible not only because of advances in oncology but because of the parallel development of surgery, radiology, radiotherapy as well as supportive care.

In Hong Kong, we have experienced similar trend of changes and development though there were often some degree of lagging behind. The advance in diagnostic testing and monitoring has evolved over time contributing to the advance in our clinical practice. Outcome has improved for many childhood illnesses, both neoplastic and non-neoplastic. In this article, we have outlined briefly the historical perspectives of Paediatric Haematology and Oncology. Then we have selected 3 areas including laboratory diagnosis, transfusion safety, haematopoietic stem cell transplant, and 3 types of childhood diseases, namely leukaemia, thalassaemia and haemophilia, and discussed under each topic the concerns in the past, the road to the present and future developments. The article can only be a brief overview of Hong Kong situation with background reference to the situation overseas.

Historical Perspectives

The field of haematology started to develop slowly in last century. Howard Pearson summarised the key milestones in the development during these early years.² Primitive microscope was used in 1674 by Leeuwenhoek (Dutch) to achieve accurate description of red blood corpuscles. Development of compound microscope with 2 lenses enabled big advance. Early evolution of the field was due to quantitation of blood cell elements at the end of 18th century using a gridded chamber called haemocytometer. Previously these parameters were determined by microscopy with considerable observer variability. The attempt at a more accurate determination of any one of these parameters was a laborious, time-consuming enterprise relegated only as a demonstration in physiology laboratories. Subsequent development of automated electronic blood-counting equipment, which was pioneered in 1956 by Wallace H. Coulter, enabled valuable red cell parameters such as mean corpuscular volume (MCV) and red cell distribution width (RDW) to be applied in routine clinical practice. This advance permitted the reclassification of anaemias based on red cell indices. Normal reference range with different age groups was then developed, giving the groundwork for clinical work and future studies. Bone marrow description was first described in 1937. In first half of 19th century, many paediatric haematological disorders were described and they were very different from adult diseases. Some examples are Fanconi anaemia, Cooley's anaemia, Diamond-Blackfan anaemia and haemophilia. In the second half of 19th century, there were steady developments in the understanding of various paediatric haematological and oncological disorders.

Current Status

In retrospect, it is amazing to see how diagnostic measures and treatment have progressed so much while the outcome of sick children was transformed.³ The discovery of the various genes responsible for Fanconi anaemia and other inherited bone marrow failure syndromes has revealed underlying pathogenesis including DNA repair, telomere maintenance, ribosome biology and other new fields of biology. The group of congenital hemolytic anaemias can now be identified as separate and distinct enzymopathies and membrane defects. With improvement in electrophoretic technology and genetic methods, haemoglobinopathies and thalassaemia are diagnosed quickly with short turnaround time.

The treatment outcomes of many non-neoplastic haematological disorders are very different from the past. Aplastic anaemia has been transformed from a deadly disease to one with cure in 90% of patients, using either immunosuppressive therapies or hematopoietic stem cell transplantation. For immune thrombocytopenia (ITP), the commonest haematological disorder affecting children, we often use intravenous gamma-globulin or steroid during the acute phase if platelet count is <10x10⁹/L or the child has significant bleeding. For persistent or chronic ITP, we now can consider using 2 drugs which were not available in the past, namely Eltrombopag or Rituximab. Eltrombopag was shown to activate the thrombopoietin receptor leading to increased proliferation and differentiation of megakaryocytes. It has recently been found to have beneficial effects on patients with aplastic anaemia. Rituximab is an anti-CD20 antibody which suppresses B-cells proliferation and hence reduction of auto-antibodies against platelets.

For neoplastic conditions, in addition to conventional treatment modalities including chemotherapy, surgery and external beam irradiation, there are new treatment modalities, namely immunotherapy and targeted therapy. Immunotherapy can be sub-classified into 5 types, namely monoclonal antibodies, immune checkpoint inhibitor, cancer vaccine, adoptive cell therapy and cytokines. Some of the drugs are already in clinical use. Targeted therapy refers to therapeutic agent which blocks the growth of cancer cells by interacting with specific molecules needed for carcinogenesis. The most famous agents are various tyrosine kinase inhibitors (TKI) with imatinib being the prototype. The use of TKIs has largely transformed the outlook of patients with chronic myeloid leukaemia (CML). They will need to take TKI orally and regularly for long term, and very few need a bone marrow transplant in big contrast to the past. There are many new targeted drugs for clinical use or for clinical trial. Some examples are listed as follows with drug name (target): Bevacizumab (VEGF), Bortezomib (proteasome), Vorinostat (histone deacetylase), Quizartinib or Sorafenib (Flt-3), mTOR inhibitor (mammalian target of rapamycin), Crizotinib (Alk), Venetoclax (Bcl-2), Apatinib (VEGF receptor 2), Trametinib (MEK), Entrectinib (NTRK or ROS1). The targeted drug is often active against specific type of cancer with the corresponding actionable mutation or molecule expression.⁴ We need to learn the updated information about these drugs from clinical studies and accumulate own experience in their usage.

Laboratory Diagnosis and Monitoring

In the 1980s, there were limited batteries of investigatory tools provided by haematology and histopathology laboratory. Other than full blood count and microscopic examination on morphology of blood cells, the tests for haemolytic anaemia, coagulopathy, thrombophilia, platelet dysfunction were limited or only available in a few laboratories. Over past quarter century, investigatory tools for leukaemia have advanced from simple morphology with cytochemical staining to immunophenotyping, cytogenetics and molecular genetics. The use of flow cytometry on live cells has enabled improved immunophenotyping in contrast to the old APPAP (Alkaline Phosphatase anti Alkaline Phosphatase) method on slides with fixed blood cells. Cytogenetics study provides important information on clonal chromosomal aberrations associated with leukaemia. Other genetics tests such as FISH (florescence in-situ hybridization) technique enable detection of small genetic changes and supplement karyotype analysis. The use of molecular technique RT-PCR (reverse transcriptase - polymerase chain reaction) can detect fusion transcript which occurs in leukaemia cells with recurrent chromosomal translocation, such as RUNX1-RUNX1T1 in AML with t(8;21).

The French-American-British (FAB) classification was published in 1976 aiming to unify classification of acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML) basing on morphological study only.⁵ This was a starting point when acute leukaemia classification could be standardised and clinical studies could be compared. In addition to morphology, MIC classification in 2001 incorporated immunophenotype and cytogenetics. In the updated version of 2008 World Health Organization (WHO) Classification of Haematological Malignancies, cytogenetics study was supplemented by molecular genetics such as FISH and RT-PCR. The 2016 revision to the WHO classification of myeloid neoplasms and acute leukaemia is the most updated version and the simple FAB classification of AML (M0-M7) is now changed to a diversified classes and subclasses of leukaemia with cytogenetic and molecular genetic information which can have prognostic implications⁶ (Figure 1).

Monitoring for response in leukaemia after chemotherapy is done by blood count and by morphological assessment for number of residual blasts in bone marrow. Now we can use flow cytometry to look for minimal residual disease (MRD) i.e. small number of residual leukaemia cells if we can identify leukaemia associated immunophenotype (LAIP) for the leukaemia case under treatment. We can also use molecular method for detection of MRD such as quantitative RT-PCR if leukaemia expresses fusion transcript such as RUNX1-RUNX1T1 in AML with t(8;21). The latter method is more sensitive than the flow cytometric analysis.

With advance in technology, there will be more and more investigatory tools for research and for clinical use. Some of the potential tools include digital imaging and artificial intelligence in morphology, next generation flow cytometry (NGF), next generation sequencing (NGS), ultra-deep MRD monitoring, single cell analysis etc. (personal communication with Dr Jason So). Only through clinical studies, we can find out which new tool can be applied in clinical use.

Figure 2 Transfusion safety is enhanced at Hong Kong Red Cross Blood Transfusion Service over past 30 years.

Transfusion Safety

In the 1980s, transfusion of blood components and products was practiced widely in clinical care and in the field of haematology. There were concerns about inadequate supply of various blood components and blood products. Transfusion-transmitted virus infections were the major hazards at that time and indeed a proportion of patients were infected through transfusion. In Hong Kong, 34% of thalassaemia patients were infected with HCV reported in a study published in 2010.⁷ In many other places, these have led to long period of disputes and legal proceedings regarding the responsibilities of blood providers and health authorities. In France, the court pronounced the verdict convicting three former officials of having knowingly distributed blood extracts contaminated with HIV and the head officials were sentenced to imprisonment.⁸ It was 10 years later that the supreme court ruled that these officials cannot be held for delays in blood screening which resulted in thousands of people infected with HIV.⁹ In 1993 the Hong Kong Government set up AIDS Trust Fund to assist the HIV-infected haemophiliacs and to strengthen the medical and support services. The transfusion-transmitted infections have causes nightmares and tragedies to many patients and their families, and it is a painful lesson for health care providers.

Hong Kong Red Cross Blood Transfusion Service (BTS) is all along the only organiser of blood and blood component provision in Hong Kong. Transfusion safety in Hong Kong has progressively been enhanced, from the introduction of serologic testing for hepatitis C in 1991 to the implementation of rapid nucleic acid testing (NAT) for various infectious agents, and full compliance with the ISO international standards in the late 2000s (Figure 2). A number of patients developed sepsis after platelet transfusion.¹⁰ A study conducted by the BTS found that short term aerobic bacterial culture surveillance system was able to reduce bacterial infection through blood transfusion. The system was subsequently incorporated into the surveillance system.

It is still possible that new or emerging infective agents can cause threats in transfusion.¹¹ Virucidal or pathogen reduction systems for individual blood units are now applicable such as methylene blue treated fresh frozen plasma (FFP). Artificial blood substitutes are theoretically safer but its application in clinical care is still not practical.

Haematopoietic Stem Cell Transplant

Allogeneic haematopoietic stem cell transplantation (HSCT) is now established as a standard therapeutic modality for a variety of malignant and non-malignant diseases both in adults and in children. HSCT not only replaces the diseased hematopoietic system, but also provides various immunocompetent donor cells to combat malignant cells, an effect called graft-versus-tumour (GVT). Thus, HSCT is a prototype of cellular therapy. The first successful allogeneic HSCT was done in the USA in 1968.¹² We performed the first allogeneic HSCT in Hong Kong in 1990. Initially, only HLA-identical sibling was used as the donor. With the establishment of Hong Kong Marrow Donor Registry in 1991, we started to use human leukocyte antigen (HLA) matched unrelated donor for transplant. Severe graft-versus-host disease (GVHD) was a major complication in the early era as the HLA matching was crude. Throughout the past decades, transplant outcomes continue to improve with advancement in molecular HLA typing techniques, development of potent immunosuppressants, refinement of transplant conditioning and supportive care, as well as diagnostics and therapeutics of infective and other complications. Apart from HLA-matched related and unrelated donors, we also increasingly utilise unrelated cord blood units as stem cell source, in parallel with expansion of public and private cord blood banks. Cord blood transplant has significant advantages of fast availability, absence of donor risk, and less stringent requirement for HLA matching. Nowadays, outcomes of standard HSCT in Hong Kong are on a par with most developed countries. Long-term survival after HSCT is about 60% for high risk or relapsed leukaemia and 90% for severe aplastic anaemia (unpublished data).

Nevertheless, a substantial proportion of patients lack HLA-matched donors or appropriate cord blood units. Some of these patients had HLA-mismatched HSCT performed. However, employing the usual methods as for HLA-matched transplant frequently results in graft rejection, GVHD, and worse survival.¹³ Rejection and GVHD are thought to be mediated by alloreactive T cells from the recipient and the donor respectively. Attempts have been made to overcome rejection by megadose of donor stem cells and more intensive pre-transplant immunosuppression; and various in vitro and in vivo methods have been employed to remove donor T cells to reduce GVHD. These approaches have gradually improved outcomes of HLA-mismatched or haploidentical family donor HSCT¹⁴ and broadened the donor choices so that virtually all patients would have at least one readily available donor for HSCT.

One of the commonly used stem cell engineering approaches to facilitate successful HLA-mismatched HSCT is positive selection of CD34+ cells from harvested peripheral blood stem cells by monoclonal antibodies using large scale immunomagnetic methods. By infusion of high doses of purified CD34+ stem cells, HLA barrier can be successfully overcome with good engraftment rate and low incidence of GVHD.^15,16 However, infection risk is high as immune reconstitution is slow.¹⁷ Relapse of malignancy is also a major problem.¹⁷ Another approach is negative selection by depletion of CD3+ T cells, usually combined with depletion of CD19+ B cells to prevent post-transplant lymphoproliferative disease. Such approach preserves natural killer cells, myeloid precursors and other cells which may facilitate engraftment. Immune recovery is faster with reduced infections and transplant-related mortality.¹⁸ Depletion of T cell receptor alpha-beta positive T cells while retaining gamma-delta T cells may also reduce GVHD while preserving anti-infective and anti-tumour effects.^19-21 We have adopted such approach for haploidentical transplant in Hong Kong since 2014.

To augment anti-infective and anti-tumour effects or to promote donor chimerism, donor lymphocytes are sometimes infused after HSCT.²² However, unmanipulated donor lymphocyte infusion is associated with a high risk of severe GVHD. CD45RA depletion, which removes naïve T cells while retaining memory T cells, would protect the transplant recipient against various infections, promote engraftment and immune reconstitution, and possibly reduce recurrence of malignancy^23,24 while limiting GVHD, and we have started to utilise such approach since 2016.

Apart from simple cell sorting, selection and depletion based on cell surface markers, antigen-specific T cells can be selected and enriched as another form of adoptive cellular therapy. Since 2016, we have started to apply allogeneic antigen-specific T cells purified on the basis of gamma-interferon secretion upon specific antigen stimulation. This can be an effective treatment for cytomegalovirus, Ebstein-Barr virus, adenovirus and other viruses in severely immunocompromised patients. Adverse effects are minimal due to high specificity of the infused cells.

A recent major breakthrough in cellular therapy for oncology patients is the use of genetically modified chimeric antigen receptor (CAR) T cells,²⁵ which shows great promise in multiply relapsed or refractory B cell acute lymphoblastic leukaemia and various B cell lymphomas.²⁶ Its use continues to expand to other malignancies. Currently we are actively developing this state-of-art cellular therapy in Hong Kong.

ALL: acute lymphoblastic leukaemia, AML: acute myeloid leukaemia, HL: Hodgkin lymphoma, NHL: non-Hodgkin lymphoma, CNS tumour: central nervous system tumour, CNS GCT: central nervous system germ cell tumour, PNS tumour: peripheral nervous system tumour, STS: soft tissue sarcoma, GCT: germ cell tumour

Figure 3 Childhood Cancer Statistics 2006-2015 (10 years' data from Hong Kong Paediatric Haematology & Oncology Study Group. Total number: 1755).

Acute Leukaemia

Childhood cancer is rare, with estimated annual incidence of 150 cases per million children <15 years of age. In Hong Kong patients <18 years old are usually treated in the paediatrics and adolescent unit in the public hospitals. From local data collected over 10 years' period, (2006 -2015), an average of 170 new cases was registered each year for patients <18 years of age. Acute lymphoblastic leukaemia is the commonest cancer type and this does not differ from other cities in the world. Acute lymphoblastic leukaemia accounts for 22% while acute myeloid leukaemia accounts for 9%. Brain tumour accounts for 15% and lymphoma (non-Hodgkin's and Hodgkin) accounts for a total of 11% (Figure 3).

Concerns in the past related to acute leukaemia are mainly relapse, refractory leukaemia, and toxicities from treatment. In the old days, we often treated patients by adopting protocols from overseas centre or oncology group. Over the last 2 decades, the Hong Kong Paediatric Haematology and Oncology Study Group (HKPHOSG) has got the chance to join international studies. The I-BFM ALL 2002 was one of the early international studies our Group participated and this resulted in improved outcome of Hong Kong patients.²⁷ The subsequent two clinical trials on ALL are CCLG-2008 and CCCG-2015, both being national trials involving a number of oncology units in mainland.²⁸ The most recent CCCG-2015 protocol is still ongoing. Over the years, we have gained experience in different aspects including ways to conduct clinical trials and use of flow MRD in patient stratification. More important is that patients have improved outcome and cranial RT prophylaxis was largely avoided. For relapse and refractory cases, we can now consider use of immunotherapy i.e. blinatumomab (bi-specific antibody against CD19/CD3), and Inotuzumab Ozogamicin (antibody against anti-CD22). CAR-T cell therapy, one form of adoptive T-cell therapy has shown promising results in achieving remission for refractory leukaemia. This treatment facility is not yet available in Hong Kong while the cost charged by drug firm is enormous. So, there is a need to develop these treatment modalities locally.

For AML, our Group had the chance to join an international relapse AML protocol using Liposomal Daunorubicin (DaunoXome). Then we started to join the NOPHO AML 2007 protocol. This study has examined the benefits of post-consolidation use of Mylotarg in a randomised control study and the results only showed the drug delayed relapse and did not improve outcome.^29,30 Currently we are joining the NOPHO AML 2012 protocol which stratifies patients based on presence of Flt-3 mutation (poor prognostic marker) and in-vivo response by assessing post-treatment bone marrow MRD by flow cytometry. The interim analysis shows improved survival with the new protocol compared with previous 2004 protocol (unpublished data). For relapse case and refractory cases, use of Clofarabine, Mylotarg (antibody against CD33), and Flt-3inhibtor should be considered.

Haemophilia

The incidences of haemophilias A and B in Hong Kong have not been well-defined. Patients with haemophilias can lead a near normal life with adequate coagulation factor support but pose significant economic costs to the health care system.

In the 1980s many patients were managed by 'treatment on demand' regimen with factor replacement. Recurrent bleeding and chronic arthropathy occurred not infrequently with this approach. Risks of transfusion-transmitted infections were main concerns at that time. Cohort of 90 children and adolescents with haemophilia were recruited in a cross-sectional study which showed 46.4% had chronic arthropathy.³¹ HCV infection was present in 12 patients, 2 had HBV and none had HIV. 8.1% had inhibitor. From 2004, factor replacement has moved towards prophylactic use. Chronic arthropathy is now uncommon in the young generation. A bigger cohort of 222 patients (all age) was surveyed and reported in 2011. The study showed 26 patients have HIV, 100 have HCV and 14 have HBV, and most of the infected subjects are in older age group.³²

In Hong Kong, plasma-derived factor VIII and IX concentrates are manufactured from plasma of normal blood donors. This local source of factor concentrates, while adequate for haemophilia B patients, is inadequate for the bigger population of haemophilia A patients, so that plasma-derived factor VIII concentrates are needed from other suppliers. For plasma derived product, infection risk is much reduced with heat treatment and monoclonal technology. As recombinant product came to market in the 20th century, there was discussion on whether the new product should replace the plasma derived product in Hong Kong. Nowadays it remains that plasma derived product is provided to most patients while recombinant product as a self-financed item.

Inhibitor development in haemophiliacs poses a very challenging problem for the clinicians. Studies comparing the risk of inhibitor development in patients with plasma derived product or recombinant product have not shown conclusive results. When a patient develops significant inhibitor level and has excessive bleeding, this often necessitates the use of bypassing agents such as Novo Seven or FEIBA. In some patients, immune tolerance induction can be tried. Emicizumab (Hemlibra^®) is a bispecific humanised monoclonal antibody that restores the function of missing activated FVIII by bridging activated FIX and FX to facilitate effective haemostasis in patients with haemophilia A.³³ Subcutaneous Emicizumab is approved in the USA for use as routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adults and paediatric patients with haemophilia A with FVIII inhibitors. Subcutaneous Emicizumab is awaiting approval in several countries worldwide.

Innovations mainly focus on long acting factor using different technology, e.g. Fc protein fusion or PEGylated factor. Clinical trials with adeno-associated virus vectors have documented a significant success for haemophilia gene therapy demonstrating potential to transform haemophilia treatment.³⁴

Thalassaemia

In early 1980s when the first author started working as a paediatric trainee, he was given an impression that thalassaemia was a 'bad' disease with gloomy outcome. Patients were inadequately transfused and had characteristic Cooley's facies and hepatosplenomegaly. They were under threat of transfusion-transmitted infections. Complications including endocrinopathies and cardiomyopathies due to iron overload were destined to develop with time. Iron chelation with subcutaneous desferrioxamine was started in Hong Kong in the late 1970s and early 1980s.³⁵ Since then, regular blood transfusion and subcutaneous desferrioxamine has become the standard management. However, complications due to iron overload still occurred in significant number of patients. This was partly due to poor compliance to the demanding chelator injection, partly related to efficiency of the chelator, and also related to lack of tool to monitor iron overload except serum ferritin. Haematopoietic stem cell transplant facilities were not available till 1990. Infections by Klebsiella spp. at different body sites were commonly encountered, which could lead to significant morbidity and mortality.³⁶ Other desferrioxamine-associated complications such as skeletal dysplasia were occasionally observed

In 2009, it was estimated that 9.5% of the blood supply in Hong Kong (13,460 units) was utilised by about 380 transfusion-dependent thalassaemia patients, with a predicted annual consumption increment of 0.8%.³⁷ Thalassaemia patients have been provided with pre-storage filtered blood as a standard for the past 20 years.

Deferiprone was shown in a randomised controlled study to significantly reduce ferritin levels in poorly chelated Chinese patients when combined with desferrioxamine.³⁸ Therefore, combination therapy of desferrioxamine with deferiprone is frequently used in poorly-chelated patients, with benefits validated by MRI T2*.³⁹ The use of validated MRI software to assess organ iron is one the major innovations which has transformed thalassaemia care as clinicians can now adjust iron chelation regimen based on degree of iron overload in specific organs. Deferasirox is another oral iron chelator which was available in Hong Kong public hospitals since 2010. It was recommended for first-line treatment in children aged between 2-6 years, and for second-line treatment for children older than 6 years, who are not responding optimally to combined desferrioxamine with deferiprone. Renal tubular dysfunction has been observed to be a frequent but reversible adverse effect.⁴⁰

In Hong Kong, HLA-matched sibling HSCT for thalassaemia started initially with marrow in 1991, and with cord blood in 1994.⁴¹ Employing conditioning regimens containing anti-thymocyte globulin, HSCT results in transfusion-independence in over 90% of recipients. Pre-implantation genetic diagnosis (PGD) and embryo selection for unaffected HLA-matched sibling for transplant was successfully done for a few cases. Improved outcomes of unrelated donor transplant and availability of haploidentical donor transplant have also transformed the outlook of transfusion-dependent thalassaemia patients.

Despite high prevalence of thalassaemia carrier rate in Hong Kong, preventive measures by antenatal screening and prenatal diagnosis have dramatically reduced the birth of severe forms of thalassaemia. However occasional couples with affected fetus have decided to carry on the pregnancy after being counselled on the current state of thalassaemia care. Some of the patient with Hb Bart disease were born this way and they were given intra-uterine transfusion which reduce the detrimental effects of severe anaemia.⁴²

Thalassaemia is now becoming an adult disease with much improved outlook, reduced morbidities and mortality. Many of the patients achieved a lot in life both in careers and parenthood with the current improvements in treatment, including different chelation regimens that individualise and optimise to achieve normal or near normal iron overload status. More iron chelators may come up in the future.

The most exciting developments in recent years are on gene therapy which requires transfer (ex-vivo viral transduction) to haematopoietic stem cells of large globin gene expression cassettes driven by complex regulatory elements. Preclinical and early clinical studies proved safety and efficacy of stem cell-based gene therapy while showing hurdles and limitations of the existing technology.^43,44 Although the number of patients in the two studies are small, a significant proportion of patients achieved transfusion free. Stem cell procurement, cell dose, transduction efficiency, gene expression level, conditioning regimen, and patient's age at the time of intervention are key factors affecting the therapeutic range and clinical efficacy of gene therapy. There will be refinements in the gene therapy methodology. At the same time haematopoeitic stem cell transplant will also improve. A comparison between the 2 approaches is tabulated (Figure 4).

Another approach in gene therapy is gene (genome) editing in which no viral transduction is required. Nucleases are employed to either repair, disrupt or to activate certain globin genes with different approaches aiming at alleviating globin chain imbalance in intermediately severe forms of beta thalassaemia. One of the popular nuclease systems is the CRISPR-Cas9, which was adapted from a naturally occurring genome editing system in bacteria.⁴⁵ Challenges include selection of the most effective genome editing tools, optimising their delivery to haematopoietic stem cells (HSCs), improving specificity and better understanding potential off target effects, particularly those that are biologically relevant.

Figure 4 Comparison between haematopoietic stem cell transplant (HSCT) and gene therapy.

Future Challenges

Major changes in service delivery model of paediatric care are occurring after Hong Kong Children's Hospital (HKCH) has commenced operation. Out-patient clinic service started in December 2018 and in-patient service started on 27 March 2019. In the subsequent four months, the 5 parent oncology units, 2 of them providing HSCT have moved to HKCH and the teams merged to provide patient care at HKCH. In the coming 1 year, other tertiary and quaternary services in paediatrics and surgical specialties will be translocated to HKCH in phases. The HKCH serves as the tertiary referral centre for complex, serious and uncommon paediatric cases requiring multidisciplinary management, providing diagnosis, treatment and rehabilitation services for patients with relevant clinical needs, from birth to 18 years of age over the territory, while the paediatric departments in the other 13 public hospitals continue to provide secondary, acute, emergency and community paediatric care. This new "hub-and-spoke" health care delivery model⁴⁶ is expected to bring about a coordinated and coherent paediatric service network and enhance the overall service quality.

For paediatric haematology and oncology, children with cancer will be treated largely at HKCH. There are however a lot of different haematology practices happening in regional units and in the community. Close communication and consultation with regional units and private sectors by HKCH is therefore critical to achieve provision of comprehensive care to children.

Local patient population remains small and many haematological and oncological disorders are relatively rare. We need to join research studies, both clinical and laboratory through national or international collaboration. New drugs and treatment modalities are often pioneered by commercial companies and we need to explore feasibility to participate in sponsored clinical trials. Globalisation of healthcare and medical tourism have inevitably been happening and this poses pressure and momentum for local providers to develop treatment modalities which are not yet available locally such as proton therapy, CAT-T cell therapy for acute lymphoblastic leukaemia, and gene therapy. The surge in healthcare costing is imminent and financing issue will be continual challenges to the Government.

With all the changes and hurdles, we feel hopeful that that the new service model can help to raise the standards of paediatric care in Hong Kong, with support from the Government, health care authorities, and non-government organisations. The success of course relies very much on the dedication, team spirits, and close collaboration among health care providers at different units within the "hub-and-spoke" network.

Declaration of Interest

The authors have no conflicts of interest to disclose.

Acknowledgement

We wish to thank Dr Jason So (Department of Pathology, Hong Kong Children's Hospital) and Dr Lee Cheuk-kwong (Hong Kong Red Cross Blood Transfusion Service) for information sharing. We would like to express gratitude to members of Hong Kong Paediatric Haematology and Oncology Study Group for the support and collaboration in past quarter century. This article was based on a presentation given at Annual Scientific Meeting of the Study Group on 16th March 2018.

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