FWT Cheng, GKS Lam, DKL Cheuk, CW Luk, CH Li, SC Ling, AKS Chiang, MHL Ng, CK Li; On behalf of the Hong Kong Paediatric Haematology and Oncology Study Group

Abstract

In this report, we review the landmark and achievement in treatment of acute lymphoblastic leukaemia (ALL) in Hong Kong over the past 35 years. With the joint efforts from different professionals, lining up with parties in various specialties not only in Hong Kong, but also in mainland and worldwide, we are achieving our goals in enhancing the event-free survival of Hong Kong children with ALL. Through collaboration with major childhood cancer networks in joining international trials 17 years ago and in the last 10 years, we started collaboration with working group in China and conducting national multi-center studies. We worked through different treatment protocols with advancement in treatment outcome. The 5-year event-free survival of children with ALL in Hong Kong has improved from 65% to now 87%. The next step will be the advance in cancer genetics. This serves a dual purpose of better categorising of ALL subtypes with different prognostic significance and also identifying potential druggable targets for ALL with known adverse outcome. With the translocation of territory-wide paediatric oncology service to Hong Kong Children's Hospital, it opens a new page and a unified platform for basic and clinical research in children with cancers. This will bring further achievement in care of children who suffer from cancers in Hong Kong.

Introduction

In Hong Kong, around 180 new cases of childhood malignancies are diagnosed every year. Acute lymphoblastic leukaemia (ALL), the most common childhood malignancy, accounts for about 40 cases each year. The annual incidence is 38.6 cases per 1,000,000 children.¹

The peak age of onset of childhood ALL is 3-5 years old. In Hong Kong, infants younger than 12 months with ALL are treated under a separate protocol by the same centres. Patients with ALL who are older than 18 years are treated by the specialists in medical haematology and clinical oncology units.

The treatment of childhood ALL is chemotherapy-based therapy. The first 7-8 weeks of treatment is known as induction. It serves the purpose to decrease leukaemia burden and brings the active disease to remission in which steroid, vincristine, doxorubicin and L-asparaginase are the key agents. The next phase of treatment is known as consolidation treatment, including high dose methotrexate and 6-mercaptopurine. Re-induction phase is another very important treatment block in which the agents similar to induction phase are repeated. This has been shown to remarkably reduce relapses. After 8 months of the above intensive chemotherapy, the patient will then proceed to milder but prolonged maintenance therapy. The whole treatment duration is 2.5 years started from initiation of therapy.

With the advancement of central nervous system (CNS) disease control by intrathecal chemotherapy, prophylactic cranial radiotherapy, which is associated with significant long-term cognitive impairment and life-long risk of second malignancy, can now be eliminated.

Patients are being stratified into different risk groups according to the chance of relapse, thus patients can be treated with the most appropriate intensity of treatment. Development of Minimal Residual Disease (MRD) monitoring, mostly by flow cytometry and supplemented by PCR methods, makes this precision medicine possible. With the advancement in treatment protocol and also supportive care for childhood ALL, the 5-year EFS of standard risk childhood ALL is now approaching 90%.

This review overviews the progress in treatment of ALL in the past 35 years. With the joint efforts from different professionals, lining up with parties in various specialties not only in Hong Kong, but also in mainland and worldwide, we are achieving our goals in enhancing the EFS of Hong Kong children with ALL.

HKALL-93

With the establishment of Hong Kong Paediatric Haematology and Oncology Study Group (HKPHOSG) in 1993 with joint efforts from 5 hospitals covering the whole paediatric oncology service in Hong Kong, HKPHOSG conducted the first population-based territory-wide Chinese children HKALL-93 study from 1993-1977. All newly diagnosed ALL patients from 1 to 16 years old in Hong Kong received the uniform treatment protocol which was modified from United Kingdom MRC UKALL XI.² One hundred forty-five eligible children were recruited. This was once the largest report of Chinese children ALL series on one study protocol with complete follow-up. The risk stratification (Standard Risk (SR); Intermediate Risk (IR); High Risk (HR)) was based on patient's age; initial white blood cell (WBC) count, lineage of blasts, status of Philadelphia chromosome (Ph') and status of CNS disease. Prophylactic cranial radiotherapy was given to all HR patients which accounted for 26.2% of the cohort. The overall survival (OS) and 5-year EFS for the whole group was 81.3% and 62.6% respectively. When the analysis of outcome according to risk groups, the 5-year OS was 96%; 73%; 68% for SR, IR and HR respectively. However, the 5-year EFS was 79%, 49% and 61% for SR, IR and HR respectively (Figure 1). The 5-year EFS, especially IR, was inferior to reports in similar period as most studies reported EFS over 70%. The inferior outcome was mainly attributed to relapse, majority were bone marrow relapses and isolated CNS relapses. From later analysis, the reason of high relapse rate in IR group was due to low treatment intensity (without delayed intensification) in this protocol.³

HKALL-97

Although HKALL-93 showed that the treatment outcome was similar to western reports based on similar UK treatment protocol, but the result was suboptimal as compared with other contemporary treatment protocols namely German and North American protocols. This led to HKPHOSG to commence another new clinical study in 1997 (HKALL-97) that adopted the German Berlin-Frankfurt-Munster 95 (BFM 95) approach. The main differences between this German protocol versus UK protocol was (i) in-vivo response to 7-day of steroid as one of the major stratification criteria (good steroid responder versus poor steroid responder); (ii) high WBC no longer a risk stratification feature between IR and HR, therefore lesser number of patients classified as high risk to receive prophylactic cranial radiotherapy with well-documented life-long risk of second malignancies and cognitive impairment; (iii) addition of a delayed intensification block with regimen similar to induction started from 22-29 weeks after diagnosis.

From November 1997 to December 2002, one hundred seventy-one children aged 1 to 17.9 years with diagnosis of ALL were recruited in this study. Although the OS was similar between the 81.8% for HKALL-93 and 86.5% in HKALL-97 protocol (P=0.51), there was significant advance in EFS for HKALL-97 protocol (65% for HKALL-93 vs 79% for HKALL-97, P=0.007) (Figure 2). For the IR and HR group, there was a statistical significant trend of better EFS in HKALL-97 versus HKALL-93 (IR: 75.6% versus 53.1%, P=0.06; HR: 59% versus 49%, P=0.14).⁴ There was also limitation of prophylactic cranial irradiation to 17.7% of patients.

Figure 1 Event-free survival of HKALL-93 protocol.

Figure 2 Comparison of event-free survival of HKALL-97 versus HKALL-93 protocol.

ALL-IC-BFM 2002

The major limitation of past two Hong Kong territory-wide population-based studies was small subject number as our population was only about 7 millions. The only way to move forward was to collaborate with international study groups and participated in large multi-centre study. From 2002-2007, the International Berlin-Frankfurt-Munster (I-BFM) Study Group conducted a prospective randomised clinical trial in ALL (ALL InterContinental-BFM 2002). This was the first time that our group participated in a multi-national study which involved 5060 patients from 130 centres in Europe, Asia (Hong Kong) and South America. Hong Kong contributed 155 subjects in this study. This was a platform of wide international collaboration in paediatric oncology. In this study, although the risk stratification was similarly based on a combination of clinical and laboratory stratification approaches, a new morphological assessment on day 15 was included as early response criteria. There were also research questions on randomisation of different intensity of delayed intensification phases on the event-free survival and treatment-related toxicity.

At that time, the clinical significance and importance of measurement of minimal residual disease (MRD) in predicting relapse was just established. This technique was incorporated in the risk stratification in several treatment protocols in world major cancer study groups.⁵ MRD testing by Polymerase Chain Reaction (PCR) was incorporated into risk group stratification of AIEOP-BFM ALL 2000 trial. However, this technique and logistics in performing MRD was highly technology dependent, time consuming, logistically demanding and relatively expensive. In order to ensure reliability and credibility of results, it required regular inter-laboratory quality assurance. Therefore, at that time, MRD by PCR was still not widely applicable to many laboratories around the world.⁶

With the chance of joining IC-BFM group and participation in the ALL-IC-BFM 2002 study, Hong Kong could establish the technique and logistic of routine MRD testing. Acquiring the technology of MRD analysis was very important for Hong Kong as it paved our way for next phase of MRD-directed therapy in future study. With the generous support from Children's Cancer Foundation, our group started the research on establishing MRD analysis for childhood ALL in Hong Kong. In this IC-BFM ALL 2002 study, with correlation of clinical, morphological and haematological stratifications with MRD clearance and response to therapy, we learnt that MRD reduction at first 3 months of therapy correlated with the risk group stratifications. However, there was a great overlap between intermediate (IR) and low risk (LR) group in which by ALL IC risk stratification criteria, a significant number of IR patients could assign therapy reduction based on MRD results. At 5 years, the OS and EFS of ALL-IC-BFM 2002 protocol for the whole group was 82% and 74% respectively.⁷ With our longer-term follow-up of the Hong Kong cohort, the 7-year OS and EFS was 86.9% and 78% respectively, i.e. better than the whole group result.

Technology of MRD Monitoring

For the technique in performing MRD, apart from by PCR analysis of immunoglobulin / T-cell receptor (Ig / TCR) gene rearrangement, the other technique is by flow cytometry. The advantage of flow cytometry is faster, more cost-effective and more widely applicable to most centres' setting by using standardised reagents and gating strategies. Moreover, apart from using bone marrow as specimen, our group also found that peripheral blood could be an alternative MRD monitoring method in some types of ALL. According to multivariate analysis, MRD assessment by PCR and flow cytometry could independently predict patients' prognosis and risk of relapse.⁸

CCLG 2008

With the improvement in socio-economic condition and establishment of national insurance system, more and more children in mainland can receive appropriate treatment of ALL in mainland.⁹ The HKPHOSG would like to contribute to the development of cancer service for children in China, and applied the experience we gained from international studies for the first large scale national study for childhood ALL.

From 2008, this was the first time Hong Kong joined the Chinese Children Leukaemia Group (CCLG-ALL) 2008 study which was a prospective clinical trial designed to improve treatment outcome of childhood ALL through the first national-wide collaborative study in China. Total 2231 patients were recruited from 10 tertiary hospitals in 8 cities. Since most of the participating centres were not equipped with the skill and expertise of performing MRD, thus a pilot study of MRD-directed protocol was limited to Hong Kong and Beijing Children's Hospital. At 5 years, the OS and EFS of the whole group was 85.3% and 79.9% respectively. The OS and EFS of SR patients was 91.5% and 87.9% respectively. The cumulative incidence of relapse of all patients was 15% at 5 years.

The incidence of relapse in SR was 9.7%. These data were comparable with major studies worldwide. This signified large scale multicentre national trial in China was feasible (Figure 3).⁹ When MRD-directed arm was compared with non-MRD-directed arm, it also showed significant improvement of EFS, 82.4% vs 78.3%. With the extended protocol in Hong Kong before the new study opened, we recruited 221 patients in total. The 5-year OS and EFS was excellent, at 93% and 87% respectively.

Figure 3 Overall survival, event-free survival and cumulative incidence of relapse of all patients in CCLG 2008 protocol (Data from whole cohort).

CCCG 2015

Hong Kong participated in the second multi-centre national study since 2015. The study protocol was modified from St Jude Children's Research Hospital Total XV for children with newly diagnosed ALL. Up till now, more than 5000 patients were recruited, and the preliminary outcome data was comparable with major series worldwide. The study is still ongoing and we hope with the advancement in MRD-directed therapeutic approach, this would positively reflect in the survival data.¹⁰

Finally, we summarised the 5-year OS of HKALL-93, HKALL-97, ALL-IC-BFM 2002 and CCLG 2008 were as follow: 78.9%; 85.9%; 88.0% and 93.1% respectively (Figure 4). The 5-year EFS were 60.3%; 78.3%; 79.7% and 87.1% respectively (Figure 5). The data showed improvement in quality of management of childhood ALL in Hong Kong.

Figure 4 Overall survival of HKALL-93, HKALL-97, ALL-IC-BFM 2002 and CCLG 2008 protocol (Data include only Hong Kong patients).

Figure 5 Event-free survival of HKALL-93, HKALL-97, ALL-IC-BFM 2002 and CCLG 2008 protocol (Data include only Hong Kong patients).

Continuation of International Collaboration

After we participated in the mainland ALL studies since 2008, we did not stop our international collaboration. We continued to participate in some large international studies of rare ALL subtypes. The Interfant 1999 and 2006 studies were the largest international studies in the world on the ALL of infants, i.e. <1 year. This group of patients carries the poor prognostic genotypes, MLL gene rearrangement, and has inferior survival outcomes even with intensive chemotherapy. Randomised studies on different chemotherapy arms were conducted to test the appropriate treatment approach.^11,12 Another uncommon subtype of ALL with poor outcome is Philadelphia chromosome positive ALL. Two large international studies were conducted in the past 10 years and Hong Kong group also participated in these studies.^13,14 We continue to participate in the most recent EsPhALL 2017 Study.

Pharmacogenetics in Chinese Patients

Asian population is observed to have lower tolerance to some chemotherapeutic agents, in particular mercaptopurine. Genetic variants between Caucasians and Chinese populations play a role in modifying the dosage of chemotherapy. Namely thiopurine S-methyltransferase (TPMT) diverts 6-mercaptopurine, which is a key chemotherapeutic agent in treating ALL, into inactive metabolites. Thus, TPMT deficiency plays an important role in pathogenesis of thiopurine-induced leukopenia. However, in Chinese population, TPMT variants in Asian population is not common (2.3% in Asian vs 6-11% in Caucasian population). In contrary, the more common genetic variant is Nudix Hydrolase 15 (NUDT15). It has a much stronger association with thioguanine-induced leukopenia in Chinese population. A gene-dose effect was also seen. With the clinical relevance of NUDT15 testing in local Chinese patients, we advocated prospective NUDT15 testing together with TPMT genotyping routinely for all ALL patients. Dose recommendations and modifications can be guided by NUDT15 / TPMT genotyping results.¹⁵ Pharmacogenetic study in dose modifications may be applicable to avoiding vincristine associated neuropathy, anthracycline-related cardiotoxicity or L-Asparaginase induced pancreatitis. Further studies are needed to confirm the value of pharmacogenetics in these aspects.

Long-term Survivorship of ALL

With the improvement in event-free survivals of childhood ALL, the number of long-term survivors is increasing. This is a large area of research potential warrants further development in Hong Kong.

Although the survival of children with cancers significantly improves in the past decades, mortality of long-term survivors remains higher when compare with age-matched general populations. The long term adverse outcome of the patient cohort is prospectively being kept track and monitored. Different aspects of long term adverse effects are also studied in various long term follow up studies.

In ALL, anthracycline is one of the major chemotherapeutic agents to treat ALL, assessing the long-term non-cancer morbidity and mortality, in which subclinical cardiovascular dysfunction may be one of the areas. This may be an early manifestation of cardiac damage in long term survivors.

Li et al assessed 97 leukaemia survivors in term of diastolic wall strain and myocardial stiffness, they found that adult survivors of childhood leukaemia, despite the preservation of left ventricular ejection fraction, there was an increased in left ventricular wall stiffness and was associated with myocardial fibrosis and impaired left diastolic function.¹⁶ With the increase in number of cancer survivors, subtle or subclinical major organ dysfunctions is one of the major areas that warrants further studies.

Future Direction

Although the event-free survival rate of standard risk / low risk ALL is approaching 90%, there are still around 10%-15% of children suffer from relapse of ALL. For early relapse of ALL or ALL run in a refractory course, the prognosis was very poor even with haematopoietic stem cell transplantation.¹⁷ Although a number of therapeutic approaches are emerging to tackle these difficult conditions, the chance of survival remains grave. We have to work on this direction and tackle this difficult condition with international / regional collaborations, participating in national-wide or multi-centres study so as to maximise the chance of survival of children with refractory or relapsed ALL. Immunotherapy as bridging salvage therapy for refractory leukaemia has been approved by drug regulatory authorities, blinatumomab and inotuzumab ozogamicin as target therapy. In recent years, chimeric antigen receptor-T (CART) cell therapy is the most promising treatment for the relapsed/refractory ALL. However, the FDA approved product is at an extreme high cost, USD 0.47 million, which is not affordable to most patients. Future research for other methods of CART therapy is actively investigated in other centres.

Conclusions

This article reviews the progress and achievement in management of childhood ALL in Hong Kong over the past 35 years. With the kick start of Hong Kong Children's Hospital, a dream of several generations of paediatricians, this serves an optimal platform for incorporating research in clinical practice, collaborations with different oncology groups, participating or leading national / regional-wide clinical or basic science researches. The ultimate aim is to benefit the children who suffer from cancers in Hong Kong and nearby regions.

Conflict of Interest

The authors have no conflicts of interest to disclose.

Acknowledgement

We express most sincere thanks to Children Cancer Foundation for the funding support for various research studies in the past 20 years.

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