Table I. Country-wise responses to questions regarding the diagnosis, therapy and follow-up of a 15-year-old girl. Diagnostic tools at diagnosis Ovarian tissue preservation Prognostication and initial therapy Definition of CR and actions upon accomplishment Management of long-term follow-up Brazil

CBC, PB and BM smears

IP

Cytogenetics

qPCR or FISH

CSF cytospin analysis

Specialised analyses usually outsourced

Not available

NCI stratification

CNS status

LR and HR rearranged

MRD response D15/D19

Pre-phase with prednisone with IT. Then Brazilian protocol GBTLI with a VCR, DNR, L-ASAP backbone plus MTX IT

Blast cells on BM smear less than 5% and signs of peripheral blood count recovery

MRD response end induction to HR stratification, qPCR intended, but to be replaced by FCM

MRD positive at end of consolidation phase defines alloHCT

Onco-haematologist monthly in first 6 months; bi—monthly in second semester. Every 3 months in second year. Every 6 months in third year tapering to annually.

Endocrinologist, cardiologist, ophthalmologist, dentist, gynecologist schematised

Others professionals on demand

India

CBC, PB and BM smear and a LP

IP

Cytogenetics

FISH

qPCR, including for Ph1 chromosome

Specialised analyses not available in most centres

Though cryopreservation facilities are available in selected centres, expertise in oocyte cryopreservation methods are very limited and cost-intensive

Paediatric-inspired ALL prognostication and treatment in the AYA group

She will receive the InPOG-ALL-15-01 (Intermediate risk) with protocol with a VCR, DNR, L-ASAP backbone plus MTX IT

BM examination with adequate cellularity and <5% myeloblasts with no lymphoblasts, absence of blasts in CSF

MRD by BM. In Ph+ ALL, MRD by qPCR is done additionally.

Patients with poor prednisolone response, CNS disease, post-induction and HR transition to the HR protocol

Controls every 3 months for the first 2 years, every 6 months between the 3rd and 5th years, and annually thereafter. Long-term toxicities and late effects are monitored by clinical evaluation, with a focus on musculo-skeletal challenges in the near-term followed by metabolic syndrome, endocrine, and cardiac effects on longer follow-up Ireland

CBC with blood smear

BM aspirate for

Cytomorphology

IP by eight-colour FCM

Cytogenetics, FISH and SNP array

BM trephine biopsy

histology and immunohistochemistry)

MRD assessment by RQ-PCR (Ig/TCR)

TPMT genotyping

Oocyte cryopreservation possible

NCI—HR pre-B ALL.

Initial treatment allocation will be following risk-directed UKALLK 2019 Interim Guideline with VCR, DNR, L-ASAP (pegylated) backbone plus MTX IT

MRD monitoring has redefined remission in ALL. Further stratification will be by cytogenetic risk and MRD level at D29 and recovery from consolidation at week 14.

After MRD transition to either UKALLK 2019 regimen B (LR) or regimen C (HR), i.e. augmented BFM

Transition into a dedicated AYA Cancer Unit for survivorship/long-term follow-up Mali CBC, blood film and bone smear for morphological evaluation Not available

Age, leukocyte count, bulky disease, CNS signs, response to pre phase steroids

French-African Pediatric Oncology Group Protocol

4 drug VCR, DNR, L-ASAP backbone plus MTX IT

BM assessment at D 42: Blast cells on BM smear less than 5% concomitantly with a neutrophil count more than 1 × 109/l and a platelet count of more than 100 × 109/l.

Intensification with repeated 4-drug regimen plus high-dose MTX IV

Control with clinical review and CBC every 2 months for the first year after maintenance therapy, every 3 months for the second and third year and then every year until age 18.

She will be referred to adult haemato-oncologist

Tanzania

CBC

PB smear FCM

CSF cytospin

BM analysis only if PB smear or flow non-diagnostic

Not available

Age; African ethnicity; highest pre-treatment white cell count; ALL cell subtype; Bulky disease, CNS involvement & response to treatment of same; testicular involvement; Response to pre-phase steroids; D28 MRD analysis (FCM)

UKALLK 2003 plus steroid pre-phase based cytoreduction (PEG asparaginase replaced by L-ASAP due to cost; triple IT therapy instead of monotherapy)

Assessment at Remission Induction D28:

MRD less than 0·1% sensitivity: continue current treatment

MRD 0·1–5%: escalate to UK ALL2003 regimen C treatment;

MRD <5%: palliate with maintenance or oral etoposide/cyclophosphamide treatment for B-cell; continue to Augmented Consolidation for T-cell.

Assessment at end of Augmented Consolidation (where RI MRD was positive)

MRD-negative: continue treatment

MRD-positive: palliate

Maintenance treatment given at shared cared sites. Follow-up off treatment every 3 months X2 years and 6 months X3 years and annually thereafter - with clinical review and CBC. Shared care sites report on children at weekly virtual meetings with National Hub.

No other special investigations offered routinely

Thailand

CBC, blood smear

BM aspiration for morphology

BM FCM for AML, ALL

BM cytogenetics

BM core biopsy

BM RT-PCR for BCR–ABL1 P190 and P210

Not routinely done

Ph-negative ALL:

VHR paediatric-based ALL protocol (ThaiPOG-ALL-13-3)

VCR, DOX, L-ASAP backbone plus MTX IT

Ph1+ ALL:

Ph+ ALL protocol (ThaiPOG-ALL-1304)

VCR, DOX, L-ASAP backbone plus triple ITimatinib 340 mg/m2

CR:

BM lymphoblast is less than 5% by morphology and FCM

Indications for HSCT:

Post-induction assessment D29 shows either induction failure, hypodiploidy cytogenetically or Ph1+

CBC

1st year: every 1–2 months

2nd year: every 2 months

3rd year: every 3 months

4th year: every 6 months

5th year and later: yearly

Optional as clinically indicated:

1st year: BMA, BUN, Cr, AST, ALT, echo, EKG, LP

Reproduction aspect: avoid pregnancy within the first 6-month period following chemotherapy

ALL, acute lymphoblastic leukaemia; alloHCT, allogeneic stem cell transplantation; ALT, alanine aminotransferase; AML, acute myeloid leukaemia; AST, aspartate aminotransferase; AYA, adolescents and young adults; BFM, Berlin–Frankfurt–Münster; BM, bone marrow; BMA, bone marrow aspirate; BUN, blood urea nitrogen; CBC, complete blood count; CNS, central nervous system; Cr, creatinine; CR, complete remission; CSF, cerebrospinal fluid; D15, day 15; DNR, daunorubicine; DOX, doxorubicine; EKG, electrocardiogram; FCM, flow cytometry; FISH, fluorescence in-situ hybridisation; HR, high risk; HSCT, haematopoietic stem cell transplant; Ig/TCR, immunoglobulin/T cell receptor; IP, immunophenotyping; IT, intrathecal; IV, intravenous; L-ASAP, L-asparaginase; LP, lumbar puncture; LR, low risk; MRD, minimal residual disease; MTX, methotrexate; NCI, National Cancer Institute; PB, peripheral blood; Ph, Philadelphia; qPCR, quantitative polymerase chain reaction; RI, reduced intensity; RT-PCR, real-time qPCR; SNP, single nucleotide polymorphism; TMPT, thiopurine methyltransferase; VCR, vincristine; VHR, very high risk.

Tackling ALL in childhood and focusing on low- to medium-income countries entails the most complicated issues in this series, and choices and omissions had to be made in preparation for the receival of the contributions. Thus, reflecting upon the heterogeneity in health systems and medical traditions, the contributions herein are very different in length, reflecting the status of therapy as well as the diverse history by which the presently employed cytoreductive protocols were arrived at in the widely different settings. Regarding the latter, we have chosen Brazil to show how protocols have evolved concurrently with the expansion of multicentre collaborations. Along these lines, Ireland was chosen as an example of a high-income country to illustrate what might be considered as a gold standard of approach to a patient like the present one.

Moreover, the purpose of these endeavours is to give the reader the present state of caring for such patients and not to look forward to what might happen in the future. This could perhaps be a subject for a separate wider perspective contribution. Furthermore, space constraints do not allow us to look at an array of other issues such as biobanking, the existence and extent of registries, and the inclusion into centres of excellence for the different locations. We nevertheless hope that this exercise brings home to practicing clinicians that there is more than one ‘right’ way to manage patients. The case history and questions posed to the experts are shown in Boxes and , and their responses are summarised in Table I. There are always things to learn from the way other experts practice. Moreover, there is much to learn from our colleagues working in strained economies. Overall, this exercise teaches us that we should be nuanced in our perception of how and why treatments differ worldwide.

The perspective from Brazil (MLM Lee) Q1 diagnosis

Epidemiological studies have demonstrated that ALL has a higher incidence rate in the Latino population with outcomes in both paediatric cases and adults drastically worse than international standards. The underlying cause of these observations is unknown, although several hypotheses have been postulated including disparities in socioeconomic status, environmental risks, inherited genetic mutations, or a combination of factors.1, 2

In Brazil, the geographical distribution of ALL is of particular interest. The overall age-adjusted incidence rate (AAIR) of ALL in children is about the same as in Non-Hispanic White Americans (35·2 per million × 35·6 per million); the highest incidence rate (56·6 per million) is observed in children of Native American ancestry in the Brazilian North Region (Brazilian Amazon region).3, 4 In contrast, along the Atlantic coast in Brazil, the incidence of ALL ranges from 21·6 to 43·6 per million.1

The Brazilian Cooperative Trials for Treatment of Acute Lymphoblastic Leukemia in Children (Brazilian Pediatric Acute Lymphoblastic Leukaemia Cooperative Treatment Group, GBTLI) was initiated by Brandalise, Odone, and Pereira in 1980, and six consecutive trials were performed (GBTLI LLA 80, 82, 85, 93, 99, 2009 studies). Since then, significant advances have been made in paediatric ALL in our country, from improvements in diagnostic tools to a progressive increase in survival curves, from an event-free survival (EFS) of 24·8% ± 3% and an overall survival (OS) of 34·1 ± 3·9% in GBTLI LLA 80 to 66·1 ± 1·7% and 70·0 ± 1·6% in GBTLI LLA 93.5, 6

In general, presently patients with the disease will be handled in an inpatient setting, given that Brazil is a low-income country and intensified support for patient and family is usually needed.7 A recent survey realised by the Brazilian Pediatric Acute Lymphoblastic Leukemia Cooperative Treatment Group (GBTLI LLA) (P. Godinho, unpublished data) found that 97·4% of services registered in the Brazilian Society of Pediatric Oncology (SOBOPE) for the treatment of paediatric ALL perform cytomorphological analysis of bone marrow as well as immunophenotyping. In addition, 92·2% perform cytogenetics and 87% have access to some type of diagnostic molecular biology [real-time quantitative polymerase chain reaction (RT-qPCR)] or fluorescence in-situ hybridisation (FISH). However, 24·6% of these replied that neither ETV6–RUNX1 rearrangements nor PBX1–TCF3 were routinely performed. Another relevant fact reported is that of the 77 registered centres in SOBOPE that responded to the survey, only 23 (30%) perform the diagnostic examinations in an in-house setting, implying that there is a great challenge in a country of continental dimensions such as Brazil in terms of dissemination of the relevant methodologies.

Considering the case in question, the tools that are usually performed in Brazil to diagnose acute leukaemia include cytologic examination of the bone marrow (BM) and peripheral blood (PB) and immunophenotyping is mandatory. Conventional cytochemistry is not routinely required, but may be helpful in some Brazilian services.

In addition, conventional cytogenetics with high-resolution G-banding is the gold standard, and molecular genetics (qPCR or FISH) to investigate prognostically important fusion genes (ETV6–RUNX1, TCF3–PBX1, BCR–ABL1) is recommended for all cases. In contrast, the investigation of Philadelphia (Ph)-like ALL (also seen at higher rates in Latinos), intra-chromosomal amplification of chromosome 21 (iAMP21) and IKAROS deletions are not performed routinely considering the age of the patient.1, 8, 9 Neither is the investigation of GATA3 single nucleotide polymorphisms, which are also increased in Philadelphia chromosome-positive (Ph+) Hispanics.10

Prior to chemotherapy, standard evaluations include blood chemistry profiles, viral serology, echocardiography and abdominal ultrasound. In addition, dental examination is recommended, but not performed in all centres.

Q2 Fertility preservation

Counselling about preserving one's fertility should be offered to all patients.11 Despite that, in the Brazilian Public Healthcare System, which is responsible for the treatment of the vast majority of patients, female fertility preservation is not widely available at the present time. Moreover, even within private services, this option is not easily accessible for nearly all patients.

Q3 Prognostication and induction

According to National Cancer Institute (NCI) risk stratification, this patient has the initial risk classification of high risk (both by age and initial white-cell count). The outcome for older children, especially adolescents, has improved significantly over time. Five-year survival rates for adolescents aged 15 to 19 years increased from 36% (1975–1984) to 72% (2003–2009).12 The risk stratification for B-cell precursor leukaemia based on NCI criteria was introduced in Brazilian Protocol GBTLI LLA 99 and continues in GBTLI 2009.

Given that it has become clear that in adolescents and young adults (AYA) ALL has superior survival when treated with paediatric-based regimens, this has led to their adoption by an increasing number of adult centres.13-15 Unfortunately, in Brazil, one of the important features of the health system is that all patients older than 13 years of age will be referred to adult departments/centres, where treatment is often inadequate for this group of patients.

The strategies for cytoreduction/induction in Brazilian GBTLI protocols changed (GBTLI 80, 82, 83, 93, 99) from absence of a pre-phase, to the introduction of a pre-phase with prednisone (60 mg/m²/day × 7 days) and one methotrexate (MTX) IT administration in the latest study (GBTLI LLA 2009). Despite cytoreduction, the induction death rate in GBTLI 2009 (6·2%) was similar to that in the previous GBTLI study (GBTLI ALL 99: 6·7%) and higher than in GBTLI ALL 85 (2·6%) and GBTLI ALL 93 (3·2%), reflecting a more intensive induction phase.5

The two studies conducted in the 90s, GBTLI 93 and 99, included a total of 2 237 patients. These studies introduced the concept of modern childhood ALL therapy in Brazil, with the use of high-dose methotrexate (HDMTX), the intensification of post-consolidation therapy, the use of prophylactic central nervous system (CNS) radiotherapy just for the high-risk (HR) group, and a reduction in maintenance therapy regimen for 18 months. The complete cytogenetic response (CCR) rate observed was 95·7% and 92·1%, respectively, with an EFS and OS of 66·1% ± 1·7% and 70% ± 1·6% in GBTLI 93, and 67·9% ± 1·6% and 71·5% in study 99. Simultaneously, a reduction in death rates in complete remission (CR) from 7·5% to 4% was observed. Of interest, there was a significant improvement in the EFS for T-cell-derived ALL from 48·6% ± 5·8% in study 93 to 65·9% ± 4·1% in study 99. In GBTLI 2009, patients stratified as NCI low risk were assigned to receive either continuous 6-mercaptopurine (6-MP) and weekly MTX or intermittent 6-MP with intermediate-dose MTX, as maintenance treatment. The randomised trial comparing two different maintenance regimens for patients with LR ALL demonstrated that children treated in an intravenous (IV) MTX/intermittent 6-MP schedule had lower severe grades 3 and 4 of hepatic and haematologic toxicities and a lower death rate in CR (2%) than those receiving the standard continuous schedule (6%). Boys allocated to the intermittent regimen had significantly better EFS than those receiving the continuous schedule.5, 16

In 1994, an international partnership was initiated between Instituto de Medicina Integral Professor Fernando Figueira, a public paediatric hospital in Recife, and St Jude Children's Research Hospital. Thus, during the period from April 1997 to December 2002, patients were treated according to the St Jude Total XIIIB protocol. These actions led to a significant increase in survival from 47% to 63% over a 10-year period.17 From December 2005 to June 2015, the newly diagnosed ALL patients were treated using the uniform guidelines of the Recife ALL pilot study (RELLA-05). A five-day prednisone pre-phase was introduced with the objective of initial clinical stabilisation of the patient; intrathecal (IT) therapy was postponed to the fifth day after the beginning of treatment, thus avoiding an invasive procedure in the period of greater clinical instability and minimising traumatic punctures with consequent contamination by blasts.18

Q4 Definition of CR and follow-up

In the current Brazilian protocol, CR is defined by the absence of disease-related symptoms, less than 5% of blasts in a BM smear (confirmed by immunophenotyping analysis), and signs of PB count recovery at the end of the induction phase. The GBTLI LLA 2009 protocol introduced several changes to the previous study, defining distinct timepoints to measure treatment response. The blast count on D8 was incorporated as a risk-stratifier; the evaluation of minimal residual disease (MRD) by flow cytometry (FCM) on day 15 (D15) and by RT-qPCR on D35 was introduced as standard for risk stratification, focusing on the speed of response as an important prognostic factor establishing the concept of fast responder and slow responder. D15 fast responder MRD < 0.01% defines a very-low-risk group pre-B ALL (8·2%), who will receive a less intensive induction. In contrast, the slow responder group displays an MRD ≥ 10% (21·5%), which will be allocated to more intensive therapy [detailed in the GBTLI LLA 2009 Nov 2018 report (unpublished)]. At the end of induction (four weeks of chemotherapy), patients with MRD levels ≥ 10−3 were planned to be referred to blood and marrow transplantation (BMT). However, since MRD by PCR was not feasible in most paediatric centres, this option could not be carried out stringently, and in the upcoming study (GBTLI LLA 2021), MRD will therefore be performed by FCM.

Q5 Long-term follow-up

Brazilian healthcare is notoriously heterogeneous in quality. Structured and well-equipped cancer centres are located mostly in the southeastern and southern states. The management of survivors of childhood cancer is even more disparate: although most of the country struggles with cancer screening and detection, some regions have pioneered cancer survivorship programmes, offering multidisciplinary long-term follow-up since the late 90s, and in this context, patients have access to all medical specialties, i.e. endocrinologist, cardiologist, ophthalmologist, gynaecologist, dentist, and others specialist professionals without additional cost. Thus, in most of the Brazilian paediatric oncology services, only the paediatric haematologist/oncologist continue with this follow-up.19 The clinical returns are performed monthly in the first six months, bi-monthly in the second semester; every three months in the second year, every six months in the third year and then yearly until 10 years off treatment.

We used to refer the patients to a gynaecologist to choose the best contraceptive method in an effort to avoid pregnancy during the first year after treatment was completed. However, being a low-income country with different social-cultural issues, it is not uncommon that patients become pregnant soon after treatment is completed.

The perspective from India (VS Radhakrishnan and M Chandy) Q1 Diagnosis

India has a young population and a large proportion, 44%, belong to the 0–24-years-old age group [India, in The World Factbook (Internet). CIA.gov. 2021 (cited June 9, 2021_; available from: https://www.cia.gov/the-world-factbook/countries/india/#people-and-society]. It is estimated that annually 75 000–100 000 individuals in this group are diagnosed with cancer, and leukaemias are the most common, accounting for more than 27% of all diagnosed cancers.20 A low middle income country (LMIC) economy with a ‘real (per-capita) gross domestic product (GDP, estimated 2019)’ of $ 6700, an annual healthcare expenditure less than 4% of the GDP, a physician density of 0·86 per 1000 population, and a limited number of trained oncology professionals, India has significant limitations in the delivery of optimal cancer care for all.21 Despite improvement in healthcare services in the past few decades, more than 80% of Indians do not have healthcare insurance. A significant proportion of the insured individuals have limited coverage and often require out-of-pocket expenditure for cancer care.22 The situation is often such that low-income households, mostly uninsured, very often resort to distress means to finance cancer care.23 In the absence of a well-structured healthcare system, an organised referral pathway for cancer care is nearly non-existent. The care of the young with cancer, leukaemia in particular, is often a story of ‘missed opportunities’. A combination of factors is responsible for this and includes, among others, late presentation with a high tumour burden, delayed diagnosis, treatment denial or abandonment, higher treatment toxicity due to undernutrition and poor supportive treatments, and suboptimal care.24 There are only a limited number of tertiary-care centres with the expertise to treat ALL of the young in organised treatment protocols, in a multi-disciplinary environment.

There is a paucity of data from India, and a majority are retrospective series from tertiary centres. Regimens used in childhood ALL are predominantly western paediatric non-contemporaneous protocols or their modifications, and commonly include MCP-841 and Berlin–Frankfurt–Münster (BFM)-95. Based on the CONCORD statement (global surveillance of trends in cancer survival), the five-year net OS rate in children with ALL in India was estimated to be in the range of 54–75%.25 A recent review of retrospective data of childhood ALL from various Indian tertiary care centres reported an OS and EFS in the range 45–81% and 41–70% respectively.26 In the AYA group, treatment regimens have varied between paediatric-inspired protocols (BFM-based), increased-dosage cyclophosphamide, vincristine (VCR) and daunorubicin (DNR) (hyper-CVAD), or adult protocols (e.g., GMALL). A systematic review of AYA ALL reported the five-year OS rates from different Indian retrospective series to be in the range of 38–58%.27 Multicentre collaborative efforts are attempting to address several real-world clinical questions encountered by haematologists/oncologists treating ALL of the young in India, and early results are promising.28, 29 Many of these treatments are possible in India due to the availability of generics, and biosimilar preparations of drugs like L-asparaginase (L-ASAP) and rituximab. However, challenges remain.30, 31

Our institution is a not-for-profit trust-based comprehensive cancer centre located in eastern India, and we are a regional referral institution. Referral pathways for cancer care in most of India are a work-in-progress, and are currently based on geographical access, payment patterns, and treatment experience and reputation of the centres. This is very relevant in the care of the young, with the added dimension of significant emotional challenges associated with a leukaemia diagnosis in the family.32 Payment patterns in our institution are predominantly out-of-pocket with generous subsidies or financial assistance provided on named-patient basis, by philanthropic initiatives by different non-governmental and government organisations.

Our institution has the full complement of in-house diagnostic and imaging services, as applicable to a tertiary-care comprehensive cancer centre treating haematological and solid-organ cancers. They are compliant with country-specific standards for accreditation and are enrolled in national and international external quality assessment (EQAS) programmes. For this patient, apart from ordering for a complete blood count (CBC), peripheral smear, serum chemistries [including lactate dehydrogenase (LDH)], electrolytes, renal and liver functions, etc., coagulation panel, serology (HIV-1&2, HBsAg, hepatitis core antibody and anti-HCV antibodies), we would request for a BM aspirate and trephine biopsy, and a lumbar puncture (LP) (with IT chemotherapy). Further, we would request BM aspirate immunophenotyping (including ploidy), karyotyping, and FISH-based cytogenetic testing to look for recurrent cytogenetic abnormalities. In addition, the molecular laboratory has the clinical testing facility for PCR-based detection and quantification of entities such as Philadelphia chromosome-positive (Ph1+) ALL. The MRD platforms, using FCM and qPCR for BCR–ABL1, are used routinely in the management of ALL at our centre. In the research domain, high-throughput sequencing-based approaches are being used in ALL and are occasionally accessed clinically on a case-by-case basis (e.g., Trusight®, New York, NY, USA; myeloid panel for early T-cell precursor ALL). The turnover time(s) are within hours for routine laboratory investigations, while the BM morphology is reported within 72 h for aspirates and five days for biopsy. FCM reports are generally available within 48–72 h, while cytogenetics reports take 7–10 days for karyotyping and 3–5 days for the FISH panel. Routine PCR-based molecular studies, like BCR–ABL1 reporting, take around 10 working days.

In the rest of India, facilities for comprehensive in-house laboratory testing for malignant disorders are few and far between. In most centres, many of the afore-mentioned tests are outsourced to private laboratories, or to referral institutions across the country. Many laboratories are compliant with country-specific accreditation norms, a few are also compliant with international accreditations and EQAS programmes. However, these cannot be generalised for all labs in the country, and India faces significant challenges on this account.33 Turnover times vary from days to weeks for outsourced tests and may potentially affect real-world clinical management of patients. This challenge is identified as a felt need in the country and regional hubs for testing are being mooted by the Government and professional organisations.

Q2 Fertility preservation

In our country, most patients present with a heavy disease burden at a late stage and the immediate priority for most haematology/oncology clinicians would be to stabilise the patient and begin cytoreduction at the earliest. A majority of clinicians skip discussions on fertility preservation due to some of the following reasons: lack of patient and physician awareness, lack of time to discuss in a busy clinic, availability of onco-fertility expertise, lack of an organised system for referral, additional costs of care, anticipated delay in initiating cancer-specific treatment, and prioritisation of cancer treatment by patient and family stakeholders.34-36 At our centre, most clinicians do mention fertility-related issues related to treatment during the counselling process. We do not have an in-house facility for the same. Though sperm cryopreservation facilities are available, expertise in oocyte cryopreservation methods is very limited and cost-intensive in our region. Further, very few patients prioritise this aspect of clinical care due to cost constraints and anticipated delays in initiating cancer treatment.

Q3 Prognostication and induction

This patient, who belongs to the AYA age group (15–40 years), in India is likely to be treated by a paediatric haemato-oncologist, adult haematologist, medical oncologist, or occasionally by clinicians who have undergone brief training periods in cancer care at tertiary centres. This would essentially depend on the geographic location of the centre that the patient reports to. Most referral institutions in the country are now transitioning towards paediatric-inspired protocols for the treatment of ALL in the adolescent and young adult group of patients. A recent systematic review and large retrospective studies indicate this transition in treatments.27, 37 This has also been facilitated by an increasing crosstalk and collaboration occurring between adult and paediatric haemato-oncology physicians within and outside their respective institutions.

We would first stabilise the patient with standard tumour lysis prophylaxis approach, inclusive but not restricted to hydration, allopurinol and/or rasburicase. We would prognosticate the patient-based established and ongoing paediatric-inspired ALL treatment protocols appropriate for pre-B ALL. She is likely to receive the In POG-ALL-15-01 protocol which is an ongoing multi-centre national clinical trial in India for childhood ALL. She will be stratified in the intermediate risk group based on her age and high total leucocyte count (TLC, >50 × 109/l). The protocol includes a corticosteroid pre-phase, and the tyrosine kinase inhibitor (TKI) used in this protocol for BCR–ABL1-positive ALL is imatinib.

With growing experience, our group is increasingly using paediatric-inspired ALL protocols in the AYA age group, up to the age of 40 years. This has occurred over the last 5–6 years, with a clearer understanding of the nuances of delivering more intensive therapy, which includes scheduling of L-ASAP, increased supportive care needs and higher costs of hospitalisations, among others. Availability of a reliable MRD platform, MRD-based treatment stratification, intensive-care support, and greater interaction with the paediatric haematology group have further facilitated this transition. Other paediatric-inspired protocols in common use in India are adaptations from non-contemporaneous western protocols.37, 38 A reduction in relapse and ALL-related mortality has been observed at an incremental cost of treatment-related toxicity. It would be worthwhile to mention here that an early protocol used in India, MCP-841, continues to be used in some centres in India, especially in institutions where cost constraints and logistic challenges of delivering intensive therapies are of significant clinical and administrative concern.27, 39

Q4 Definition of CR and follow-up

At our institution, post-induction CR (approximately by D35) is defined by all the following: complete recovery from symptoms and physical findings at presentation, haematological CR on PB (± recovery of blood counts) examination, morphological CR on BM examination with adequate cellularity and <5% myeloblasts with no lymphoblasts, absence of blasts in cerebrospinal fluid (CSF), and where appropriate, resolution of testicular involvement/mediastinal mass documented by the modality of imaging, as at diagnosis. MRD monitoring by BM aspirate FCM is undertaken after the induction (in all patients) and consolidation (in most patients) phases of therapy. In Ph+ ALL, MRD by qPCR is done additionally. Patients with poor prednisolone response, central nervous system (CNS) disease, post-induction MRD-positive status, and HR cytogenetics [MLL/KMT2A rearranged leukaemia, low hypodiploidy, t(17;19) (q22;p13) (TCF3–HLF), intrachromosomal amplification of chromosome 21 (iAMP21) and t(9;22) (q34;q11) (BCR–ABL1)] transition to the HR protocol.

Allogeneic haematopoietic cell transplantation (alloHCT) in this setting is offered for patients at higher risk of relapse, owing to HR cytogenetics (low hypodiploidy, MLL/KMT2A rearranged), persistent MRD status (post-consolidation) or failure of remission induction. In patients with Ph+ ALL, alloHCT is now offered only when MRD is >10−4 post interim maintenance. We use a total body irradiation (TBI)-based myeloablative conditioning regimen and have the requisite expertise in matched related donor and alternative donor transplantations. There is a paucity of data regarding transplant outcomes in ALL in the AYA group from India. The rate of uptake of alloHCT in India is poor owing primarily to cost constraints followed by fear of side-effects. Available retrospective data are suggestive of a one-year EFS of 64·8% in the childhood ALL group, which included teenagers.40 In the Ph+ ALL setting in the AYA age group, overall EFS at four years was in the range of 36%.41 With the formation of the Indian Society of Blood and Marrow transplantation (ISBMT) recently and a registry programme preceding it, we hope to see consolidated alloHCT outcomes in ALL for different age groups soon enough.

Q5 Long-term follow-up

Maintenance therapy in ALL is hospital-based in our centre. On occasions, where patients come from distant geographic locations, and with the ongoing SARS-CoV-2 pandemic, clinicians liaise with local healthcare facilities and use teleconferencing facilities to manage patients. Hospital-based follow-up involves monthly visits for physical examination, blood tests, growth monitoring, clinical disease assessment, drug toxicity management, dose optimisation of 6-mercaptopurine and methotrexate, and other-directed investigations. Post maintenance, the long-term follow-up strategy includes periodic review every three months for the first two years, every six months between the third and fifth years, and annually thereafter. This is the practice in most tertiary-care centres in India. Long-term toxicities and late effects are monitored by clinical evaluation, with a focus on musculo-skeletal challenges in the near term followed by metabolic syndrome, endocrine, and cardiac effects on longer follow-up.

Most patients do not opt for fertility preservation or cannot afford them. In our practice, we advise marriage or conception only after two years of cessation of all maintenance therapy. There are scanty data on long-term toxicities in ALL patients from India. Retrospective single-institutional studies, which used older treatment protocols in multiple cancer sites including ALL, report growth defects in 4·5–23% of patients, neurocognitive defects in 15%, metabolic syndrome in 6% and fertility-related challenges in 24·5% of patients.42-44 Only a multi-institutional systematic approach and data collection are likely to address the information deficit in this area.

The perspective from Ireland Q1 Diagnosis

In Ireland this young adolescent would be seen by her general practitioner in the first instance. Given her non-specific symptoms, namely five-month history of progressive fatigue with associated menstrual irregularities, she most likely would have been seen on a number of occasions in the primary-care setting before being referred to a paediatric hospital for further evaluation.

Although ALL is the most common cancer in individuals from birth to 21 years of age,45 it is still rare and its clinical presentation is usually of sudden onset, with the majority of patients presenting with a short history of fatigue or spontaneous bleeding. Therefore, it is not surprising that ALL was not considered early in her diagnostic pathway. It should also be remembered that AYA patients have a prolonged diagnostic pathway when compared with children and older adults despite having an increase in primary-care use.46 The reason for delay is most likely multifactorial involving non-specific symptomatology and low awareness of cancer occurrence in the AYA population by general practitioners and not solely related to late presentation of AYA with cancer to primary care or hospital setting.46

This 15-year-old girl would be transferred to the National Children’s Cancer Service at Children’s Health Ireland (NCCS/CHI), where all children and young adolescents (0–15 years and 364 days) with cancer in Ireland are referred for diagnostic and therapeutic planning.

Her initial blood diagnostic work-up would include full blood count, blood smear, blood immunophenotyping by eight-colour FCM, coagulation screen with fibrinogen, renal–bone–liver biochemistry profile (including LDH and uric acid), and viral serology (CMV, VZV, HSV and EBV) and immunoglobulins. Under general anaesthesia BM aspirate for cytomorphology, FCM, cytogenetic, FISH and single-nucleotide polymorphism (SNP) array together with trephine biopsy for histology and immunohistochemistry would be procured. If the diagnosis of ALL was made on the initial blood work-up, then LP for cerebrospinal fluid (CSF) cell count, cytospin and FCM with instillation of therapeutic IT chemotherapy would be performed at the same time as initial BM examination.

MRD assessment (BM) by qPCR of rearranged immunoglobin/T-cell receptor genes (Ig/TCR) and thiopurine methyltransferase (TMPT) genotyping would be requested.

Prior to commencing chemotherapy, baseline echocardiography, adolescent gynaecology consultation, pregnancy testing, and fertility counselling would be carried out. As the patient is under 16 years old, written informed consent will be required from the parents/legal guardian but she will be asked for her assent.

Q2 Fertility preservation

Ireland currently has no publicly provided fertility preservation programme for children and young adolescents with cancer. While oocyte freezing is available in the private sector, it is on an ad-hoc basis. Ovarian tissue cryopreservation in not available at the time of writing.

Presently, a feasibility study to establish a National Programme for Fertility Preservation in children, AYA (0–24 years) across NCCS/CHI and the Merrion Fertility Centre at the National Maternity Hospital (MFC/NMH) is being conducted. The study is funded (2020–2023) by the non-governmental organisation the Irish Cancer Society and it is anticipated that long-term funding for this programme will be allocated through our public health service providers, the Health Service Executive, in the near future.

Q3 Prognostication and induction

Her age (>10 years) places her in NCI HR and she will receive a four-drug induction consisting of dexamethasone, VCR, DNR and PEG-L-ASAP according to the risk-directed UKALLK 2019 Interim Guideline v1/NCRI UK-ALL 2011 (EudraCT number 2010-020924-22, version 7) protocol and will be placed on Regimen B. If she has HR cytogenetics (KMT2A gene fusions, low hypodiploid/near haploid, iAMP21 and t(17;19)(q23;p13)/TCF3–HLF) or fails to remit at D29 she will receive the same four-drug induction followed by Regimen C augmented consolidation. Further therapy will then be directed by post-consolidation MRD status.

For over four decades, Ireland has entered children and young adolescents into UK evidence-based randomised peer-reviewed ALL trials. All children and young adolescents with ALL in Ireland during the period 2003–2011 were entered into the UK-ALL 2003 protocol (EudraCT number 2007-004013-34) that turned out to be the first randomised clinical trial to show that stratification of treatment by molecular response improves outcome but also that treatment reduction was feasible for patients predicted to have a low risk (LR) of relapse.47, 48

Later, in 2021, ALLTogether1 [EudraCT number 2018-001795-38—a treatment study protocol of the ALLTogether Consortium (pan-European) for children and young adults (1–45 years of age) with newly diagnosed ALL] will be open for recruiting and NCCS/CHI will act as the trial-coordinating centre for all AYA with ALL across Ireland.

Q4 Definition of CR and follow-up

As MRD monitoring has redefined CR in ALL, stratification by early cytomorphologic response has been abandoned in patients who have an adequate MRD signal at D29 in the current protocol. She will be further stratified by cytogenetic risk and MRD level at D29 and recovery from consolidation at week 14.

Scenario 1: She will be assigned to MRD LR if her MRD level is <0·005% (cytogenetic intermediate risk—all others) or <0·1% (cytogenetic good risk—ETV6-RUNX1 and hyperdiploidy) at D29 and will receive consolidation according to Regimen B. No further MRD assessment will be required.

Scenario 2: She will be assigned to MRD risk if her MRD level is ≥0·005% (cytogenetic intermediate risk—all others) or ≥0·1% (cytogenetic good risk) at D29 and will receive augmented BFM consolidation according to Regimen C. Further MRD assessment will be following count recovery from consolidation at week 14. If her MRD level is <0·05% she will continue on Regimen C but if it is >0·05% she would be deemed MRD HR and follow advice for induction failure.

Q5 Long-term follow-up

She will be 17 years old when she has finished maintenance therapy and for the first year thereafter she would be seen every three months in a long-term follow-up clinic at NCCS/CHI. At 18 years of age, she would transition to one of our eight designated adult cancer centres (closest to where she lives) for further long-term follow-up care. However, from 2022 she would transition to one of the dedicated Adolescent Young Adult Cancer Units (16–24 years) currently being developed in accordance with our National Cancer Strategy (2017–2026).

If she wishes to become pregnant, she would be referred for family planning consultation that would be organised by personnel between NCCS/CHI (AYA cancer clinician, AYA oncology nurse) and MFS/NMH (fertility specialist and specialised nurse).

The perspective from Mali Q1 Diagnosis

Our paediatric oncology centre is located in Gabriel Touré Teaching Hospital, Bamako, in