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Translation of Cure for Acute Lymphoblastic Leukaemia to all Children

2002; Wiley; Volume: 118; Issue: 4 Linguagem: Inglês

10.1046/j.1365-2141.2002.03670.x

1365-2141

Tim Eden,

DNA Repair Mechanisms

Long-term cure rates and overall survival for children with acute lymphoblastic leukaemia (ALL) is at worst 60–65% and at best in excess of 80% in the resource-rich more developed countries (Eden et al, 2000; Schrappe et al, 2000a). The key components of successful ALL therapy have emerged during the last 3–4 decades and include a sustained and intensive induction phase to reduce initial tumour load with three or four systemic agents, some therapy early in the course of treatment directed towards the central nervous system (CNS), post-remission induction consolidation, more sustained CNS-directed therapy (which can now be delivered without cranial irradiation), later intensification (tailored to prognostic risk grouping) and then a phase of continuing therapy lasting at least 2 years (Chessells et al, 1995; Burnett & Eden, 1997; Gustafsson et al, 1998; Nachman et al, 1998; Pui & Evans, 1998; Riehm et al, 1998; Hann et al, 2000). The emphasis is on a sustained therapy, adapted to the patient's risk of relapse, as defined by initial presenting features and speed of response to therapy, and avoidance of delays or gaps in therapy as far as is possible ( Schrappe et al, 2000b). Early cytoreduction, as measured by peripheral blood or marrow clearance and/or the application of molecular and cytogenetic techniques to measure minimal residual disease, are increasingly being applied as indicators for therapeutic change (Schrappe et al, 1996; Steinherz et al, 1996; Coustan-Smith et al, 1998; van Dongen et al, 1998). The role of immunophenotyping (Hann et al, 1998), and cytogenetic and/or molecular analysis (Chessells et al, 1997; Rubnitz et al, 1997) have been reviewed and related to outcome (Hann et al, 2001). In the latter UKALL XI study, treatment allocation was not determined by risk factors but multivariate analysis confirmed the dominant influence on prognosis of age, sex and presenting white cell count, with the latter being the single most significant predictor of outcome. The only other remaining significant predictors of outcome from all the initial presenting features were blast cell karyotype with high hyperdiploidy (> 50 chromosomes) being favourable, near haploidy (< 40 chromosomes) adverse, and the presence of t(4:11) translocation and abnormalities affecting the short arm of chromosome 9 both conferring poorer prognosis. Early response to treatment as measured by marrow clearance at d 8 was a very favourable feature while the small number of patients who did not achieve complete remission by the end of induction therapy had an extremely poor outcome. The clear message from all studies are that initial white count, age, sex and, indeed, disappearance of blasts from the blood and bone marrow are essential features to be collected and can predict the majority of relapses. All of the advances have only been possible with improved supportive care, including a stable, reliable and rapidly available supply of blood products, the recognition and control of infection plus shared information about drug toxicity. The most significant contribution has been the reduction of treatment-related deaths, for example the reduction reported by Hargrave et al (2001) from 9% to 2% in the Medical Research Council UK trials from 1980 to 1997 principally due to the reduction of infective mortality (bacterial sepsis, measles, pneumonitis). The recognition that bone marrow transplantation may only be required for a very selected, especially high-risk group of patients, usually only after relapse, has also reduced treatment-related mortality and financial cost without jeopardizing survival (Feig et al, 1997; Eden, 1999). All of these aspects have led to the assumption that to cure a patient with ALL appears to require a concentration of expertise, the use of expensive therapy and investigative techniques, i.e. there is a significant cost for cure, estimated in the USA to be approximately 100 000 dollars per patient per year of treatment, but it is argued with considerable justification that survivors, who have a higher rate of employment than their peers, will more than repay the costs by their subsequent contribution to society. However, the really sobering thought comes from the estimate that all of our efforts only manage to reach out to 15–20% of the world's population. The cost and complexity of treatment used in the industrialized world, combined with ‘educational and training’ constraints ‘preclude such treatment in less privileged countries’ (Ribeiro & Bonilla, 2000). It is estimated that in absolute numbers over five times as many children present with leukaemia and cancer each year in disadvantaged countries than in industrialized nations, and that the number of children is rising disproportionately in disadvantaged countries. As the traditional worldwide ‘killers’, malnutrition and infection, are beginning to decline especially in young children, the chronic conditions including leukaemia and cancer are becoming more important and will become even more so as causes of death and morbidity. What then can be done to help? Unlike in adults, where there is considerable variation incancer incidence around the world, in children the cumulative incidence for the first 15 years of life consistently lies in the range 1·0–2·5 per thousand, with age standardized annual incidence rates lying between 70 and 160 per million (Parkin et al, 1998). What does vary is the relative incidence of specific malignancies. In the white population of Western Europe, USA and Oceania, acute leukaemia accounts for approximately one-third of cancers in childhood with age standardized rates between 35 and 50 per million, with ALL constituting over 80% of the cases. Among American blacks, the relative incidence of acute leukaemia is lower at 25%, while in sub-Saharan Africa it is even lower with B-cell lymphomas predominating. The highest incidence has been recorded for Hispanics in California and in Costa Rica (Glazer et al, 1999). The major variation does relate to ALL rather than other forms of leukaemia. ALL has a higher incidence in affluent industrialized nations, especially the early childhood peak of precursor B-cell ALL, which accounts for approximately 70% of cases in white North European caucasians but accounts for less than 60% of cases in South African blacks and in Nigeria only 30%, where there is a relative and possibly absolute excess of T-cell ALL. Whether all of the variations in relative or absolute incidence are real or principally due to under recording of cases remains controversial. Clearly a lack of truly population-based registration of cancer incidence in many countries does hamper our understanding of the extent of the local problem and inhibits appropriate allocation of resources to deal with the diseases. The associations between socio-economic status, levels of public hygiene, population mixing, delayed exposure to infection, excess response to such infection and childhood ‘peak’ ALL have been well explored (Greaves, 1988; Kinlen, 1995; Smith et al, 1998; Taylor et al, 1998). These go a considerable way to explain worldwide variations but also imply that if socio-economic conditions improve and deaths from infections early in life decline then childhood leukaemia will become a much greater problem in developing countries. Indeed where rapid economic advances have already been made, e.g. in Malaysia and in some South American countries, such increases have already been seen. The age-standardized rates of acute myeloid leukaemia (AML) (4–9/million) are much more constant throughout the world with the exception of indigenous Pacific Island populations and some variation in subtypes, e.g. excess of monocytic leukaemia in Northern Turkey. Individual, national and local poverty are clearly the first obstacles to be overcome if treatment is to be attempted, let alone prove successful. Ribeiro & Bonilla (2000) reported that the mortality for childhood leukaemia was 90% in San Salvador in 1993 after the civil war there, which had increased poverty, resulting in at least 50% of the population living on a subsistence income. In other countries, for example India, it has been estimated that up to 700 000 000 of the population of over 1 billion may be similarly compromised because of subsistence income and gross poverty. If you can barely afford to feed your family, parents cannot afford the cost of cytotoxic agents; supportive care and the loss of any family member who is a key earner (e.g. mothers or older children) to stay with a child in hospital can lead to the family falling into greater poverty and malnutrition. Very few disadvantaged countries can provide free or even subsidized care and need to pass all costs on to the individual patient/family. The cost of establishing treatment centres, supportive care including a safe and reliable blood transfusion and microbiology services, let alone training medics, nurses and ancillary staff is prohibitive for countries with unstable economies, major international debt and other perceived priorities. The problems are complex as eloquently described by Butta (2000) for South Asia. Despite the establishment of a modern industrial infrastructure, in many ways leading the world in information technology and having developed a nuclear capability, both India and Pakistan still report maternal and child health death rates amongst the highest in the world. In the UK, with a population of 58 million, 5411 children under the age of 5 years die annually and so do 70 mothers during pregnancy or labour. In countries with extreme poverty, which includes approximately 46% of the world's population (where deaths under the age of 5 years are greater than one in 20), childhood deaths are 40- and maternal deaths 180-fold higher than in the UK. Furthermore, the rate of death in the first 5 years of life has decreased in the 25 richest countries of the world by 41% in the last decade. In the 25 most disadvantaged countries, the decrease has been just 15%. Butta (2000) has also suggested that South Asia has a problem in recognizing the needs of women and children, establishing healthcare research into disease causation and prevention, and prioritization of the use of funds available. External international funding agencies too frequently appear to dictate what is to happen. Local and national professionals in co-operation with families can achieve far more when driven by evidence and experience, not by ‘political expediency’. Even if units can be established and the financial costs of treatment lifted from the individual family, the difficulties (poor transportation infrastructure) and cost of travel to treatment centres almost inevitably distant from places of residence pose a major obstacle to compliance with treatment. The loss of parental income, disintegration of the family and change in roles required when both parents are normally essential workers in order to maintain family income are all recognized in Western countries, but they are even more critical in disadvantaged countries and the major causes cited for abandonment of treatment. Where infections, anaemia and malnutrition remain endemic, allocation of resources to cancer treatment is not given priority but where they are coming under control, leukaemia and cancer emerge as priorities. It has also been suggested that the relative rarity of lymphoblastic leukaemia in some countries may be purely due to misdiagnosis or indeed because infections mask the underlying pathology. Clearly, high prevalence of infection also poses greater risks for any individual who develops leukaemia and where treatment is attempted. The lack of education and knowledge about uncommon diseases amongst local health workers and communities very frequently leads to delay in diagnosis, lack of understanding about the need for treatment, and poor subsequent patient and family compliance. Many communities still rely on ‘traditional’ medicines and many have unrealistic preconceptions of the inevitability of death when a child develops certain illnesses, particularly malignancies. In Swahili, cancer is described as ‘the never healing sore’, resulting in zero expectation of cure and by some a total reluctance to even try to treat. The most spectacular advances in diagnosis, management and cure of leukaemia in disadvantaged countries have come from families of children with cancer who have had the vision to recognize the value of creating a partnership with a centre or centres in a resource-rich country. Following the establishment by a Salvadoran mother (whose child had been treated at St Jude Children's Hospital, Memphis, Tennessee) of the ‘Fundacion Ayudame a Vivir’ (the help-me-to-live foundation) which aimed to improve the outcome for children with cancer, the survival of ALL has risen from under 10% in 1990 to now over 50%. How this was achieved in less than a decade is truly remarkable. The Foundation spent 2 years raising funds, getting the support of hospital administrators and politicians, and identifying local needs, including a supply of drugs, committed and trained staff, support services and population education. They then approached St Jude Children's Hospital which has developed an outstanding outreach programme based on such partnerships. They mutually developed training programmes in Mexico to ‘circumvent barriers and inflexible training requirements’ (Ribeiro & Bonilla, 2000). This is an important aspect relevant not just for the USA but also throughout Western Europe where current training programmes significantly curtail the ability to train people from disadvantaged countries. St Jude arranged for individual hospital staff to ‘visit’ Memphis to learn particular procedures and become involved in specific protocol development. Jointly the Foundation and St Jude ensured supplementation of salaries to enable those medics who were being trained to stay on in paediatric oncology and not to have to spend time in earning a private income. This is required by many doctors throughout the world in order to keep their own family alive and in food. Paediatric oncology ‘does not pay’ for the doctor who practices in the developing world! For the nurses a local training programme at the Benjamin Bloom Hospital in San Salvador was established and the hospital was convinced that such trained nurses should be ‘permanently assigned’ to the paediatric oncology programme. The commitment and dedication of these nurses, for little extra income, has been one of the major success stories of the programme (Wilimas & Ribeiro, 2001). St Jude have used their sophisticated technology to assist in diagnostic testing and provide quality control, e.g. for immuno-phenotyping and also flow cytometry initially established by electronic transfer, but always with the intention to build local self reliance. Standard protocols were initiated but required modification as a result of local experience, especially of infection and toxicity (see below). Unlike the cost cited before in this paper of 100 000 US dollars per child per year treated, the El Salvador treatment cost is 15 000 US dollars, 75% of which is covered by the Foundation and the Salvadoran government. The annual cost to St Jude of their support has amounted to approximately the cost of treating a single USA patient. This is clearly an excellent investment of money. The outreach programme has extended throughout Latin America, the Middle East and China, and provides an exemplary model for the rest of the world. Similar global partnerships and twinning have been established between Italian centres and units in Central America (Masera et al, 1998). Both programmes emphasize the need for local enthusiasm and drive with the external funding, expertise and support not used to dictate what is done locally but used to support and promote self reliance. Masera and colleagues have managed even to persuade Italian families to individually sponsor children in Latin America, a fine example of global partnership between cancer units of Northern countries and the disadvantaged. The key elements to the successful development of a service in a disadvantaged country can be summarized: Recognition of a need in the centre/country itself. Mobilization of the local community (especially parents and families) to raise funds, put pressure on medical services, administrators and politicians to recognize the need and provide support, moral and ideally financial. The priority is to get attention and start to activate priority setting by authorities. Find an external partner unit which is already established and willing to help but will not dictate what is to happen in the country (or the unit), i.e. like the St Jude (Ribeiro & Bonilla, 2000) or La Mascota (Masera et al, 1998) programmes. Development of medical, nursing and paramedical expertise in the diseases to be treated – this can often be done first by ‘visiting’ fellowships whereby a short stay in an established unit in an industrialized country will provide specific expertise but in the long run must be developed ‘in house’ or at least ‘in country’. Both the St Jude and Italian outreach programmes have excelled in this but also developed regional programmes bringing together countries with similar cultures and languages. The initiation of long-term recruitment, training, accreditation and retention of trained staff is important. Improvement of supportive care facilities, especially protection from those with infectious diseases and development of a safe and reliable blood transfusion service. Development of ‘subsidised’ travel, home from home facilities, etc. to lessen the burden on parents. Development of appropriate protocols for each disease entity: these must be locally practicable with minimum cost and maximum efficacy. The process can be greatly enhanced by the formation of a co-operative group bringing together all the professionals involved in the speciality within a country or region to share expertise and develop training programmes. Such a co-operative group should act as an advocate for children with cancer in collaboration with civic groups and parent support groups, ‘in order to lobby for the optimal care for children with life threatening conditions’. The key to all successful programmes has been to develop protocols where drugs are available locally and relatively cheap but which offer a significant chance of cure for a majority of patients. The availability of individual drugs is not uniform throughout the world. A major obstacle throughout the world to the development of effective therapy relates to reluctance by the ever decreasing number of large multinational drug companies to show any real interest first of all in paediatrics, then in licensing drugs for children and most importantly ever considering subsidizing drugs for disadvantaged countries. Given the potential worldwide market which is only 15–20% currently tapped, their approach is remarkably short-sighted. No wonder that countries are developing their own products, but sadly in some instances with poor quality control. This is an area where resource-rich countries can help by carrying out quality control on drugs available to ensure that they are safe and adequate for the purpose designed. Efforts to centrally collect and distribute discounted drugs have had little worldwide success to date. The presence of a dedicated and trained paediatric haematologist/oncologist and nurses, blood and platelet banking facilities, basic haematology and diagnostic imaging services (ultrasound and chest radiography), and ideally computer facilities to access the internet (for E-mail links, Medline searches and to install patient databases) are the basic requirements. Just a few years ago, to suggest that internet access was essential would have seemed quite preposterous but in many countries it is now far easier to connect to the ‘net’ than it is to obtain clean water. Provided electricity supplies can be maintained, the internet and E-mail provide a far more reliable method of communication with expertise elsewhere in the world than by letter, telephone, fax etc. It is far cheaper now than using standard textbooks. Such contact enables isolated units to seek advice and be supported by others far removed from their country, and to do so very rapidly. Registration of cases, ideally on a true population basis, provides evidence about the extent of disease, and facilitates demographic and outcome analysis crucial to any developing unit. As demonstrated by Ribeiro & Bonilla (2000) andMasera et al (1998) links between developing and established units clearly facilitate the development of standardized treatment and supportive care protocols, provide back-up for diagnostic problems/conundrums, enable educational exchange visits and foster research (if only into health care delivery). There is no doubt that international links and visiting faculty do increase the local profile of units and catch the attention of government and non-governmental organizations. The International Society for Paediatric Oncology (SIOP) through its Paediatric Oncology in Developing Countries Committee has attempted to provide support principally through two aspects, education/training and development of protocols. All of the successful outreach projects have promoted ‘in-house’ or at least ‘in-country’ training programmes. The All India Cascade Programme, initiated by the Indian Academy of Paediatric Haematology & Oncology Chapter (1996–2000) (B. R. Agarwal, personal communication), was also sponsored by SIOP with World Health Organization help. This started with a small dedicated national core of trained specialists in India who with a limited international faculty drew up a core curriculum for paediatric oncology at a meeting in Mumbai in 1997. A network of teachers throughout India, with wide representation from all zones, proposed and established a training module that is a mixture of problem-based and programmed learning. This is being used as the basis for training courses around India, involving 80–100 paediatricians every year being trained in practical paediatric oncology. The courses involve lectures and practical demonstrations. This obviously does not cover all aspects of paediatric oncology but aims to cover epidemiology and natural history, treatment modalities, the concept of a multidisciplinary approach, the management of emergencies and knowledge of practical procedures. A total of 16 training courses have now been conducted. Clearly, the cascade downwards to all those with an ambition to become paediatric haematologists and oncologists is certainly working. This scheme provides an opportunity for a degree of testing and accreditation of participants, and of course it provides a national ownership of the training programme, a key process towards self reliance. In the past, too many trainees from disadvantaged countries have gone abroad or have been sent abroad for longer term training but have not always returned to their countries of origin or found that if they did that they had been forgotten and lost position during their absence. Local training in circumstances directly relevant to future practice with short-term visiting fellowships for specific item training as practised by the St Jude scheme seems a much better option. Faced with limited resources and facilities, many individual physicians and newly emerging co-operative groups have strived to pull out the essentials of how to manage ALL and achieve a reasonable degree of cure. The essentials of the diagnostic work-up must include a full blood count, blood film and a bone marrow aspirate with of course a competent person to interpret the basic morphology, and preferably also the significance of supportive staining which must include Periodic Acid Schiff and Sudan Black stains (hence the need for haematological training). Immunophenotyping and cytogenetics are expensive to set up with guaranteed good quality control. They are not first-line essentials when a unit is being developed, but from the Salvadoran/St Jude experience it is possible to establish flow cytometry which is initially capital expensive but in the long run cheap to run, with data transferred electronically to a physician/scientist abroad with specific expertise. Such a link provides ongoing education for the people developing the unit. Harris & Tanner (2000) have stressed ‘the need for funding to be made available to scientists in developing countries and to organizations that support such in-country training and research’ and that there must be up-to-date technology transferred in this mutual way. In the St Jude Outreach programme, there has been progressive development with the help of such technology transfer, for example in the establishment of local immunophenotyping. Immunophenotyping is performed in Guatemala for centres in El Salvador, Honduras and Guatemala (Lorenzana et al, 2000). Lumbar puncture with a cerebrospinal-fluid cell count and cytospin to examine for any leukaemic blast cells is required along with a plain chest radiograph, especially in the presence of any ‘airway’ symptoms and in countries where T-cell disease is more common. Stress must be placed on simple, reliable and reproducable basic tests initially, with the development of more investigations as training and technology take root, but only that which is essential for effective management of patients. Either because of delayed diagnosis, or related to an increased relative or indeed absolute incidence of higher risk patients, biochemical disturbance as a result of rapid tumour lysis is reported more commonly from many disadvantaged countries with an increased early mortality. An awareness of the risk, administration of copious intravenous isotonic fluids, allopurinol and close monitoring of urinary output are clearly necessary, and in the majority of cases do prove adequate. In view of the reported higher mortality from such lysis, many units in disadvantaged countries use a regimen of gradually increasing steroids at the start of therapy for ALL. The use of prednisolone monotherapy for 1 week to assess response, as pioneered by the Berlin–Frankfurt–Munster group (Schrappe et al, 1995), also has the coincidental benefit of modulating cell lysis to some degree. Four weeks of oral steroids plus weekly vincristine will result in remission rates of 85–90% for the majority of ALL cases. Dexamethasone, which in many countries is not more expensive than prednisolone, has been substituted for prednisolone because of its reported increased CNS penetrance and possible increased cell kill rate (Balis et al, 1987; Veerman et al, 1996). The dosage of dexamethasone has been adjusted by risk stratification by some (A. K. Sutaryo, personal communication). The most difficult induction question is whether to add a third agent, especially asparaginase which is claimed to increase remission duration when given 3–4 times per week (dependent on the form used), aiming to deplete the body of asparagine for 3–4 weeks. This proves to be too expensive for many countries. Whether less frequent dosing adds anything to the basic combination of vincristine and prednisolone is far from clear. ‘Reliable’ asparaginase supplies are frequently not available or too expensive to utilize and some protocols use one of the much more freely available anthracyclines as a substitute (doxo- or daunorubicin) or sometimes in addition to asparaginase in high-risk patients. In countries with significant malnutrition, anthracyclines have been reported to increase not only mucositis but also infection risks as a result of their profound mylosuppressive effect. In countries with prevalent poverty, malnutrition and infections, even simple ALL therapy is associated with early high mortality rates. Isolation of oncology patients from others, especially those with overt infections, good infection control coupled with vigilance and early treatment of neutropenic sepsis are essential. Basic effective intravenous antibiotic regimens suitable for the local predominant flora (for which monitoring must be implemented) need to be selected. Failure of early blood or marrow clearance by d 7–14 and especially by d 28 of induction puts any patient into a higher ‘risk of relapse’ category. Where resources are limited, such patients are probably incurable by conventional means. Clearly during induction, some component directed towards the CNS is required and this can be achieved with intrathecal methotrexate only, using a dosage based on age of the patient. Indeed, provided an adequate number of intrathecal injections is given (15–20 throughout treatment) central nervous system control can be achieved in the majority of patients. For the overwhelming majority of patients, cranial irradiation is not now required nor is expensive high-dose systemic methotrexate, although some protocols have included either intravenous or oral doses of slightly higher dose methotrexate than the standard oral dose of 20 mg/m2/week. If cranial irradiation is considered safer than repeated lumbar punctures in view of infection risks, standard CNS therapy should be with 5–6 doses of intrathecal methotrexate over the first 8 weeks of treatment or so, plus cranial irradiation to a total dose of 18 Gy (10 fractions of 1·8 Gy). Higher CNS irradiation dosages do not significantly increase CNS or total body control of the leukaemia but do increase toxicity. Very basic therapy consisting of simple induction, CNS irradiation and continuing maintenance therapy as per the Medical Research Council protocol UKALL VIII (modified from the CCG protocol 162) run between 1980 and 1984 led to an overall event free survival of 54% (± 1·7) at 10 years with results ranging from 32% (± 7·1) for high white count T-cell patients to 59% (± 2·4) for low white count common/pre-B ALL. Even high white count patients with common/pre B had a 10-year event-free survival of 50% on this protocol (Eden et al, 2000). Following identification by Riehm et al (1998) of the value of intensification of therapy post induction, the use of such therapy to consolidate remission and intensify treatment has resulted in significantly improved survival. On review of the worldwide use of such intensification modules, drug availability and cost which is so variable between countries proves to be a major obstacle to adoption of such intensive treatment. The cheapest additional drugs in most countries have proved to be cyclophosphamide and cytosine arabinoside; intensification modules using these agents in a continuous way over a 2–3 week period appear in general to be well tolerated and have been reported to be especially effective in T-cell ALL. However any such intensification does carry with it myelosuppression and risks of infection and even increased mortality. There appears to be little benefit in tinkering with the restof the standard ‘maintenance’ therapy based on daily oral 6-mercaptopurine, weekly oral methotrexate, and monthly/6 weekly pulses of intravenous vincristine and oral steroids. Duration of maintenance appears to be crucial with at least 2 years and optimally 3 years, especially for boys, required following induction and consolidation. The answer clearly is yes, as exemplified by the St Jude outreach programme, Masera and colleagues, the International Society of Paediatric Oncology in the Developing Countries Committee (chaired by Professor H. P. Wagner), and the All India Training Programme. Physicians and nurses can be trained, brought together into professional self-supporting groups, and the level of supportive care and treatment offered to children significantly improved. In fact in many countries, the development of paediatric oncology services appears to have also lifted overall care for children in hospitals. The dramatic improvement in survival in the Salvadoran experience testifies to this and suggests that with the help and support of parent and voluntary groups so much can be achieved (Ribeiro & Bonilla, 2000). From resource-rich countries, the least we can offer at quite modest cost is long-term support, technological expertise and our knowledge (Godlee et al, 2000; Harris & Tanner, 2000). We can develop partnerships between either whole units or countries with good resources and those in need. Such collaborations benefit therapy but also should include research programmes which ultimately benefit all children in the world who develop serious illnesses (Costello & Zumla, 2000). The decision about what is needed and especially about what research should be conducted must lie with the developing unit (Lee & Mills, 2000; Sitthi-amorn & Somrongthong, 2000), not the external partner or funding agency. We owe it to our colleagues worldwide not to dictate what they should do but to help them when they seek to cure the majority of all children with ALL, no matter where they are born.