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An update on leukaemia
SYMPOSIUM: ONCOLOGY
An update on leukaemia
2. Development of strategies to prevent central nervous system (CNS) relapse: even with multidrug systemic therapy, many children who had a systemic response had a CNS relapse leading to treatment failure. The CNS is a sanctuary site for leukaemia and it became apparent that to prevent CNS relapse, treatment directed towards the CNS was needed. This was initially achieved with prophylactic radiation treatment to the central nervous system in early treatment protocols for ALL 3. Development of randomized clinical trials to test newer drugs or schedules: this concept of a structured framework in which to test drugs and schedules has allowed leukaemia treatment to sequentially and progressively improve. This established the components of treatment that are still used today e these being remission induction, consolidation and CNS directed therapy, re-induction (or intensification), and continuing maintenance therapy. In more recent years the lessons learned from the early years of treatment have been carried forward into clinical trials and in the UK, national UK ALL trials have realized a step wise improvement in prognosis from a 5-year event free survival (EFS) of 35% in 1972 to 87% in 2010. With the improvement in cure rate came the realization that survivors had long-term effects associated with treatment, particularly radiation treatment which had adverse effects on growth, neurocognitive and endocrine function. Thus as well as focussing on improving cure rates, the more recent trials have also sought to reduce long-term sequelae. The most important recent findings of the successive UK ALL trials are 1. UKALL 11 found that CNS irradiation is not required to prevent CNS relapse. This is a major milestone in the success of leukaemia treatment. Cranial irradiation has now been abolished as standard therapy in UK trials and only intrathecal and systemic therapy are used. This is as effective as radiation in preventing relapse but is not associated with the adverse effects seen with radiation therapy 2. Dexamethasone is superior to prednisolone in preventing CNS relapse 3. Mercaptopurine is as efficacious but less toxic than thioguanine and is the preferred purine to use in maintenance therapy 4. Improvements in delivering risk-directed treatment. Modern treatment protocols use risk adapted stratification systems to allocate patients to treatment arms of different intensity. Risk stratification aims to avoid over treatment in those children with low risk disease and avoid under-treatment in those with high risk disease. The National Cancer Institute has developed a classification based on age, white cell count at presentation and cytogenetics of the leukaemic cells. This was introduced in UK ALL 97 trial. However this in itself is inaccurate as some children with apparently good risk disease will relapse and many with apparently poor risk will do well. The risk assessment tool can be improved by including the response of the disease to initial therapy. This can be crudely done by the morphological assessment of blast disappearance. More recently the use of more sophisticated techniques to quantitate minimal residual disease (MRD) has been employed to aid risk assessment. The first MRD stratified protocol for acute leukaemia in the UK,
Denise K Bonney
Abstract As a group, the leukaemias represent the most common malignant conditions of childhood. The treatment of childhood leukaemia, and in particular the treatment of acute lymphoblastic leukaemia (ALL), has shown tremendous improvement in outcome in the last 40 years. Much of the success is due to the improvements in leukaemia therapy demonstrated in improved disease-free survival and reduced relapse rates in clinical trials but improvements in supportive care over the years have also had a very significant contribution. Over the last 30 years we have also seen reduced treatment related mortality due to better management of complications and better detection and treatment of infections. The emphasis of treatment as well as being cure is now focussing on targeting therapy to reduce the treatment burden in good risk disease and identify and intensify treatment for those with poor risk disease. The development of molecularly targeted therapies has changed the therapeutic landscape and this last decade has seen many improvements in outcome associated with these new agents. This review will give a brief overview of current treatment protocols used in childhood leukaemia, focussing specifically on the latest improvements and strategies in treating these conditions.
Keywords acute lymphoblastic leukaemia; acute myeloid leukaemia; chronic myeloid leukaemia; paediatric
Acute lymphoblastic leukaemia Acute lymphoblastic leukaemia, the most common of the childhood leukaemias, accounts for around 25% of malignant diagnoses in childhood and accounts for around 85% of all childhood leukaemias. In the UK the incidence is 30 per million children per year. It has a peak incidence between the ages of 2 and 5 years. ALL is defined by an uncontrolled proliferation of immature lymphoid (B or T) cells. The leukaemic cells proliferate and the clinical signs and symptoms of ALL can be explained by the proliferation of leukaemic cells within the bone marrow or other organs. ALL treatment has proceeded from palliation to cure since the 1940s. The advances made in the early years of treatment were 1. Development of multidrug therapy: early attempts at cure with monotherapy resulted in only transient responses. Combining drug therapies was more successful leading to cure in some patients and overcoming the problems due to drug resistance seen with monotherapies. The use of separate multi drug schedules in the sequential parts of ALL therapy remains the backbone of leukaemia therapy
Denise K Bonney MBChB MRCPCH PhD FRCPath is Consultant Paediatric Haematologist in the Department of Paediatric Haematology/Oncology at the Royal Manchester Children’s Hospital, Manchester, UK. Conflicts of interest: none declared.
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UKALL 2003, opened in October 2003 and has just completed recruitment in June 2011. MRD results at week 4 and week 11 were used to randomize patients to receive more or less intensive chemotherapy depending on whether they had high or low levels of MRD at these time points. While final results will not be available for some time, the interim analysis of UKALL 2003 reveals a 5-year EFS 87.7% and overall survival (OS) of 91.3% and UKALL 2003 has confirmed the predictive value of MRD. A three-fold increase in relapse risk (RR) is seen in MRD high risk group (5-year EFS 80.7%) compared to MRD low risk group (5-year EFS 95.6%). This concept of MRD is discussed in further detail below.
as lymphoid markers and there is a very high incidence of structural abnormalities of chromosome 11. These abnormalities often result in rearrangement of 11q23 within the MLL gene which confers poor prognosis. When treated with standard ALL protocols, the results for infants with ALL were poor with a one in four chance of long-term survival. The development of trials specifically focussed on improving outcome in infants with ALL has significantly improved the outlook for these patients. As the disease is rare, the trials set up have been pan European. Interfant 99 involved 22 countries and enrolled almost 500 patients. This study was set up to try and answer three main questions 1. Would a different treatment protocol would improve survival? 2. Would a more intensive treatment following initial therapy would improve survival? 3. Are there specific factors that could be used to predict survival chances? In view of the hybrid nature of infant ALL, the treatment schedule was based upon a so-called hybrid therapy, consisting of elements from both ALL and AML treatment schedules. All patients received a week of prednisolone therapy and were then divided into two risk groups (standard risk and high risk) based on whether they had a good response to this. Following stratification all patients received the same induction and also two further hybrid courses. After three courses the poor risk group underwent haemopoietic stem cell transplantation (HSCT) if donor available or were randomized to maintenance with or without further intensive therapy. The good risk group were randomized to maintenance with or without a further course of intensive therapy (intensive versus standard treatment). The trial also measured MRD at multiple time points to ascertain if MRD levels could determine prognosis in this disease. The trial showed a disease-free survival (DFS) at 4 years of 47%, a marked improvement on previous results. Within the good risk group 55e60% of patients were disease-free at 4 years and within this group there was no difference in outcome between the standard therapy and intensive treatment arm. However there was more toxicity in the intensive arm. Thus the hybrid approach does improve outcome but there is little benefit to adding in further intensive therapy after the initial three courses. The trial demonstrated that the following factors predicted for poor prognosis Age less than 6 months at diagnosis Presence of MLL gene rearrangement WCC more than 300 109 per litre at presentation Poor response to initial treatment. Infants without any of these factors are low risk and in Interfant 99 had a 2-year EFS of 87%. Infants with MLL gene rearrangement, less than 6 months of age at diagnosis with high WCC or poor response to initial treatment are classified as high risk and in Interfant 99 had a 2-year EFS of 15.9%. All other cases are medium risk and had a survival of 49.5%. Results from Interfant 99 published in 1999 showed that high levels of MRD measured immediately before the penultimate course of intensive chemotherapy identified a group of patients with a significantly reduced disease-free survival. Interfant 2006 stratifies patients into good, medium and high risk categories depending on the presence or absence of the
Risk stratified therapy and minimal residual disease in leukaemia: when acute lymphoblastic leukaemia is diagnosed in a patient, the total number of leukaemia cells is approximated to 1012e1013. The majority of patients reach complete remission (CR) as judged by a blast cell count of less than 5% in the bone marrow by microscopic analysis after 4 weeks of chemotherapy. However, complete remission does not mean that leukaemia cells are totally eradicated from the body but that their level is below the sensitivity level of classical morphological analysis method (e.g. 1e5%). At this time, many malignant cells can still remain in the patient. They represent the minimal residual disease (MRD). Techniques which are more sensitive than morphology are now available that permit detection of these residual blasts and thus the burden of residual disease. Techniques aimed at studying MRD rely on the detection of a leukaemia cell specific marker which enables blasts to be distinguished from normal marrow cells. Such markers have to be detected with high sensitivity, to be present in all leukaemia cells and to be stable during disease evolution. Two kinds of markers are currently used: genetic markers, which can be detected by PCR, and immunophenotypic markers, which can be detected by flow cytometry. PCR based strategies can be directed to two types of genetic targets: breakpoints of leukaemia-related chromosome aberrations, and antigen-receptor gene rearrangements. The high sensitivity of polymerase chain reaction (PCR) makes it possible to consistently detect one leukaemia cell among 105 normal cells (105). It is now established that the level of MRD represents a powerful prognostic factor and is in fact the strongest predictor of outcome in children undergoing identical therapies. Future ALL trials: UKALL 2011 is due to open in autumn 2011 and will build on lessons learned from UKALL 2003. Although the details are not yet finalized, the trial will look at whether further refinement of treatment based on MRD based risk stratification at end of induction improves survival while reducing the overall burden of treatment. Acute lymphoblastic leukaemia in infants Fewer than 5% of children presenting with ALL are infants. Infant ALL is biologically distinct from ALL in older children. Infant ALL often presents with very high blast counts, hepatosplenomegaly and CNS involvement e features that are uncommon in older children. The blasts cells express a more primitive immunophenotype with expression of myeloid as well
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prognostic factors identified in Interfant 99. Infants in the low risk category have three courses of intensive chemotherapy followed by maintenance chemotherapy for a total of 2 years (standard therapy). Infants in the medium and high risk group are randomized to standard therapy as per low risk arm or a more intensive chemotherapy arm involving four courses of intensive chemotherapy rather than three before maintenance. Infants in high risk group and those infants in medium risk group with high MRD on commencing penultimate course of intensive therapy are eligible for HSCT. This trial is still open and continuing to recruit.
stratification and predict outcome. In its initial form, patients were allocated to good and poor risk groups depending on their initial response to steroid therapy, assessed by the rate of clearance of lymphoblasts from the blood. Good risk patients were randomized to receive imatinib or not in addition to standard therapy. In this group those with a well-matched donor went on to have transplant and those without a donor continued to receive chemotherapy imatinib. The poor risk patients all received imatinib in addition to standard therapy with the expectation that most of this group would go on to receive a transplant if any suitable donor was available. The trial was amended in February 2010 to remove the randomization for imatinib and instead all patients on the trial now receive imatinib. This amendment was made following interim analysis of the trial results in light of the very encouraging results found by the COG AALL0031 study which showed that the addition of the imatinib to conventional ALL therapy had dramatically improved the outcome and in fact doubled the 3-year EFS from 35% to 80% for children and adolescents with this form of ALL. Analysis of EsPhALL data showed a trend to improved survival in the good risk group who received imatinib (3-year EFS of 72.3% vs 60.2%) and the poor risk group, who all received imatinib did significantly better than poor risk patients in any non-imatinib protocol. Also the addition of imatinib was well tolerated and did not increase the toxicity of the treatment. Thus the trial steering committee closed the randomization and proposed continuous imatinib exposure to all patients The EsPhALL trial is still open and recruiting. There is some early suggestion that low/negative MRD levels at the end of induction treatment may predict for a group of patients in whom chemotherapy and imatinib alone will be curative and thus MRD may help clarify the role of HSCT in this disease. As newer and more potent tyrosine kinase inhibitors are now available further trials in this disease will investigate the use of these agents. At present only patients who are resistant to or intolerant of imatinib are eligible for enrolment in these phase I and II trials.
Philadelphia Positive acute lymphoblastic leukaemia 3e5% of children with ALL carry the Philadelphia chromosome in their leukaemic cells. This abnormality results from a reciprocal translocation between chromosomes 9 and 22. The result of the translocation is the oncogenic BCR-ABL gene fusion, located on the shorter derivative 22 chromosome. This gene encodes the Bcr-Abl fusion protein which has kinase activity. Depending on the precise location of the fusion the molecular weight of the protein can range from 185 to 210 kDa. In cases of Philadelphia positive ALL (Phþ ALL), the majority (85%) express the p185 fusion protein and most of the rest express the p210 fusion protein which is more commonly seen in CML e see below. Until recently the outlook for children with Phþ ALL was dismal. Only around 30% of children and adolescents with the disease were long-term survivors with conventional chemotherapy treatment including HSCT. It was recognized that there were three features which predicted which children were likely to do better Good initial response to steroids Age less than 10 years WCC less than 50 109/litre at presentation. However even children with this constellation of good risk features had long-term survival of less than 50%. The outcome seemed to be improved in some patients with HSCT e particularly from matched family donor and thus children were offered HSCT as the long-term outcome from chemotherapy alone was so poor. Employing clinical trials to study and improve the outcome in this disease is challenging as the numbers of children diagnosed with this form of leukaemia is low e only 8e10 children in the UK are diagnosed each year. Therefore trials aimed at improving outcome PhþALL require a collaborative approach. The EsPhALL trial which opened in the UK in 2004 and is still running, is an international trial of children and adolescents with PhþALL. At the time this trial was opened many studies were reporting the results of trials using tyrosine kinase inhibitor drugs which inhibit the fusion protein produced as a result of the Philadelphia translocation in the treatment of Philadelphia positive diseases. The first of these drugs, imatinib mesylate, is effective (albeit temporarily) in Phþ ALL as well as CML. In one study of patients (mainly adults) with refractory or resistant PhþALL, imatinib resulted in improvement in 75% of patients and 25% achieved a complete remission. The aim of the EsPhALL trial was to evaluate the safety and efficacy of imatinib in addition to chemotherapy in children with Phþ ALL. This trial also measures MRD in patients with Phþ ALL at defined time points to determine if we can use this in future to improve risk
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Acute myeloid leukaemia Acute myeloid leukaemia (AML) is the second most common type of childhood leukaemia and accounts for 15% of childhood leukaemias and 5% of childhood malignancies. The incidence is 6.5 children per million per year. The cause(s) of AML is unknown in most instances. One clearly identified risk factor is exposure to very high radiation levels such as experienced after the atom bomb explosions in Japan in 1945. Very few, if any, children in the Western world are exposed to levels of radiation high enough to increase the risk of leukaemia. AML is more common in children with certain syndromes such as Down syndrome and congenital bone marrow failure syndromes (Fanconi anaemia, severe congenital neutropaenia, Shwachman Diamond syndrome). AML therapy is based on induction chemotherapy with an anthracycline combined with cytarabine and in paediatric patients etoposide is also used in induction. Two induction courses are given. Following this patients receive consolidation courses, though the number of consolidation blocks varies between different trials. The importance of CNS therapy is
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unclear as CNS relapse is uncommon in AML however children receive CNS directed treatment as intrathecal injections aimed at preventing CNS relapse. The cure rate for AML although improved over the last decades is still much less than for ALL and up to a third of children relapse following treatment. Thus in discussing strategies for treating AML it is also relevant to mention treatment of relapsed disease. Between 1988 and 2002, children with acute myeloid leukaemia (AML) were treated on Medical Research Council (MRC) AML 10 and AML 12 trials. AML 10 compared different combinations of anthracycline and cytarabine based chemotherapy for induction and tested the role of bone marrow transplantation following four blocks of intensive chemotherapy. The trial found no difference in efficacy between the induction schedules, but using mitoxantrone as anthracycline in place of daunorubicin increased myelotoxicity. The addition of either autologous or allogeneic haemopoietic stem cell transplantation significantly reduced the relapse risk (RR), but was associated with an increase in treatment related deaths which largely offset the reduction in relapse. Analysis of AML 10 data demonstrated that karyotype of leukaemia cells was a major determinant of prognosis, with t(8;21), inv(16) and t(15;17) being favourable whilst monosomy 7, abnormal 5q, abnormal 3q or complex karyotypes being adverse. All other karyotypes were intermediate risk. In AML 12, risk group stratification into good, standard and poor risk groups based on cytogenetics derived from MRC AML 10 and response to the first course of chemotherapy was used to deliver risk-directed therapy. In this trial, allo-BMT was limited to standard and poor risk patients and autologous transplant procedures were not employed. Instead, the benefit of an additional block of treatment was tested by randomizing children to receive either four or five blocks of treatment in total. The 5-year OS, DFS, EFS and RR in MRC AML 12 are 66, 61, 56 and 35%, respectively; at present superior to MRC AML 10, which had a 5year OS, DFS, EFS and RR of 58, 53, 49 and 42%, respectively. The results of MRC AML 12 did not show a survival advantage for a fifth course of treatment. The most recent publication on the results of AML 12 reported that HSCT showed a significant survival benefit only for poor risk patients. The next trial AML 15, opened in 2002 and completed recruitment in 2009. This trial asked a number of important questions 1. Which induction regimen is best e the use of induction regimen FLAG-Ida which was showing good results in relapsed adult AML was tested against the now standard cytarabine, daunorubicin and etoposide paediatric induction chemotherapy. The main question being asked was whether use of FLAG-Ida reduced the relapse rate 2. Does five courses result in better outcome than four e this was carried through from AML10 to permit meta analysis of the results of four versus five courses randomization from both trials as when this trial was designed and enrolling the long-term results of AML 12 were not available 3. Can anthracycline dosage be reduced (therefore reducing risk of long-term cardiotoxicity) without compromising outcome by comparing standard MRC anthracycline-based consolidation with high-dose cytarabine based consolidation? This randomization is particularly important for children
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4. Do poor risk children benefit from a transplant procedure after induction courses compared to children who receive further chemotherapy 5. Can the amount of intrathecal therapy delivered as CNS prophylaxis safely be reduced. In AML 10 four course of intrathecal therapy were given. In AML12 this was reduced to three without any increase in CNS relapse rate. In AML 15 two course of intrathecal chemotherapy were given 6. Does introduction of targeted therapies e Mylotarg and CEP701 improve outcome. AML 15 was the first of the UK AML trials to use molecularly targeted therapy. Mylotarg or gemtuzumab ozogamicin (GO) is an immunoconjugate combining a humanized anti CD33 antibody to the DNA intercalating agent, calicheamicin. CD33 is expressed on some haemopoetic progenitors and on more than90% of blasts cells in AML. Thus mylotarg acts as a targeted chemotherapy by binding to AML blasts cells allowing calicheamicin to act. In AML 15 patients were randomized to receive mylotarg with consolidation. FLT3 is a receptor tyrosine kinase with important roles in haematopoietic stem/progenitor cell survival and proliferation. It is mutated in about 1/3 of acute myeloid leukaemia (AML) patients. Mutation results in a constitutively activated FLT3. Many studies have shown that AML patients with FLT3 mutations have poor cure rates due to relapse. This has led to the development of a number of small molecule tyrosine kinase inhibitors with activity against FLT3. CEP-701 is an inhibitor of FLT3, which has been demonstrated to be of some benefit in older patients with AML considered unfit for conventional chemotherapy. Patients over the age of 16 years entered into AML15 with FLT3 mutations were eligible for randomization to receive CEP-701 or not. The full results of AML 15 are not yet available but the following have been reported 1. There was no significant difference in efficacy between induction schedules tested, however the FLAG e Ida chemotherapy was associated with more toxicity which offsets any decrease in relapse rate 2. There was no difference seen in outcome with four or five courses of chemotherapy e thus no benefit of fifth course 3. Thus far there are no differences in outcome between anthracycline and cytarabine based consolidation. All children will now receive cytarabine base consolidation unless there unexpected findings with later follow-up of AML 15 4. The role of HSCT in AML in first remission is limited in first CR and that there may be a ceiling of benefit from current or conventional chemotherapy 5. Mylotarg reduces the relapse risk. The initial results of the first 1115 patients in AML 15 that received mylotarg, which included mainly adults, have been reported recently. As yet, there is no significant difference in overall survival (56% for the mylotarg group compared to 46% in the no mylotarg group at 3 years), but there was a significant difference in relapse rate (37% in the mylotarg group versus 52%; p ¼ 0.01), which resulted in an improved disease-free survival (51% versus 40%). Although the full results of Mylotarg randomization AML 15 are not yet published the evidence shows that the patients with good risk cytogenetics e inversion 16 or t(8;21) are most likely to derive benefit from Mylotarg 6. The full results of CEP-701 randomization in AML 15 are not yet known, but the use of CEP-701 has been carried forward into
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AML 17 where children and adults with Flt3 mutations will be randomized to receive Flt 3 inhibitors if they have a mutation 7. The interim results at 3 years indicate OS of 74%, DFS of 60% and RR of 35%.
The optimum treatment strategy for this disease is still the subject of study. Many studies continue to investigate the optimum drug therapy and it is now clear that molecular monitoring of MRD quantifying PML-RARa transcript levels by PCR technology can direct more precise tailoring of therapy. MRD positivity has been shown to provide an independent risk factor for relapse. Italian studies in children and adults have established that patients with PML-RARa transcripts still detectable at the end of consolidation (who account for w5% of cases overall) or those subject to a later recurrence of PCR positivity (molecular relapse) are destined to undergo subsequent haematological relapse, which may in both instances be averted by additional therapy. In terms of optimum drug therapy, results for APML patients treated on AML 10 and AML 12 trials were excellent with 3-year OS of 83% when given ATRA plus four or five courses of standard AML therapy. In 1999, a Spanish group reported a 2-year survival of 92% using a modified ATRA plus anthracycline-based chemotherapy regimen including extended maintenance therapy. This protocol had much reduced myelosuppression and thus fewer side effects and less time spent in hospital. In AML 15 adult patients with APML were randomized to standard therapy or the Spanish protocol. The Spanish protocol was found to be superior and the randomization closed with all adults subsequently receiving the therapy as per the Spanish approach. However patients under the age of 16 years with APML were not eligible for treatment with the Spanish protocol and instead received standard AML chemotherapy treatment and ATRA. The role of arsenic tri-oxide in treatment of APML continues to be evaluated. Studies have tested ATO as a single agent or in combination with ATRA in relapsed or refractory APML. ATO as a single agent was able to induce durable molecular remission after two cycles in the majority of patients treated for disease recurrence. Confirmation of the high efficacy of ATO in relapsed APL was provided successively by several trials conducted worldwide which reported CR rates more than70% and 1e3-year survival rates in the range of 50e70%. In addition to trials in which ATO was used a single agent, some studies investigated its efficacy and toxicity profile in combination with other agents including ATRA. Synergism with ATRA and increased anti-leukaemic efficacy in APML was demonstrated in a Chinese randomized study comparing ATOþATRA vs. either ATO or ATRA used as single agents. No significant additional toxicity was reported in this or in other studies which analyzed the effect of ATRA and ATO combination. Following the experience of ATO in relapsed patients and based on the favourable toxicity profile, investigators have more recently explored the effect of ATO in newly diagnosed APL patients and reported preliminary findings in front-line therapy. The combination of ATO and ATRA compared with ATRA alone or arsenic alone during induction chemotherapy followed by conventional consolidation and maintenance therapy has been tested in both adult and paediatric patients with APL. The study in adults showed that the CR rate was the same among all three induction regimens, although CR was achieved sooner with the combination regimen (median 25.5 days) compared with ATRA alone (median 40.5 days) or arsenic alone (median 31 days). Additionally, the combination of ATRA and arsenic resulted in an increased disease-free survival (DFS) compared with the patients treated with the combined results of chemotherapy with ATRA
Acute myeloid leukaemia 17: AML 17 opened in 2010 and builds on findings of previous trials whilst also for the first time incorporating MRD monitoring into AML treatment. Children will receive standard ADE induction for two courses. The children are risk stratified following induction into high or non-high risk groups. The risk stratification is no longer based solely on cytogenetics and response to first course of treatment but is now a risk score which as well as incorporating the above factors in age at diagnosis, presenting white cell count, sex and whether leukaemia is primary or secondary. The aims of the trial for the paediatric population are 1. To assess impact of mylotarg therapy given with induction: children will be randomized to two different doses of mylotarg or none with induction. As the results of AML 15 become known, alterations are being made to AML 17. For example, leukaemias with inv(16) or t(8;21) seem to derive the most benefit from mylotarg e so all children with these cytogenetic findings will now receive this drug even if they were randomized not to receive it diagnosis 2. To assess the impact of Flt3 inhibitor in AML with Flt3 mutations: children without CBF leukaemias who are not high risk and are Flt3 positive will be randomized to receive CEP-701 or placebo with consolidation 3. To assess impact of stem cell transplant in high risk children: the new high risk score includes more prognostic features than cytogenetic stratification alone. The risk score was derived from statistical analysis of factors which significantly influenced survival in AML 10 and 12. The new risk score increases the number of patients in the poor risk category as it identifies patients who have a poor prognosis for reasons other than their cytogenetics. The high risk group have a 70% chance of relapse. Poor risk individuals will then go on to receive FLAG-Ida chemotherapy (two courses) as consolidation and a transplant if there is a donor available. If no donor available children will have a third course of FLAGIda 4. To monitor MRD in AML: in AML the presence of MRD measured by flow cytometry on count recovery after course 1 predicts relapse. However not all MRD positive patients relapse and about a third of patients who do relapse are MRD negative after course 1. The role of MRD in AML is thus still not fully clarified and in this trial the first aim will be to validate times points and levels of sensitivity before using MRD to guide therapy. Acute promyelocytic leukaemia Acute promyelocytic leukaemia (APML) is an uncommon distinct subtype of acute myeloid leukaemia and accounts for 8% of childhood AML. It is characterized by its distinctive morphology, a t(15;17) translocation leading to PML-RARa fusion gene, and by a life-threatening coagulopathy. The PML-RARa fusion protein functions as an aberrant retinoid receptor that is resistant to physiological concentrations of retinoic acid. This resistance can be overcome by using all-transretinoic acid and arsenic tri-oxide.
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alone or arsenic alone. In the paediatric study, the results (EFS, DFS, OS) from the combination of ATRA and arsenic were comparable to the groups treated with ATRA alone or arsenic alone. The OS for the entire group of 65 patients was approximately 91% with a median follow-up of 38 months. Currently there are no UK studies open for paediatric APML patients but there is an international study, ICC APL 01, which is recruiting. The study aims to limit the use of anthracyclines, assess the role of ATO and ATRA in refractory/relapsed disease and stratify treatment by risk group: standard risk e WBC less than 10 109/litre:high risk e WBC 10 109/litre. All-trans retinoic acid (ATRA) is included in all phases of therapy and intermediate dose Ara-C (IDARAC) is given during consolidation treatment. Following one induction course of treatment standard risk patients have two consolidation blocks whilst high risk patients have three consolidation blocks. The PML e RARa transcript level (MRD) will be monitored throughout and standard risk patients with detectable MRD at the end of the second consolidation block will receive a third consolidation block identical to high risk patients. Patients who are MRDþ for PMLRARa after completion of the third block of consolidation therapy will be candidates for refractory/relapse treatment, but will remain on study. Refractory/relapsed patients will be treated with combination of ATRA and ATO and those who remain MRDþ for PML-RARa will be candidates for allogeneic HSCT, whilst those who become MRD e for PML e RARa will have individualized treatment with ongoing MRD monitoring.
presentation is 12e13 years. The natural history of the disease in children is the same as that seen in adults where before the development of molecularly targeted therapy showed a median survival of 5e8 years and a 10-year survival of 5%. The abnormal haemopoietic precursor cells of chronic myeloid leukaemia (CML) in 95% of patients carry the characteristic cytogenetic abnormality known as the Philadelphia translocation t(9;22)(q34;q11) which can be picked up on routine cytogenetic analysis. Most of the other patients with CML have detectable Bcr-Abl fusion genes even though the Philadelphia translocation cannot be detected by standard cytogenetics. The Bcr-Abl fusion protein produced as a result of this new oncogene is a constitutively active tyrosine kinase which mediates an array of effects on signal transduction pathways affecting cell survival, proliferation and genetic stability. The end-result of these abnormal signalling processes is a bi- or triphasic clinical disease. Initially, CML is characterized by the presence of an excess of myeloid progenitor cells and their mature progeny. This is chronic-phase CML and is followed, either directly or with an intervening ’accelerated phase’, by a stage where primitive blast cells predominate called blast crisis. The poor long-term outcome of the disease has led to an aggressive approach in treatment of CML in young patients with haemopoietic stem cell transplantation being the only curative therapy. However the most significant milestone in the treatment of CML, which has currently changed the role of transplantation, is the development of molecularly targeted therapy. This has significantly changed the natural history of the disease in many patients. The first drug developed was imatinib mesylate which is an inhibitor of tyrosine kinase. The results of the landmark IRIS trial in adults and updates from 6-year follow-up have indicated that since the introduction of imatinib the overall survival is 95% at 6 years with an event free survival of 83%. The results in children are similar to those in adults. Imatinib has been licensed for use in children since 2003 and is the currently recommended first line treatment in the UK. However as time elapses it is becoming clear from more recent studies that up to 15e25% of patients fail initial treatment or become intolerant of imatinib. The development of second-generation TKIs nilotinib and dasatinib for use in new or imatinib refractory CML have resulted in favourable rates of progression-free survival (PFS) and overall survival. Data from the ENESTnd (nilotinib) and DASISION (dasatinib) trials in newly diagnosed adults with chronic-phase CML demonstrated more robust and rapid complete cytogenetic (77e80%) and major molecular responses (43e46%) at 12 months compared with imatinib (65e66% and 22e28%) suggesting that these agents may be more potent than imatinib. As the disease behaves in a similar way in children, one would expect these results to be similar in the paediatric population. Further study is needed to determine the long-term efficacy of these agents. Whether any of these molecularly targeted therapies can result in long-term cure of CML remains to be seen and at present they are considered to control rather than cure the disease. In paediatric CML access to these second line drugs is only possible in the context of a clinical trial if patients are resistant to or intolerant of imatinib. The accepted current second line therapy in paediatrics in children who are intolerant, or who fail to respond/lose their response to imatinib is haemopoietic stem cell transplant with the best available donor.
Acute myeloid leukaemia in Down syndrome Children with DS have a 10e20-fold increased risk of developing leukaemia. They have an excellent response to treatment which seems to be due to the marked sensitivity of their blasts to cytarabine. Cytarabine based protocols with reduced anthracyclines and extra vigilance to infectious complications give these patients equal and often superior results to other groups of children with AML. Relapsed AML Despite advances in treatment, AML relapses in 30% of children. The probability of survival at relapse is low at less than 40% at 4 years. The relapsed AML 2001/01 international trial looked at adding in liposomal daunorubicin to FLAG chemotherapy for remission induction in relapsed or refractory AML before HSCT. The study found that the outcome was particularly poor in patients who relapsed very early (within 6 months) and improved as the time from initial diagnosis to relapse increased. The addition of liposomal daunorubicin to FLAG increased the response rate and has been carried forward into the new relapsed AML trial AML 2009/01. This will be the standard induction arm on the new trial, AML 2009/01, and patients will be randomized to receive Mylotarg or not with induction. The ‘g’ part of FLAG which is GCSF will be omitted as it is concluded to have no beneficial effect. Following induction patients in remission are eligible for HSCT, patients not in CR after induction would then be eligible for phase I/II studies with novel agents.
Chronic myeloid leukaemia Chronic myeloid leukaemia (CML) constitutes 2e3% of leukaemias in children and has an incidence of 0.6e1.2 per million per year. There is a slight male preponderance. The median age at
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Summary
Roberts IA, Dokal IS. Chronic myeloid leukemia. In: Arceci RJ, Hann IM, Smith OP, eds. Pediatric Hematology. 3rd Edn. Oxford, UK: Blackwell Publishing Ltd, 2007. Smith OP, Hann IM. Clinical features and therapy of lymphoblastic leukemia. In: Arceci RJ, Hann IM, Smith OP, eds. Pediatric hematology. 3rd Edn. Oxford, UK: Blackwell Publishing Ltd, 2007. Suttorp M. Innovative approaches of targeted therapy for CML of childhood in combination with paediatric haematopoietic SCT. Bone Marrow Transplant 2008; 42: S40e6. Will A. Update on leukaemia. Paediatr Child Health 2008; 18: 107e11. Wynn RF. Acute lymphoblastic leukemia. In: Estlin EJ, Gilbertson RJ, Wynn RF, eds. Pediatric hematology and oncology. Oxford, UK: Wiley-Blackwell, 2010. Xavier AC, Ge Y, Taub J. Unique clinical and biological features of leukemia in Down syndrome children. Expert Rev Hematol 2010; 3: 175e86. Review.
Treatment of leukaemia in childhood continues to improve and change as our knowledge of the diseases and their behaviour in response to treatment increases. The development of targeted therapies such as Mylotarg and Flt 3 inhibitors in AML, Imatinib in PhþALL and CML, ATRA and ATO in APML are showing benefits e some of which are remarkable e in clinical trials. Some targeted therapies are now in routine clinical use. The use of MRD in ALL to risk stratify treatment intensity is helping to reduce the treatment burden for patients with good risk disease and better predict those who may relapse; this risk based treatment strategy may well extend to all childhood leukaemia in the coming years. The developments made in the treatment of childhood leukaemias are possible through the early incorporation of scientific advances into clinic trials and the importance of recruitment and adherence to national and international protocols cannot be overemphasized. A
FURTHER READING Barr RD. Imatinib mesylate in children and adolescents with cancer. Pediatr Blood Cancer 2010 Jul 15; 55: 18e25. Review. Bomken S, Vormoor HJ. Childhood leukaemia. Paediatr Child Health 2009; 19: 345e50. Burnett AK, Hills RK, Goldstone AH, et al. Attempts to optimize induction and consolidation treatment in acute myeloid leukemia: results of the MRC AML12 trial. J Clin Oncol 2010; 28: 586e95. Kaspers GJ, Zwaan CM. Pediatric acute myeloid leukemia: towards highquality cure of all patients. Haematologica 2007; 92: 1519e32. Review. Kean LS, Arceci RJ, Woods WG. Acute myeloid leukemia. In: Arceci RJ, Hann IM, Smith OP, eds. Pediatric hematology. 3rd Edn. Oxford, UK: Blackwell Publishing Ltd, 2007. Millot F, Baruchel A, Guilhot J, et al. Imatinib is effective in children with previously untreated chronic myelogenous leukemia in early chronic phase: results of the French national phase IV trial. Expert Rev Hematol December 2010; 3: 665e73. Moppett J, Burke GA, Steward CG, Oakhill A, Goulden NJ. The clinical relevance of detection of minimal residual disease in childhood acute lymphoblastic leukaemia. J Clin Pathol 2003; 56: 249e53. Review.
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Advances in understanding of leukaemia biology have led to the development of targeted therapies which are increasingly successfully incorporated into treatment algorithms for childhood leukaemias. With further study the precise role of these new targeted therapies will become clearer e in some diseases the targeted therapy alone may be sufficient for controlling the disease (CML), in other diseases targeted therapy is used in conjunction with conventional therapy (AML). Response to treatment as measured by minimal residual disease monitoring allows stratification of treatment intensity in ALL and may well prove to be useful in risk stratifying treatment for other childhood leukaemias in future. Current and future clinical trials will continue to combine maximizing cure with minimizing toxicity of treatment. This is crucial in minimizing both the short-term and long-term adverse effects of treatment.
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An update on leukaemia
2. Development of strategies to prevent central nervous system (CNS) relapse: even with multidrug systemic therapy, many children who had a systemic response had a CNS relapse leading to treatment failure. The CNS is a sanctuary site for leukaemia and it became apparent that to prevent CNS relapse, treatment directed towards the CNS was needed. This was initially achieved with prophylactic radiation treatment to the central nervous system in early treatment protocols for ALL 3. Development of randomized clinical trials to test newer drugs or schedules: this concept of a structured framework in which to test drugs and schedules has allowed leukaemia treatment to sequentially and progressively improve. This established the components of treatment that are still used today e these being remission induction, consolidation and CNS directed therapy, re-induction (or intensification), and continuing maintenance therapy. In more recent years the lessons learned from the early years of treatment have been carried forward into clinical trials and in the UK, national UK ALL trials have realized a step wise improvement in prognosis from a 5-year event free survival (EFS) of 35% in 1972 to 87% in 2010. With the improvement in cure rate came the realization that survivors had long-term effects associated with treatment, particularly radiation treatment which had adverse effects on growth, neurocognitive and endocrine function. Thus as well as focussing on improving cure rates, the more recent trials have also sought to reduce long-term sequelae. The most important recent findings of the successive UK ALL trials are 1. UKALL 11 found that CNS irradiation is not required to prevent CNS relapse. This is a major milestone in the success of leukaemia treatment. Cranial irradiation has now been abolished as standard therapy in UK trials and only intrathecal and systemic therapy are used. This is as effective as radiation in preventing relapse but is not associated with the adverse effects seen with radiation therapy 2. Dexamethasone is superior to prednisolone in preventing CNS relapse 3. Mercaptopurine is as efficacious but less toxic than thioguanine and is the preferred purine to use in maintenance therapy 4. Improvements in delivering risk-directed treatment. Modern treatment protocols use risk adapted stratification systems to allocate patients to treatment arms of different intensity. Risk stratification aims to avoid over treatment in those children with low risk disease and avoid under-treatment in those with high risk disease. The National Cancer Institute has developed a classification based on age, white cell count at presentation and cytogenetics of the leukaemic cells. This was introduced in UK ALL 97 trial. However this in itself is inaccurate as some children with apparently good risk disease will relapse and many with apparently poor risk will do well. The risk assessment tool can be improved by including the response of the disease to initial therapy. This can be crudely done by the morphological assessment of blast disappearance. More recently the use of more sophisticated techniques to quantitate minimal residual disease (MRD) has been employed to aid risk assessment. The first MRD stratified protocol for acute leukaemia in the UK,
Denise K Bonney
Abstract As a group, the leukaemias represent the most common malignant conditions of childhood. The treatment of childhood leukaemia, and in particular the treatment of acute lymphoblastic leukaemia (ALL), has shown tremendous improvement in outcome in the last 40 years. Much of the success is due to the improvements in leukaemia therapy demonstrated in improved disease-free survival and reduced relapse rates in clinical trials but improvements in supportive care over the years have also had a very significant contribution. Over the last 30 years we have also seen reduced treatment related mortality due to better management of complications and better detection and treatment of infections. The emphasis of treatment as well as being cure is now focussing on targeting therapy to reduce the treatment burden in good risk disease and identify and intensify treatment for those with poor risk disease. The development of molecularly targeted therapies has changed the therapeutic landscape and this last decade has seen many improvements in outcome associated with these new agents. This review will give a brief overview of current treatment protocols used in childhood leukaemia, focussing specifically on the latest improvements and strategies in treating these conditions.
Keywords acute lymphoblastic leukaemia; acute myeloid leukaemia; chronic myeloid leukaemia; paediatric
Acute lymphoblastic leukaemia Acute lymphoblastic leukaemia, the most common of the childhood leukaemias, accounts for around 25% of malignant diagnoses in childhood and accounts for around 85% of all childhood leukaemias. In the UK the incidence is 30 per million children per year. It has a peak incidence between the ages of 2 and 5 years. ALL is defined by an uncontrolled proliferation of immature lymphoid (B or T) cells. The leukaemic cells proliferate and the clinical signs and symptoms of ALL can be explained by the proliferation of leukaemic cells within the bone marrow or other organs. ALL treatment has proceeded from palliation to cure since the 1940s. The advances made in the early years of treatment were 1. Development of multidrug therapy: early attempts at cure with monotherapy resulted in only transient responses. Combining drug therapies was more successful leading to cure in some patients and overcoming the problems due to drug resistance seen with monotherapies. The use of separate multi drug schedules in the sequential parts of ALL therapy remains the backbone of leukaemia therapy
Denise K Bonney MBChB MRCPCH PhD FRCPath is Consultant Paediatric Haematologist in the Department of Paediatric Haematology/Oncology at the Royal Manchester Children’s Hospital, Manchester, UK. Conflicts of interest: none declared.
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UKALL 2003, opened in October 2003 and has just completed recruitment in June 2011. MRD results at week 4 and week 11 were used to randomize patients to receive more or less intensive chemotherapy depending on whether they had high or low levels of MRD at these time points. While final results will not be available for some time, the interim analysis of UKALL 2003 reveals a 5-year EFS 87.7% and overall survival (OS) of 91.3% and UKALL 2003 has confirmed the predictive value of MRD. A three-fold increase in relapse risk (RR) is seen in MRD high risk group (5-year EFS 80.7%) compared to MRD low risk group (5-year EFS 95.6%). This concept of MRD is discussed in further detail below.
as lymphoid markers and there is a very high incidence of structural abnormalities of chromosome 11. These abnormalities often result in rearrangement of 11q23 within the MLL gene which confers poor prognosis. When treated with standard ALL protocols, the results for infants with ALL were poor with a one in four chance of long-term survival. The development of trials specifically focussed on improving outcome in infants with ALL has significantly improved the outlook for these patients. As the disease is rare, the trials set up have been pan European. Interfant 99 involved 22 countries and enrolled almost 500 patients. This study was set up to try and answer three main questions 1. Would a different treatment protocol would improve survival? 2. Would a more intensive treatment following initial therapy would improve survival? 3. Are there specific factors that could be used to predict survival chances? In view of the hybrid nature of infant ALL, the treatment schedule was based upon a so-called hybrid therapy, consisting of elements from both ALL and AML treatment schedules. All patients received a week of prednisolone therapy and were then divided into two risk groups (standard risk and high risk) based on whether they had a good response to this. Following stratification all patients received the same induction and also two further hybrid courses. After three courses the poor risk group underwent haemopoietic stem cell transplantation (HSCT) if donor available or were randomized to maintenance with or without further intensive therapy. The good risk group were randomized to maintenance with or without a further course of intensive therapy (intensive versus standard treatment). The trial also measured MRD at multiple time points to ascertain if MRD levels could determine prognosis in this disease. The trial showed a disease-free survival (DFS) at 4 years of 47%, a marked improvement on previous results. Within the good risk group 55e60% of patients were disease-free at 4 years and within this group there was no difference in outcome between the standard therapy and intensive treatment arm. However there was more toxicity in the intensive arm. Thus the hybrid approach does improve outcome but there is little benefit to adding in further intensive therapy after the initial three courses. The trial demonstrated that the following factors predicted for poor prognosis Age less than 6 months at diagnosis Presence of MLL gene rearrangement WCC more than 300 109 per litre at presentation Poor response to initial treatment. Infants without any of these factors are low risk and in Interfant 99 had a 2-year EFS of 87%. Infants with MLL gene rearrangement, less than 6 months of age at diagnosis with high WCC or poor response to initial treatment are classified as high risk and in Interfant 99 had a 2-year EFS of 15.9%. All other cases are medium risk and had a survival of 49.5%. Results from Interfant 99 published in 1999 showed that high levels of MRD measured immediately before the penultimate course of intensive chemotherapy identified a group of patients with a significantly reduced disease-free survival. Interfant 2006 stratifies patients into good, medium and high risk categories depending on the presence or absence of the
Risk stratified therapy and minimal residual disease in leukaemia: when acute lymphoblastic leukaemia is diagnosed in a patient, the total number of leukaemia cells is approximated to 1012e1013. The majority of patients reach complete remission (CR) as judged by a blast cell count of less than 5% in the bone marrow by microscopic analysis after 4 weeks of chemotherapy. However, complete remission does not mean that leukaemia cells are totally eradicated from the body but that their level is below the sensitivity level of classical morphological analysis method (e.g. 1e5%). At this time, many malignant cells can still remain in the patient. They represent the minimal residual disease (MRD). Techniques which are more sensitive than morphology are now available that permit detection of these residual blasts and thus the burden of residual disease. Techniques aimed at studying MRD rely on the detection of a leukaemia cell specific marker which enables blasts to be distinguished from normal marrow cells. Such markers have to be detected with high sensitivity, to be present in all leukaemia cells and to be stable during disease evolution. Two kinds of markers are currently used: genetic markers, which can be detected by PCR, and immunophenotypic markers, which can be detected by flow cytometry. PCR based strategies can be directed to two types of genetic targets: breakpoints of leukaemia-related chromosome aberrations, and antigen-receptor gene rearrangements. The high sensitivity of polymerase chain reaction (PCR) makes it possible to consistently detect one leukaemia cell among 105 normal cells (105). It is now established that the level of MRD represents a powerful prognostic factor and is in fact the strongest predictor of outcome in children undergoing identical therapies. Future ALL trials: UKALL 2011 is due to open in autumn 2011 and will build on lessons learned from UKALL 2003. Although the details are not yet finalized, the trial will look at whether further refinement of treatment based on MRD based risk stratification at end of induction improves survival while reducing the overall burden of treatment. Acute lymphoblastic leukaemia in infants Fewer than 5% of children presenting with ALL are infants. Infant ALL is biologically distinct from ALL in older children. Infant ALL often presents with very high blast counts, hepatosplenomegaly and CNS involvement e features that are uncommon in older children. The blasts cells express a more primitive immunophenotype with expression of myeloid as well
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prognostic factors identified in Interfant 99. Infants in the low risk category have three courses of intensive chemotherapy followed by maintenance chemotherapy for a total of 2 years (standard therapy). Infants in the medium and high risk group are randomized to standard therapy as per low risk arm or a more intensive chemotherapy arm involving four courses of intensive chemotherapy rather than three before maintenance. Infants in high risk group and those infants in medium risk group with high MRD on commencing penultimate course of intensive therapy are eligible for HSCT. This trial is still open and continuing to recruit.
stratification and predict outcome. In its initial form, patients were allocated to good and poor risk groups depending on their initial response to steroid therapy, assessed by the rate of clearance of lymphoblasts from the blood. Good risk patients were randomized to receive imatinib or not in addition to standard therapy. In this group those with a well-matched donor went on to have transplant and those without a donor continued to receive chemotherapy imatinib. The poor risk patients all received imatinib in addition to standard therapy with the expectation that most of this group would go on to receive a transplant if any suitable donor was available. The trial was amended in February 2010 to remove the randomization for imatinib and instead all patients on the trial now receive imatinib. This amendment was made following interim analysis of the trial results in light of the very encouraging results found by the COG AALL0031 study which showed that the addition of the imatinib to conventional ALL therapy had dramatically improved the outcome and in fact doubled the 3-year EFS from 35% to 80% for children and adolescents with this form of ALL. Analysis of EsPhALL data showed a trend to improved survival in the good risk group who received imatinib (3-year EFS of 72.3% vs 60.2%) and the poor risk group, who all received imatinib did significantly better than poor risk patients in any non-imatinib protocol. Also the addition of imatinib was well tolerated and did not increase the toxicity of the treatment. Thus the trial steering committee closed the randomization and proposed continuous imatinib exposure to all patients The EsPhALL trial is still open and recruiting. There is some early suggestion that low/negative MRD levels at the end of induction treatment may predict for a group of patients in whom chemotherapy and imatinib alone will be curative and thus MRD may help clarify the role of HSCT in this disease. As newer and more potent tyrosine kinase inhibitors are now available further trials in this disease will investigate the use of these agents. At present only patients who are resistant to or intolerant of imatinib are eligible for enrolment in these phase I and II trials.
Philadelphia Positive acute lymphoblastic leukaemia 3e5% of children with ALL carry the Philadelphia chromosome in their leukaemic cells. This abnormality results from a reciprocal translocation between chromosomes 9 and 22. The result of the translocation is the oncogenic BCR-ABL gene fusion, located on the shorter derivative 22 chromosome. This gene encodes the Bcr-Abl fusion protein which has kinase activity. Depending on the precise location of the fusion the molecular weight of the protein can range from 185 to 210 kDa. In cases of Philadelphia positive ALL (Phþ ALL), the majority (85%) express the p185 fusion protein and most of the rest express the p210 fusion protein which is more commonly seen in CML e see below. Until recently the outlook for children with Phþ ALL was dismal. Only around 30% of children and adolescents with the disease were long-term survivors with conventional chemotherapy treatment including HSCT. It was recognized that there were three features which predicted which children were likely to do better Good initial response to steroids Age less than 10 years WCC less than 50 109/litre at presentation. However even children with this constellation of good risk features had long-term survival of less than 50%. The outcome seemed to be improved in some patients with HSCT e particularly from matched family donor and thus children were offered HSCT as the long-term outcome from chemotherapy alone was so poor. Employing clinical trials to study and improve the outcome in this disease is challenging as the numbers of children diagnosed with this form of leukaemia is low e only 8e10 children in the UK are diagnosed each year. Therefore trials aimed at improving outcome PhþALL require a collaborative approach. The EsPhALL trial which opened in the UK in 2004 and is still running, is an international trial of children and adolescents with PhþALL. At the time this trial was opened many studies were reporting the results of trials using tyrosine kinase inhibitor drugs which inhibit the fusion protein produced as a result of the Philadelphia translocation in the treatment of Philadelphia positive diseases. The first of these drugs, imatinib mesylate, is effective (albeit temporarily) in Phþ ALL as well as CML. In one study of patients (mainly adults) with refractory or resistant PhþALL, imatinib resulted in improvement in 75% of patients and 25% achieved a complete remission. The aim of the EsPhALL trial was to evaluate the safety and efficacy of imatinib in addition to chemotherapy in children with Phþ ALL. This trial also measures MRD in patients with Phþ ALL at defined time points to determine if we can use this in future to improve risk
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Acute myeloid leukaemia Acute myeloid leukaemia (AML) is the second most common type of childhood leukaemia and accounts for 15% of childhood leukaemias and 5% of childhood malignancies. The incidence is 6.5 children per million per year. The cause(s) of AML is unknown in most instances. One clearly identified risk factor is exposure to very high radiation levels such as experienced after the atom bomb explosions in Japan in 1945. Very few, if any, children in the Western world are exposed to levels of radiation high enough to increase the risk of leukaemia. AML is more common in children with certain syndromes such as Down syndrome and congenital bone marrow failure syndromes (Fanconi anaemia, severe congenital neutropaenia, Shwachman Diamond syndrome). AML therapy is based on induction chemotherapy with an anthracycline combined with cytarabine and in paediatric patients etoposide is also used in induction. Two induction courses are given. Following this patients receive consolidation courses, though the number of consolidation blocks varies between different trials. The importance of CNS therapy is
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unclear as CNS relapse is uncommon in AML however children receive CNS directed treatment as intrathecal injections aimed at preventing CNS relapse. The cure rate for AML although improved over the last decades is still much less than for ALL and up to a third of children relapse following treatment. Thus in discussing strategies for treating AML it is also relevant to mention treatment of relapsed disease. Between 1988 and 2002, children with acute myeloid leukaemia (AML) were treated on Medical Research Council (MRC) AML 10 and AML 12 trials. AML 10 compared different combinations of anthracycline and cytarabine based chemotherapy for induction and tested the role of bone marrow transplantation following four blocks of intensive chemotherapy. The trial found no difference in efficacy between the induction schedules, but using mitoxantrone as anthracycline in place of daunorubicin increased myelotoxicity. The addition of either autologous or allogeneic haemopoietic stem cell transplantation significantly reduced the relapse risk (RR), but was associated with an increase in treatment related deaths which largely offset the reduction in relapse. Analysis of AML 10 data demonstrated that karyotype of leukaemia cells was a major determinant of prognosis, with t(8;21), inv(16) and t(15;17) being favourable whilst monosomy 7, abnormal 5q, abnormal 3q or complex karyotypes being adverse. All other karyotypes were intermediate risk. In AML 12, risk group stratification into good, standard and poor risk groups based on cytogenetics derived from MRC AML 10 and response to the first course of chemotherapy was used to deliver risk-directed therapy. In this trial, allo-BMT was limited to standard and poor risk patients and autologous transplant procedures were not employed. Instead, the benefit of an additional block of treatment was tested by randomizing children to receive either four or five blocks of treatment in total. The 5-year OS, DFS, EFS and RR in MRC AML 12 are 66, 61, 56 and 35%, respectively; at present superior to MRC AML 10, which had a 5year OS, DFS, EFS and RR of 58, 53, 49 and 42%, respectively. The results of MRC AML 12 did not show a survival advantage for a fifth course of treatment. The most recent publication on the results of AML 12 reported that HSCT showed a significant survival benefit only for poor risk patients. The next trial AML 15, opened in 2002 and completed recruitment in 2009. This trial asked a number of important questions 1. Which induction regimen is best e the use of induction regimen FLAG-Ida which was showing good results in relapsed adult AML was tested against the now standard cytarabine, daunorubicin and etoposide paediatric induction chemotherapy. The main question being asked was whether use of FLAG-Ida reduced the relapse rate 2. Does five courses result in better outcome than four e this was carried through from AML10 to permit meta analysis of the results of four versus five courses randomization from both trials as when this trial was designed and enrolling the long-term results of AML 12 were not available 3. Can anthracycline dosage be reduced (therefore reducing risk of long-term cardiotoxicity) without compromising outcome by comparing standard MRC anthracycline-based consolidation with high-dose cytarabine based consolidation? This randomization is particularly important for children
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4. Do poor risk children benefit from a transplant procedure after induction courses compared to children who receive further chemotherapy 5. Can the amount of intrathecal therapy delivered as CNS prophylaxis safely be reduced. In AML 10 four course of intrathecal therapy were given. In AML12 this was reduced to three without any increase in CNS relapse rate. In AML 15 two course of intrathecal chemotherapy were given 6. Does introduction of targeted therapies e Mylotarg and CEP701 improve outcome. AML 15 was the first of the UK AML trials to use molecularly targeted therapy. Mylotarg or gemtuzumab ozogamicin (GO) is an immunoconjugate combining a humanized anti CD33 antibody to the DNA intercalating agent, calicheamicin. CD33 is expressed on some haemopoetic progenitors and on more than90% of blasts cells in AML. Thus mylotarg acts as a targeted chemotherapy by binding to AML blasts cells allowing calicheamicin to act. In AML 15 patients were randomized to receive mylotarg with consolidation. FLT3 is a receptor tyrosine kinase with important roles in haematopoietic stem/progenitor cell survival and proliferation. It is mutated in about 1/3 of acute myeloid leukaemia (AML) patients. Mutation results in a constitutively activated FLT3. Many studies have shown that AML patients with FLT3 mutations have poor cure rates due to relapse. This has led to the development of a number of small molecule tyrosine kinase inhibitors with activity against FLT3. CEP-701 is an inhibitor of FLT3, which has been demonstrated to be of some benefit in older patients with AML considered unfit for conventional chemotherapy. Patients over the age of 16 years entered into AML15 with FLT3 mutations were eligible for randomization to receive CEP-701 or not. The full results of AML 15 are not yet available but the following have been reported 1. There was no significant difference in efficacy between induction schedules tested, however the FLAG e Ida chemotherapy was associated with more toxicity which offsets any decrease in relapse rate 2. There was no difference seen in outcome with four or five courses of chemotherapy e thus no benefit of fifth course 3. Thus far there are no differences in outcome between anthracycline and cytarabine based consolidation. All children will now receive cytarabine base consolidation unless there unexpected findings with later follow-up of AML 15 4. The role of HSCT in AML in first remission is limited in first CR and that there may be a ceiling of benefit from current or conventional chemotherapy 5. Mylotarg reduces the relapse risk. The initial results of the first 1115 patients in AML 15 that received mylotarg, which included mainly adults, have been reported recently. As yet, there is no significant difference in overall survival (56% for the mylotarg group compared to 46% in the no mylotarg group at 3 years), but there was a significant difference in relapse rate (37% in the mylotarg group versus 52%; p ¼ 0.01), which resulted in an improved disease-free survival (51% versus 40%). Although the full results of Mylotarg randomization AML 15 are not yet published the evidence shows that the patients with good risk cytogenetics e inversion 16 or t(8;21) are most likely to derive benefit from Mylotarg 6. The full results of CEP-701 randomization in AML 15 are not yet known, but the use of CEP-701 has been carried forward into
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AML 17 where children and adults with Flt3 mutations will be randomized to receive Flt 3 inhibitors if they have a mutation 7. The interim results at 3 years indicate OS of 74%, DFS of 60% and RR of 35%.
The optimum treatment strategy for this disease is still the subject of study. Many studies continue to investigate the optimum drug therapy and it is now clear that molecular monitoring of MRD quantifying PML-RARa transcript levels by PCR technology can direct more precise tailoring of therapy. MRD positivity has been shown to provide an independent risk factor for relapse. Italian studies in children and adults have established that patients with PML-RARa transcripts still detectable at the end of consolidation (who account for w5% of cases overall) or those subject to a later recurrence of PCR positivity (molecular relapse) are destined to undergo subsequent haematological relapse, which may in both instances be averted by additional therapy. In terms of optimum drug therapy, results for APML patients treated on AML 10 and AML 12 trials were excellent with 3-year OS of 83% when given ATRA plus four or five courses of standard AML therapy. In 1999, a Spanish group reported a 2-year survival of 92% using a modified ATRA plus anthracycline-based chemotherapy regimen including extended maintenance therapy. This protocol had much reduced myelosuppression and thus fewer side effects and less time spent in hospital. In AML 15 adult patients with APML were randomized to standard therapy or the Spanish protocol. The Spanish protocol was found to be superior and the randomization closed with all adults subsequently receiving the therapy as per the Spanish approach. However patients under the age of 16 years with APML were not eligible for treatment with the Spanish protocol and instead received standard AML chemotherapy treatment and ATRA. The role of arsenic tri-oxide in treatment of APML continues to be evaluated. Studies have tested ATO as a single agent or in combination with ATRA in relapsed or refractory APML. ATO as a single agent was able to induce durable molecular remission after two cycles in the majority of patients treated for disease recurrence. Confirmation of the high efficacy of ATO in relapsed APL was provided successively by several trials conducted worldwide which reported CR rates more than70% and 1e3-year survival rates in the range of 50e70%. In addition to trials in which ATO was used a single agent, some studies investigated its efficacy and toxicity profile in combination with other agents including ATRA. Synergism with ATRA and increased anti-leukaemic efficacy in APML was demonstrated in a Chinese randomized study comparing ATOþATRA vs. either ATO or ATRA used as single agents. No significant additional toxicity was reported in this or in other studies which analyzed the effect of ATRA and ATO combination. Following the experience of ATO in relapsed patients and based on the favourable toxicity profile, investigators have more recently explored the effect of ATO in newly diagnosed APL patients and reported preliminary findings in front-line therapy. The combination of ATO and ATRA compared with ATRA alone or arsenic alone during induction chemotherapy followed by conventional consolidation and maintenance therapy has been tested in both adult and paediatric patients with APL. The study in adults showed that the CR rate was the same among all three induction regimens, although CR was achieved sooner with the combination regimen (median 25.5 days) compared with ATRA alone (median 40.5 days) or arsenic alone (median 31 days). Additionally, the combination of ATRA and arsenic resulted in an increased disease-free survival (DFS) compared with the patients treated with the combined results of chemotherapy with ATRA
Acute myeloid leukaemia 17: AML 17 opened in 2010 and builds on findings of previous trials whilst also for the first time incorporating MRD monitoring into AML treatment. Children will receive standard ADE induction for two courses. The children are risk stratified following induction into high or non-high risk groups. The risk stratification is no longer based solely on cytogenetics and response to first course of treatment but is now a risk score which as well as incorporating the above factors in age at diagnosis, presenting white cell count, sex and whether leukaemia is primary or secondary. The aims of the trial for the paediatric population are 1. To assess impact of mylotarg therapy given with induction: children will be randomized to two different doses of mylotarg or none with induction. As the results of AML 15 become known, alterations are being made to AML 17. For example, leukaemias with inv(16) or t(8;21) seem to derive the most benefit from mylotarg e so all children with these cytogenetic findings will now receive this drug even if they were randomized not to receive it diagnosis 2. To assess the impact of Flt3 inhibitor in AML with Flt3 mutations: children without CBF leukaemias who are not high risk and are Flt3 positive will be randomized to receive CEP-701 or placebo with consolidation 3. To assess impact of stem cell transplant in high risk children: the new high risk score includes more prognostic features than cytogenetic stratification alone. The risk score was derived from statistical analysis of factors which significantly influenced survival in AML 10 and 12. The new risk score increases the number of patients in the poor risk category as it identifies patients who have a poor prognosis for reasons other than their cytogenetics. The high risk group have a 70% chance of relapse. Poor risk individuals will then go on to receive FLAG-Ida chemotherapy (two courses) as consolidation and a transplant if there is a donor available. If no donor available children will have a third course of FLAGIda 4. To monitor MRD in AML: in AML the presence of MRD measured by flow cytometry on count recovery after course 1 predicts relapse. However not all MRD positive patients relapse and about a third of patients who do relapse are MRD negative after course 1. The role of MRD in AML is thus still not fully clarified and in this trial the first aim will be to validate times points and levels of sensitivity before using MRD to guide therapy. Acute promyelocytic leukaemia Acute promyelocytic leukaemia (APML) is an uncommon distinct subtype of acute myeloid leukaemia and accounts for 8% of childhood AML. It is characterized by its distinctive morphology, a t(15;17) translocation leading to PML-RARa fusion gene, and by a life-threatening coagulopathy. The PML-RARa fusion protein functions as an aberrant retinoid receptor that is resistant to physiological concentrations of retinoic acid. This resistance can be overcome by using all-transretinoic acid and arsenic tri-oxide.
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alone or arsenic alone. In the paediatric study, the results (EFS, DFS, OS) from the combination of ATRA and arsenic were comparable to the groups treated with ATRA alone or arsenic alone. The OS for the entire group of 65 patients was approximately 91% with a median follow-up of 38 months. Currently there are no UK studies open for paediatric APML patients but there is an international study, ICC APL 01, which is recruiting. The study aims to limit the use of anthracyclines, assess the role of ATO and ATRA in refractory/relapsed disease and stratify treatment by risk group: standard risk e WBC less than 10 109/litre:high risk e WBC 10 109/litre. All-trans retinoic acid (ATRA) is included in all phases of therapy and intermediate dose Ara-C (IDARAC) is given during consolidation treatment. Following one induction course of treatment standard risk patients have two consolidation blocks whilst high risk patients have three consolidation blocks. The PML e RARa transcript level (MRD) will be monitored throughout and standard risk patients with detectable MRD at the end of the second consolidation block will receive a third consolidation block identical to high risk patients. Patients who are MRDþ for PMLRARa after completion of the third block of consolidation therapy will be candidates for refractory/relapse treatment, but will remain on study. Refractory/relapsed patients will be treated with combination of ATRA and ATO and those who remain MRDþ for PML-RARa will be candidates for allogeneic HSCT, whilst those who become MRD e for PML e RARa will have individualized treatment with ongoing MRD monitoring.
presentation is 12e13 years. The natural history of the disease in children is the same as that seen in adults where before the development of molecularly targeted therapy showed a median survival of 5e8 years and a 10-year survival of 5%. The abnormal haemopoietic precursor cells of chronic myeloid leukaemia (CML) in 95% of patients carry the characteristic cytogenetic abnormality known as the Philadelphia translocation t(9;22)(q34;q11) which can be picked up on routine cytogenetic analysis. Most of the other patients with CML have detectable Bcr-Abl fusion genes even though the Philadelphia translocation cannot be detected by standard cytogenetics. The Bcr-Abl fusion protein produced as a result of this new oncogene is a constitutively active tyrosine kinase which mediates an array of effects on signal transduction pathways affecting cell survival, proliferation and genetic stability. The end-result of these abnormal signalling processes is a bi- or triphasic clinical disease. Initially, CML is characterized by the presence of an excess of myeloid progenitor cells and their mature progeny. This is chronic-phase CML and is followed, either directly or with an intervening ’accelerated phase’, by a stage where primitive blast cells predominate called blast crisis. The poor long-term outcome of the disease has led to an aggressive approach in treatment of CML in young patients with haemopoietic stem cell transplantation being the only curative therapy. However the most significant milestone in the treatment of CML, which has currently changed the role of transplantation, is the development of molecularly targeted therapy. This has significantly changed the natural history of the disease in many patients. The first drug developed was imatinib mesylate which is an inhibitor of tyrosine kinase. The results of the landmark IRIS trial in adults and updates from 6-year follow-up have indicated that since the introduction of imatinib the overall survival is 95% at 6 years with an event free survival of 83%. The results in children are similar to those in adults. Imatinib has been licensed for use in children since 2003 and is the currently recommended first line treatment in the UK. However as time elapses it is becoming clear from more recent studies that up to 15e25% of patients fail initial treatment or become intolerant of imatinib. The development of second-generation TKIs nilotinib and dasatinib for use in new or imatinib refractory CML have resulted in favourable rates of progression-free survival (PFS) and overall survival. Data from the ENESTnd (nilotinib) and DASISION (dasatinib) trials in newly diagnosed adults with chronic-phase CML demonstrated more robust and rapid complete cytogenetic (77e80%) and major molecular responses (43e46%) at 12 months compared with imatinib (65e66% and 22e28%) suggesting that these agents may be more potent than imatinib. As the disease behaves in a similar way in children, one would expect these results to be similar in the paediatric population. Further study is needed to determine the long-term efficacy of these agents. Whether any of these molecularly targeted therapies can result in long-term cure of CML remains to be seen and at present they are considered to control rather than cure the disease. In paediatric CML access to these second line drugs is only possible in the context of a clinical trial if patients are resistant to or intolerant of imatinib. The accepted current second line therapy in paediatrics in children who are intolerant, or who fail to respond/lose their response to imatinib is haemopoietic stem cell transplant with the best available donor.
Acute myeloid leukaemia in Down syndrome Children with DS have a 10e20-fold increased risk of developing leukaemia. They have an excellent response to treatment which seems to be due to the marked sensitivity of their blasts to cytarabine. Cytarabine based protocols with reduced anthracyclines and extra vigilance to infectious complications give these patients equal and often superior results to other groups of children with AML. Relapsed AML Despite advances in treatment, AML relapses in 30% of children. The probability of survival at relapse is low at less than 40% at 4 years. The relapsed AML 2001/01 international trial looked at adding in liposomal daunorubicin to FLAG chemotherapy for remission induction in relapsed or refractory AML before HSCT. The study found that the outcome was particularly poor in patients who relapsed very early (within 6 months) and improved as the time from initial diagnosis to relapse increased. The addition of liposomal daunorubicin to FLAG increased the response rate and has been carried forward into the new relapsed AML trial AML 2009/01. This will be the standard induction arm on the new trial, AML 2009/01, and patients will be randomized to receive Mylotarg or not with induction. The ‘g’ part of FLAG which is GCSF will be omitted as it is concluded to have no beneficial effect. Following induction patients in remission are eligible for HSCT, patients not in CR after induction would then be eligible for phase I/II studies with novel agents.
Chronic myeloid leukaemia Chronic myeloid leukaemia (CML) constitutes 2e3% of leukaemias in children and has an incidence of 0.6e1.2 per million per year. There is a slight male preponderance. The median age at
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Summary
Roberts IA, Dokal IS. Chronic myeloid leukemia. In: Arceci RJ, Hann IM, Smith OP, eds. Pediatric Hematology. 3rd Edn. Oxford, UK: Blackwell Publishing Ltd, 2007. Smith OP, Hann IM. Clinical features and therapy of lymphoblastic leukemia. In: Arceci RJ, Hann IM, Smith OP, eds. Pediatric hematology. 3rd Edn. Oxford, UK: Blackwell Publishing Ltd, 2007. Suttorp M. Innovative approaches of targeted therapy for CML of childhood in combination with paediatric haematopoietic SCT. Bone Marrow Transplant 2008; 42: S40e6. Will A. Update on leukaemia. Paediatr Child Health 2008; 18: 107e11. Wynn RF. Acute lymphoblastic leukemia. In: Estlin EJ, Gilbertson RJ, Wynn RF, eds. Pediatric hematology and oncology. Oxford, UK: Wiley-Blackwell, 2010. Xavier AC, Ge Y, Taub J. Unique clinical and biological features of leukemia in Down syndrome children. Expert Rev Hematol 2010; 3: 175e86. Review.
Treatment of leukaemia in childhood continues to improve and change as our knowledge of the diseases and their behaviour in response to treatment increases. The development of targeted therapies such as Mylotarg and Flt 3 inhibitors in AML, Imatinib in PhþALL and CML, ATRA and ATO in APML are showing benefits e some of which are remarkable e in clinical trials. Some targeted therapies are now in routine clinical use. The use of MRD in ALL to risk stratify treatment intensity is helping to reduce the treatment burden for patients with good risk disease and better predict those who may relapse; this risk based treatment strategy may well extend to all childhood leukaemia in the coming years. The developments made in the treatment of childhood leukaemias are possible through the early incorporation of scientific advances into clinic trials and the importance of recruitment and adherence to national and international protocols cannot be overemphasized. A
FURTHER READING Barr RD. Imatinib mesylate in children and adolescents with cancer. Pediatr Blood Cancer 2010 Jul 15; 55: 18e25. Review. Bomken S, Vormoor HJ. Childhood leukaemia. Paediatr Child Health 2009; 19: 345e50. Burnett AK, Hills RK, Goldstone AH, et al. Attempts to optimize induction and consolidation treatment in acute myeloid leukemia: results of the MRC AML12 trial. J Clin Oncol 2010; 28: 586e95. Kaspers GJ, Zwaan CM. Pediatric acute myeloid leukemia: towards highquality cure of all patients. Haematologica 2007; 92: 1519e32. Review. Kean LS, Arceci RJ, Woods WG. Acute myeloid leukemia. In: Arceci RJ, Hann IM, Smith OP, eds. Pediatric hematology. 3rd Edn. Oxford, UK: Blackwell Publishing Ltd, 2007. Millot F, Baruchel A, Guilhot J, et al. Imatinib is effective in children with previously untreated chronic myelogenous leukemia in early chronic phase: results of the French national phase IV trial. Expert Rev Hematol December 2010; 3: 665e73. Moppett J, Burke GA, Steward CG, Oakhill A, Goulden NJ. The clinical relevance of detection of minimal residual disease in childhood acute lymphoblastic leukaemia. J Clin Pathol 2003; 56: 249e53. Review.
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Advances in understanding of leukaemia biology have led to the development of targeted therapies which are increasingly successfully incorporated into treatment algorithms for childhood leukaemias. With further study the precise role of these new targeted therapies will become clearer e in some diseases the targeted therapy alone may be sufficient for controlling the disease (CML), in other diseases targeted therapy is used in conjunction with conventional therapy (AML). Response to treatment as measured by minimal residual disease monitoring allows stratification of treatment intensity in ALL and may well prove to be useful in risk stratifying treatment for other childhood leukaemias in future. Current and future clinical trials will continue to combine maximizing cure with minimizing toxicity of treatment. This is crucial in minimizing both the short-term and long-term adverse effects of treatment.
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