Acute myeloid leukaemia
Richard F StevensRoyal Manchester Children's Hospital, Manchester, UK
There has been considerable progress in the understanding and treatment of childhood acute myeloid leukaemia over the past two decades. In particular, cyto-and molecular genetics offer the potential for more specific diagnosis of what is basically a heterogeneous disease.To date treatment has been based on a steady increase in cytotoxic chemotherapy with or without the addition of bone marrow transplantation. Randomised therapeutic trials are difficult to perform in what is a rare disease.The best way forward is for paediatric trial groups worldwide to collaborate in developing common, or parallel, therapeutic protocols.
Acute myeloid leukaemia (AML) in children is a rare disease. There are about 70 newly diagnosed cases in the UK per year and AML accounts for 1 5 % of all childhood leukaemia. The incidence of AML is relatively stable throughout the childhood years but then slowly rises through early adult life before a progressive rise occurs above the age of 55.
Epidemiology Correspondence fo: Richard F Stevens, Consultant Paediatric Haematologist, Royal Manchester Children's Hospital, Pendlabury, Manchester M274HA, UK
In the vast majority of cases no known predisposing factor can be identified, but some of the factors which are associated with an increased incidence are listed in Table 1. The strongest association is with Down's syndrome1 and children with trisomy 21 are 20 times as likely to develop
leukaemia (although the ratio of AML to ALL mirrors that of children in general). A marked leukaemoid reaction can occur in neonates with Down's syndrome which usually regresses spontaneously within a few weeks (see following chapter by SJ Passmore &c IM Hann, this issue).
Although a genetic predisposition for AML has not been conclusively identified, it is well recognised that identical twins can codevelop the disease2. This risk is in the region of 2 0 % at the age of about 5 years but
is much greater in infants and raises the possibility of transplacental transfer of malignant cells3.
Acute myeloid leukaemia
Table 1 Condition* associated with childhood AML
Down's syndrome Fanconi's ancwnia Bloom's syndrome Kojtmann's syndrome Diamond—BJodrfan anaemia
Drugs (alkytating agents and epipodophyilotoxins) Ionising irradiation
Myelodysplasio
Clinical features
In the majority of patients, the clinical features of AML and ALL are similar. These are usually the result of marrow failure due to malignant infiltration with anaemia, neutropenia and thrombocytopenia. There are, however, certain characteristics of childhood AML. Disseminated intravascular coagulation can occur in any subtype but is particularly associated with acute promyelocytic leukaemia (M3) as a result of thromboplastin release from the cytoplasmic granules in the blast cells4. Chloromas (localised leukaemic deposits named after their greenish colour) may be seen, particularly in the periorbital regions, and generalised skin infiltration (leukaemia cutis) is most commonly associated with infantile leukaemia. Central nervous system leukaemia is uncommon but is particularly associated with myelomonocytic (M4) and monoblastic (M5) subtypes and high presenting white cell counts5.
Biology
There is strong evidence that AML results from malignant transforma-tion in an early haematopoietic stem cell and that the subsequent leukaemic cells are the clonal progeny of this single cell. AML frequently involves specific chromosomal karyotypic abnormalities present in each leukaemic cell as opposed to nonhaematopoietic cells which do not show the chromosomal abnormality. Similarly, X chromosome inactivation studies in AML indicate monoclonality similar to that seen in chronic myeloid leukaemia6-7.
It is suggested that AML results from a transformed malignant cell which retains considerable similarity to the normal haematopoietic stell cell in contrast to ALL where the malignant blast cells show maturation arrest8. In AML, proliferation and differentiation are closely inter-related. The differentiated population is more susceptible to chemotherapy BritithMa&al Bulletin 1996;52 (No. i) 765
Cancor in children
whereas the smaller population of cells which show a higher capacity for self renewal (but less differentiation) are less chemosensitive. This hypothesis is supported by the observation that patients in morphological remission may sometimes show persisting genetic markers of the leukaemic clone and these 'clonal remissions' may persist for several years.
Surface markers
Monoclonal antibodies are useful in confirming the diagnosis of AML versus ALL in about 10% of leukaemia cases, which previously were unclassifiable on the basis of morphology and cytochemistry. At least one of the monoclonal markers CD33, CD13, CD14, CD15, CD11 are expressed on more than 90% of AML cases and less than 10% ALL leukaemic blasts. Previously unclassifiable leukaemias may now be labelled as FAB MO. Megakaryoblastic (M7) leukaemia may require the demonstration of surface platelet glycoprotein (CD61), and erythroleu-kaemia (M6) the presence of glycophorin membrane antigen. 'Mixed lineage' leukaemias expressing both lymphoid and myeloid markers may be identified and have important implications as regards treatment.
It was anticipated that immunophenotyping would eventually replace routine FAB morphological and cytochemical classification. However, the correlation between morphology and immunophenotye is not always close and the different techniques should not be considered in isolation. Compared with normal marrow precursors, AML blasts often express early and late differentiation membrane antigens and, within a single case, there is considerable heterogeneity of membrane antigen expression and certainly much more than seen in most cases of ALL. Although morphology and immunophenotype may not always show strong correlation, there does appear to be specific subtypes such as undifferentiated (MO), promyelocytic (M3), monocytic (M4, M5), erythroid (M6) and megakaryoblastic (M7) which show characteristic membrane immunophenotypes.
Cytogenetics and molecular genetics
Over 80% of cases of childhood AML show cytogenetic abnormalities and it is possible that ultimately all cases will be shown to possess a defect. There is a strong association between specific AML subtypes and karyotypes the commonest of which are shown in Table 2.
Acute myeloid leukaemia
Table 2 Chromosomal abnormalities in AML Karyotype FAB subtype
t(8;21) M2 (my»loid with maturation) HI5,17] M3 (acute promydocytk:)
invl6 M4Eo(myelomonocyticwimootinophilia) t(9;ll) M5o (ocuts monoblostic)
t(l;21) M 7 (acul* nwgalcaryoblast'c)
These karyotypic abnormalities are clonal in origin and are present only in the malignant cells. Chromosomal abnormalities seen at diagnosis are not detectable cytogenetically when complete remission is achieved but can reappear at relapse, sometimes with additional or even different abnormalities9.
Cytogenetic abnormalities seen in AML are either numerical or structural and may occur either alone or in combination. Trisomy 8 is the commonest numerical abnormality seen in AML and, although not usually associated with a particular FAB type, is seen most frequently in Ml, M4 and M5. Total or partial deletions of chromosomes 5 and 7 are particularly associated with secondary or therapy related myelodysplasia and AML.
The t(8;21) translocation was first described in 197310 and over 90% of patients with t(8;21) are M2, whereas about 40% of M2 have a t(8;21) translocation. The translocation has recently been described at a molecular level11 with the genes involved being eto on chromosome 8 and AML1 on chromosome 21. The fusion of these genes results in a novel chimeric gene protein and message.
AML M3 is a good example of a disease associated with a specific chromosomal abnormality, t(15;17)(q21;q21). This translocation has not been described in any other malignancy and is thought to occur in all cases of M312. The molecular basis of the t(15;17) is the fusion of the retinoic acid receptor rara gene on chromosome 17 with the pml gene on chromosome 15 forming a chimaeric pml/rara gene. The treatment of M3 with a\\-trans retinoic acid (ATRA) is based on the premise that the promyelocytes are induced to differentiate and die rather than proliferate. Inv 16 is characteristic of M4Eo and up to 90% of patients with this karyotype have the morphological subtype. The molecular basis of the inversion is still not certain, but recently it has been demonstrated that the inversion can be detected by in situ hybridisation using probes specific for sequences on the p arm13.
Another way of considering chromosomal changes in AML is in terms of 'balanced' and 'unbalanced' aberrations. Examples of balanced changes include the translocations, e.g. t(8;21), t(15;17), and unbalanced aberrations the total or partial chromosomal deletions, e.g. - 7 or - 5 . It
Cancer in children
has been suggested that balanced aberrations seen in de novo and therapy related cases of AML may be the result of illegitimate recombinations related to the activity of DNA-topoisomerase II, whereas the unbalanced aberrations may develop as a result of alkylation of DNA or other cellular targets9.
The overall importance of cytogenetics is illustrated in the ongoing Medical Research Council AML 12 trial where patients are now being placed into different prognostic treatment groups on the basis of chromosomal karyotypes. Patients with t(15;17), t(8;21) and inv 16 are considered to have a better prognosis and are not to be offered allogeneic marrow transplantation in first remission.
In summary, it is clear that chromosomal and clonal genetic abnormalities have an important impact on diagnosis, prognosis and hence management. However the validity of some of these observation is not totally clear, partly because of the relatively small number of children so far analysed, and the fact that there is still the possibility that the same chromosomal abnormality may have a different prognostic influence in children as opposed to adults.
Drug resistance in AML
Intrinsic resistance to chemotherapy is thought to be the major cause of treatment failure in acute leukaemia14. Among different mechanisms of resistance, the appearance of the multidrug resistance (MDR) phenotype is the most frequently observed in many malignant cell lines including leukaemia. MDR is related to the expression of the tndrl gene which codes for the P-glycoprotein that functions as a transmembrane drug efflux pump, expelling the drug (anthracyclines and epipodophyllotoxins in particular) out of the tumour cell, thus decreasing the level of cytotoxic drug in the tumour cell15. Although tndrl is expressed in many normal tissues, there is a higher frequency of expression in AML. Between one-third and one-half of patients show MDR expression at diagnosis and a higher percentage in refractory cases. However the MDR phenotype is associated with other poor prognosis markers such as CD7 and CD34. The drugs verapamil and cyclosporin A are modulators of P-glycopro-tein, however the capacity of these inhibitors varies substantially amongst patients. In a recent study two-thirds of patient's P-glycoprotein function was completely inhibited by these modulators but these same patients expressed a significantly higher level of CD34 than those in which P-glycoprotein activity could not be inhibited16. Only large multicentre randomised studies of modifier agents will tell if tndrl gene over-expression is of clinical importance in childhood AML.
Acute myeloid leukaemia
Treatment
Remission induction therapy
The aim of any therapeutic regimen for AML is to achieve a long term survival that will eventually translate into a cure. The initial step is that of obtaining remission which is arbitrarily defined as less than 5% leukaemic blast cells in the marrow with good evidence of regeneration of normal marrow elements. Failure to achieve remission is due either to the persistence of resistant leukaemia or death from toxicity, either disease or treatment related. In about half of the cases of remission failure due to resistant disease, chemotherapy results in severe marrow hypoplasia but repopulation is with leukaemic blasts. Achieving remission may take more than one course of treatment. In the Medical Research Council's recent trial of childhood acute myeloid leukaemia (AML10), just over 70% of patients who achieved complete (CR) remission did so after one course of treatment and a further 20% required further courses36.
Most remission induction protocols in use today have evolved from early studies used in the 1960s, when it became evident that combination chemotherapy based on the antimetabolite cytosine arabinoside (ara-C) and anthracyclines could achieve remission rates of 60-70% as compared to 30-50% when these agents where used alone17. Thus these two drugs became the mainstay of treatment in the 1970s18. The use of 4 or 5 drug combinations increased the remission rates to 70-80%.
Over the past two decades, trials have been performed where attempts have been made to modify cell cycle or reduce drug cross resistance. In the St Jude AML-76 study, therapy was administered on day 1 to kill some of the leukaemic load and recruit the remainder into S phase. At 72 h, other chemotherapy was given when the blasts cells were theoretically more susceptible19. However remission rates were no better than when drugs were given sequentially over 1 week20 or an extended 8 week period21.
A second theory of remission induction therapy is still being used today. The Goldie-Coldman hypothesis suggests that failure of treatment is due to the appearance of resistant clones as a result of spontaneous mutation22. The potential for drug resistance is greatest at the beginning of therapy when the tumour load is highest and the theory suggests that the greatest effect will be achieved when multiple drugs are given simultaneously. During the 1980s, therapeutic trials using multidrug induction therapy have not shown much benefit for remission induction as compared with ara-C plus an anthracycline. For example, the Children's Cancer Study Group trial CCG-213 showed no advantage in using a 5 drug intensive induction regimen23.
Cancer in children
The Medical Research Council in its recent AML 10 trial compared a 3 drug induction regimen using cytosine, thioguanine and daunorubicin as against cytosine, etoposide and daunorubicin in a randomised trial24.
This has resulted in a CR rate of 90% which represents the best so far achieved in a large trial of paediatric AML.
Post remission therapy
The cessation of treatment following remission induction is associated with relapse usually within 12 months24. Post remission therapy can be
considered in terms of essentially three treatment strategies: (i) maintenance therapy, in which lower dose less myelotoxic therapy is used; (ii) consolidation therapy, where similar drugs and doses used for remission induction are employed; and (iii) intensification therapy, where myelosuppresive doses of different (non-cross reactive) drugs are used.
Considerable debate exists as to the place of maintenance therapy in paediatric AML. Early trials from St Jude's Hospital19 and the Children's
Cancer Study Group in the US25 involved a 2 year period of maintenance
with event free survival (EFS) plateauing at about 20%. A randomised trial comparing 8 months of relatively intensive maintenance as against the same drugs given over 3 years showed no difference in terms of long term survival26, whereas another study using more intensive post
remission therapy achieved an EFS approaching 40%2 7.
The Paediatric Oncology Group followed remission induction with a single course of consolidation followed by cranial irradiation. Children were then randomised to one of two maintenance therapies which lasted for 2 years. Although overall results were improved on previous trials, there was no difference between the maintenance arms28. In the German
BFM-78 trial, intensive remission induction was followed by intensive consolidation (including cranial irradiation) and 2 years of maintenance. An EFS of 3 5 % was achieved at over 5 years follow up, but it is difficult to judge the role of maintenance in what was a non-randomised study21.
There is increasing evidence that relapse occurs relatively soon after achieving CR where maintenance therapy follows on from remission induction treatment. In contrast, relapse tends to be delayed in patients who received consolidation or intensification. In fact, there appears to be little benefit of maintenance therapy when it follows intensive consolida-tion as born out by the CCG-213 study which indicated that a 4 month post remission intensive phase was superior to a 2 year period of maintenance23.
During the 1980s the trend for the treatment of AML changed towards shorter duration but more intensive therapy, mainly as a result of the
Acute myoloid leukaemia
Table 3 Paediatric AML studies over the past decade
Group/study M R C - A M L 1 0 " B F M - 8 7 " EORTC4* A I E O P - 8 7 " POG3 0 CCG-2133 1 NOPHO5 2 Dutah-AN 11^87" StJude's43 No. of patients 318 210 91 197 730 621 193 78 87 CR(%) 92 78 77 76 85 78 80 85 72 RFP%(rime) 61 (4 years) 5 6 (4 years) — — — — — — — DFS%(Hme] 5 4 (4 years) 5 4 (4 years) — 32 (3 years) 4 0 (3 years) — 50 4 3 (2 years) — EFS%(Hme) 4 9 (4 years) 41 (4 years) 38 (3 years) — 3 4 (3 years) 31 (5 years) 42 41 (2 years) 2 9 (2 years) OS% 56 — — — — 39 — — —
withdrawal of maintenance therapy29. In the St Jude AML-83 trial, a total of 7 drugs were given in sequentially rotated pairs in an attempt to expose resistant leukaemic cells to as many agents as possible. In the German BFM-83 trial, an intensive 8 day induction was followed by a similarly intensive consolidation course. The St Jude study did not show any improvement in survival over previous studies30, whereas the German study claimed an EFS of nearly 50%31. The reasons for this improvement are not entirely clear. The German trial included what are usually considered as ALL drugs in the form of vincristine and prednisolone and some patients who died before actually receiving therapy were not included in the analysis.
This trend towards increasing the intensity of treatment has continued throughout the 1980s and early 1990s. For example, high-dose ara-C was introduced into several studies32"35. One of the most intensive therapeutic regimens has been adopted by the Medical Research Council in their AML 10 trial, where patients received 4 courses of intensive myeloablative therapy with or without allogeneic or autologous bone marrow transplantation. The majority of patients received their therapy within 6 months and no maintenance treatment was given. This study has achieved a CR rate of over 90% and an overall survival of 50% at 5 years follow up36. At the present time, these results seem to set the standard and once again raise the place of maintenance therapy into question. These various studies are summarised in Table 3.
Central nervous system prophylaxis
Until recently, the high rate of bone marrow relapse in AML tended to precede CNS relapse and, therefore, the importance of prophylactic CNS treatment was unknown. Although the presence of CNS leukaemia at diagnosis does not appear to significantly affect the long term
Cancer in children
prognosis37, CNS relapse occurs in up to 2 0 % of children who have not
received CNS directed therapy38. Some studies have shown that
intrathecal methotrexate with or without cranial irradiation prevents CNS relapse in the vast majority of cases21-39, whereas others have
suggested that intrathecal chemotherapy alone (usually with methotrex-ate, hydrocortisone and cytosine) is equally effective. In the German BFM-87 trial, there was a randomisation between cranial irradiation and intrathecal cytotoxics versus intrathecal chemotherapy alone40. Although
there was no difference between the randomised groups, patients who were not randomised and who had not received cranial irradiation had a higher bone marrow relapse rate. The German group took these results to indicate the necessity for cranial irradiation in the prevention of both CNS and marrow relapse. In the MRC AML-10 trial36 there have been
only 4 CNS relapses (of which 2 were combined) in over 300 patients. CNS prophylaxis consisted of triple intrathecal chemotherapy with each of 4 intensive courses of systemic treatment and raises into question the role of prophylactic cranial irradiation in paediatric AML.
Bone marrow transplantation
The assessment of allogeneic bone marrow transplantation (allo-BMT) in paediatric AML is fraught with difficulties41. For some time there has been
a tendency for clinicians to assume that the availability of a sibling donor and a subsequent allo-BMT is associated with an improved long term survival. However, a comparison of patients who receive allo-BMT with those who do not may be potentially seriously biased for two reasons. Firstly, the patients selected for transplant may have a different intrinsic prognosis and one might expect any such bias to be in favour of allo-BMT, since there will be patients with a matched sibling donor who are not transplanted because they are not considered fit enough. Secondly, the median time from CR to transplant is usually about 5 months (with a considerable range) so patients who receive a BMT already have an improved prognosis by virtue of having remained in CR long enough to get to transplant. Many collaborative groups are in the process of conducting trials of paediatric BMT but in the absence of any randomised trials, the problem of selection factors can only be overcome if analysed using genetic ('Mendelian') randomisation. Several studies have performed comparisons of allo-BMT versus chemotherapy but it has been the case that patients without a donor have received additional intensive therapy so the exact contribution of the transplant has been very difficult to evaluate43^*5.
Although the rate of bone marrow relapse is higher for patients receiving chemotherapy alone, increased treatment related mortality
Acute myeloid leukaemia
associated with allogeneic transplantation has narrowed the difference in overall survival between these two treatment approaches. As supportive care and treatment of transplantation related complications improves, the survival of children undergoing transplantation will undoubtedly improve. The probability of having a matched sibling donor is a random process depending on the assortment of genes at conception. Thus, a comparison of all patients with a matched sibling, most of whom will be transplanted, with those who do not have a donor is essentially unbiased. Such an analysis has been carried out in the Medical Research Council AML trial42, and the survival curves for patients with and without a donor
where very similar, providing no evidence that allo-BMT is of benefit to children with AML in first CR. The patient numbers were, however, small and it is feasible that there is a distinct benefit, or harm, of allo-BMT and more unbiased data are required from other clinical trials to confirm or refute these findings.
At the present time, there is increasing evidence that sibling allo-BMT in first remission should be reserved for those patients considered to be at a higher risk of relapse, other than patients with specific chromosomal abnormalities (e.g. t(15;17), t(8;21) and inv 16) and those who are less chemosensitive and have an excess of marrow blasts after the first course of treatment. Improved results for chemotherapy are reducing the apparent therapeutic advantage previously seen for allo-BMT.
Only about a third of children with AML have an HLA-matched donor and, therefore, autologous bone marrow transplantation (ABMT) is an attractive alternative. Because of the risk of residual leukaemic cells, many investigators have developed techniques of 'purging' marrow of residual disease. These include incubation with specific monoclonal antibodies, or the use of cytotoxic agents such as 4-hydroperoxycyclophosphamide (4-HC)46'47. Although there is currently a bias towards the use of purged
bone marrow, there is as yet no study which has shown conclusively the benefit of this procedure. Such a study would require a large number a patients followed up for a long period. The results of ABMT in children are still under evaluation, but the possibility remains that more intensive chemotherapy may negate the possible benefit of ABMT.
AML relapse
AML relapse usually occurs within 2 years of completing chemotherapy. Until recently, disease relapse was associated with a very poor prognosis. It is now becoming evident that, with further intensive therapy, a minority but increasing number of patients may become long term survivors. In particular, this applies to children who had better
Cancer in children
prognostic features at diagnosis. There is increasing evidence that allogeneic BMT can be offered in second remission and this includes a comprehensive search for an unrelated donor if circumstances allow.
The future
References
Paediatric AML is no longer the poor neighbour in childhood cancer. Realistic long term survival rates are now approaching 50%, however this is mainly the result of ever increasing chemotherapy (including BMT) and there is little doubt that the long term effects of therapy will become increasingly apparent.
There have been significant advances in our understanding of the biology of AML, particularly in terms of genetics. This has resulted in new approaches to therapy such as the use of a\\-trans retinoic acid in the treatment of M3 t(15;17) AML. Hopefully similar strategies will become available for other subtypes.
There has been little development in terms of new drugs over the past decade, rather a continuing trend to use basically familiar drugs in increasing doses or more complex combinations.
New forms of therapy are required if continuing therapeutic improvement is to be achieved. There is an increasing awareness that the enhancement of cell survival is distinct from cellular mechanisms that control proliferation and differentiation. Most AML trials are still focused on the use of increasing doses of highly toxic chemotherapy. Clinical regimens should maximise the benefits of agents currently available whilst adding new therapies as they become available and emphasising specific treatment modifications based upon our increasing knowledge of the biology of this heterogeneous disease.
It is encouraging that about 50% of children with AML may be cured of their disease. This represents a major improvement in the treatment of a disease that was almost inevitably fatal only 30 years ago. Nevertheless, half the children with AML are likely to die, directly or indirectly, of their disease. Over the forthcoming years it is unlikely that the momentum of future advances will be maintained, particularly as childhood AML is a rare disease. The best way of making further progress may be for paediatric trial groups worldwide to collaborate in developing common protocols regarding biology and therapy.
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