Table of Contents

HK J Paediatr (New Series)
Vol 1. No. 1, 1996

HK J Paediatr (New Series) 1996;1:31-36

Feature Article

Childhood Acute Lymphoblastic Leukaemia - Some Outstanding Issues

HP Lin


Abstract

Even though the cure rate of childhood acute lymphoblastic leukaemia (ALL) has improved to about 70%, mainly because of early intensification of treatment, many outstanding issues remain. These include the feasibility of risk-adapted treatment, an ideal concept based on biological disease heterogeneity and contingent upon rigorous and reliable risk assignment. Until recently criteria for risk assignment are not uniform, making comparison of results difficult. Early intensification of treatment has improved the prognosis of both high and lower-risk patients. The benefit to high-risk patients are more obvious because these are easier to identify. While genuine lower-risk ALL patients do not need intensive treatment, many still receive such therapy, mainly because their risk criteria are not reliable. The best method of CNS directed treatment with the least neurotoxicity is still controversial. Regular intrathecal (IT) chemotherapy with or without IV methotrexate (MTX) has been increasingly used but its long term neuropsychological sequelae are uncertain.

Keyword : CNS directed treatment; Early intensification; Leukaemia; Risk-adapted treatment


There has been a steady improvement in the results of treatment for acute lymphoblastic leukaemia (ALL) over the past 20 years. With optimal treatment an average cure rate of about 70% has been reported from many good centres.1-8 Although there are many reasons contributing to this improved survival, two major factors are responsible - the use of early intensive therapy and central nervous system (CNS) directed treatment. Post-remission intensification of chemotherapy has improved the long-term prognosis even of patients at high-risk of relapse.4-9 However ALL is prognostically and biologically heterogeneous10,11 and probably not all patients need such treatment. Ideally it should be reserved only for patients at high risk of treatment failure and less toxic treatment be given for lower-risk patients.

This concept of risk-adapted treatment is contingent upon rigorous risk assessment. Accuracy of risk assessment is critical especially for lower-risk patients because an incorrect assignment leading to the institution of less intensive early treatment may seriously jeopardise the patient's chance of a long-term cure. Several related outstanding issues must therefore be addressed:

1. How accurate and reliable are present methods of risk assignment? What are the major problems associated with their application?
2. With our current knowledge, can treatment be adapted to risk without compromising cure?
  2.1 What is the role of early intensive treatment in nullifying the negative impact of poor prognostic factors in high-risk ALL?
  2.2 Do lower-risk ALL patients need intensive treatment?
3. What is the optimal mode of CNS-directed therapy for the various risk categories of patients?

Risk Assignment

Rigorous risk assignment must precede risk-adapted treatment. How accurate and reliable are present methods of risk assignment? This question is difficult to answer because, until recently, there is no general consensus on criteria for risk assessment. Different ways of stratifying risk groups have made comparison of treatment results from different centres difficult. It must be remembered that the results and conclusions obtained from a clinical trial in leukaemia relate only to the method of risk assessment and protocol used in that trial. There is now a better understanding of the biology of childhood ALL but paradoxically this has made risk assessment and the stratification of treatment into various risk groups more complex. However there is general agreement on the broad principles of risk assignment based on clinical and biological features as well as on the patient's early response to treatment.

High-risk ALL is easier to recognise (Table Ia). There are many features that are generally accepted to be associated with a high risk of treatment failure. An elevated total white blood cell (TWBC) count, accurately reflecting a high cancer burden, is a reliable indicator but unfortunately, until recently, there is no agreement as to what level constitutes a high TWBC count. Infants and older children are also known to have a higher risk of relapse but again there is no uniform definition of at-risk age-groups. A recent workshop sponsored by the National Cancer Institute (NCI), USA, recommended that patients with high-risk ALL be defined as those less than 1 year and older than 9 years of age or those having a TWBC of >50 x109/L.12 Some chromosomal translocations e.g. t(9;22); t(4;11) in infants13 or t(1;19) in about a quarter of patients with the pre-B immunophenotype are well known to be associated with a high risk of treatment failure.10,11 T-cell and B-cell ALL are well recognised to be poor prognostic factors.11 The presence of lymphoblasts which express myeloid (My+) antigens was thought to be associated with a poor outcome despite the use of intensive treatment14 but this view has been challenged.15 A poor early response to treatment as shown by the presence of >5% lymphoblasts in the day 15 bone marrow is a good indicator of bad long-term prognosis.16 The ALL-BFM 86 trial have demonstrated that a blast cell count of >1000/cu.mm after one week of treatment with steroids is a simple and reliable means of identifying high-risk ALL.5 Such patients with "prednisone-poor response constituting about 10% of all their children with ALL, are predominantly boys, have T-cell ALL or high initial TWBC.5,17 Among them is a subgroup with an even higher risk of relapse presence of My+ associated antigens, T-cell ALL and TWBC >100 x 109/L.17

Table Ia Criteria of High-Risk ALL

I.

Clinical features
1. TWBC >50 x 109/L
2. Age <1 year and >9 years
3. Presence of extramedullary leukaemia at diagnosis
II. Biological features
1. presence of chromosomal translocations t(9;22) or t(4;11) or t(1;19)
2. T-cell ALL
3. B-cell ALL
4. Myeloid-associated antigen (My+) ALL
III. Early Response to Therapy
1. D15 BM : >5% blasts or
2. D8 peripheral blood blast cell count >1000/ul

Lower-risk ALL is more heterogeneous and more difficult to define. Other than being in the recommended age group of 1 to 9 years and possessing a TWBC of <50 x 109/L, lower-risk ALL patients must not have features known to be associated with high risk of relapse (Table Ib). The presence of hyperdiploidy (>50 chromosomes) identifies a subgroup of ALL with a very favourable long-term outcome of about 90% with non-toxic treatment, irrespective of the TWBC or age.18 This correlates reliably well with a DNA index of 1.16 to 1.6 -- obtained with a simpler and quicker method using flow cytometry.19

Rigorous risk assessment requires good facilities for immunophenotyping and cytogenetics. Unfortunately these are often not available except in a few renowned centres. Most of the world's children with leukaemia in third word countries have no access to them.

Table IIa Criteria of Lower-Risk ALL

1.

Age between 1 and 9 years
2. TWBC count <50 x 109/L
3. Absence of i) extramedullary leukaemia at diagnosis
ii) t(9;22)
iii) t(4;11)
iv) t(1;19) and the pre-B immunophenotype
v) >5% blasts on D15 bone marrow examination
vi) >1000/ul blasts in the blood after 1 week of treatment with steroids
4. Presence of hyperdiploidy (chromosomes >50) or a DNA index between 1.16 and 1.6.

Role of Early Intensive Treatment

The rationale of early intensive treatment is based on the Goldie-Coldman hypothesis which states that intensive front-end therapy is most effective in the prevention of emergence of drug-resistant clones of cancer cells. Increasingly over the past two decades, this concept has been applied successfully on both non-stratified as well as specific subsets of patients with ALL. Long term disease-free survival rates from such treatment average about 70% overall and as high as 90% for low-risk patients.4-6,8 The large UKALL X randomised controlled trial7 involving more than 90% of unselected patients from the United Kingdom but non-stratified into prognostic groups, showed that post-remission intensification of treatment improves event-free survival (71 % among intensively treated patients versus 57% among controls). The non-randomized Berlin-Frankfurt-Munster (BFM) studies 76 and 79 have shown that the addition of a post-remission re-induction Protocol II has produced overall long-term event-free survival rates of about 64% compared to 38% without Protocol II from a historical control series.4 Subsequent BFM Studies have not only reaffirmed the value of Protocol II but have also demonstrated the role of intensive therapy in nullifying the negative impact of poor prognostic factors in high-risk ALL.5 Patients with T-cell leukaemia, long regarded as having a poor outlook on conventional treatment, have an event-free survival (EFS) of nearly 70% with the BFM 86 protocol.5 This encouraging result has been attributed to the use of high-dose methotrexate. A similar result has been reported from the Dana Faber Cancer Institute, Boston - this being attributable to the use of high-dose asparaginase and adriamycin.6 The prognostic strength of other known bad prognostic factors may also be abolished with intensive treatment e.g. high TWBC count and t (1;19).20 For patients considered to have intermediate-risk ALL by the Children's Cancer Group (CCG), USA, the use of the delayed intensification phase in the randomised controlled study CCG-105 improved their EFS to 73% compared to 61% among controls.21,22 Even in B-cell ALL, the EFS with intensive short-term therapy has improved to about 60-70%,23 not withstanding the recent French report of an impressive 87% cure rate using the LMB-89 protocol.24 The fact that many poor prognostic features in ALL can be made inconsequential with aggressive treatment establishes the point that the type of treatment received by a patient is the single most important prognostic factor.

However there remains a few bad prognostic features where the value of early intensive treatment has not been established. Patients with Philadelphia (Ph) chromosome [BCR-ABL, t (9;22)] ALL continue to have a dismal prognosis despite intensive chemotherapy25 although promising results with the use of bone marrow transplantation (BMT) have been reported.26 In those with the 11q23 gene rearrangement, present in about 5% of childhood ALL and in about 70% of infants with the t(4;11) (q21:q23) MLL-AF4 fusion gene, intensive chemotherapy has not made a significant impact in improving the poor prognosis.14 The prognostic significance of My+ - associated antigen, reported in up to 24% of childhood ALL, is unclear as there are reports of both good and poor outcome with intensive treatment. Contrasting three-year EFS rates of 85% and 32% have been reported.14,16 The value of intensification of treatment in patients with poor early response to treatment is still uncertain. In the ALL-BFM 86 trial, the prognosis of patients with prednisone-poor response has not improved despite intensification of treatment.5 The probability of EFS for this group of patients remains below 50%.17

Do Low-Risk ALL Patients Need Intensive Treatment?

This is controversial because the literature on this point is conflicting. There are reports of good results using relatively non-intensive treatment among non-high-risk patients e.g. the 83% EFS of the Dutch ALL VI Study27 and the up to 90% EFS in patients with a favourable DNA index of 1.16 - 1.6, irrespective of age and TWBC count.2,18 On the other hand there are reports of children with standard-risk ALL on relatively non-intensive treatment getting long-term results which are even inferior to those with high-risk features but treated intensively.4 The need for post-remission re-induction among low-risk ALL patients was tested in the randomised trial ALL-BFM 83.4,28 Their "standard-risk, low" patients not given delayed induction Protocol III had a significantly inferior event-free survival compared to controls, but these became apparent only after 2 years of follow-up.4 This need for delayed intensification of treatment for standard risk "SRG" patients was confirmed in their next ALLBFM 86 Study. The 6-year EFS for their first 110 "SRG" patients not given re-induction therapy was only 58 ± 5% compared to 87% ± 3% for the next 175 patients given re-induction therapy.5 The confusion for this apparent difference relates firstly to differences used in the definitions of "low-risk ALL" and secondly to differing interpretation of what is meant by "intensive treatment". Presently-defined lower-risk ALL is a large heterogeneous group. Genuine low-risk ALL patients needing less toxic treatment probably exists but how can they be identified reliably?

What is the Best Mode of CNS Directed Treatment?

CNS directed treatment is a very important component of ALL treatment, without which almost all patients would suffer a CNS relapse. However the best mode of subclinical CNS leukaemia treatment is still controversial.4

Cranial irradiation (CXRT) with intrathecal methotrexate (IT MTX) is the most established method and is effective in reducing the CNS relapse rate to about 5% or less.4-9,29 However its major disadvantage is significant long-term neuropsychological sequelae particularly with respect to language ability, mathematics skills, memory and mental concentration.30 The search for alternative effective but less neurotoxic modes of CNS prophylaxis has led to studies demonstrating that triple intrathecal chemotherapy (MTX, cytosine arabinoside and hydrocortisone) during maintenance therapy could be substituted for CXRT in the most favourable group of patients without an increase in frequency of CNS or bone marrow relapses.31 Subsequent studies have shown that triple IT chemotherapy confers no added advantage compared to IT MTX and that MTX given intravenously (IV) in medium or high doses together with IT MTX is safe and effective.29,32

The choice of the optimal mode of CNS preventive therapy depends on several factors:

  1. the risk of CNS leukaemia;

  2. the effectiveness of CXRT, IT MTX, IV MTX or dexamethasone as preventive CNS therapy which in turn is dependent on their doses used and frequency of administration;

  3. the intensity of systemic therapy.

If the risk of CNS relapse is high (Table II) many would still opt for CXRT for its proven efficiency e.g. the use of a CXRT dose of 24 Gy for T-cell leukaemia.5-8 However in Norway, IV intermediate-dose MTX together with IT MTX has been used effectively for many years to prevent CNS leukaemia in all cases including those at high-risk of developing CNS relapse.33 For intermediate-risk ALL patients less than 10 years of age, the randomised trial CCG-105 involving 1388 patients has demonstrated that regular IT MTX for one year provided CNS prophylaxis comparable to that provided by CXRT and IT MTX on the condition that intensive systemic therapy is also given.29 Intermittent IT MTX can be used together with IV MTX for durations shorter than a year, depending on the risk of CNS relapse, the dose of IV MTX and the intensity of systemic therapy used. In the randomised ALL-BFM 81 Study, "standard-risk, low" patients, i.e. those with a risk factor (RF) of <= 0.8 who were given intermediate dose MTX at 0.5 gms/m2 for 4 doses together with IT MTX (4X) had CNS relapse rates similar to those given CXRT.4,32 However, such intermediate doses of IV MTX with IT MTX are insufficient CNS prophylaxis for their medium-risk ALL patients (RF 0.8 to <1.2).4,32 For the latter, subsequent ALL-BFM 83 and 86 trials showed the effectiveness of high-dose MTX (5 gms/m2 x 4) and IT MTX (4X) followed subsequently by CXRT, either 12 Gy or 18 Gy. For medium-risk ALL patients treated according to BFM protocols the use of high-dose MTX together with IT MTX is effective CNS prophylaxis.4,5,32 However the optimal single dose of IV MTX, e.g. whether 2 is as effective as 5 gms/m2, remains to be determined. Blasts in the CSF with a normal cell count at diagnosis (present in about 5% patients and termed CNS 2 status in the proposed St. Jude Classification) merits special consideration. There are conflicting reports as to whether these patients have a higher subsequent CNS relapse rate.35,37 The reasons for the difference relate mainly to differences in the 1) methods of systemic and CNS preventive therapy employed and 2) the patient risk categories. Such patients treated on St. Jude total therapy studies XI and XII with regular IT triple chemotherapy every 8 weeks in the first year without CXRT had a higher CNS relapse rate.34 Results form the Childrens Cancer Group Study CCG-10535 on such patients with intermediate ALL given intensive systemic treatment and either early 18 Gy CXRT plus IT MTX or IT MTX alone throughout maintenance showed no increase in the CNS relapse rate. Another study from the Paediatric Oncology Group (POG) demonstrated that although there is a 1.9 fold increase in the CNS relapse rate among such patients these occurred mainly in those with poor prognostic features not given early prophylactic CXRT.36,37 It would appear that the effective options for the management of CNS 2 status should include intensive systemic therapy plus either 1) more frequent IT chemotherapy or 2) CXRT in the first year of treatment.

The use of dexamethasone early in induction of remission and regularly as part of pulse-maintenance therapy is said to be responsible for less CNS relapse. Studies have shown that dexamethasone penetrates the CSF better compared to prednisolone so that its CSF level stays longer and higher.38,39 In the Dutch ALL VI Study27 on non-high-risk ALL where dexamethasone is used as described above, together with IV and IT MTX, CNS relapse occured in only 2 out of 190, even though a relatively non-intensive systemic regimen is used.

The long term neuropsychological sequelae of high-dose MTX and IT MTX have yet to be determined although it is hoped, at least on a theoretical basis, that they will be less compared to CXRT. A recent report30 on a small study involving 49 patients comparing the IQ of patients given CXRT (18Gy) together with IT MTX (RT group) versus IV and IT MTX (MTX group) is a cause for concern. 14 out of 23 patients (61%) in the RT group and 16 out of 26 (61%) in the MTX group lost >15 IQ points on standard IQ tests performed soon after remission induction and repeated at a median of 6 years after cessation of chemotherapy. Although these results need to be confirmed in a bigger study, they underline the importance of a continual search for an optimal effective but non-neurotoxic mode of subclinical CNS leukaemia therapy.

Conclusions

Early intensification of treatment has improved the prognosis of most children with ALL, both high-risk and lower-risk. It has raised the EFS rate of most patients with high-risk ALL to approach that of those at lower-risk with the exception of those with t (9;22), t (4;11) and those with poor early response to therapy. But why has this same approach not produced better results among the lower-risk? The two groups must be biologically different requiring different approaches to treatment. The concept of risk-adapted treatment is very attractive -- with intensive treatment being reserved only for those at high-risk of relapse and lower-risk patients getting non-toxic therapy. However, at present, many studies have shown that most "low-risk" patients still need early intensification of treatment for good results with the exception perhaps of those with hyperdiploidy. But this is mainly because there is still no reliable criteria for identifying "real" low-risk ALL, itself a very heterogeneous group. Only through a better understanding of the biology of leukaemia will this problem be overcome.

The question of the best mode of CNS directed treatment is still not settled. Regular IT chemotherapy, with or without IV MTX is mostly as effective as CXRT but its long-term neuropsychological sequelae are still uncertain.

Much progress has been made in the treatment of childhood ALL but with a failure rate of 30%, due mainly to bone marrow relapse, obviously much remains to be done.

Acknowledgement

The help given by Dr CH Pui, St. Jude Children's Research Hospital, Memphis is gratefully acknowledged.


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