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The treatment of childhood lymphoblastic leukaemia has been one of the success stories of haematology, but despite this triumph 25–30% of children still relapse. Relapsed lymphoblastic leukaemia (R-ALL) is thus as common as most paediatric solid tumours, and more common than acute myeloid leukaemia in childhood. The treatment of R-ALL is usually unsuccessful, causes heartache and stress for both families and staff, and consumes large amounts of time and resources. There have been few randomized therapeutic trials to inform the choice of treatment and intense medical and lay interest in high-dose therapy and all variants of stem cell rescue. The increased availability of bone marrow or stem cells donors raises the vision that, in theory, BMT could be available to all children with R-ALL at least in societies whose resources permit this option. Yet high-dose therapy carries at least a 10–20% risk of immediate death and a much greater risk of delayed complications such as growth failure, infertility, organ damage and neuropsychological impairment, and is itself associated with a high relapse rate.

This article will attempt to review the therapeutic options for the child with R-ALL, to make recommendations based on the limited evidence available about choice of treatment, and to suggest priority areas for research. It must, however, be recognized that this whole topic is clouded by a lack of randomized trials, difficulties over selection bias, and publications involving small numbers of patients.

Methods

  1. Top of page
  2. Methods
  3. Classification of relapses
  4. Survival after relapse: unselected results
  5. Factors influencing outcome after relapse
  6. Management of relapse
  7. Long-term results of intensive chemotherapy for treatment of relapses involving the bone marrow
  8. High-dose chemoradiotherapy and stem cell rescue
  9. Comparisons of alternative forms of high-dose therapy
  10. Evaluation of ABMT and UD BMT in marrow relapse
  11. CNS relapse as a first event
  12. Other extramedullary relapses
  13. New approaches to treatment
  14. Management of relapse: a personal viewpoint
  15. Future directions
  16. Acknowledgements
  17. References

References were retrieved from the Silver Platter CANCER-CD database from 1987 until mid-1997, using the terms lymphoblastic and lymphocytic leukaemia and relapse and recurrence; they were confined to English Language publications. These were supplemented by references from the author's own database, articles and abstracts cited in those found in the literature search, and by personal communication with groups working on this area.

Classification of relapses

  1. Top of page
  2. Methods
  3. Classification of relapses
  4. Survival after relapse: unselected results
  5. Factors influencing outcome after relapse
  6. Management of relapse
  7. Long-term results of intensive chemotherapy for treatment of relapses involving the bone marrow
  8. High-dose chemoradiotherapy and stem cell rescue
  9. Comparisons of alternative forms of high-dose therapy
  10. Evaluation of ABMT and UD BMT in marrow relapse
  11. CNS relapse as a first event
  12. Other extramedullary relapses
  13. New approaches to treatment
  14. Management of relapse: a personal viewpoint
  15. Future directions
  16. Acknowledgements
  17. References

It is usual to classify relapses as early, intermediate and late as determined by the length of the first remission, or alternatively, in the case of relapses occurring off treatment, the time elapsing since treatment was electively stopped. There is no uniform definition of these terms and not all publications include a class of intermediate relapse, but the definition of early relapse always includes those occurring in the first 18 months from diagnosis and usually in the first 2 years. Most relapses in ALL occur during the first 5 years from diagnosis, but in a population-based study from the Nordic countries 6.9% of children who were still in first remission at 5 years from diagnosis had relapsed by 10 years ( Nygaard et al, 1989 ). Combined relapses, that is those with overt bone marrow and extramedullary relapse, tend to occur later than isolated marrow relapses ( Gaynon et al, 1998 ). Isolated central nervous system (CNS) relapse tends to occur within 3 years from diagnosis ( Gaynon et al, 1998 ) and testicular relapses after treatment is electively stopped. Other sites of recurrence such as the iris, skin, lymph nodes or ovaries are rare and may occur in apparent isolation or with obvious marrow involvement.

Survival after relapse: unselected results

  1. Top of page
  2. Methods
  3. Classification of relapses
  4. Survival after relapse: unselected results
  5. Factors influencing outcome after relapse
  6. Management of relapse
  7. Long-term results of intensive chemotherapy for treatment of relapses involving the bone marrow
  8. High-dose chemoradiotherapy and stem cell rescue
  9. Comparisons of alternative forms of high-dose therapy
  10. Evaluation of ABMT and UD BMT in marrow relapse
  11. CNS relapse as a first event
  12. Other extramedullary relapses
  13. New approaches to treatment
  14. Management of relapse: a personal viewpoint
  15. Future directions
  16. Acknowledgements
  17. References

The overall outlook for patients with R-ALL has always been poor ( Cornbleet & Chessells, 1978; Chessells et al, 1987 ) and remains so. 1 Table I shows the event-free survival (EFS) in second remission figures from recent publications selected either because they are population based (Holland, Scandinavia) or they report the follow-up of all patients relapsing after large first-line trials of treatment (American Children's Cancer Group CCG and MRC UKALL protocols). These reports confirm the widespread clinical impression of the very poor prognosis for children with early marrow relapse, which has not improved in the last 20 years. In the era of modern treatment, fewer than 1 in 10 children with a marrow relapse during the first 1–3 years from diagnosis are cured. The outlook is somewhat better following later bone marrow or extramedullary relapses, but very-long-term follow-up is needed to assess the results of a second course of chemotherapy in such cases, since second recurrences may occur many years from diagnosis ( Chessells et al, 1994 ; Miniero et al, 1995 ).

Table 1. Table I. Survival in second remission in patients with relapsed ALL. Behrendt et al (1990 ) Bleyer et al (1986 ) Schroeder et al (1995 ) Gaynon et al (1998 ) Wheeler et al (1998 ) Thumbnail image of

Factors influencing outcome after relapse

  1. Top of page
  2. Methods
  3. Classification of relapses
  4. Survival after relapse: unselected results
  5. Factors influencing outcome after relapse
  6. Management of relapse
  7. Long-term results of intensive chemotherapy for treatment of relapses involving the bone marrow
  8. High-dose chemoradiotherapy and stem cell rescue
  9. Comparisons of alternative forms of high-dose therapy
  10. Evaluation of ABMT and UD BMT in marrow relapse
  11. CNS relapse as a first event
  12. Other extramedullary relapses
  13. New approaches to treatment
  14. Management of relapse: a personal viewpoint
  15. Future directions
  16. Acknowledgements
  17. References

The most important factors influencing the chance of remaining in second remission are the length of the first remission (Fig 1) and the type of relapse (Fig 2) ( Wheeler et al, 1998 ; Gaynon et al, 1998 ). Despite the fact that there is frequently molecular evidence of disease in the bone marrow of children with apparent isolated extramedullary relapse ( Goulden et al, 1994 ; Neale et al, 1994 ), patients with isolated extramedullary relapse as defined by conventional bone marrow examination, in particular those involving the testicle, have a good prognosis ( Wheeler et al, 1998 ; Gaynon et al, 1998 ). It has been suggested that children with combined marrow relapses have a better prognosis than those with bone marrow disease only ( Buhrer et al, 1993 ), but this may be in part related to their relative lengths of first remission ( Gaynon et al, 1998 ).

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Figure 1. 997; no patient has been lost to follow-up.

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Figure 2. Fig 2. Survival by type of relapse in the same group of patients as in Fig 1.

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Older patients ( Wheeler et al, 1998 ) and those with T-ALL ( Henze et al, 1991 ; Wheeler et al, 1998 ) have a worse prognosis: no patient in the Berlin-Frankfurt-Munster (BFM) relapse study with a relapse within 18 months of diagnosis or with T-ALL has survived beyond 15 months ( Henze et al, 1991 ). The length of second remission, in contrast to that of first remission, is not influenced by presenting leucocyte count or by gender ( Henze et al, 1991 ; Wheeler et al, 1998 ).

The primary treatment of ALL has become progressively more intensive over the last 10 years, and it might be expected that the intensity of initial treatment would influence the duration of second remission and survival. Both the recent MRC UKALL X and the American Children's Cancer Group (CCG) 100 series of protocols involved randomization to one or more blocks of intensive treatment, and in neither was there evidence that the intensity of previous treatment had a significant influence on survival ( Wheeler et al, 1998 ; Gaynon et al, 1998 ).

The other recent change in management of ALL has been the avoidance of cranial irradiation and reliance on regular intrathecal chemotherapy for CNS-directed therapy. The CCG 105 protocol randomized a large number of children with intermediate-risk ALL to receive regular intrathecal methotrexate with or without additional cranial irradiation ( Tubergen et al, 1993 ). The results showed that intrathecal methotrexate, in combination with intensified systemic therapy, afforded equivalent CNS protection in the younger child to that provided by additional cranial irradiation. Patients with CNS relapse despite cranial irradiation had an increased risk of death in comparison with unirradiated patients, but this did not reach statistical significance ( Gaynon et al, 1998 ).

A recent review of the results of treatment of R-ALL by the BFM study group ( Buhrer et al, 1996 ) showed that, among 260 children with isolated marrow relapse occurring over 6 months off therapy, the 38 without circulating blasts at the time of recurrence had a significantly better 10-year probability of EFS at 64% (SD 11) than the 171 with up to 10 × 109/l at 32% (SD 5) or the 51 with more than 10 × 109/l at 10% (SD 6). Only a length of first remission >48 months was an additional prognostic factor in this subset of patients. This finding, which relies on the differential leucocyte count, contrasts with previous reports where leucocyte count at the time of relapse had no prognostic significance ( Henze et al, 1991 ; Wheeler et al, 1998 ) and requires confirmation by further studies.

Patients with relapsed ALL often exhibit morphological shifts from the small L1 blasts at diagnosis to the larger more pleomorphic L2 blasts, which in untreated ALL have a worse prognosis ( Abshire et al, 1992 ; Lilleyman et al, 1995 ) and may show shifts in immunophenotype, usually to a more undifferentiated type, with, for example, loss of HLA-DR or CD10 antigen ( Abshire et al, 1992 ; van Wering et al, 1995 ). Sequential study of cytogenetics disclosed major changes in karyotype in 10% of patients in one study from St Jude Children's Research Hospital, but these patients had received very intensive treatment and developed therapy-induced secondary leukaemia ( Raimondi et al, 1993 ). Less obvious evolution in karyotype has been reported in other groups of patients ( Heerema et al, 1992 ; Farah et al, 1997 ), and it has been claimed that change in karyotype is associated with a worse prognosis after relapse ( Vora et al, 1996 ), a report not confirmed by other studies ( Farah et al, 1997 ). Molecular genetics may also influence prognosis; it has recently been reported that children with R-ALL in association with the TEL-AML 1 fusion transcript had significantly longer second remissions than those without ( Seeger et al, 1997 ). Analysis of cellular drug resistance has shown that cells from children with relapsed ALL are more resistant to steroids, L-asparaginase, anthracyclines and thiopurines than those with newly diagnosed leukaemia ( Klumper et al, 1995b ). These investigations support the clinical observation that disease after relapse is more refractory to therapy and afford the hope that further studies of the biology of relapsed ALL may perhaps help to refine prognosis.

Management of relapse

  1. Top of page
  2. Methods
  3. Classification of relapses
  4. Survival after relapse: unselected results
  5. Factors influencing outcome after relapse
  6. Management of relapse
  7. Long-term results of intensive chemotherapy for treatment of relapses involving the bone marrow
  8. High-dose chemoradiotherapy and stem cell rescue
  9. Comparisons of alternative forms of high-dose therapy
  10. Evaluation of ABMT and UD BMT in marrow relapse
  11. CNS relapse as a first event
  12. Other extramedullary relapses
  13. New approaches to treatment
  14. Management of relapse: a personal viewpoint
  15. Future directions
  16. Acknowledgements
  17. References

Reinduction

Standard three-drug induction with prednisolone, vincristine and L-asparaginase, induces a complete remission in >95% of children with newly diagnosed lymphoblastic leukaemia ( Ortega et al, 1977 ), but in fewer of those who relapse. 2 Table II shows the results of more intensive combinations of therapy in children who have relapsed on more recent first-line protocols, and it can be seen that the addition of an anthracycline can increase the remission rate to >80% in most of the studies, even in children who have been treated on modern intensive chemotherapy. Most of these protocols assessed remission after 4–5 weeks of these drugs, with additional intensification therapy given after this induction. The BFM relapse protocol uses more extended induction with multiple drugs for high-risk patients so that remission is assessed later in treatment. As shown in 2 Table II, most of the protocols involve the use of anthracyclines; however, their use may in practice be restricted by cardiotoxicity if anthracyclines have been used during first-line therapy ( Steinherz et al, 1992 ). There have been no recent randomized trials of reinduction therapy except for that recently published by the Childrens' Cancer Group ( Feig et al, 1996 ), the details of which are shown in Table II. A dose of idarubicin at 12.5 mg/m2 per week proved more myelotoxic than daunorubicin at 45 mg/m2/week and the dose was reduced to 10 mg/m2 ; however, 2-year event-free survival proved significantly superior at 27% (SE 18) for children who received the higher dose of idarubicin, compared to 10% (SE 8) for daunorubicin and 6% (SE 12) for the lower dose of idarubicin. The difference was not sustained at 3 years and the overall results, despite intensive continuing chemotherapy were poor (see Table III).

Table 2. Table II. Reinduction for first marrow relapse in paediatric ALL. Buchanan et al (1988 ) Culbert et al (1991 ) Henze et al (1991 ) Giona et al (1994 ) Feig et al (1996 ) Billett et al (1997 ) Thumbnail image of
Table 3. Table III. Results of intensive chemotherapy for bone marrow relapse. Rivera et al (1986 ) Buhrer et al (1993 ) Sadowitz et al (1993 ) Feig et al (1996 ) Rivera et al (1996 ) Billett et al (1997 ) Thumbnail image of

CNS-directed therapy

Early protocols for relapsed ALL were complicated by a high incidence of CNS relapse, and the need for CNS-directed therapy became apparent in these cases, as in newly diagnosed lymphoblastic leukaemia ( Chessells et al, 1984 ; Buhrer et al, 1994 ). Most protocols have incorporated regular intrathecal methotrexate, with or without hydrocortisone and cytarabine and some, in addition, moderate or high dose intravenous methotrexate.

The BFM study group randomized patients with relapsed ALL to receive either intravenous methotrexate 12 g/m2 as a 4 h infusion or 1 g/m2 as a 36 h infusion; the randomization was stopped after it became apparent that the 37 patients receiving high-dose MTX did not achieve better systemic control or CNS protection than intermediate-dose methotrexate ( Henze et al, 1991 ). The group have subsequently introduced cranial irradiation and triple intrathecal chemotherapy in children with late isolated BM relapse because of their concerns about the risk of CNS relapse, but this has been done empirically and not in a randomized fashion ( Buhrer et al, 1994 ).

There seems clear evidence that children who relapse should, like those at presentation, receive adequate CNS-directed therapy, but the relative additional benefits of high-dose systemic chemotherapy and/or cranial irradiation in addition to intensive intrathecal chemotherapy remain unclear.

Long-term results of intensive chemotherapy for treatment of relapses involving the bone marrow

  1. Top of page
  2. Methods
  3. Classification of relapses
  4. Survival after relapse: unselected results
  5. Factors influencing outcome after relapse
  6. Management of relapse
  7. Long-term results of intensive chemotherapy for treatment of relapses involving the bone marrow
  8. High-dose chemoradiotherapy and stem cell rescue
  9. Comparisons of alternative forms of high-dose therapy
  10. Evaluation of ABMT and UD BMT in marrow relapse
  11. CNS relapse as a first event
  12. Other extramedullary relapses
  13. New approaches to treatment
  14. Management of relapse: a personal viewpoint
  15. Future directions
  16. Acknowledgements
  17. References

The survival figures for unselected patients with ALL have been shown in Table I. Table III summarizes the results of recently published standardized intensive treatment protocols for such patients: all incorporate drugs additional to thiopurines and methotrexate throughout treatment. The number of patients — and the paucity of randomized studies — is disappointing, but again it is apparent from these, as from population-based studies, that few children with early marrow relapses respond to intensive treatment and that a proportion of such children relapsing later may be cured. For example, in the study by Billett et al (1997 ) in 27 of the late-relapsing patients, whose initial remission was >4 years, the 4-year EFS was 52.4% (SE 11). The event-free survival for late relapses, variously defined in 3 Table III, ranges from 24% to 65%, but the best results, as always, have involved relatively small cohorts of patients.

High-dose chemoradiotherapy and stem cell rescue

  1. Top of page
  2. Methods
  3. Classification of relapses
  4. Survival after relapse: unselected results
  5. Factors influencing outcome after relapse
  6. Management of relapse
  7. Long-term results of intensive chemotherapy for treatment of relapses involving the bone marrow
  8. High-dose chemoradiotherapy and stem cell rescue
  9. Comparisons of alternative forms of high-dose therapy
  10. Evaluation of ABMT and UD BMT in marrow relapse
  11. CNS relapse as a first event
  12. Other extramedullary relapses
  13. New approaches to treatment
  14. Management of relapse: a personal viewpoint
  15. Future directions
  16. Acknowledgements
  17. References

It is now more than 20 years since the demonstration that some end-stage patients with leukaemia could be cured by high-dose chemoradiotherapy and allogeneic transplantation from a histocompatible sibling donor ( Thomas et al, 1977 ). BMT has been accepted as a form of treatment for ALL in second remission for many years ( Sanders et al, 1987 ), but the indications for BMT in ALL are still not fully established. The majority of publications on this topic come from transplant centres or registries; they therefore incorporate an inevitable selection bias because of the instability of second remissions ( Chessells et al, 1986 ) and the fact that most patients lack a histocompatible sibling. Transplant-related mortality (TRM) has decreased in recent years ( Frassoni et al, 1996 ) and therefore the main obstacle to success in this, as in other forms of treatment, is relapse of leukaemia. The Minneapolis BMT team recently analysed the factors influencing outcome of BMT in second remission of ALL from a histocompatible sibling donor. They identified length of previous remission, initial leucocyte count, and previous CNS infiltration as adverse prognostic factors ( Weisdorf et al, 1994 ); the overall risk of leukaemic relapse in 123 patients was 56% (SE 11) with no relapses beyond 2.2 years. The most widely used preparative regimen for BMT remains the combination of cyclophosphamide and fractionated total body irradiation; but a variety of other protocols have been used, as indicated in 4 Table IV. However, as shown in 4 Table IV, most of these reports are single-centre studies involving small numbers of patients and there is a regrettable absence of prospective randomized trials comparing various preparative regimens. There is no convincing evidence that any one preparative regimen is superior to the others; the lowest relapse rate has been reported after the use of hyperfractionated total body irradiation and cyclophosphamide ( Brochstein et al, 1987 ).

Table 4. Table IV. BMT for ALL in second remission: some results from preparative regimens other than conventional cyclophosphamide and total body irradiation. Brochstein et al (1987 ) Weyman et al (1993 ) Moussalem et al (1995 ) Uderzo et al (1995a ) Thumbnail image of

The late effects of total body irradiation are significant, particularly in the young child, and include growth retardation, hypothyroidism, infertility ( Sanders et al, 1986 ; Leiper et al, 1987 ), and, especially in children who have received previous cranial irradiation, significant neuropsychological problems ( Longeway et al, 1990 ; Christie et al, 1994 ). Although there has been preliminary development of preparative regimens which avoid TBI in ALL, there have been few reports of their use in children.

The majority of patients do not, of course, have a histocompatible sibling donor and this has led to interest in autologous BMT (ABMT). ABMT has a much lower TRM than BMT but in contrast to chemotherapy involves relatively short-term treatment; it is, however, associated with a high risk of relapse. The best results, as always, are single-centre studies, and the event-free survival in a group of 51 children with first remissions of at least 24 months was 53% (standard error, SE 7) after high-dose chemotherapy, total body irradiation and infusion of purged autologous marrow; however, the patients were clearly a highly selected group since the most significant predictor of leukaemia-free survival (LFS) was length of first remission and the duration of second remission before ABMT ( Billett et al, 1993 ).

More recently the pool of potential donors has been expanded by the use of unrelated volunteers ( Caspar et al, 1995 ) and possibly other sources such as cord blood stem cells. Two recent publications ( Oakhill et al, 1996 ; Hongeng et al, 1997 ), both from single centres, have reported identical event-free survival for recipients of sibling donor and volunteer unrelated (UD) donors. In the largest of these studies the event-free survival for a group of 50 consecutive children receiving unrelated donor transplants in second remission of ALL was similar to that of children with histocompatible siblings 53% at 2 years (Oakhill et al, 1996). A further recent report indicates that UD transplants may achieve stable remissions in some children in third remission ( Davies et al, 1997 ).

Comparisons of alternative forms of high-dose therapy

  1. Top of page
  2. Methods
  3. Classification of relapses
  4. Survival after relapse: unselected results
  5. Factors influencing outcome after relapse
  6. Management of relapse
  7. Long-term results of intensive chemotherapy for treatment of relapses involving the bone marrow
  8. High-dose chemoradiotherapy and stem cell rescue
  9. Comparisons of alternative forms of high-dose therapy
  10. Evaluation of ABMT and UD BMT in marrow relapse
  11. CNS relapse as a first event
  12. Other extramedullary relapses
  13. New approaches to treatment
  14. Management of relapse: a personal viewpoint
  15. Future directions
  16. Acknowledgements
  17. References

There are no randomized trials comparing chemotherapy and high-dose therapy in the management of relapsed leukaemia, and all other types of comparison are confounded by potential selection bias. Except for one small early study ( Chessells et al, 1986 ) there have been no analyses on an intention-to-treat basis comparing outcome for patients with R-ALL with and without sibling donors.

Attempts have been made to compare BMT and chemotherapy since the early 1980s ( Johnson et al, 1981 ; Bacigalupo et al, 1986 ), and the first systematic comparison from the International Bone Marrow Transplant Registry suggested that BMT was superior to chemotherapy in children with a first remission of <18 months ( Butturini et al, 1987 ).

Table V lists the studies reported in the last 10 years which have involved a formal comparison of chemotherapy and BMT. None involve comparison on a donor/no donor basis, but all have made some form of attempt to allow for bias in terms of time to transplant. Most involve relatively small numbers of patients. The German study ( Dopfer et al, 1991 ) and the Italian study ( Uderzo et al, 1995b ) both indicated that BMT was statistically superior to chemotherapy for patients with early relapses. The largest study involved a comparison ( Barrett et al, 1994 ) between 540 children treated with American Pediatric Oncology Group (POG) standard protocols between 1983 and 1991 and 376 children receiving a BMT in second remission of ALL during that time who were reported to the International Bone Marrow Transplant Registry. After preliminary analysis to identify variables associated with treatment failure, an attempt was made to select pairs of children matched for these variables. The leukaemia-free survival at 5 years for the whole BMT group was 36% (SE 3) and for the chemotherapy group 16% (SE 2), a highly significant difference (P < 0.001). The results for matched-pair analysis are shown in Table V, and a significant benefit for BMT was shown both for early and late relapse, and also in the 36 matched pairs of children with an initial relapse >48 months or the 18 with remissions >60 months. Wheeler et al (1998 ) have attempted to use the adjusted survival curves allowing for prognostic factors and time to transplant and have also showed some benefit for BMT irrespective of the length of first remission. It can be seen from Table V that survival after BMT usually appears superior to chemotherapy. However, this difference does not necessarily reach conventional statistical significance in patients with late relapse, and, despite the efforts made by the authors, none of these comparisons is likely to be free from bias.

Table 5. Table V. Comparisons of BMT and chemotherapy in second remission ALL. Torres et al (1989 ) Dopfer et al (1991 ) Barrett et al 1994 ) Hoogerbrugge et al (1995 ) Uderzo et al (1995b ) Feig et al (1997 ) Wheeler et al (1998 ) * Allowance made for early relapses and time to bone marrow transplant.† Case–control studies matching for length of first remission and other prognostic factors.‡ Survival curves adjusted for relapse type, timing and age.§ 95% confidence intervals rather than standard error.Thumbnail image of

An interesting finding which emerges from these studies is the relative proportion of children who received a BMT. Since none of these was randomized, the decision presumably reflects the preference of families and physicians, the public perceptions around bone marrow transplantation, and economic factors. The bias in the U.K. is clearly towards BMT, with this procedure being performed in 110/489 patients relapsing from MRC UKALL X, 83 from a histocompatible sibling and 27 from volunteer unrelated donors. In contrast, a lower proportion of patients in Germany and the U.S.A., as judged from published results ( Feig et al, 1996 ; Henze et al, 1991 ), are treated with BMT in second remission. Most reports unfortunately do not give a detailed analysis of results of BMT by length of first remission.

Evaluation of ABMT and UD BMT in marrow relapse

  1. Top of page
  2. Methods
  3. Classification of relapses
  4. Survival after relapse: unselected results
  5. Factors influencing outcome after relapse
  6. Management of relapse
  7. Long-term results of intensive chemotherapy for treatment of relapses involving the bone marrow
  8. High-dose chemoradiotherapy and stem cell rescue
  9. Comparisons of alternative forms of high-dose therapy
  10. Evaluation of ABMT and UD BMT in marrow relapse
  11. CNS relapse as a first event
  12. Other extramedullary relapses
  13. New approaches to treatment
  14. Management of relapse: a personal viewpoint
  15. Future directions
  16. Acknowledgements
  17. References

The risks of allogeneic transplantation and the lack of histocompatible siblings have led to interest in the use of ABMT in relapsed leukaemia. Table VI shows the results of studies comparing ABMT with varying alternative forms of treatment and, again, none of these studies was randomized. The early study by Kersey et al (1987 ) compared consecutive patients referred to a single transplant unit and was not confined to patients in second remission. Transplant-related mortality was high (26%) for the BMT group and the relapse rate was higher for the ABMT group. The matched-pair analysis by Parsons et al (1996 ) was confined to patients with late relapse and included only a small number of allografts. The Medical Research Council Working party on childhood leukaemia attempted to perform a randomized trial comparing ABMT and chemotherapy in children with no histocompatible sibling donor, but only 15 patients were randomized; unrandomized outcomes adjusted for age, leucocyte count and length of first remission, as shown in 56 Tables V and VI, show that BMT is superior to chemotherapy and that there is no significant difference between ABMT and chemotherapy. Similarly, matched-pair analysis by the BFM group ( Borgmann et al, 1995b ) and a study by the Italian group ( Uderzo et al, 1995b ) showed no significant difference in outcome between ABMT and chemotherapy.

At present, there is little information available concerning unrelated donor transplants. A report from Seattle comparing the outcome in patients with leukaemia who received either BMT from an unrelated donor or ABMT involved a very heterogenous group of patients and showed a similar outcome for both procedures ( Busca et al, 1994 ). A more recent publication from Europe involved a larger number of patients with ALL, the majority of whom were in second remission and included adults as well as children. Leukaemia-free survival was similar in the two groups but TRM was higher in the BMT group (42% v 17%) and relapse was reduced (32% v 61%) ( Ringden et al, 1997 ). In contrast, TRM in two recent single-centre studies of unrelated donor BMT was in the order of 20% ( Hongeng et al, 1997 ; Oakhill et al, 1996 ).

CNS relapse as a first event

  1. Top of page
  2. Methods
  3. Classification of relapses
  4. Survival after relapse: unselected results
  5. Factors influencing outcome after relapse
  6. Management of relapse
  7. Long-term results of intensive chemotherapy for treatment of relapses involving the bone marrow
  8. High-dose chemoradiotherapy and stem cell rescue
  9. Comparisons of alternative forms of high-dose therapy
  10. Evaluation of ABMT and UD BMT in marrow relapse
  11. CNS relapse as a first event
  12. Other extramedullary relapses
  13. New approaches to treatment
  14. Management of relapse: a personal viewpoint
  15. Future directions
  16. Acknowledgements
  17. References

The long-term outlook following a first episode of central nervous system leukaemia is clearly illustrated by a report from the CCG with a minimum of 10 years follow-up ( Ortega et al, 1987 ). One hundred children in a randomized trial of CNS-directed therapy, which included one option of short-term intrathecal methotrexate only, developed CNS relapse as a first event. The disease-free survival after CNS relapse was only 16%; most patients subsequently developed a marrow relapse or chronic CNS disease. The time to initial CNS relapse was the most important factor for predicting outcome; an observation confirmed by more recent reports where all children have received CNS-directed therapy in first remission ( Gaynon et al, 1998 ; Wheeler et al, 1998 ). Children with a first CNS relapse are at high risk of subsequent marrow relapse ( Pinkerton & Chessells, 1984; George et al, 1985 ; Behrendt et al, 1989 ), therefore further intensification of systemic therapy is as important as control of CNS disease. There are a number of problems in identifying the best treatment for CNS relapse. The incidence of isolated CNS relapse as a first event is now <10%, therefore any trials of therapy must inevitably involve small numbers of patients or widespread collaboration. There has been a major alteration in primary CNS-directed treatment, therefore fewer children now receive cranial irradiation. A further problem is the lack of an agreed definition of CNS leukaemia, since a low cerebro-spinal fluid (CSF) cell count with recognizable blasts has been accepted for diagnosis in some studies ( Odom et al, 1990 ; Ribeiro et al, 1995 ) but not in others ( Tubergen et al, 1994 ). Table VII shows the results of treatment for CNS relapse in recent publications, the largest of which by far is that conducted by the Pediatric Oncology Group where CNS directed treatment was uniform but patients were randomized to one of two regimens for systemic therapy. The 4-year event-free survival was 46% (SE 7) with no statistical difference between the two treatment arms. As expected, length of first remission was an important prognostic factor and the major cause of failure was bone marrow relapse. This paper showed that effective CNS control can be achieved in most children without recourse to spinal irradiation but again highlights the need for intensified systemic therapy ( Winick et al, 1993 ).

Table 7. Table VII. Outcome following isolated CNS relapse as a first event. Land et al (1985 ) Mandell et al (1990 ) Ribeiro et al (1995 ) Ritchey et al (1993 ) Winick et al (1993 ) Messina et al (1998 ) Thumbnail image of

In view of the overall poor prognosis of early CNS relapse, bone marrow transplantation could be deemed a reasonable approach, but there are few reports of results of BMT in this situation. A retrospective comparison between chemotherapy and BMT or ABMT from the BFM group showed no significant difference between BMT and ABMT and superior results for chemotherapy; however, there were only 31 children in the transplant group ( Borgmann et al, 1995a ). The Italian group have suggested that ABMT may be an appropriate treatment for isolated extramedullary relapse in first remission and the 5-year event-free survival for 34 children in second remission was 67.7% ( Messina et al, 1996 ). This group have more recently reported the outcome of ABMT in patients with early CNS relapse which compared favourably with chemotherapy ( Messina et al, 1998 ) ( Table VII).

Other extramedullary relapses

  1. Top of page
  2. Methods
  3. Classification of relapses
  4. Survival after relapse: unselected results
  5. Factors influencing outcome after relapse
  6. Management of relapse
  7. Long-term results of intensive chemotherapy for treatment of relapses involving the bone marrow
  8. High-dose chemoradiotherapy and stem cell rescue
  9. Comparisons of alternative forms of high-dose therapy
  10. Evaluation of ABMT and UD BMT in marrow relapse
  11. CNS relapse as a first event
  12. Other extramedullary relapses
  13. New approaches to treatment
  14. Management of relapse: a personal viewpoint
  15. Future directions
  16. Acknowledgements
  17. References

The next most common site of relapse is the testicle, usually presenting within a year after elective cessation of therapy. A number of previous protocols for ALL involved end of treatment testicular biopsies, and therefore publications may include cases of either occult or overt testicular leukaemia. Recent results of treatment of testicular relapse are shown in Table VIII; all show long-term event-free survival for patients with late isolated testicular relapse treated with further intensive systemic and intrathecal chemotherapy and local irradiation. Patients relapsing earlier have a worse prognosis. These results indicate that conventional therapy is appropriate for children with late relapse. A recent provocative report from Holland ( Van den Berg et al, 1997 ) documents five boys in whom testicular irradiation was omitted in favour of high-dose methotrexate, with apparent continued testicular remission.

Table 8. Table VIII. Isolated testicular relapse: treatment and outcome. Uderzo et al (1990 ) Nachman et al (1990 ) Buchanan et al (1991 ) Wofford et al (1992 ) Finklestein et al (1994 ) Grundy et al (1997 ) Thumbnail image of

Relapse in the ovaries is, in contrast, rare, usually presenting with an abdominal mass; most reported cases have occurred within the first 3 years and some patients have survived intensive retreatment ( Pais et al, 1991 ). Ocular relapses frequently present within the first year off treatment ( Bunin et al, 1987 ) with local iritis, and again local irradiation and intensive treatment may afford control in some patients, but there is a high risk of marrow relapse ( Lo Curto et al, 1994 ).

New approaches to treatment

  1. Top of page
  2. Methods
  3. Classification of relapses
  4. Survival after relapse: unselected results
  5. Factors influencing outcome after relapse
  6. Management of relapse
  7. Long-term results of intensive chemotherapy for treatment of relapses involving the bone marrow
  8. High-dose chemoradiotherapy and stem cell rescue
  9. Comparisons of alternative forms of high-dose therapy
  10. Evaluation of ABMT and UD BMT in marrow relapse
  11. CNS relapse as a first event
  12. Other extramedullary relapses
  13. New approaches to treatment
  14. Management of relapse: a personal viewpoint
  15. Future directions
  16. Acknowledgements
  17. References

Unfortunately, new approaches to treatment in R-ALL have not been notably successful. Drug combinations such as methotrexate and tenoposide ( Ochs et al, 1991 ), idarubicin and cytarabine ( Bernstein et al, 1997 ) and idarubicin with fludarabine and cytarabine ( Dinndorf et al, 1997 ) have shown some activity in refractory or second relapse of ALL and there has also been interest in PEG- L-asparaginase ( Kurtzberg et al, 1993 ). However, no combination of drugs has been shown to be of significant benefit, and the limited studies of the newer anthracyclines in vitro have at least demonstrated significant cross resistance between the various drugs ( Klumper et al, 1995a ). Studies of multidrug resistance and its modulation ( McKenna & Padua, 1997) have largely been devoted to myeloid leukaemias, and a preliminary study in childhood ALL has not demonstrated any effect of resistance modifiers in vitro ( Pieters et al, 1992 ).

Relapse is also the major obstacle to successful BMT, and if transplants from unrelated donors prove relatively non-toxic it is conceivable that such donors may eventually prove preferable to histocompatible siblings. There has been recent interest in the use of donor lymphocyte infusions to induce a graft-versus-leukaemia effect despite the risks of induction of severe graft-versus-host disease and myelosuppression. This treatment has produced the most encouraging results in chronic myeloid leukaemia where durable remissions have been achieved, but has been less successful in ALL ( Kolb et al, 1996 ; Collins et al, 1997 ). However, three of four children with ALL relapsing after BMT achieved remission following lymphocyte infusions, albeit at the price of chronic graft-versus-host disease in two cases ( Atra et al, 1997 ). Clearly there are ethical issues in the use of infusions from young sibling donors, but this form of treatment is worth systematic prospective evaluation in management and may perhaps prevent relapse after BMT. An alternative experimental approach is a second bone marrow transplant, reputedly successful after long first remissions ( Giralt & Champlin, 1994) but possibly of more value in acute myeloid leukaemia ( Bosi et al, 1997 ).

Management of relapse: a personal viewpoint

  1. Top of page
  2. Methods
  3. Classification of relapses
  4. Survival after relapse: unselected results
  5. Factors influencing outcome after relapse
  6. Management of relapse
  7. Long-term results of intensive chemotherapy for treatment of relapses involving the bone marrow
  8. High-dose chemoradiotherapy and stem cell rescue
  9. Comparisons of alternative forms of high-dose therapy
  10. Evaluation of ABMT and UD BMT in marrow relapse
  11. CNS relapse as a first event
  12. Other extramedullary relapses
  13. New approaches to treatment
  14. Management of relapse: a personal viewpoint
  15. Future directions
  16. Acknowledgements
  17. References

The conservative approach

Children treated with intensive re-induction have an excellent chance of second remission. Whatever the site of relapse, all need CNS-directed treatment with intensive intrathecal chemotherapy; the benefits of additional high-dose intravenous therapy and/or cranial irradiation are not clear, but these treatments are incorporated in some protocols.

Radiation therapy is indicated for children with overt CNS relapse, with or without marrow disease, but can probably be delayed pending further intensification therapy since the main risk to these children is a subsequent marrow relapse. There is now evidence to justify the use of cranial irradiation with intensive intrathecal chemotherapy rather than craniospinal irradiation, thus avoiding myelosupression and the late effects of spinal irradiation. A similar approach, with bilateral testicular irradiation, is indicated for children with overt testicular relapse. Treatment should be continued for 18 months to at least 2 years, and intensification of treatment is indicated throughout therapy.

This conventional approach to treatment will cure the majority of patients with late testicular relapses and many children with late CNS relapse, and will produce long marrow remissions in some children who have had long first remissions. Most children who relapse a second time are incurable, but some, with long second remissions or a second relapse which is extramedullary ( Adams et al, 1997 ), may be rescued by a transplant in third remission ( Borgmann et al, 1997 ).

The role of high-dose therapy and stem cell rescue

There have been several recent attempts to develop guidelines for the role of BMT in childhood leukaemia ( Dini et al, 1996 ; Niethammer et al, 1996 ; Gordon-Smith et al, 1997 ). In the absence of randomized trials the evidence from comparative studies indicates that following bone marrow relapse of leukaemia high-dose chemotherapy and transplantation of bone marrow from a histocompatible sibling affords a greater chance of leukaemia-free survival than conventional chemotherapy. This benefit is seen in children with both early and late relapses, although in the author's experience the outcome of BMT for very early marrow relapses within 2 years from diagnosis is extremely poor. There is little evidence for any role for ABMT outwith the context of a clinical trial. The choice between BMT and chemotherapy for children with late relapses is a balance between concerns about transplant-related mortality, risk of chronic graft-versus-host disease and late effects of chemoradiotherapy on the one hand and the risk of treatment failure on the other. The availability of UDBMT lends another dimension to this choice and is clearly justifiable in early marrow relapses. It may afford a greater graft-versus-leukaemia effect than use of a sibling donor. If UDBMT is truly no more toxic than that from a histocompatible sibling donor, as claimed by single-centre reports, then it should be considered on an equal footing with BMT for later relapses.

The best way to resolve uncertainties about treatment is a prospective randomized trial, and clearly a strong case could be made for a such a trial in children with late marrow relapses with a randomization to chemotherapy or BMT (either from a sibling or volunteer unrelated donor) with the option of transplant in third remission for those who fail chemotherapy. However parents, patients and doctors, perhaps not surprisingly, all have strong views on the management of ALL, and the chances of completing such a trial in this climate of opinion seem poor.

Future directions

  1. Top of page
  2. Methods
  3. Classification of relapses
  4. Survival after relapse: unselected results
  5. Factors influencing outcome after relapse
  6. Management of relapse
  7. Long-term results of intensive chemotherapy for treatment of relapses involving the bone marrow
  8. High-dose chemoradiotherapy and stem cell rescue
  9. Comparisons of alternative forms of high-dose therapy
  10. Evaluation of ABMT and UD BMT in marrow relapse
  11. CNS relapse as a first event
  12. Other extramedullary relapses
  13. New approaches to treatment
  14. Management of relapse: a personal viewpoint
  15. Future directions
  16. Acknowledgements
  17. References

Treatment of relapsed ALL involves much heartache and discomfort for patients and families, including the risk of short-term and late effects of therapy, and consumes large amounts of resources. Continued efforts are essential both to avoid relapse by improving first-line treatment and to develop a better understanding of the biological factors influencing the chance of sustained second remission. There is clearly a need for continuing prospective, preferably randomized, trials of relapsed ALL and for generally agreed definitions of early, intermediate and late relapse. This will facilitate the national and international comparisons which are necessary to define the best approach to management, although review of present results of treatment does not suggest that any one particular chemotherapeutic approach is superior to the others. There is clearly continued scope for further investigation of new agents or innovative approaches to therapy. Although randomized trials of bone marrow transplantation may be difficult to achieve there should be less difficulty in ensuring uniform preparative regimens in multicentre studies, randomized trials of novel preparative regimens, and audit of transplant-related mortality and morbidity. Such efforts are essential if children with lymphoblastic leukaemia are to be given an effective second chance of cure.

References

  1. Top of page
  2. Methods
  3. Classification of relapses
  4. Survival after relapse: unselected results
  5. Factors influencing outcome after relapse
  6. Management of relapse
  7. Long-term results of intensive chemotherapy for treatment of relapses involving the bone marrow
  8. High-dose chemoradiotherapy and stem cell rescue
  9. Comparisons of alternative forms of high-dose therapy
  10. Evaluation of ABMT and UD BMT in marrow relapse
  11. CNS relapse as a first event
  12. Other extramedullary relapses
  13. New approaches to treatment
  14. Management of relapse: a personal viewpoint
  15. Future directions
  16. Acknowledgements
  17. References
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