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Oncology Unit, The Children's Hospital at Westmead (Royal Alexandra Hospital for Children), Sydney, NSW, Australia. Summary: We evaluated the role of BMT ...
Bone Marrow Transplantation (2002) 30, 1–7  2002 Nature Publishing Group All rights reserved 0268–3369/02 $25.00 www.nature.com/bmt

Acute lymphoblastic leukaemia Allogeneic bone marrow transplantation for childhood relapsed acute lymphoblastic leukemia: comparison of outcome in patients with and without a matched family donor M Bleakley, PJ Shaw and JM Nielsen Oncology Unit, The Children’s Hospital at Westmead (Royal Alexandra Hospital for Children), Sydney, NSW, Australia

Summary: We evaluated the role of BMT in a cohort of 56 children with ALL relapsing after uniform initial treatment protocols in a single institution between 1990 and 1997. The patients were commenced on a single intensive chemotherapy regimen. All patients with a matched family donor (MFD) were recommended to receive BMT. The outcome was significantly better for patients with a MFD. The overall survival at 8 years was 60.0% (95% CI 35.7–77.6%) and 13.5% (95% CI 4.0–28.6%) for patients with and without MFDs (log-rank chi = 7.50 P = 0.0062). The event-free survival at 8 years was 55.0% (95% CI 11.1–31.3%) and 9.2% (95% CI 2.0–23.3%) for patients with and without MFDs (log-rank chi = 8.87 P = 0.0029). Multivariate analysis confirmed the survival advantage of BMT. There was no statistically significant difference in survival for patients initially relapsing within 3 years of first remission compared to children relapsing beyond 3 years. BMT provides a clear survival advantage for children following their first relapse of ALL. We recommend BMT for all children following first relapse of ALL if a MFD is available. Bone Marrow Transplantation (2002) 30, 1–7. doi: 10.1038/sj.bmt.1703601 Keywords: ALL; BMT; pediatric ALL

Although the majority of children with ALL can be cured with their initial chemotherapy, the prognosis for those who relapse is guarded. In the past, there have been various reports of improving prognosis for children suffering their first marrow relapse of ALL, with protocols reporting longterm leukemia-free survival rates ranging from under 20% to 31%.1–5 However, many of these reports do not include patients relapsing after initial treatment with contemporary intensive chemotherapy. With the current intensification of front-line protocols and further improved identification of Correspondence: Marie Bleakley, Oncology Unit, The Children’s Hospital at Westmead (Royal Alexandra Hospital for Children), Sydney, NSW 2145, Australia Received 7 January 2002; accepted 11 April 2002

high risk groups at diagnosis, patients who relapse tend to have resistant disease. Further intensification of chemotherapy, often including BMT is the major option.6–18 How much advantage BMT in second clinical remission (CR2) offers over intensive chemotherapy alone remains controversial.8–14 In particular, it has not been conclusively established whether BMT should be the preferred treatment option for children suffering relapses late after first remission, or at all sites. There have been no randomized trials of chemotherapy vs BMT in CR2 in children. It is unlikely that such trials will be conducted because of the clinical impression that BMT offers a survival advantage and consequent ethical concerns about withholding BMT from children with a suitable BMT donor. Donor vs no donor studies are one form of analysis that offer a relatively unbiased comparison between BMT and alternative treatment options.19 ‘Biological randomization’ is achieved in donor vs no donor studies by the allocation of all patients with suitable family donors to the BMT group and comparing their outcome to that of children without a suitable donor using intention to treat analysis. We report the outcome of a cohort of pediatric patients suffering a first relapse of ALL treated with a uniform intensive induction chemotherapy protocol, and compare the outcome of children with a matched family donor (MFD) with those lacking a MFD. The surviving patients have been followed-up for a median of 6.7 years. Patients and methods All children who presented with their first relapse of ALL at the Children’s Hospital Westmead (RAHC) between 1990 and 1997 were eligible for treatment with NYII. Treatment was given according to the modified NYII protocol. The New York-II (NYII) protocol is an intensive chemotherapy regimen designed for children newly diagnosed with ALL who are at high risk of relapse.20 We modified the protocol for use for patients with relapsed disease. All patients received intrathecal therapy as part of the NYII reinduction chemotherapy. For patients who continued on chemotherapy, those who had already received cranial irradiation as part of their initial therapy were not re-irradiated. Of those who had never been irradiated, half received prophylactic cranial irradiation and half received

Relapsed ALL: BMT or continued chemotherapy? M Bleakley et al

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systemic and intrathecal chemotherapy alone as part of NYII. We have previously described the modified treatment regimen and reported similar rates of remission, early morbidity and mortality as in newly diagnosed patients.21 Children were eligible for inclusion in the donor vs no donor analysis if they had suffered a first relapse of ALL, commenced treatment on the NYII protocol, and had undergone tissue typing. Definition of remission was less than 5% blasts in a normocellular marrow aspirate and a clear CSF. Tissue typing was initiated soon after relapse. All patients who had a matched family donor (MFD, defined as a 6/6 antigen matched sibling or 10/10 matched parent) were offered allogeneic transplant in second remission. If there was no MFD, treatment was discussed between the treating oncologist and the family. Most patients continued on NYII; but some underwent transplantation from alternative donors. The outcome of all patients with a MFD was compared with all patients lacking a donor using intention to treat analysis. For those patients undergoing BMT, pre-transplant conditioning was with fractionated total body irradiation (TBI), 1320 cGy in eight fractions over 4 days, and cyclophosphamide, 60 mg/kg for 2 days. CNS prophylaxis was with cranial irradiation as part of total body irradiation. Cyclosporin and short-term methotrexate were used as graftversus-host disease (GVHD) prophylaxis, with aggressive early tapering to maximize the graft-versus-leukemia effect.22 For the statistical analysis of continuous variables Student’s t-test was used. The chi-square test, or Fisher’s exact test were used for the analysis of dichotomous variables. For the analysis of time to event data univariate comparisons were made using the log-rank test and Cox proportional hazards regression analysis. Multivariate analysis was performed using Cox proportional hazards regression analysis. Survival curves were made according to the method of Kaplan and Meier. The start date for this analysis was the date of first relapse. For event-free survival (EFS), patients were regarded as failures at failure to achieve remission, further relapse or death. They were censored at the date of last follow-up. Results Sixty-one patients presented with relapsed ALL between 1990 and April 1997. All had received their initial treatment for ALL through this center. Five were not treated with NYII: four received other re-induction protocols and one had no further therapy. A total of 56 patients started on modified NYII. The initial therapy used was similar for most patients; 34 were treated on the Australian and New Zealand Children’s Cancer Study Group (ANZ-CCSG) protocol V,23 19 on ANZ-CCSG VI and three according to NYI. There were no significant differences in baseline characteristics between patients with MFDs and patients without donors (Table 1). There were five induction failures. Two patients died of infection 11 and 39 days after relapse. Two initially failed to achieve remission with NYII, but subsequently achieved remission with an alternative treatment regimen. The fifth

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Table 1

Patient characteristics

Age at diagnosis (years) mean standard deviation range Age at relapse (years) mean standard deviation range Gender (%) male female Initial chemotherapy (%) study V study VI other Site of relapse BM CNS BM and CNS testicular BM and testicular Site of relapse BM or combined BM and extramedullary Extramedullary Duration of CR1 (years) mean standard deviation Relapse on or off treatment (%) on off Relapse before or after 3 years from CR1 ⬍3 years ⭓3 years Immunophenotype precursor B (CALLa) proB (null) T cell not known

Donor

No donor

5.04 3.42 1.32–12.56

5.11 3.24 0.61–15.66

7.51 3.76 2.07–15.98

7.74 3.77 3.05–19.1

13 (65) 7 (35)

22 (65) 12 (35)

9 (45) 9 (45) 2 (10)

23 (68) 10 (29) 1 (3)

10 (50) 4 (20) 4 (20) 1 (5) 1 (5)

24 (71) 7 (21) 2 (6) 1 (3) 0 (0)

15 (75) 5 (25)

26 (76) 8 (24)

2.78 2.31

2.59 1.53

8 (40) 12 (60)

17 (50) 17 (50)

13 (65) 7(35)

26 (76) 8 (23)

16 (80) 0 (0) 1 (5) 3 (15)

31 0 0 3

(91) (0) (0) (9)

patient failed to achieve remission. The remaining 51 patients went into remission, giving a re-induction rate of 91%. Of 56 patients, 18 are still alive with a median followup of 6 years 7 months (range 3 years 6 months to 11 years 4 months). Of the 18 surviving patients, 15 remain in CR2 and three are alive beyond CR2. The majority of deaths (81%) within the cohort were due to relapse of the leukemia. Ninety-one percent of our patients suffering a second relapse died. The probability of event-free survival and overall survival of the whole group (ie 56 patients) is 26.2% (95% confidence interval 15.41–39.6%) and 28.4% (95%CI 16.1–42.8) at 10 years, respectively. At 5 years the EFS was also 26.2% (95% confidence interval 15.41–39.6%), while the overall survival was 37.0% (95% CI 24.5– 49.5%). Fifty-four patients were included in the donor vs no donor analysis. The two patients who died early of infection were not tissue typed and therefore were excluded. Of the 54 tissue typed patients, 20 had a MFD; 19 had a 6/6 HLA matched sibling and one a 10/10 matched mother. The outcome of this group is illustrated in Figure

Relapsed ALL: BMT or continued chemotherapy? M Bleakley et al

Table 2

Outcome following second relapse No. patients

Table 3

No. who relapsed (%)

After relapse Dead (%)

Donor No donor Total

20 34 54

5 (25) 27 (79) 32 (59)

3

Cause of death No. patients

No. deaths (%)

Not dead (%)

4 (80) 25 (93) 29 (91)

1(20) 2 (7) 3 (9)

Donor No donor Total

20 34 54

8 (40) 28 (82) 36 (67)

Death Disease (%)

Other (%)

4 (50) 25 (89) 29 (81)

4 (50) 3 (11) 7 (19)

100

patients started on NYII 2

died early 34

20 matched family donor CR2 17 CR3 1 Relapse 2

no matched family donor

20 underwent BMT 4 5 4 1

11

2

32 continue on NYII

2

relapse again

27 relapse again

on therapy

died of TRT

2

no treatment

25

treatment

CR

Figure 1 Outcome of total cohort.

CR

60 50 30 20 10 0 0

Figure 2

2000 Days

2500

3000

3500

4000

Overall survival.

100

1

died of TRT

1

CR

90 80 70 60 50

Donor No donor

40

ABMT; died

20

URD/MMFD

10

CR

1500

The outcome of patients with MFDs was significantly better than that of patients without MFDs. The overall survival (OS) at 8 years was 60.0% (95% CI 35.7–77.6%) and 13.5% (95% CI 4.0–28.6%) for patients with and without MFDs, respectively (log-rank chi = 7.50 P = 0.0062) (Figure 2). The EFS at 8 years was 55.0% (95% CI 11.1– 31.3%) and 9.2% (95% CI 2.0–23.3%) for patients with and without MFDs, respectively (log-rank chi = 8.87 P = 0.0029) (Figure 3).

4

died

1000

Statistical analysis

30

2

500

these received further chemotherapy; four underwent autologous and five unrelated or mismatched BMT. The only survivors in this group of 27 patients are two of those who underwent unrelated BMT (Table 2). Overall, 28 of the of the 34 patients without donors died (Table 3); 25 of recurrent disease, one of infection, one from intracranial haemorrhage and the patient with GVHD mentioned above.

chemo; died

3

Donor No donor

40

16

5 3

70

unrelated BMT

died of TRT

died

80

EFS (%)

56

90

OS (%)

1. All 20 underwent BMT. The patients underwent BMT in CR2 (n = 17), CR3 (1), refractory relapse (1) and hypocellular with occasional blasts (1). The median time between relapse and transplantation was 188 days (range 69–642). There were four transplant-related deaths in this group. Two patients died 24 and 28 days after transplantation of adult respiratory distress syndrome. One died of respiratory syncytial pneumonia. The fourth patient (who was the only patient whose donor was not a matched sibling) died 3 years post BMT of chronic GVHD. A total of five patients had a subsequent marrow relapse following BMT. Four died and one is receiving therapy after a third relapse (Table 2). Eleven of the 20 patients who had an HLA MFD BMT are disease free with a median follow-up of 6 years 4 months (range 4.5–8.5years) from relapse. Of the 17 patients who underwent MFD BMT in CR2, 11 are alive in CR2. The patient transplanted from a MFD in CR3 and the two patients not in remission when transplanted from a MFD all died. The remaining 34 patients did not have an HLA MFD (Figure 1). Two of these underwent unrelated BMT in second remission; one died of GVHD and one is alive and well. Three other patients remain alive in CR2. There have been 27 subsequent relapses in this group. Twenty-five of

0

Figure 3

0

500

1000 1500 2000 2500 3000 3500 4000 4500 Days

Event-free survival. Bone Marrow Transplantation

Relapsed ALL: BMT or continued chemotherapy? M Bleakley et al

4

100

100

90 80

75

50

EFS (%)

EFS (%)

70 Late Early

25

60 50

Late–donor Late–no donor Early–donor Early–no donor

40 30 20

0

0

500

1000 1500 2000 2500 3000 Days

10

3500 4000 4500

0

Figure 4 Event-free survival by length of first remission.

The OS and EFS of patients in the following subgroups were compared: (1) bone marrow or combined relapses vs extramedullary relapses; (2) first relapse within or beyond 3 years from CR1; (3) patients initially treated on study V vs study VI; (4) patients with WCC count at diagnosis ⬍10 ⫻ 109/l, 10–50 ⫻ 109/l, ⬎50 ⫻ 109/l. There were no statistically significant differences. However, there was a trend towards better OS and EFS for patients initially relapsing at 3 years or beyond first remission compared to patients relapsing within 3 years of initial remission (log-rank chi = 3.53 P = 0.0602 for OS and chi = 2.46 P = 0.1169 for EFS) (Figure 4). A stratified log-rank analysis was performed to examine the effect of BMT within subgroups of patients relapsing early and late after first remission. The availability of a MFD significantly influenced OS and EFS among patients relapsing within the first 3 years of initial remission, but not amongst patients relapsing at 3 years or beyond initial remission. (Table 4, Figure 5). A Cox proportional hazards regression analysis was performed to assess the influence of BMT on outcome controlling for other factors that may potentially influence the probability of relapse and survival in patients with ALL after first relapse. Univariate analysis of overall survival found that the availability of a MFD significantly reduced the risk of death (hazard ratio 0.35, 95% CI 0.16–0.77, likelihood ratio chi 8.06 P = 0.0045). There was a trend toward increased risk of death among patients relapsing early after first remission (hazard ratio 2.10, 95% CI 0.95–4.63, likelihood ratio chi 3.81 P = 0.0509). The following factors were not found to significantly influence OS on univariate analysis: age at diagnosis, age at relapse, initial chemotherapy regimen, site of relapse, relapse on or off therapy, duration Table 4

0

500 1000 1500 2000 2500 3000 3500 4000 4500 Days

Figure 5 Event-free survival by length of first remission and donor status.

of CR1 (as a continuous variable), or WCC at diagnosis. In the univariate analysis of EFS only the availability of a MFD significantly influenced outcome (hazard ratio 0.33, 95% CI 0.16–0.71, likelihood ratio chi 9.47 P = 0.0021). There was a trend towards reduced EFS among patients relapsing early after first remission (hazard ratio 1.77, 95% CI 0.86–3.65, likelihood ratio chi 2.60 P = 0.1070). None of the other factors analyzed had a significant effect on EFS. Multivariate models including time from first remission (as a dichotomous variable) and MFD status were constructed. The availability of a MFD significantly improved OS and EFS in these models (likelihood ratio 8.63 P = 0.003 for OS, LR 9.35 P = 0.0022 for EFS, 1 degree freedom). Multivariate models using backwards stepwise regression analysis and initially including all variables with P values of less than 0.25 on univariate analysis were also constructed. In the final model for OS which included the variables initial chemotherapy regimen, site of relapse, early or late relapse and MFD status, the availability of a MFD remained significant (likelihood ratio 14.29 P = 0.0002 1 degree freedom). In the final model for EFS, which included site of relapse, early or late relapse and MFD status, the availability of a donor also retained significance (likelihood ratio 9.24 P = 0.0024, 1 degree freedom).

Survival by duration of first remission and donor status n

Early relapse (⬍3 years CR1) Late relapse (⬎3 years CR1)

39 15

Bone Marrow Transplantation

Overall survival

Event-free survival

OS donor (%) (95% CI)

OS no donor (%) (95% CI)

LR chi

P

EFS donor (%) (95% CI)

EFS no donor (%) (95% CI)

LR chi

P

62 (31–82) 57 (17–84)

9 (2–25) 23 (13–62)

7.85

0.0051

0.0185

0.8293

10 (2–26) 0

5.55

0.05

54 (25–76) 57 (17–84)

2.09

0.1478

Relapsed ALL: BMT or continued chemotherapy? M Bleakley et al

Discussion We evaluated the role of BMT in a cohort of 56 children with ALL relapsing after uniform initial treatment protocols in a single institution between 1990 and 1997. We have followed this cohort for over 5 years and found that BMT from a MFD is associated with a significantly better longterm overall and disease-free survival compared to intensive chemotherapy alone. The advantage of MFD transplant was confirmed in multivariate models controlling for factors known to influence relapse and survival after relapse, including site of relapse and duration of first remission. This group of 5 patients relapsing between 1990 and 1997 had an estimated 10 year OS of 28.4% and EFS of 26.2%. This result is similar to the overall experience reported in the last 10 years by some,3,10 but not all6 other groups. The reported overall outcome of a cohort of relapsed ALL patients is likely to be influenced by a number of factors including duration of follow-up, process of selection of the cohort, rate of attainment of second remission, and intensity of initial treatment received by the patients in first remission, as well as the nature of the therapy delivered to the patients following second remission. Our report has the advantage of a substantial follow-up with 83% of surviving patients followed for more than 5 years. The majority of events occurred early, with all of the relapses, and 92% of the deaths occurring within 5 years of initial relapse. We can therefore be confident that the Kaplan–Meier estimates of survival are a reasonable reflection of the long-term outcome of our patients suffering their first relapse of ALL. Our study represents the experience of a group of children treated within a single institution from diagnosis. The vast majority of children suffering first relapses of ALL in our institution during the study period is included in this report, including patients who died early after first relapse. Our study thus avoids the selection bias associated with selective referral of better risk patients into a cohort. This bias is likely in reports from institutions who treat children referred from other institutions after relapse, and in multicenter studies who may not enroll patients who die quickly after relapse. A number of factors may alter patients’ response to relapse therapy. One factor that is always difficult to compare is the nature and intensity of the initial therapy. Although most front-line protocols incorporate broadly similar agents in comparable doses, there are substantial differences in the selection of agents, dosage regimens and permitted modifications that impact on delivered dose intensity. It is plausible, but unproven, that patients who are relapsing now have less sensitive disease because of more intensive prior therapy than patients relapsing 10 years ago. This may generate patients with disease that is less sensitive to re-treatment. We evaluated the outcome of patients following their first relapse of ALL by potential prognostic factors including duration of first remission and relapse. There were no significant differences found in outcome. We observed a different pattern of relapse among patients with early or late first relapses, with those patients who had late first relapses tending to have later second relapses (Figure 4). The finding of no significant difference in outcome between initial

early or late relapsing patients appears to differ from the findings of previous studies.6,10,13 However, these studies report a shorter follow-up than our cohort. The differences in outcome between initial early and late relapsing patients may also become less apparent with further follow-up in those cohorts. We found allogeneic transplantation to be the most effective antileukemic therapy for relapsed patients. Allogeneic transplantation has the theoretical advantage over chemotherapy alone of the additional immunotherapy of the graft-versus-leukemic effect. Whether the anti-leukemic immunotherapy of allogeneic transplantation translates into a better outcome for patients depends on the balance of reduction of relapse and the potential increase in treatmentrelated mortality of the procedure. There have been no randomized controlled trials of BMT vs chemotherapy alone for pediatric ALL following first relapse. Comparisons of patients receiving BMT with those receiving only chemotherapy have an inherent bias because patients who do not survive long enough to receive a transplant are included in the chemotherapy group, making the outcome of this group worse. The best available comparative studies are those that avoid this bias by statistical adjustment or study design. The Mantel–Byar method is an adjustment to a log-rank analysis in which patients start of at risk in the chemotherapy group and only become counted in the BMT group at the time of transplant.24 The landmark approach compares patients surviving a fixed time beyond CR2.25 These methods avoid the bias associated with early deaths. However, there may still be selection bias associated with the allocation of patients to the chemotherapy only group based on a perceived better prognosis of the patient. Donor vs no donor comparative studies, using intention to treat analysis, avoid both potential forms of bias by using biological randomization. All patients are tissue typed and the outcome of patients with a MFD are compared with the outcome of all patients without a donor.19 Several donor vs no donor comparisons have been performed to determine the role of BMT in pediatric AML in second remission.26,27 There has been one previous donor vs no donor study in pediatric ALL.7 We are the first group to report the outcome of a cohort of pediatric ALL patients after first relapse within a single institution using biological randomization with intention to treat analysis to determine the effect of BMT on outcome. The additional advantages of our study include: (1) all patients in the cohort were initially treated within the institution, avoiding the bias associated with referral of selected patients for BMT; (2) all patients were treated on a single intensive chemotherapy relapse protocol with or without BMT; and (3) all patients in the MFD group underwent the planned therapy. Our findings of an improved event-free survival for patients allocated to BMT are consistent with the findings of some previous comparative studies8,13 but differ from the results of the MRC UKALL R1 trial.7 In the UKALLR1 study the 5-year EFS was 45% in both the donor and no donor group. The major difference in outcome between our patients and the patients reported in the UKALLR1 study is a much poorer outcome among our patients without donors compared to the British cohort lacking suitable family donors. Conversely, the outcome of our patients allocated

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Relapsed ALL: BMT or continued chemotherapy? M Bleakley et al

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to receive BMT may have been better than the comparable UK group. The outcome of our patients lacking MFDs was poor with OS and EFS of 13.5% (95% CI 4.0–28.6%) and 9.2% (2.0–23.3%), respectively. A number of factors may account for this outcome. The vast majority of patients in our no donor group received chemotherapy only in second remission. Thus, the no donor status reflects the treatment effect of chemotherapy alone. In contrast, the no donor group in the UKALLR1 trial included 29% of patients receiving matched unrelated donor transplants in second remission, and the outcome of these patients was better than that of the group as a whole. In our experience treatment with chemotherapy alone following relapse of ALL does not provide an adequate antileukemic effect. We chose a modified version of the the NYII protocol because it used intensive combinations of chemotherapy which contrasted with the initial therapy on which the patients had failed.21 This protocol has been used in pediatric patients with relapsed ALL.8 Despite this, our patients had a subsequent relapse rate of 79% in the no donor group. The outcome of our no donor group is similar to the experience of some,13,14 but not all3,7–12,28 previous groups reporting the outcome of patients treated with chemotherapy only following relapse. Among the studies whose results for relapsed patients treated with chemotherapy alone appear substantially better than ours, only the UKALLR1 study reports on patients relapsing in the 1990s who had received initial chemotherapy on intensive frontline protocols. Children treated with chemotherapy alone on the UKALLR1 trial, including patients with early relapse in 46% of cases, had a 5-year EFS of 44% after adjustment for other prognostic variables.6 This is a very promising result. However, the children were referred to the study from multiple institutions introducing the potential of some selection bias due to the highest risk patients being treated off protocol. In contrast, our study involved children relapsing in only one center and included almost all ALL relapses within that time period. The outcome of our patients who had a MFD, all of whom received BMT, compared favorably with the results of patients receiving BMT in other comparative studies where EFS in the range of 40–62% are reported.3,6,8–14 It is important to note that these studies have analyzed patients by treatment received so exclude patients with suitable donors who relapsed prior to receiving BMT biasing their results towards a more favorable outcome. We used intention to treat analysis avoiding this bias. Death related to relapse was relatively low (20%) in our donor group emphasizing the effective anti-leukemic effect of BMT. The treatment-related mortality experienced by our BMT patients was moderate with 20% of patients dying of transplant-related complications. In our subsequent experience the transplant-related mortality of MFD has declined overtime and one could expect an even better overall outcome for relapsed ALL patients with MFDs at the present time. We found a clear advantage in OS and EFS of having a donor available for patients relapsing within the first 3 years from first remission. There was no significant advantage of donor availability for patients relapsing beyond 3 years.

Bone Marrow Transplantation

However, there were only small numbers of patients in the later subgroup and there was a trend in the direction of an advantage in EFS. The strength of our conclusions for patients relapsing late is limited by inadequate power to detect a true difference if one exists. Furthermore, a difference in outcome between the donor and no donor chemotherapy groups may become more apparent with further follow-up for the late relapsing subgroup. Other investigators have found that children with a short first remission benefited most from a related allograft.8,29 The benefit in the late first relapse subgroup in these studies may also become evident with further follow-up. Our study has only addressed the role of HLA-identical MFD BMT for pediatric patients with ALL after first relapse. Our conclusions cannot extend to the role of unrelated donor transplant in this situation. Unrelated donor transplant in CR2 was used in only two of our patients in the no donor group. One of these patients is a long-term survivor. Historically, URD BMT has been associated with a greater risk of treatment-related mortality, and therefore with a different risk benefit profile relative to chemotherapy, than MFD transplant. However, we are encouraged by recent reports of improving outcomes for pediatric ALL patients receiving MUDs with reported results comparable to MFD BMT.30–32 The relative advantage of BMT compared to chemotherapy for patients with relapsed ALL will need continual re-evaluation with further developments in BMT technology and related procedures. The ability to measure MRD status prior to transplantation and modify conditioning, immunosuppression and post-transplant administration of DLI and targeted cellular immunotherapy accordingly promise to improve the outcome of BMT. Further understanding and ability to measure leukemic cell drug resistance may also help to target post-relapse chemotherapy more effectively, or alternatively indicate where further chemotherapy alone is futile and the immunotherapy of BMT is required.

Acknowledgements This work was carried out whilst Ms Nielsen was an elective student, supported by the Johan Vermeij Stichting and the Free University fund. Marie Bleakley is supported by the Leukaemia Research and Support Fund.

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Relapsed ALL: BMT or continued chemotherapy? M Bleakley et al

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18 Chessells JM, Leiper AD, Plowman PN et al. Bone-marrow transplantation has a limited role in prolonging second marrow remission in childhood lymphoblastic leukaemia. Lancet 1986; 1: 1239–1241. 19 Gray R, Wheatley K. How to avoid bias when comparing bone marrow transplantation with chemotherapy. Bone Marrow Transplant 1991; 7 (Suppl. 3): 4–12. 20 Steinherz PG, Redner A, Steinherz L et al. Development of a new intensive therapy for acute lympoblastic leukemia in children at increased risk of early relapse. Cancer 1993; 72: 3120–3130. 21 Morland BJ, Shaw PJ. Induction toxicity of a modified Memorial Sloan-Kettering-New York II protocol in children with relapsed acute lymphoblastic leukemia: a single institution study. Med Pediatr Oncol 1996; 27: 139–144. 22 Shaw PJ, Afify Z. Rapid Tapering of cyclosporin to maximize the graft-versus-leukemia effect. Bone Marrow Transplant 1999; 23: 232–233. 23 Waters KD. A randomized clinical trial of modified BFM therapy versus modified high dose asparaginase therapy in childhood acute lymphatic leukaemia by the Australian and New Zealand Children’s Cancer Study Group. Med Pediatr Oncol 1992; 20: 391. 24 Mantel N, Byar DP. Evaluation of response-time data involving transient states: an illustration using heart transplant data. J Am Stat Assoc 1974; 69: 81–86. 25 Klein JP, Zhang MJ. Statistical challenges in comparing chemotherapy and bone marrow transplantation for leukemia. In: Jewell NP, Kimber AC, Lee MTL, Whitmore (eds). Lifetime Data: Models in Reliability and Survival Analysis. Kluwer Academic Publishers: Boston, 1996, pp 175–186. 26 Bleakley M, Lau L, Shaw PJ. Autologous bone marrow transplantation for paediatric acute myeloid leukemia in first remission: systematic review and meta-analysis of randomised controlled trials. Med Pediatr Oncol 2001; 37: 264 (Abstr. P224). 27 Bleakley M, Lau L, Shaw PJ. Autologous bone marrow transplantation for paediatric acute myeloid leukemia in first remission: systematic review and meta-analysis of prospective cohort studies. Med Pediatr Oncol 2001; 37: 265 (Abstr. P225). 28 Rivera GK, Hudson MM, Liu Q et al. Effectiveness of intensified rotational combination chemotherapy for late hematologic relapse of childhood acute lymphoblastic leukemia. Blood 1996; 88: 831–837. 29 Chessells JM, Leiper AD, Plowman PN et al. Bone marrow transplantation has a limited role in prolonging second marrow remission in childhood lymphoblastic leukemia. Lancet 1986; 1: 1239–1241. 30 Davies SM, Wagner JE, Shu X et al. Unrelated donor bone marrow transplantation for children with acute leukemia. J Clin Oncol 1997; 15: 557–565. 31 Green A, Clarke E, Hunt L et al. Children with acute lymphoblastic leukemia who receive a T-cell depleted HLA mismatched marrow allografts from unrelated donors have an increased incidence of primary graft failure but a similar overall transplant outcome. Blood 1999; 94: 2236–2246. 32 Saarinen-Pihkala UM, Gustafsson G, Ringden O et al. No disadvantage in outcome of using matched unrelated donors as compared with matched sibling donors for bone marrow transplantation in children with acute lymphoblastic leukemia in second remission. J Clin Oncol 2001; 19: 3406–3414.

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