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Keywords:

  • relapsed acute lymphoblastic leukaemia; childhood

Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. References

We have examined the toxicity and overall outcome of the Medical Research Council UKALL R1 protocol for 256 patients with relapsed childhood acute lymphoblastic leukaemia (ALL). Second remission was achieved in over 95% of patients. Two patients died during induction and seven patients died of resistant disease. The overall actuarial event-free survival (EFS) at 5 years for all patients experiencing a first relapse was 46% (95% CI 40–52). Duration of first remission, site of relapse, age at diagnosis and sex emerged as factors of prognostic significance. Five-year EFS was only 7% for children relapsing in the bone marrow within 2 years of diagnosis, but was 77% for those relapsing without bone marrow involvement > 2.5 years from diagnosis. All analyses in this report are by treatment received. For those receiving chemotherapy alone, the 5-year EFS was 48%; for autologous bone marrow transplantation (BMT), the 5-year EFS was 47%; for unrelated donor BMT, it was 52%; and for related donor BMT, the 5-year EFS was 45%. The groups, however, were not comparable with respect to risk factor profile, and therefore direct comparison of EFS is misleading. Adjustment for time to transplant and prognostic factors was used to reduce the effects of biases between treatment groups, but did not suggest benefit for any particular treatment. There was failure of our planned randomization scheme in this trial with only 9% of those eligible being randomized, which highlights the difficulties in running randomized trials especially in patients who have relapsed from a previous trial. The optimal treatment for relapsed ALL therefore remains uncertain. Alternative approaches are clearly needed for those with early bone marrow relapse if outcome is to improve.

Treatment of childhood acute lymphoblastic leukaemia (ALL) has become more successful over the last three or four decades, with long-term event-free survival rates of 70–80% being achieved with multiagent chemotherapy. This means, however, that 20–30% of these patients still relapse ( Chessells, 1998). When compared with newly diagnosed ALL, relapsed disease is much more difficult to cure, and the optimal treatment is uncertain. Over 70% of patients with relapsed disease are reported to attain a second remission with chemotherapy, with higher rates in those with late relapse ( Henze et al, 1991 ; Sadowitz et al, 1993 ; Chessells et al, 1994 ; Rivera et al, 1996 ; Billett et al, 1997 ; Giona et al, 1997 ). Once remission is achieved, how to maintain it is less clear, and it is especially difficult to determine those who might benefit from bone marrow transplantation (BMT) or in whom chemotherapy alone would suffice ( Johnson et al, 1981 ; Bacigalupo et al, 1986 ; Chessells et al, 1986 ; Butturini et al, 1987 ; Sanders et al, 1987 ; Dopfer et al, 1991 ; Henze et al, 1991 ; Billett et al, 1993 , 1997; Sadowitz et al, 1993 ; Barrett et al, 1994 ; Borgmann et al, 1995a , b; Hoogerbruggeet al, 1995 ; Niethammer et al, 1996 ; Rivera et al, 1996 ; Chessells, 1998; Wheeler et al, 1998 ).

Before 1991, there was no uniform UK protocol for the treatment of relapsed ALL in children. In January 1991, therefore, the Medical Research Council introduced a protocol UKALL R1 for all cases of relapsed childhood acute lymphoblastic leukaemia, with the aim of standardizing therapy.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. References

The basis of the MRC UKALL R1 protocol was to evaluate a new intensive treatment protocol with the aim of improving overall survival in relapsed childhood ALL. It incorporated a common reinduction and consolidation regimen before either matched sibling allogeneic transplantation or a continuation treatment phase. The protocol included a randomization between autologous transplantation and conventional chemotherapy for patients without a matched allogeneic sibling donor (Fig 1).

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Figure 1. : summary of treatment options.

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The aims were to evaluate the chemotherapy regimen with respect to salvage of patients after first relapse of ALL, to compare autologous BMT with chemotherapy and to compare sibling donor BMT with chemotherapy. Patients were eligible if they were less than 15 years old at original diagnosis and had suffered their first relapse at any site. Exclusions included patients with multiple relapses and prior history of toxicity or organ damage, such that completion of the protocol was felt unlikely. Patients with isolated testicular relapse who were more than 6 months off treatment were not to be randomized but were to receive the chemotherapy arm.

Reinduction therapy

This consisted of a 4-week, four-drug regimen (dexamethasone, vincristine, asparaginase and epirubicin) with two doses of triple intrathecal chemotherapy (methotrexate, cytarabine and hydrocortisone) (Fig 2).

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Figure 2. Fig 2. Induction protocol.

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Consolidation therapy

This was an intensive 6-week phase with an eight-drug regimen (etoposide, cytarabine, dexamethasone, asparaginase, epirubicin, vincristine, thioguanine and cyclophosphamide) with three doses of intrathecal methotrexate (Fig 3).

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Figure 3. Fig 3. Consolidation phase.

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Randomization was performed once the patient was in complete remission and once it was known that there was not a suitable sibling donor. The median time from initial relapse to randomization was 69 days (range 15–135).

Continuation therapy (for patients not receiving a transplant)

This was a 9-week cycle repeated eight times, including a combination of drugs (prednisolone, vincristine, mercaptopurine, methotrexate, thioguanine, etoposide, cytarabine and cyclophosphamide) with two doses of intrathecal methotrexate (Fig 4).

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Figure 4. Fig 4. Continuation treatment.

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Central nervous system (CNS)-directed and testicular therapy

For those with bone marrow relapse

This consisted of three courses of high-dose intravenous methotrexate with folinic acid rescue (for those aged 1–4 years, 8 g/m2; those aged 4–15 years, 6 g/m2; those less than 1 year from previous cranial irradiation received intrathecal methotrexate only).

For those with CNS relapse

This included triple intrathecal chemotherapy weekly until the cerebrospinal fluid (CSF) was clear. An extra dose of intrathecal methotrexate was given during the consolidation phase, a CNS boost was given if receiving a BMT (dose was dependent on patient age and time elapsed from previous CNS prophylaxis) and craniospinal radiotherapy was given if chemotherapy was to continue (24 Gy midplane dose in 15 fractions of 1.6 Gy each). No intrathecal chemotherapy was given during continuation therapy for those receiving craniospinal radiotherapy.

For those with testicular relapse who were less than 6 months off treatment

These patients were eligible for a sibling bone marrow transplant if they had a suitable donor and were eligible for randomization between continuation chemotherapy and autologous transplantation if there was no suitable donor. Continuation therapy was with high-dose intravenous methotrexate (three courses; doses as for bone marrow relapse) and testicular radiotherapy (24 cGy in 12 fractions, using an anterior rectangular field including both spermatic cords up to the deep inguinal ring). A testicular boost was given to those undergoing transplantation (usually 400 cGy).

For those with testicular relapse who were more than 6 months off treatment

In these patients, there was a recommendation not to randomize and that patients should receive the chemotherapy arm of the protocol, which included testicular radiotherapy (Fig 1).

Statistical methods

Too few patients were randomized to enable statistical comparison by randomized allocation to be meaningful. Therefore, this report only assesses the toxicity and overall outcome of the UKALL R1 protocol. All analyses are by treatment received. A further report will assess the impact of related donor BMT by the unbiased comparison of groups according to donor availability.

The Wilcoxon two-sample test and the Mantel–Haenszel test for trend were used to test for differences in length of first remission and age by the levels of other initial factors, second remission rate and treatment in second remission ( SAS Procedures Guide, 1990). Fisher's exact test was used in 2 × 2 tables to test for associations between prognostic factors and for differences in second complete remission rate and treatment received in second remission ( SaS Procedures Guide, 1990).

Actuarial event-free survival curves were calculated by the method of Kaplan and Meier and the effect of possible prognostic factors was assessed by means of the log rank test ( Peto et al, 1977 ). Outcomes after chemotherapy alone, chemotherapy with allogeneic BMT or chemotherapy with autologous BMT were compared by Mantel–Byar analysis, which provides an adjustment to the log rank test. Patients start off in the chemotherapy arm and move into the relevant transplant group on the date of transplant, so allowing for time to transplant. In an attempt to minimize the effects of biases, treatment outcomes were additionally adjusted for the main prognostic factors. As the protocol specified that induction and consolidation should be given before transplant, events within this time contributed to the chemotherapy arm and not to the transplant arm. Patients not in second remission at 10 weeks after relapse are excluded from the analysis of treatment received, as is the one patient who had a transplant within this time period. All P-values are two-tailed.

Event-free survival (EFS) was defined as the time from initial relapse to a second relapse or death in second remission with patients surviving event free censored at 31 October 1998, when follow-up was complete for over 89% of patients.

Complete remission (CR) was defined as normal peripheral blood counts with < 5% blasts in bone marrow, clear CSF and no clinical evidence of disease. Achievement of CR was not formally assessed in patients without bone marrow involvement at relapse.

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. References

Two hundred and fifty-six patients were entered into the trial between 1 February 1991 and 28 April 1995 and follow-up was to October 1998, giving a median follow-up of 59 months (range 34–92). Initial treatment was with the appropriate MRC protocol at the time of diagnosis (UKALL 8, n = 2; infant protocol, n = 4; UKALL X, n = 140; UKALL XI, n = 110). Treatment duration of UKALL X and UKALL XI was 2 years. All relapses after 2 years were considered to be off treatment.

The types of relapse at entry were 121 isolated bone marrow, 43 combined bone marrow and CNS (including three combined bone marrow/CNS/testicular), 26 combined bone marrow and testicular and seven combined bone marrow and other site. Twenty-four patients experienced an isolated CNS relapse without bone marrow involvement, one experienced a CNS and testicular relapse and one patient experienced a CNS and ocular relapse. Thirty-three patients had relapse at other sites (30 isolated testicular, three isolated ocular).

The median duration of first remission was 2.6 years (range 0.7–10.7). Relapses with CNS involvement were associated with a shorter first CR (CNS relapses, median 2.4 years; non-CNS relapses, median 2.7 years; P = 0.0002) and bone marrow relapses with a longer first CR (bone marrow relapses, median 2.6 years; non-bone marrow relapses, median 2.3 years; P = 0.0006).

Second remission was achieved in 187/197 (95%) of bone marrow relapse patients, with a median time to CR from start of treatment of 28 days (range 8–140). Two patients died during induction and seven died of resistant disease. Patients aged ≥ 10 years at diagnosis and those aged ≤ 4 years at relapse were less likely to attain second CR (P = 0.06 and P = 0.02 respectively).

Event-free survival

The overall actuarial EFS at 5 years for all patients is 46% (95% CI 40–52) and for patients receiving chemotherapy alone 47% (95% CI 39–56).

Event-free survival by prognostic factors

Table 1. Table I. Event-free survival (EFS) from relapse by prognostic factors. † Stratified by duration of ‡ first remission, § BM relapse or ¶ both.*P < 0.05, **P < 0.01, ***P < 0.001. P-values are for trend (duration of first remission and age) or heterogeneity (sex, null/C/pre-B vs. T-cell immunophenotype and BM vs. no BM involvement at initial relapse). Thumbnail image of
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Figure 5. Fig 5. Event-free survival from first relapse by site of relapse and duration of first remission.

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Figure 6. Fig 6. Event-free survival from first relapse by sex.

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Table 2. Table II. Event-free survival (EFS) at 5 years from relapse by duration of first remission and site of first relapse. Thumbnail image of

Treatment received and event-free survival

Table 3. Table III. Treatment received in second remission by prognostic factors. * Excludes 10 patients who were not in remission at 10 weeks and three who received non-protocol treatment.Thumbnail image of

Table IV shows the type of event by treatment group and shows that relapse is the major cause of treatment failure in the chemotherapy alone (P = 0.05) and autologous transplant groups, whereas death in second remission was more often seen in the allogeneic transplant group (P < 0.001). Figure 7 illustrates EFS by treatment group, with a 5-year EFS of 45% for related allogeneic BMT, 47% for autologous BMT, 48% for chemotherapy alone and 52% for unrelated donor BMT [not significant (ns)]. Although the treatment groups were not comparable with respect to risk factors and analysis was by treatment received rather than by randomized allocation, which made comparison of outcomes difficult, it is nevertheless important to note that after adjustment for time to transplant and prognostic factors the 5-year EFS was 44% for related allogeneic BMT, 47% for autologous BMT, 44% for chemotherapy alone and 31% for unrelated donor BMT. There is thus no clear benefit for any one treatment.

Table 4. Table IV. Type of event by treatment received in second remission. * Excludes 10 patients who were not in remission at 10 weeks and three who received non-protocol treatment.† Allogeneic BMT (related or unrelated) versus chemotherapy group allowing for time to transplant, site of initial relapse (bone marrow vs. other site) and duration of first remission: P < 0.001 for deaths in second remission and P = 0.05 for second relapse. Thumbnail image of
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Figure 7. % for autologous BMT, 31% for unrelated donor BMT and 44% for related donor BMT.

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Toxicity of induction and consolidation treatment

5 Table V shows the numbers of patients receiving full-dose therapy and shows the toxicity of the three treatment schedules in terms of documented infection and hospital stay. Ninety-one per cent received full-dose induction therapy, with infection reported in 66%. There were two induction deaths (1%), both of which were a result of sepsis. The majority of those patients who were eligible received full-dose consolidation and high-dose methotrexate. One patient achieved second remission but died of sepsis during consolidation. There were no other deaths in remission associated with consolidation or high-dose methotrexate.

Table 5. Table V. Toxicity. * One hundred and eighty-six patients also had full dose induction.† Sixty-eight patients also had full dose induction and consolidation.Thumbnail image of

Compliance and randomization

Sixty-seven patients eligible for transplant had an HLA-identical sibling donor and 63 received a transplant. A patient with isolated bone marrow relapse received an unrelated rather than related transplant because of the relative donor being unfit, and a patient with combined bone marrow and skin relapse did not receive a transplant because of parental refusal. Two patients with isolated testicular relapse < 6 months off treatment received chemotherapy rather than a transplant (reason not given). One further patient with an isolated testicular relapse > 6 months off treatment who was recommended chemotherapy only received a related donor transplant (reason not given).

Of the 164 patients without an HLA identical sibling donor who were eligible for randomization, only 15 (9%) were randomized. Of the seven randomized to transplant, one relapsed early, one received chemotherapy and five received autologous grafts. All eight patients who were randomized to chemotherapy received it. A further 10 non-randomized patients received autologous grafts. Forty-one patients received an unrelated transplant and two were given alternative treatment (these patients were withdrawn from the protocol because of toxicity). The remaining patients followed the continuing chemotherapy arm. Reasons for non-randomization were parent/family/patient preference (33%), physician preference (49%; 17% because of a planned unrelated donor transplant), clinical decision (7%) and other (3%). No data were available in 9% of cases for the failure of randomization.

It is interesting to note that patients with bone marrow relapse were less likely to be randomized (6% vs. 24%; P = 0.006) and that those patients with an isolated testicular relapse < 6 months after cessation of treatment were more likely to be randomized (44% vs. 7%; P = 0.004).

Mortality

Fourteen (12%) transplant patients died without relapse [related donor, seven patients (11%); unrelated donor, seven (17%)], of whom five had graft failure. Other causes of death were graft versus host disease (GVHD) (two patients), sepsis (two), drug toxicity (one), pulmonary haemorrhage (one), acute respiratory distress syndrome (ARDS) (one), pneumonitis (one) and disseminated adenovirus (one).

Three patients who had received chemotherapy alone died in second remission, causes of death were second malignancy, sepsis and bronchopneumonia. Two of these deaths occurred more than 2 years after the start of treatment.

Six patients died in remission after a second relapse. Four of these had initially received chemotherapy only, and all received an unrelated donor transplant during the third remission. Causes of death were multiorgan failure (one patient), GVHD of gut and liver (one) and pneumonitis (two). Two patients had received a related allogeneic transplant in second remission and both died 2 months after second relapse, causes of death were GVHD with pulmonary infiltrates in one patient and gastrointestinal (GI) haemorrhage in the other.

Second relapse

Forty-six per cent of patients achieving second remission suffered a second relapse. The majority of relapses involved bone marrow (80%; 82% of which were isolated and 18% of which were combined). There were 11 cases of isolated testicular relapse, seven cases of isolated CNS relapse, one case of isolated bone relapse and four cases of other relapses (skin, one; eye, one; breast, one; unknown, one).

The median length of second remission was 38 months (range 2–92) and this correlated with the length of first remission (P = 0.0006).

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. References

Relapse remains one of the major obstacles to cure in childhood ALL and, despite improvements in first-line therapy, continues to occur in 20–30% of patients. What constitutes the best treatment for these patients has been the subject of much debate over recent years, and a consensus has not, as yet, been reached. A recent review ( Chessells, 1998) addresses many of the issues involved.

There is, however, agreement in certain areas. Namely, that overall 5-year EFS in second remission is poor, with figures of < 15% for those relapsing early (on treatment or within 6 months of stopping treatment) in the bone marrow, and generally < 50% for those with later (up to 36 months from diagnosis) bone marrow relapse or isolated extramedullary relapse. Very late (more than 36 months from diagnosis) isolated extramedullary relapse, however, has a 5-year EFS rate of > 50% ( Behrendt et al, 1990 ; Henze et al, 1991 ; Miniero et al, 1995 ; Schroeder et al, 1995 ; Billett et al, 1997 ; Gaynon et al, 1998 ; Wheeler et al, 1998 ).

The prognostic factors that influence the length of second remission have been consistently found in many studies and include duration of first remission, site of relapse, age and immunophenotype. In most studies, white cell count, sex and intensity of primary treatment do not appear to have any prognostic significance with respect to duration of second remission ( Behrendt et al, 1990 ; Henze et al, 1991 ; Buhrer et al, 1993 ; Miniero et al, 1995 ; Schroeder et al, 1995 ; Billett et al, 1997 ; Gaynon et al, 1998 ; Wheeler et al, 1998 ). Combined bone marrow relapses appear to do better than isolated bone marrow relapse in some studies ( Buhrer et al, 1993 ; Gaynon et al, 1998 ), but not in others ( Schroeder et al, 1995 ). More recently, the presence and level of minimal residual disease, measured by molecular or immunological methods, during the course of treatment has been shown to be of prognostic significance, although the majority of these studies have been performed in patients with newly diagnosed acute leukaemia ( Cave et al, 1998 ; Ciudad et al, 1998 ). In addition, the rate of disease reduction during induction remission therapy is thought to provide additional prognostic information ( Lilleyman et al, 1997 ).

After relapse, most reinduction regimens produce a high second remission rate, with CR rates of 95% for bone marrow relapse in this study and > 70% in most others ( Henze et al, 1991 ; Chessells et al, 1994 ; Billett et al, 1997 ; Giona et al, 1997 ).

Chemotherapy alone after bone marrow relapse can be curative in some cases, with EFS rates at 5 years of 47% in this study and rates of 20–65% reported elsewhere. For patients with early bone marrow relapse, however, results with chemotherapy alone are poor, with 5-year EFS rates of ≈ 20% in this study and generally < 20% in others ( Behrendt et al, 1990 ; Henze et al, 1991 ; Sadowitz et al, 1993 ; Miniero et al, 1995 ; Uderzo et al, 1995a ; Rivera et al, 1996 ; Billett et al, 1997 ). For isolated extramedullary relapse, chemotherapy alone can offer a chance of cure, with a 5-year EFS rate of 60% in this study and > 40% in most other studies ( Uderzo et al, 1990 ; Winick et al, 1993 ).

Bone marrow transplantation has been accepted as a form of treatment for relapsed ALL for many years, although its exact role remains controversial. Matched sibling bone marrow transplantation in second remission has been reported to give an EFS of 20–64% at 2 years. Factors affecting outcome after allogeneic transplant include site of relapse, duration of first remission, disease status at transplantation and presence of acute or chronic GVHD. Relapse still occurs after sibling allogeneic BMT in ≈ 20% of cases, and there is a transplant-related mortality of ≈ 20% ( Brochstein et al, 1987 ; Butturini et al, 1987 ; Sanders et al, 1987 ; Dopfer et al, 1991 ; Barrett et al, 1994 ; Weisdorf et al, 1994 ; Pinkel, 1995; Uderzo et al, 1995a , b; Gordonet al, 1997 ; Bordigoni et al, 1998 ).

Although there have been no prospective randomized trials, evidence from non-randomized studies suggests that matched sibling donor transplantation may be superior to chemotherapy for children with relapsed ALL in second remission, especially for those with short first remission, but the difficulty of allowing for selection bias means that this is still an open question ( Johnson et al, 1981 ; Butturini et al, 1987 ; Dopfer et al, 1991 ; Barrett et al, 1994 ; Uderzo et al, 1995a ; Wheeler et al, 1998 ).

The role of autologous BMT in marrow-relapsed ALL also remains unanswered, despite the benefit of wider availability and reduced toxicity. Five-year EFS after autologous BMT has been reported at 10–53% ( Sallan et al, 1989 ; Billett et al, 1993 ). There have been no randomized studies comparing autologous BMT with other forms of treatment, although attempted comparisons suggest no significant difference from chemotherapy alone ( Borgmann et al, 1995b ; Wheeler et al, 1998 ) and that allogeneic BMT is superior ( Giona et al, 1994 , 1997; Bordigoni et al, 1998 ).

There are very limited available data on the efficacy of alternative donors in childhood-relapsed ALL. However, 2-year EFS rates similar to those of sibling transplants of 40–56% have been reported ( Kernan et al, 1993 ; Balduzzi et al, 1995 ; Casper et al, 1995 ; Davies et al, 1995 ; Oakhill et al, 1996 ).

For isolated extramedullary relapses, chemotherapy alone may produce a cure, and the role of BMT is even more controversial. In general, late isolated CNS relapse can be cured with chemotherapy alone, whereas more intensive treatment with BMT may be of benefit for early relapse with results for allogeneic and autologous grafts appearing to be similar ( Winick et al, 1993 ; Borgmann et al, 1995a ; Messina et al, 1996 , 1998). Isolated late testicular relapses are generally associated with a good prognosis with chemotherapy and local radiotherapy, although early relapses, especially those occurring on treatment, do poorly ( Uderzo et al, 1990 ; Schroeder et al, 1995 ).

The question as to what is the best treatment for relapsed ALL thus remains uncertain. The MRC UKALL R1 tried to address the role of autologous transplantation, but failure of randomization between continuation chemotherapy and autologous BMT has made this impossible. The results did, however, confirm that duration of first remission and site of relapse were significant prognostic factors (P < 0.001 and P < 0.001 respectively), as shown in previous studies. Age at diagnosis and immunophenotype were also of some prognostic significance, although T-cell disease was not of statistical significance in this study after allowance for duration of first remission and site of relapse. Interestingly, this study revealed a worse prognosis for male patients (P = 0.02).

The induction regimen used in this study of an unselected group of 256 children with first relapse of ALL has given an excellent complete remission rate of over 95%, better than that in many other reports. The toxicity of remission induction therapy was mild, with only two induction deaths. The overall EFS in this study for all patients experiencing a first relapse of ALL was 46% at 5 years. This is a good salvage rate, similar to most reports and better than many.

Despite the difficulties in this trial caused by failed randomization and differing risk profiles in the treatment groups, there was no clear difference in outcome for patients receiving different treatment after relapse. For those receiving chemotherapy alone, the 5-year EFS rate was 48%, for autologous BMT it was 47%, for unrelated donor BMT it was 52% and for related donor BMT the 5-year EFS rate was 45%. These results, however, do not allow for the biases in selection of treatment. The accepted method of reliably assessing the relative effect of two treatments is by randomized trial with analysis by intention to treat. Evaluation of transplantation based on treatment received introduces selection and time to treatment biases that invalidate direct analysis. Where treatments are not randomized, there is likely to be a difference in the proportion of high-risk patients in different treatment groups. As patients who receive transplants must remain in remission long enough to receive them, those with a short remission duration are less likely to be transplanted in complete remission than those with long remissions, thus early relapses are excluded from transplant cohorts but are included in the chemotherapy cohort. Adjustment for these known factors will reduce, but not eliminate, the effects of systematic differences between the groups, and so any comparisons should be treated with caution. Adjustments for time to transplant and known prognostic factors did not suggest benefit for any one treatment, but reduced the EFS rate for unrelated donor BMT in particular.

The type of event causing treatment failure varied between the treatment groups, with relapse being the cause in ≈ 50% of those receiving chemotherapy or autologous BMT. There were fewer relapse deaths in the allogeneic transplant group, although more deaths occurred during second remission. The results for related and unrelated BMT were similar with respect to transplant-related mortality (11% and 17% respectively) and EFS.

The lack of randomization in this study was not entirely surprising. This has been seen in many other attempted randomized studies in which lack of confidence in a treatment modality leads to failure of randomization, especially where side-effects are markedly different in the two arms. The difficulties of persuading patients and parents to accept a randomization when running a relapse protocol are even greater, when a previous trial treatment has failed. Of importance is the fact that > 50% of cases of failed randomization were due to physician preference/clinical decision. Although the trial design was initially accepted by the clinicians involved, with time they became more certain about which treatments were best for individual patients and they became less enthusiastic about autologous transplantation in particular. Large proportions of cases were not randomized because of the availability of an unrelated donor for bone marrow transplantation. Unrelated donor BMT was not included in the original trial protocol. However, as the trial progressed, evidence of the efficacy and probable superior results of unrelated donor BMT compared with chemotherapy or autologous BMT became apparent. It is likely that this is the explanation for many of the cases of failed randomization. It is important to note, however, that there were no randomized trials of unrelated donor BMT compared with chemotherapy or autologous BMT on which to base these decisions, but rather attempted comparisons suggesting that sibling donor BMT was superior to autologous BMT and evidence that results with unrelated donor BMT had improved and were similar to those with sibling donor BMT. Unrelated donor BMT has subsequently been included as a randomization in the succeeding relapse trial (UKALL R2) for those patients without a sibling donor, and it is hoped that acceptance of randomization will be superior in this trial. It is nevertheless disappointing as these decisions were not based on reliable information and the role of autologous BMT in relapsed ALL will not be answered without a truly prospective randomized trial. The same may also be said of the role of BMT in late relapse.

In conclusion, this study has revealed a high second CR rate of 95% in patients with bone marrow relapse, and an overall 5-year EFS rate of 46% in an unselected group of 256 children with a first relapse of ALL. There is currently no difference in the outcome between patients receiving chemotherapy or transplantation, although the groups are not directly comparable because of significant differences in risk profile. Because of the difficulties in this trial, it is important to note that we could not establish from these results that there was any difference between treatment groups in EFS. The lack of randomization highlights the difficulty of running randomized trials, especially in patients who have relapsed. This report is of outcome by treatment received. A further report will provide unbiased evidence on the value of related donor transplant by comparing groups according to donor availability. Patients who relapsed more than 6 months off treatment had a 5-year EFS rate of > 60%, whereas those who relapsed on treatment or within 6 months of stopping treatment had a 5-year EFS rate of 30%. Site of relapse was another prognostic feature, with bone marrow relapse faring worse than extramedullary relapse. Alternative approaches to therapy are clearly needed for those high-risk patients with early relapse at any site, and especially for those with bone marrow involvement, as the present approach with chemotherapy or conventional conditioning before BMT is salvaging only very few. Allogeneic bone marrow transplantation offers the strongest antileukaemic effect and alternative conditioning regimens may be considered. The improved EFS with allogeneic BMT, however, is often offset by the high transplant-related mortality (TRM). High TRM may be reduced by the use of less intensive non-myeloablative conditioning regimens, while still utilizing the graft versus leukaemia effect. A further option includes the use of immunotherapy, such as donor lymphocyte infusion, after BMT. These studies need, if possible, to be randomized, and, given the numbers involved, need to be performed in an international setting.

References

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. References
  • 1
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