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- PATIENTS AND METHODS
We investigated the use of a new conditioning regimen followed by allogeneic bone marrow transplantation (BMT) for treating children with acute lymphoblastic leukaemia (ALL) after relapse within 6 months of the completion of therapy. One hundred and sixteen children with acute lymphoblastic leukaemia in second or subsequent complete remission (CR) underwent allogeneic bone marrow transplantation from HLA-identical siblings after a preparative regimen comprising total body irradiation (TBI), high-dose cytosine arabinoside and melphalan (TAM regimen). The Kaplan-Meier product-limit estimate (mean ± SE) of disease-free survival (DFS) at 7 years was 59.5 ± 9% (95% confidence interval). The estimated chance of relapse was 22.5 ± 15% with a median follow-up of 88.5 months (range 51–132). 26 patients (22.4%) died with no evidence of recurrent leukaemia, mainly from interstitial pneumonitis, veno-occlusive disease or acute graft-versus-host disease (GVHD). Three factors significantly affected DFS: acute GVHD, site of relapse and, for children in second remission after a marrow relapse, the disease status at the time of transplantation. The DFS were 59.02 ± 12.6%, 37.5 ± 19.8% and 77.4 ± 15% among patients in CR2 after a marrow relapse, in CR3 or in untreated partial marrow relapse, and in CR2 after an isolated CNS relapse, respectively. The lowest DFS was seen in children with acute GVHD grades 3–4. Two significant factors were associated with relapse: the marrow status at the time of transplantation and chronic GVHD. The relapse rate was lower among children in CR2 or with chronic GVHD. We conclude that transplantation after the TAM regimen is an effective therapy for this population with acceptable toxicity, particularly for children in second remission after a very early marrow relapse, or those with early isolated CNS involvement.
Although the prognosis for children with newly diagnosed acute lymphoblastic leukaemia (ALL) has improved ( Reiter et al, 1994 ), the likelihood of long-term disease-free survival falls to below 10–30% after a relapse ( Buchanan et al, 1988 ; Henze et al, 1991 ). This is particularly true for patients with early marrow relapse (up to 6 months after stopping front-line therapy) and/or with T-ALL ( Henze et al, 1991 ), even with the best chemotherapy regimens. There is general agreement that the survival of certain subsets of children with adverse prognostic factors who experience isolated meningeal relapse remains poor ( Baruchel et al, 1995 ; Kumar et al, 1995a , b; Ribieroet al, 1995 ; Steinherz, 1995). The main problem for these patients is the very high rate of marrow relapse, whatever the intensity of reinduction protocols. These patients should be considered as candidates for allogeneic bone marrow transplantation (BMT).
Unfortunately, BMT is limited by the lack of matched sibling donors. Only 15–20% of referred patients are given related donor BMT ( Bordigoni et al, 1996 ; Giona et al, 1994 ). The benefit of allogeneic BMT for childhood ALL in second or third complete remission (CR) after an early marrow relapse is still controversial ( Pinkel, 1995).
The best conditioning regimen for such patients is not known. A combination of cyclophosphamide (Cy) and total body irradiation (TBI) provided a 5-year disease-free survival of <40% in a Seattle study ( Sanders et al, 1985 ), and 64% was reported by the Memorial Sloan Kettering Institute after hyperfractionated TBI followed by Cy for children in CR2. This improved survival was attributed mainly to a lower relapse rate after transplantation ( Brochstein et al, 1987 ). Recently, the addition of high-dose etoposide ( Dopfer et al, 1991 ) or cytosine-arabinoside (Ara-C) ( Cahn et al, 1991 ; Coccia et al, 1988 ; Gordon et al, 1997 ; Kamani et al, 1995 ; Moussalem et al, 1995 ; Weyman et al, 1993 ; Woods et al, 1990 ) to fractionated TBI has been evaluated for its antileukaemic activity with encouraging results, but only limited numbers of patients were treated.
We have therefore carried out a prospective multicentre study to evaluate the role of a new conditioning regimen, TBI followed by high-dose Ara-C and melphalan (TAM regimen), in histocompatible related donor marrow transplantation for children with ALL in CR2 or CR3 after early medullary or isolated extramedullary relapse.
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- PATIENTS AND METHODS
We report the outcome of 116 children who were given allogeneic BMT following a new preparative regimen (TAM protocol) ( Cahn et al, 1991 ; Moussalem et al, 1995 ) after they had relapsed during chemotherapy. Our results are better than those reported after Cy + TBI ( Barrett et al, 1994 ; Sanders et al, 1985 , 1987; Uderzo et al, 1995a , b), especially for those patients with unfavourable prognostic factors, such as a first remission of 18 months or less. The probability of relapse was only 17.4 ± 11.2% 7 years after BMT for children transplanted while in CR2 after a marrow relapse. Our data are similar to those other groups for comparable, but smaller, cohorts of children with ALL who underwent BMT in CR2 after high-dose ARA-C ( Coccia et al, 1988 ; Gordon et al, 1997 ; Kamani et al, 1995 ) or etoposide ( Dopfer et al, 1991 ) and TBI. There is no general agreement as to the best BMT preparative regimen. The combination of Cy and TBI has now been used to treat many children with ALL and has a probability of 5-year DFS of 20–30% in patients transplanted in CR2, whose first remission lasted 18 months or less, and 30–40% for those transplanted within 18–36 months after diagnosis ( Barrett et al, 1994 ; Sanders et al, 1985 , 1987; Uderzo et al, 1995a , b). The DFS is <20% in patients with more advanced disease. This regimen has been modified to give hyperfractionated TBI (13.2 Gy) with a booster dose of irradiation to the testicles followed by Cy. Encouraging results have been reported, with 5-year DFS of 64 ± 9%, 42 ± 14% and 23 ± 11% and probabilities of relapse of 13 ± 7%, 25 ± 13% and 64 ± 16% for patients in second, third and fourth remission or relapse respectively ( Brochstein et al, 1987 ). However, recent reports from the Minneapolis team using this regimen showed no substantial advantage over either single fraction or fractionated TBI and Cy ( Weisdorf et al, 1994 ).
High doses of Ara-C have been used as an alternative to Cy because Ara-C is an active agent in ALL, particularly for the reinduction of patients with marrow and/or CNS relapse. A paediatric pilot study ( Coccia et al, 1988 ; Gordon et al, 1997 ) reported a low relapse rate (14%) with a very long follow-up period for a group of children in second or third remission after a preparative regimen consisting of high-dose Ara-C (36 g/m2) before fractionated TBI. However, two other non-randomized studies suggest that it has no advantage over Cy-TBI ( Weyman et al, 1993 ; Woods et al, 1990 ). A recent multicentre survey ( Weyman et al, 1993 ) suggested that ARA-C/TBI is a good preparative regimen, but only for children <11 years old. Older patients suffered both more toxic deaths and more relapses that younger patients. Our data do not confirm these findings, despite a potentially more intensive preparative regimen.
The therapeutic action of high-dose etoposide in addition to or instead of Cy in TBI-containing regimens needs to be more extensively defined in children. The only data published describe small groups of patients with a short follow-up or children in CR1 and/or mixed with adults ( Blume et al, 1993 ; Dopfer et al, 1991 ).
Many authors have looked for prognostic factors that will predict the DFS and relapse after BMT. An increased risk of treatment failure is associated with age >10–11 years, an elevated WBC count at diagnosis, the T-cell phenotype, previous extramedullary leukaemia, a first remission lasting <18 months, and advanced stage of disease at the time of transplantation ( Barret et al, 1994 ; Butturini et al, 1987 ; Sanders et al, 1987 ; Uderzo et al, 1995a , b). Only this advanced disease state significantly affected the outcome of the leukaemia in our patients. Neither a CR1 of <18 months, a patient age >10 years, nor a history of extramedullary leukaemia were associated with a poor prognosis. GVHD can have both favourable or unfavourable effects on transplant outcome. It may reduce the risk of relapse, but increase transplant-related deaths. As in other reports ( Brochstein et al, 1987 ; Sanders et al, 1985 ; Uderzo et al, 1995a ), children who developed chronic GVHD had a significantly improved survival rate and a reduced incidence of relapse. Acute GVHD had no antileukaemic effect and patients with grades 3–4 acute GVHD had an extremely high transplant-related mortality rate.
Very few deaths could be directly attributed to the use of Ara-C. Only three patients developed severe, but reversible, toxicity probably attributable to the combination of Ara-C and TBI (two capillary-leak syndromes and one toxic epidermal necrolysis). Ocular and skin toxicity was significantly more frequent and severe after the TAM regimen, but the incidence of other transplantation-related complications, such as mucositis, severe diarrhoea, leuco-encephalopathy and liver disease, appeared to be similar to those after Cy and TBI.
Pulmonary toxicity from high-dose Ara-C has been reported for adults. Andersson et al (1990 ) found that respiratory failure occurred in as many as one-quarter of patients with acute myeloblastic leukaemia treated with high-dose Ara-C. Similarly, this complication has recently been described in paediatric patients ( Shearer et al, 1994 ). Most studies have established an association between the development of pulmonary insufficiency and multiple courses of Ara-C, particularly if it is given by continuous infusion. This could partly explain the somewhat higher incidence of fatal idiopathic IP in children on the TAM regimen in our series.
There is considerable debate as to whether children with ALL in second complete remission should undergo BMT, and if so, which type. Data from a matched-pair analysis from the International Bone Marrow Transplant Registry ( Barrett et al, 1994 ) and from trials with chemotherapy, or with autologous BMT (ABMT) ( Boulad et al, 1994 ; Kersey et al, 1987 ; Uderzo et al, 1995b ), suggest that allogeneic BMT has an overall advantage over chemotherapy and ABMT for treating ALL in CR2 after ‘on therapy’ marrow relapse, whatever the duration of CR1. Recently, Bordigoni et al (1996 ) and Cavazzana-Calvo et al (1996 ) used matched cohorts to compare the results of three different procedures, HLA geno-identical BMT, autologous BMT, and partially incompatible BMT, for children with ALL in CR2 after short CR1 duration (<28 months). All the patients were given the same conditioning regimen, the TAM protocol. The DFS at 5 years were 83.7 ± 7.4%, 24.6 ± 10.2% and 30.7 ± 10.8%. The difference is statistically significant (P = 0.005). The probability of relapse was 5.5 ± 5.4%, 72.4 ± 11.2% and 32.2 ± 12.1%, respectively. The difference between the geno-identical group and the other two groups is statistically significant (P = 0.0001).
Control of prior extramedullary disease was good. Of the 45 patients with prior CNS disease, only one had a subsequent CNS relapse. In terms of the probability of post-BMT CNS and/or medullary relapse, the differences are not significant from the group of patients without a history of CNS relapse, whether or not they were given additional cranial radiotherapy prior to the conditioning regimen. These results suggest that an additional cranial irradiation can be omitted for patients with CNS involvement at relapse, when TBI is included in the conditioning regimen. There is also no need for post-transplant CNS therapy ( Ganem et al, 1989 ).
The isolated CNS relapse rate for the majority of current risk-group-directed protocols is <10%. Salvage treatment has included combined intrathecal or intraventricular chemotherapy and cranial or craniospinal irradiation, but this was inherent with acute and chronic neurotoxicity ( Kumar et al, 1995b ; Ribiero et al, 1995 ). There is general agreement that the survival of children who experience meningeal leukaemia is poor. The EFS is <30–40%, particularly for certain patients with adverse prognostic factors including high WBC and immunophenotype T at diagnosis, short duration of CR1 (<18–24 months) and prior CNS prophylaxis including radiotherapy. Recently published evidence of PCR-based marrow-residual-disease in most children with isolated CNS relapse ( O'Reilly et al, 1995 ) identified a group of patients at high risk of marrow relapse. There is no definitive information from the few published studies as to whether the use of BMT (autologous or allogeneic) improves the cure rate for these children ( Baruchel et al, 1995 ; Colleselli et al, 1994 ; Hoogerbrugge et al, 1995 ; Rossetti et al, 1993 ). The small number of patients has precluded controlled studies, and the optimal therapy remains unknown. Nevertheless our data on such high-risk patients indicate that allogeneic BMT is an adequate first-choice alternative. Haematological and/or testicular relapses are, rather than a new CNS event, the main obstacle to durable survival after conventional regimens. Therefore a treatment strategy must include intensive systemic therapy. The paediatric literature and our data both indicate a very low further CNS relapse (<3%) after allogeneic BMT, whether or not the patients suffered from a prior CNS disease. Hence, we recommend allogeneic transplantation in the first haematological remission for patients who develop a very early isolated CNS relapse, or who suffer from more than one isolated extramedullary relapse while on chemotherapy.
None of the boys with testicular relapse before BMT had a subsequent testicular relapse. This is probably due to our policy of testicular irradiation before TBI. The amount of irradiation given during the conditioning regimen seems to be inadequate for males suffering from testicular relapse. Testicular irradiation before TBI is advised for all such patients ( Sanders et al, 1985 ).
Poelman & Sanders (1992) and Brochstein et al (1987 ) suggest that testicular irradiation, in addition to TBI, could benefit children in testicular remission at BMT. Our findings are appreciably different; we found that a booster dose of irradiation to the testicles had a detrimental impact on the incidence of testicular relapse and on DFS. This could be because of the small number of children included, or because of the historical comparison used to analyse the two subgroups of patients. We are therefore not using such potentially toxic therapy.
In summary, we have confirmed that allogeneic bone marrow transplantation from HLA-identical siblings is an effective treatment for children with ALL in second or third complete remission, particularly for those whose previous remission lasted <18 months, whatever the site of relapse. But we have not completely answered the question of the best treatment for those children, and we still need a well-designed prospective randomized trial of chemotherapy versus allogeneic BMT. The use of fractionated TBI followed by high-dose Ara-C and melphalan is an effective therapy with a very low incidence of relapse and a remarkably good leukaemia-free survival. The only two prognostic factors that significantly affected outcome were the disease status at the time of transplantation and acute GVHD grades 3–4. We need new approaches for leukaemic control in patients in the later stages of disease and more effective strategies to reduce the frequency of high-grade acute GVHD.
The control of extramedullary disease in these patients was good, so that prophylactic testicular or CNS irradiation given in addition to TBI can be omitted. The toxicity of the TAM regimen is considered acceptable; the early toxic deaths were mostly due to common complications of allogeneic BMT.