Long-term follow-up of the United Kingdom Medical Research Council protocols for childhood acute lymphoblastic leukaemia, 1980-1997. Medical Research Council Childhood Leukaemia Working Party.

Eden OB, Harrison G, Richards S, Lilleyman JS, Bailey CC, Chessells JM, Hann IM, Hill FG, Gibson BE.

Academic Unit of Paediatric Oncology, Christie and Royal Manchester Children's Hospital NHS Trusts, Oxford, UK.

Results of three consecutive completed UK trials (1980-1997) for childhood lymphoblastic leukaemia are presented. National accrual has progressively increased so that over 90% of all the country's ALL cases were treated on the latest trial reported, UKALLXI. From 1980 to 1990, event-free and overall survival progressively improved, following adoption of an American therapy template and use of two post-remission intensification modules. Since 1990 despite demonstration of the benefit of a third intensification module overall event-free survival (EFS) has not improved further. Survival remains high due to a good retrieval rate especially for those relapsing off treatment after receipt of two intensification pulses. Possible reasons for the plateau in event-free survival (including type and dose of induction steroid, dropping of induction anthracycline, type and dose of asparaginase, gaps early in therapy following intensification, and overall lack of compliance in maintenance) are being explored in the latest protocol ALL '97. Cranial irradiation had been successfully replaced by a long course of intrathecal methotrexate injections for the majority of patients. Age (<1 year >10 years) sex (male) and white count >50 x 10(9)/l plus slow initial bone marrow clearance were consistently the most important independent prognostic indicators during this time period. Rome/NCI criteria accurately predict standard and high-risk groups for B cell lineage, but not consistently for T cell disease. This international collaborative venture might help us to define those truly at highest risk, and how we can optimise therapy for specific subgroups including T-ALL and those with unfavourable cytogenetics.

Publication Types: Clinical Trial Meta-Analysis Randomized Controlled Trial

PMID: 11187922 [PubMed - indexed for MEDLINE]

Progressive reduction in treatment-related deaths in Medical Research Council childhood lymphoblastic leukaemia trials from 1980 to 1997 (UKALL VIII, X and XI).

Hargrave DR, Hann II, Richards SM, Hill FG, Lilleyman JS, Kinsey S, Bailey CC, Chessells JM, Mitchell C, Eden OB; Medical Research Council Working Party for Childhood Leukaemia.

Department of Paediatric Oncology, The Royal Marsden Hospital, Sutton, UK. d.hargrave@icr.ac.uk

In the last 20 years, the survival rate for children with acute lymphoblastic leukaemia (ALL) has markedly improved, largely owing to a decrease in relapses. However, children still die from complications of treatment and these are potentially preventable. We have analysed data from three large consecutive national protocols for ALL from 1980 to 1997 [Medical Research Council United Kingdom ALL (MRC UKALL) trials VIII, X and XI] to compare the incidence and causes of treatment-related deaths (TRD). The percentage of TRD has fallen from 9% to 2% (UKALL VIII to XI), largely as a result of a decrease in fatal infections. Deaths during induction have fallen from 3% to 1%, the main causes of death being bacterial, followed by fungal infection, while other causes, chiefly haemorrhage, have not declined. Remission deaths also decreased from 6% to 1%, particularly those deaths due to measles and pneumocystis carinii. More guidelines for surveillance and treatment of infections have been included within progressively more intensive protocols. Risk factor analysis showed increased TRD in patients with Down's syndrome, high leucocyte count and older age in UKALL XI. In contrast, the introduction of blocks of intensification was not associated with an increased death rate. While improved supportive care has reduced the incidence of TRD, there is still scope for further reduction by prompt treatment of suspected infection. Maintenance of herd immunity remains of vital importance in avoiding deaths from measles.

PMID: 11167821 [PubMed - indexed for MEDLINE]

Comparison of allogeneic transplant versus chemotherapy for relapsed childhood acute lymphoblastic leukaemia in the MRC UKALL R1 trial. MRC Childhood Leukaemia Working Party.

Harrison G, Richards S, Lawson S, Darbyshire P, Pinkerton R, Stevens R, Oakhill A, Eden OB.

Clinical Trial Service Unit, Radcliffe Infirmary, Oxford, UK.

BACKGROUND: Although reinduction rates are good for children with relapsed acute lymphoblastic leukaemia there is no consensus on whether bone marrow transplantation (BMT) is the most effective treatment to prolong second remission. PATIENTS AND METHODS: Analyses comparing the outcome of related donor allogeneic BMT (related allograft) with chemotherapy are unreliable because of selection biases. To avoid these biases, the MRC UKALL R1 trial was analysed by HLA-matched donor availability. RESULTS: No significant difference in outcome was found between the donor and no donor groups. The donor group had a non-significant eight-year event-free survival (EFS) advantage of 8%, (95% confidence interval -9%-24%) over the no donor group. Patients with a first remission less than two years appeared to benefit most from having a donor, although the effect was only marginally significantly different from patients with longer first remission. Analysis by treatment received gave similar results, with BMT patients having a 5% (P = 0.8) eight-year EFS advantage over patients who received chemotherapy. CONCLUSIONS: Related allograft was not found to be significantly better than chemotherapy, but there was the possibility of a moderate EFS benefit with related allograft. especially in patients with a short first remission.

Publication Types: Clinical Trial Multicenter Study

PMID: 11038037 [PubMed - indexed for MEDLINE]

Bone marrow transplantation versus chemotherapy in the treatment of very high-risk childhood acute lymphoblastic leukemia in first remission: results from Medical Research Council UKALL X and XI.

Wheeler KA, Richards SM, Bailey CC, Gibson B, Hann IM, Hill FG, Chessells JM.

John Radcliffe Hospital, Headington, Oxford, England. kate.wheeler@paediatrics.oxford.ac.uk

The role of bone marrow transplantation (BMT) in first remission of children with high-risk acute lymphoblastic leukemia (ALL) remains unclear. There were 3676 patients (aged 1 to 15 years) entered into the United Kingdom (UK) Medical Research Council (MRC) trials UKALL X and XI from 1985 to 1997. Of these patients, 473 patients (13%) were classified as very high (VH) risk and were eligible for a transplantation from a matched histocompatible sibling donor (MSD). We tissue-typed 286 patients; 99 patients had a matched related donor, and 76 patients received transplantations. Additionally, 25 children received transplantations from a matched unrelated donor (MUD) despite trial guidelines for MSD transplantations only. The median time to transplantation was 5 months (range, 2 to 19 months), and the median follow-up was 8 years. The 10-year event-free survival (EFS) adjusted for the time to transplantation, diagnostic white blood cell (WBC) count, Ph chromosome status, and ploidy was 6. 0% higher (95% confidence interval (CI), -10.5% to 22.5%) for 101 patients who received a first-remission transplantation (MSD and MUD) than for the 351 patients treated with chemotherapy (transplantation, 45.3%, vs chemotherapy, 39.3%). The transplantation group had fewer relapses (31%) compared to relapses in the chemotherapy group (55%); however, the transplantation group had more remission deaths (18%) compared to remission deaths in the chemotherapy group (3%). In contrast the adjusted 10-year EFS was 10. 7% higher (95% CI, -2.6% to 24.0%) for patients without a human leukocyte antigen (HLA)-matched donor than for those patients with a donor (no donor, 50.4%, vs donor, 39.7%). In conclusion, for the majority of children with VH-risk ALL, the first-remission transplantation has not improved EFS.

Publication Types: Clinical Trial Randomized Controlled Trial

PMID: 11001892 [PubMed - indexed for MEDLINE]

The UK experience in treating relapsed childhood acute lymphoblastic leukaemia: a report on the medical research council UKALLR1 study.

Lawson SE, Harrison G, Richards S, Oakhill A, Stevens R, Eden OB, Darbyshire PJ.

Department of Haematology, Birmingham Children's Hospital, Birmingham, UK. isaac.lawson@btinternet.com

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.

Publication Types: Clinical Trial Controlled Clinical Trial

PMID: 10759711 [PubMed - indexed for MEDLINE]

Outcomes and prognostic factors of Chinese children with acute lymphoblastic leukemia in Hong Kong: preliminary results.

Shing MM, Li CK, Chik KW, Lam TK, Lai HD, Ng MH, Cheung AY, Yuen PM.

Lady Pao Children's Cancer Centre, Department of Pediatrics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, NT. mk-shing@cuhk.edu.hk.hk

BACKGROUND: The Chinese population is the biggest ethnic group in the world. However, there are few reports on the treatment outcome of childhood acute lymphoblastic leukaemia (ALL) among the Chinese population. PROCEDURE: Sixty-five children with ALL were treated with a modified protocol of the Medical Research Council United Kingdom Acute Lymphoblastic Leukaemia protocol X(MRC UKALL X) at the Prince of Wales Hospital, Hong Kong. Most patients were ethnic Chinese. They were divided into groups A and B, depending on whether their presenting leucocyte count being was less or greater than 50 x 10(9)/l, respectively. Group A patients of received induction, early intensification (week 5), cranial irradiation, and maintenance for 3 years. Group B patients received an additional late intensification (week 20). RESULTS: The median follow-up duration was 6.8 years(range: 3.4-10.1 years). The event-free and overall survival rates of all patients at 7 years were 66% (confidence interval [CI] 53-76) and 75% (CI 63-84), respectively. The event-free survival rates of groups A and B at 7 years were 67% (CI 52-79) and 60% (CI 32-80), respectively (P= 0.39). The overall survival rates of groups A and B at 7 years were 80% (CI 66-89) and 60% (CI 32-80), respectively (P = 0.07). With this treatment protocol, the factors which adversely affected the outcome were age (<2 years and >10 years) and T-cell subtype. Sex, white blood count at diagnosis, and FAB subtypes were not statistically significant prognostic factors. CONCLUSIONS: The treatment outcomes were comparable with those reported from the MRC UKALL X trials.

PMID: 9950200 [PubMed - indexed for MEDLINE]

Severe vincristine toxicity in combination with itraconazole.

Gillies J, Hung KA, Fitzsimons E, Soutar R.

Department of Haematology, Monklands District General Hospital, Airdrie, UK.

We report two patients with acute lymphoblastic leukaemia (ALL) who were entered into the current MRC adult ALL trial (UKALL XII) in whom unusually severe vincristine induced neurotoxicity developed. This appeared to be the result of an interaction with itraconazole suspension.

PMID: 9681224 [PubMed - indexed for MEDLINE]

Clinical presentation, hematologic features and treatment outcome of childhood acute lymphoblastic leukemia: a review of 73 cases in Hong Kong.

Ma SK, Chan GC, Ha SY, Chiu DC, Lau YL, Chan LC.

Department of Pathology, University of Hong Kong, Queen Mary Hospital.

Seventy-three consecutive cases of childhood acute lymphoblastic leukemia (ALL) diagnosed and managed in Queen Mary Hospital over a 10-year period from 1985 to 1994 were retrospectively analysed for their presenting features and treatment outcome. The 48 boys and 25 girls ranged in age from 0.4 to 14.2 years (median: 4.3 years). Bone and joint pain was a relatively common presenting feature besides fever, hepatosplenomegaly and lymphadenopathy. Immunophenotyping of blast cells showed: 51 B-cell precursor ALL, one B-ALL, 10 T-ALL and three myeloid-antigen positive ALL. Eight cases were unclassified since immunophenotyping had not been performed. Out of the 73 patients, treatment outcome was analysed in 20 cases treated with UKALL-VIII regimen and 28 cases treated with either the UKALL-XI regimen or the Hong Kong Children Cancer Study Group (HKCCSG) protocol which was modelled upon UKALL-XI. Although complete remission rates were similar between the two groups, patients treated with the former regimen that was less intensified suffered more relapses than the latter (56 per cent versus 21 per cent, P = 0.04). There were, however, no significant differences both in event-free survival (38.2 +/- 11.2 per cent versus 71.3 +/- 9.3 per cent, P = 0.12) and overall survival (70.0 +/- 10.2 per cent versus 79.6 +/- 8.3 per cent, P = 0.41) between the two groups at 3 years by long-rank test. With the use of risk-directed therapy and improved supportive care, two-thirds of our patients are able to enjoy long-term event-free survival.

Publication Types: Review Review, Multicase

PMID: 9600113 [PubMed - indexed for MEDLINE]

Comparison of bone marrow transplant and chemotherapy for relapsed childhood acute lymphoblastic leukaemia: the MRC UKALL X experience. Medical Research Council Working Party on Childhood Leukaemia.

Wheeler K, Richards S, Bailey C, Chessells J.

Department of Paediatrics, Oxford Radcliffe Hospital.

We examined the outcome of the 489 children with acute lymphoblastic leukaemia (ALL) who relapsed in the UKALL X trial, and produced graphical displays of adjusted comparisons of event-free survival (EFS) for chemotherapy versus bone marrow transplantation (BMT) from a sibling or volunteer unrelated donor, and autologous BMT (ABMT). EFS at 5 years was only 3% (95% CI 0-6%) for children who relapsed in the bone marrow (BM) within 2 years of diagnosis, irrespective of type of post-relapse treatment, whereas for those with late extramedullary relapse it was 66% (95% CI 48-85%). Comparison of the types of treatment did not show benefit for ABMT. For allogeneic BMT the overall reduction in the odds of an event was 26% (95% CI 1-51%) (2P= 0.05), resulting in an absolute increase in 5-year event-free survival of 14% (from 26.4% to 40.7%). New approaches are needed for children with early BM relapses whose prognosis is virtually hopeless with current therapy; however, a conventional chemotherapy approach may be justifiable for late extramedullary relapses. For the remaining patients (71%), with later BM or early extramedullary relapses, the optimal treatment is still not clear. This uncertainty warrants a formal randomized comparison of BMT and chemotherapy, to avoid the biases due to unmeasurable selection factors.

PMID: 9576189 [PubMed - indexed for MEDLINE]

Continuing (maintenance) therapy in lymphoblastic leukaemia: lessons from MRC UKALL X. Medical Research Council Working Party in Childhood Leukaemia.

Chessells JM, Harrison G, Lilleyman JS, Bailey CC, Richards SM.

Haematology/Oncology Department, Institute of Child Health, London.

The relationship between the prescribed dose of drugs during continuing (maintenance) therapy, the degree of marrow suppression caused, and subsequent event-free survival was examined in a cohort of 740 children with lymphoblastic leukaemia treated on MRC UKALL X. Girls, younger children, and patients who had received intensification treatment, were prescribed lower doses of mercaptopurine, became neutropenic more readily, and had more interruptions of treatment. Children who had one or more episodes of neutropenia with a count of <0.5 x 10(9)/l had a better prognosis than those who never became neutropenic. We conclude that early intensification treatment influences the probability of neutropenia during continuing treatment and that patients exhibiting myelosuppression during this phase of treatment have a better chance of prolonged remission.

Publication Types: Clinical Trial Randomized Controlled Trial

PMID: 9326194 [PubMed - indexed for MEDLINE]

Mercaptopurine in childhood leukaemia: the effects of dose escalation on thioguanine nucleotide metabolites.

Lennard L, Welch J, Lilleyman JS.

University of Sheffield Department of Medicine and Pharmacology, Royal Hallamshire Hospital, Sheffield.

The current U.K. trial protocol (UKALL XI) for childhood lymphoblastic leukaemia demands mercaptopurine (MP) dose escalation in children who tolerate daily 75 mg/m2 MP (100% dose) without cytopenias. The previous trial (UKALL X) did not. MP metabolism was studied in a group of UKALL XI children (n = 21) who tolerated 100% dosages and who were matched in this respect with a similar group of UKALL X children. Red blood cell MP derived thioguanine nucleotide (TGN) concentrations were measured in both groups under comparable conditions; at 75 mg/m2 MP there was no significant difference. MP dose escalation in the UKALL XI children produced higher TGN concentrations (TGNs at 100% vs 125% dosages, median difference 90 pmol/8 x 10(8) RBCs, 95% CI 25 to 165 pmol, P < 0.02). Assayed at the time of cytopenia induced dose reduction, the UKALL XI children had accumulated significantly higher TGN concentrations than the UKALL X children (median difference 78 pmol/8 x 10(8) RBCs, 95% CI 20 to 144, P < 0.02). These findings indicate that dose escalation in children tolerant of 100% MP dosages produces higher peak TGN concentrations.

PMID: 8904630 [PubMed - indexed for MEDLINE]

Unrelated donor bone marrow transplantation for children with relapsed acute lymphoblastic leukaemia in second complete remission.

Oakhill A, Pamphilon DH, Potter MN, Steward CG, Goodman S, Green A, Goulden P, Goulden NJ, Hale G, Waldmann H, Cornish JM.

Royal Hospital for Sick Children, Bristol.

Allogeneic sibling bone marrow transplantation (BMT) is the recommended treatment for relapsed childhood acute lymphoblastic leukaemia (ALL), but appropriate donors are only available in 30% of cases. Unfortunately, BMT from unrelated donors (UD) has been associated with high rates of severe graft-versus-host disease (GvHD) and transplant-related mortality (TRM). In an attempt to improve outcome in UD-BMT we have assessed the impact of T-cell depletion using CAMPATH-1 (anti-CD52) monoclonal antibodies in 50 consecutively referred patients with relapsed ALL in second remission. All were previously treated according to MRC protocols UKALL X and XI, and then given chemotherapy on MRC R1 from relapse until UD-BMT, 19 patients had relapsed on and 31 off therapy. Patients and donors were fully matched at HLA-A, -B, -DR and -DQ loci in 29 cases and mismatched in 21 (four mismatched for more than one antigen). Pre-transplant conditioning comprised CAMPATH-1G, cyclophosphamide and total body irradiation. Bone marrow was T-cell depleted in vitro using CAMPATH-1 antibodies. Additional GvHD prophylaxis consisted of cyclosporin A (42 cases), cyclosporin plus methotrexate (four) or none (four). 47 patients engrafted. The incidence of acute GvHD was very low: two patients with grade II disease in the matched group, four with grade II-IV in the mismatched group. Only four patients have chronic GvHD. The actuarial event-free survival (EFS) at 2 years is 53%, with no significant difference between the matched and mismatched group. Further leukaemic relapse was the most important cause of failure. These results are similar to the most favourable published reports for HLA-matched sibling BMT in relapsed ALL.

PMID: 8790160 [PubMed - indexed for MEDLINE]

Intensification of treatment and survival in all children with lymphoblastic leukaemia: results of UK Medical Research Council trial UKALL X. Medical Research Council Working Party on Childhood Leukaemia.

Comment in: Lancet. 1995 Mar 11;345(8950):653.

Chessells JM, Bailey C, Richards SM.

Department of Haematology and Oncology, Institute of Child Health, London, UK.

The UK Medical Research Council trial MRC UKALL X was designed to investigate the benefit of one or two courses of additional intensification therapy in children with acute lymphoblastic leukaemia receiving standard treatment. From 1985 to 1990 1612 children, comprising more than 90% of eligible cases in the UK, were treated with intensive induction therapy, central nervous system directed therapy with cranial irradiation and intrathecal methotrexate, and continuing treatment for 2 years. 1171 children were randomised to receive additional intensification therapy at 5 weeks, 20 weeks, both, or neither. At follow-up of at least 3 years disease-free survival for all children at 5 years was 62% (95% confidence interval [Cl] 60.0-64.4), a significant improvement over the 56% (53.0-59.6) found in the preceding MRC UKALL trial. The 5-year disease-free survival was 71% (65.5-76.1) for children randomised to two blocks of intensification therapy, this being significantly better than the 62% (56.6-68.0), 61% (55.7-67.1), and 57% (50.9-62.7) rates for the groups randomised to one intensification block at 5 weeks, one at 20 weeks, and no intensification, respectively. The benefits of intensification therapy were seen irrespective of clinical factors known to influence outcome such as age, sex, and initial leucocyte count. We conclude that the addition of two courses of intensification therapy has produced a 14% improvement in disease-free survival and an 11% improvement in overall survival for the randomised patients. This additional treatment is of benefit to all children with acute lymphoblastic leukaemia, even those traditionally deemed at lower risk of relapse.

Publication Types: Clinical Trial Randomized Controlled Trial

PMID: 7823668 [PubMed - indexed for MEDLINE]

Results of Medical Research Council Childhood Leukaemia Trial UKALL VIII (report to the Medical Research Council on behalf of the Working Party on Leukaemia in Childhood).

Eden OB, Lilleyman JS, Richards S, Shaw MP, Peto J.

Royal Hospital for Sick Children, Edinburgh.

During the 1970s, despite apparently similar treatment, the prognosis for children with lymphoblastic leukaemia (ALL) improved more in some countries, notably the United States and West Germany, than in others. To find out why, the first phase of the United Kingdom (UK) Medical Research Council (MRC) childhood ALL trial, UKALL VIII, was designed to see whether similar results to the United States Children's Cancer Study Group (CCSG) could be obtained in the U.K. using an identical protocol (CCG 162). Protocol 162 was one of a series of regimens devised by the American Children's Cancer Study Group in the 1970s and was used specifically for their average risk patients (all children with ALL with an initial white cell count up to 50 x 10(9)/l except those aged 3-6 years with white cell counts under 10 x 10(9)/l). One arm (1A) of their study was adopted by the MRC for all children in the U.K. aged 0-14 years with confirmed ALL. Eight hundred and twenty-nine consecutive patients were entered between 1980 and 1984. The first 199 patients formed a single arm study as per the original protocol 162 (arm 1A), but the subsequent 630 children were randomized to receive or not two doses of daunorubicin on the first 2 d of induction. This randomization was an attempt to answer the important question as to whether event-free survival was influenced by the use of four rather than three induction agents. A second randomization between 2 and 3 years continuing therapy was also introduced at this stage as it had been by the CCSG in their protocol. With a minimum follow up period of more than 5 years, disease-free survival for the whole group is 55%, a considerable improvement on all previous UKALL trials. Results for patients directly comparable with those in CCSG 162 ('average risk' patients) and their American counterparts were similar. Daunorubicin was associated with more early deaths but improved disease-free survival for those achieving remission. More children relapsed who stopped treatment after 2 years than those who continued for 3, but this was balanced by increased treatment mortality in the third year. The fact that for UKALL VIII the results were similar to those of the CCSG suggests that previous MRC protocols were not sufficiently sustained and intensive, particularly during the maintenance phase of treatment.(ABSTRACT TRUNCATED AT 400 WORDS)

Publication Types: Clinical Trial Randomized Controlled Trial

PMID: 2064956 [PubMed - indexed for MEDLINE]