Results of Medical Research Council trial UKALL IX in acute lymphoblastic leukaemia in adults: report from the Medical Research Council Working Party on Adult Leukaemia

Summary. The MRC UKALL IX trial for patients with untreated ALL aged 14 years and over was open to new patients from July 1980 to April 1985. 266 patients were randomized between two induction schedules, M (involving intermediate dose rnethotrexate with folinic acid rescue) and D (involving daunorubicin). Schedule M resembled that used in the previous MRC adult ALL, trial (UKALL VI). while schedule D was somewhat more intensive. No difference in disease-free survival was found between the treatment arms, but patients on the daunorubicin arm went into remission earlier.
The overall remission rate was 8 7%, which is at least as good as in contemporary studies elsewhere: factors predictive of a lower remission rate were older age and higher WBC. For those who entered remission, WBC, age and sex were the most important prognostic factors. Time to achieve remission was not a significant factor after allowance was made for these.
An historical comparison does not show any improvement over the preceding MRC adult trial, although the subsequent trial does show a modest improvement at present. Because the improved outlook seen in children is not apparent in adults, and no other randomized trial has demonstrated substantial benefit for any particular regimen, the next trial, UKALL XII, will be investigating the benefit or otherwise of bone marrow transplantation.     

Failure of a new protocol to improve treatment results in paediatric lymphoblastic leukaemia: lessons from the UK Medical Research Council trials UKALL X and UKALL XI

The impact of various types of intensification therapy was examined in a cohort of 3617 children aged 1-14 years with acute lymphoblastic leukaemia (ALL) enrolled in the Medical Research Council (MRC) UKALL X (1985-90) and UKALL XI (1990-97) trials. UKALL XI was modified in 1992 to incorporate the "best arm" of UKALL X with two 5-d intensification blocks at 5 and 20 weeks, and an additional randomization in respect of a third intensification at 35 weeks but omission of two consecutive injections of daunorubicin during induction. All children were eligible for randomization irrespective of risk group. The impact of the various types of intensification therapy was examined in a stratified analysis. At a median follow up of 102 months, both trials had an identical event-free survival of 61% (95% CI 58-63%) at 8 years. Survival at 8 years in UKALL XI was significantly better in than in UKALL X, 81% (79-83%) compared with 74% (72-76%) (P = < 0.001), owing to improved management of relapse. There was a highly significant trend in reduction of the number of relapses and deaths with increased intensity of therapy both for children with initial leucocyte count < 50 x 10(9)/l (P = < 0.001) and > or = 50 x 10(9)/l (P = 0.002). Introduction of a third late intensification block compensated for omission of anthracyclines during induction but produced little additional benefit. These results show, in a large cohort of patients, that minor modifications of therapy may influence relapse rate and obviate the benefit of previous randomized trials. The failure to adapt treatment for higher risk children contributed to these disappointing results.     

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

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.     

Intensification of treatment for adults with acute lymphoblastic leukaemia: results of U.K. Medical Research Council randomized trial UKALL XA

The MRC UKALL XA trial for patients aged 15 years and over with acute lymphoblastic leukaemia was designed to evaluate short blocks of intensive 'AML-style' treatment. Between 1985 and 1992, 618 eligible patients were entered into the trial. 450 patients were randomized to receive early intensification at 5 weeks, late intensification at 20 weeks, both, or neither. Unlike the concurrent children's trial, UKALL X, which was of similar design, UKALL XA does not demonstrate a clear benefit for intensification, although there was a significant reduction in the relapse risk due to the early block. The estimated increase in disease-free survival at 5 years was 2% with 95% confidence interval from 1% reduction to 5% increase. There may be a real difference between the effect of these treatments in adults and in children, but this result may be somewhat weakened by poorer compliance, with a greater proportion of adults not receiving the treatment arm to which they were randomized.     

Early response to induction is predictive of survival in childhood Philadelphia chromosome positive acute lymphoblastic leukaemia: results of the Medical Research Council ALL 97 trial

We report on the outcome of children with Philadelphia positive acute lymphoblastic leukaemia (Ph+ ALL) treated on the UK Medical Research Council (MRC) trial for childhood ALL, MRC ALL 97, between January 1997 and June 2002. Forty-two (2.3%) patients were Ph+. Nineteen (45%) had <25% blasts in bone marrow (BM) within the first 2 weeks of treatment and were defined as a good response group (GRG), the others as a poor response group (PRG). Thirty-six (86%) achieved first complete remission (CR1) at the end of induction, of which 28 underwent BM transplantation (BMT). The median follow-up was 42 months (range, 21-84). The 3-year event-free survival (EFS; 52%, 95% CI, 36-66%) was a considerable improvement on the previous MRC UKALL XI trial (27%). EFS for the GRG and PRG were 68% (43-84%) and 39% (18-59%), respectively (P = 0.03); presenting white cell count <50 x 10(9)/l (P = 0.02) was predictive for overall survival. Changes in the MRC ALL97 trial within the study period resulted in some Ph+ ALL receiving daunorubicin and either prednisolone or dexamethasone during induction. Though the use of daunorubicin during induction was not a prospective study question, EFS was significantly better for those whose induction included this drug (P = 0.02). Steroid randomization was not stratified for Ph+ ALL patients and was not predictive for EFS. BMT in CR1 appeared to reduce the risk of a subsequent BM relapse. These results show significant improvement on previous MRC trials; future therapeutic strategies should include early intensive therapy and BMT in CR1.     

Determinants of outcome after intensified therapy of childhood lymphoblastic leukaemia: results from Medical Research Council United Kingdom acute lymphoblastic leukaemia XI protocol

The single most important prognostic determinant in childhood acute lymphoblastic leukaemia (ALL) is effective therapy and changes in therapy may influence the significance of other risk factors. The effect of intensified therapy on the importance of currently recognized phenotypic and genotypic determinants of outcome was assessed in 2090 children enrolled on the Medical Research Council United Kingdom acute lymphoblastic leukaemia XI (MRC UKALL XI) protocol. Treatment allocation was not determined by risk factors. Multivariate analysis confirmed the dominant influence on prognosis of age, sex and presenting white cell count (WCC). After allowing for these features, blast karyotype, d 8 marrow blast percentage and remission status at the end of induction therapy were the only remaining significant predictors of outcome. Organomegaly, haemoglobin concentration, French--American--British type, body mass index, presence of central nervous system disease at diagnosis, immunophenotype and presence of TEL/AML1 fusion gene (examined in a subset of 659 patients) either had no significant effect on outcome or were significant only in univariate analysis. Among karyotype abnormalities with an independent influence on prognosis, high hyperdiploidy (> 50 chromosomes) was shown to be favourable, whereas near haploidy (23--29 chromosomes), presence of the Philadelphia chromosome, t(4;11) and abnormalities affecting the short arm of chromosome 9 [abn (9p)] were adverse risk factors. Early responders to therapy, determined by residual marrow infiltration after 8 d of induction therapy, had a good outcome, while the small proportion of patients who did not achieve a complete remission by the end of induction therapy had a poor outcome. A third block of late intensification was shown to improve event-free survival by 8% at 5 years. The effect of these risk factors was not significantly different between those randomized to the third intensification block and those not randomized to a third block.     

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

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.     

The impact of risk stratification by early bone-marrow response in childhood lymphoblastic leukaemia: results from the United Kingdom Medical Research Council trial ALL97 and ALL97/99

The 1997 acute lymphoblastic leukaemia (ALL) trial (ALL97) was a randomised comparison of prednisolone versus dexamethasone and of 6-mercaptopurine versus 6-thioguanine. During the first 2 years of the trial, review of survival data showed the preceding trial, UKALL XI, was no better than its predecessor and that survival for childhood ALL in the UK had not improved in the fashion witnessed by other cooperative treatment groups. The therapy template was therefore altered to an American Children's Cancer Group (CCG) style regimen, including stratification by age, white cell count and early response to therapy by assessment of the bone marrow. This phase of the trial was designated ALL97/99. Comparison of the two phases showed that the event-free survival (EFS) for both ALL97 and ALL97/99 was better than previous UKALL trials, as was overall survival (OS) for ALL97/99. Both EFS and OS were significantly better in ALL97/99 than in ALL97 (at five years, 80·0% vs. 74·0%, P  = 0·002; and 88·0% vs. 83·5%, P  = 0·005, respectively). Isolated central nervous system (CNS) relapse for patients in ALL97/99 was half that in ALL97 (3·0% vs. 4·9%), P  = 0·03) and the overall CNS relapse rate was halved in ALL97/99 (4·4% vs. 9·6%, P  < 0·00005). There were no significant differences for non-CNS relapse, induction deaths or deaths in remission between the two phases of the trial.     

Avascular necrosis of bone following intensified steroid therapy for acute lymphoblastic leukaemia and high-grade malignant lymphoma

Five out of nine adults (55%) with lymphoblastic disease developed severe avascular necrosis of bone (AVN) when treated with a Berlin-Frankfurt-Munster (BFM) ALL protocol similar to the current joint MRC–ECOG ALL trial (UKALL XII). The principal purpose of these intensified regimens is to improve long-term disease-free survival without necessarily increasing toxicity and secondary morbidity. The presentation of all five was non-specific bone pain occurring after the re-intensification block of chemotherapy containing high doses of dexamethasone. Three types of diagnostic imaging were performed and magnetic resonance imaging (MRI) proved superior in demonstrating AVN and showed it at an earlier stage than plain radiographs or isotopic scans. We believe that the dose of corticosteroids was the major factor in the development of AVN. The five men in our series all remain in first remission with a median disease-free survival of 3·5 years (range 2–8 years) but with varying degrees of disability due to AVN. Clinicians involved in UKALL XII and similar trials should be aware of this debilitating and potentially crippling complication when using high-dose steroid-containing regimens, perform MRI scan early and modify treatment if necessary.     

Implementation of an intensive risk-stratified treatment protocol for children and adolescents with acute lymphoblastic leukemia in Lebanon

With modern risk-adapted therapy, over 80% of children with acute lymphoblastic leukemia (ALL) in high-income countries (HICs) are cured. In countries with limited resources, however, therapy results for pediatric ALL are still not encouraging. We describe our experience in treating children with ALL using a risk-adapted protocol at a tertiary referral center in Lebanon. From May 2002 to August 2009, 111 consecutive patients 1-21 years of age with newly diagnosed ALL received the CCCL ALL protocol which was based on the St. Jude Children's Research Hospital Total XV Study. The median age at diagnosis was 5 years 5 months. The male to female ratio was 1.5. Forty-six patients received the intermediate-/high-risk arm and 65 received the low-risk arm. Only one patient (0.9%) died during induction therapy. Relapse occurred in 8 (7.2%) patients. Eight (7.2%) patients died, 4 of whom were in remission. The median follow-up of the patients was 38 months. The 5-year overall survival and event-free survival were and 88.5% (95% CI: 77.1-94.4) and 78.7% (95% CI: 69.8-88.4), respectively. Our results are comparable to those in HICs in spite of the limited resources and the relatively low socioeconomic status of the Lebanese population. Children treated on this protocol experienced significant toxicity necessitating expert supportive care, but benefited from improved cure rates and prolonged survival.     

Prognosis of children with acute lymphoblastic leukemia (ALL) and intrachromosomal amplification of chromosome 21 (iAMP21)

Patients with acute lymphoblastic leukemia (ALL) and an intrachromosomal amplification of chromosome 21 (iAMP21) comprise a novel and distinct biological subgroup. We prospectively screened 1630 (84%) patients treated on the UK MRC ALL97 protocol for iAMP21 and herein present demographic, clinical, and survival data on the 28 (2%) children found to harbor this abnormality. They had a common or pre-B ALL immunophenotype, were significantly older (median 9 years vs 5 years), and had a lower white cell count (median 3.9 vs 12.4) compared with children without this abnormality. Notably, patients with iAMP21 had a significantly inferior event-free and overall survival at 5 years compared with other patients: 29% (95% confidence interval [CI], 13%-48%) versus 78% (95% CI, 76%-80%) and 71% (95% CI, 51%-84%) versus 87% (95% CI, 85%-88%), respectively. As a result of this 3-fold increase in relapse risk, newly diagnosed patients with iAMP21 recruited to the current UK MRC ALL2003 trial are being treated on the high-risk arm and are considered for bone marrow transplantation in first remission.     

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

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.     

Cytogenetics and prognosis in childhood lymphoblastic leukaemia: results of MRC UKALL X

We have analysed the prognostic influence of cytogenetic findings at diagnosis in a group of 502 children with acute lymphoblastic leukaemia (ALL), treated on MRC UKALL X, in whom clonal cytogenetic abnormalities were detected at diagnosis. Despite the overall improvement in outcome in children treated on this protocol compared with previous trials, some cytogenetically-defined groups were still associated with a poor outcome and ploidy retained some prognostic significance. Patients with high hyperdiploid ALL (39% of those with clonal abnormalities) had a favourable outcome with event free survival of 71% at 5 years. Those with near haploidy (1%), hypodiploidy (9%) and low hyperdiploidy (16.5%) had a relatively poor prognosis with event-free survival at 5 years of 17%, 42% and 49% respectively. Only two of 12 children with Ph-positive leukaemia are alive in remission and abnormalities of chromosome 11q23 were also associated with a high risk of treatment failure. In contrast, the t(1;19) was associated with improved event-free survival of 87.5% at 5 years. A number of other non-random abnormalities were identified with no clear prognostic significance.
We conclude that identification of certain genetic changes remains important in the management of acute lymphoblastic leukaemia, although whether molecular diagnosis of clinically relevant abnormalities can now supplant cytogenetics in the clinical trials context remains to be determined.     

Severe vincristine toxicity in combination with itraconazole

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.     

Haematologists' approaches to the management of adolescents and young adults with acute leukaemia

Approaches to the management of adolescents and young adults with acute leukaemia were investigated by sending a questionnaire to hospitals identified as having diagnosed or treated patients aged 15-29 years. The responses demonstrated the types of hospital treating these patients, the haematologists' perceived practice for entry of patients to Medical Research Council (MRC) leukaemia trials and reasons for non-entry. Data were linked to MRC trials data to determine the proportion of patients aged 15-29 years at diagnosis in responding hospitals actually treated in MRC leukaemia trials in the 5 years preceding the questionnaire. Eighty-two per cent of haematologists stated that they entered patients 'always' or 'whenever possible' for acute myeloid leukaemia (AML) and 76% for acute lymphoblastic leukaemia (ALL), but actual entry rates from the study hospitals were 46% of 239 AML patients and 36% of 182 ALL patients. The reasons most commonly reported for not entering eligible patients to national leukaemia trials were clinician preference for one arm of an MRC trial, a regional study or non-trial protocol, and concern about workload and ethical approval.     

Cytogenetics adds independent prognostic information in adults with acute lymphoblastic leukaemia on MRC trial UKALL XA

Cytogenetic classification of 350 adults with acute lymphoblastic leukaemia on MRC UKALL XA trial showed the following statistically significant associations: t(9;22) (11%) increased with increasing age and leucocyte counts (WBC) and most had a C/pre-B immunophenotype. t(4;11) (3%) was associated with higher WBCs, increasing age and null immunophenotype. Other abnormalities of 11q (abn11q) (4%) were associated with male sex and T-cell ALL. High hyperdiploidy (7%) and abn9p (5%) decreased with increasing WBC. High hyperdiploid patients were younger and tended to have C/pre-B ALL. Triploidy/tetraploidy (3%) decreased and pseudodiploidy (11%) increased with increasing WBC. Cytogenetic classification was prognostically important (chi-square for heterogeneity of classification = 53.36; P  < 0.0001) and added significance to age, sex and WBC. A poor prognosis for patients classed as t(9;22) (13% disease-free survival at 3 years), as t(4;11) 24% at 3 years) and hypodiploid (11% at 3 years), and good prognosis for abn12p (4% of subjects) and high hyperdiploidy (74% and 59% at 3 years respectively) were statistically significant, but the 54% 3-year disease-free survival for patients with t(1;19) was not. The prognosis of patients classed as t(9;22) was independent of other single variables. Abn12p, abnormalities of 11q (including t(4;11) cases) and hypodiploidy added prognostic significance to all other variables combined.     

Analysis of Treatment in Childhood Leukaemia

The first and second Medical Research Council UKALL trials have shown that alteration in the timing of methotrexate and 6-mercaptopurine maintenance therapy for the treatment of acute lymphoblastic leukaemia can markedly change drug induced toxicity. Maintenance chemotherapy in both trials used a similar total dosage of these drugs but the timing of their administration was different in the two schedules.     

HLA Antigens and Childhood Acute Lymphocytic Leukaemia

S ummary . HLA-A and -B antigens were determined for 94 children with acute lymphocytic leukaemia (ALL) and for 376 normal controls. Sixty-four of these 94 patients were typed for lymphocyte surface markers and 59 were defined as 'null cell' ALL. There was no difference in the distribution of the HLA-A or -B locus antigens between the control group and the entire group of patients with ALL or the 'null cell' subgroup. Patients with HLA-A9 determinants had a significant increase in early, first remission duration compared to patients without HLA-A9. This was particularly evident in the 'null cell' ALL subgroup. In addition, HLA-A9 appeared to be an independent factor affecting the length of first remission since there was no correlation between known prognostic factors such as patient age, sex or WBC and the presence or absence of the HLA-A9 antigen. Survival for the first 12–18 months was also greater in the HLA-A9 group than in the non-HLA-A9 population. Thus, the presence of HLA-A9 appears to be associated with some protective effect among patients with ALL.     

Clearance of marrow infiltration after 1 week of therapy for childhood lymphoblastic leukaemia: clinical importance and the effect of daunorubicin

At the commencement of UKALL XI, a national MRC trial for childhood lymphoblastic leukaemia (ALL), the therapy included a bolus of daunorubicin (DR) on the first 2 d of the protocol. This component of treatment was subsequently withdrawn because of concern about long-term cardiotoxicity. All children both before and after this change of policy had their marrow status at the end of the first week assessed by central review as part of the trial to examine the clinical importance of the rate of disease clearance. This also afforded an opportunity to observe the effect of DR on gross residual disease at an early stage of therapy.
1419 children were studied: 342 received DR ('recipients'), 1077 did not. 44% of the recipients completely cleared their marrow of blast cells after 8 d compared with 13% of the non-recipients (χ²=158.2, P <0.0001). The difference in the proportion with massive residual disease (>80% blasts) was less impressive but there was still a difference in favour of DR recipients (DR 9%, no DR 15%; χ²=7.7, P =0.006). The rate of disease clearance correlated with disease-free survival for both recipients and non-recipients, but there was no significant difference in outcome when comparing the two groups with each other, either in terms of disease-free or relapse-free survival.
DR accelerated the rate of blast cell disappearance from the marrow but the difference this made to disease free survival is small or non-existent. It appears to be the relative speed of response to a given therapeutic regimen that is prognostically important rather than the absolute rate of response when comparing one treatment with another.