Sue Richards

Allogeneic peripheral blood stem-cell compared with bone marrow transplantation in the management of hematologic malignancies: An individual patient data meta-analysis of nine randomized trials

PURPOSEnConsiderable uncertainty exists regarding relative effects of allogeneic peripheral blood stem cells transplantation (PBSCT) versus bone marrow transplantation (BMT) on outcomes of patients with hematologic malignancies.nnnPATIENTS AND METHODSnTo provide the totality of research evidence related to the effects of PBSCT versus BMT, we conducted an individual-patient data meta-analysis using data from nine randomized trials enrolling 1,111 adult patients.nnnRESULTSnCompared with BMT, PBSCT led to faster neutrophil (odds ratio [OR] = 0.31; 95% CI, 0.25 to 0.38; P < .00001) and platelet engraftment (OR = 0.52; 95% CI, 0.44 to 0.61; P < .00001). PBSCT was associated with a significant increase in the development of grade 3-4 acute graft-versus-host disease (GVHD; OR = 1.39; 95% CI, 1.03 to 1.88) and extensive (47% v 31% at 3 years; OR = 1.89; 95% CI, 1.47 to 2.42; P < .000001) and overall chronic GVHD (68% v 52% at 3 years; OR = 1.92; 95% CI, 1.47 to 2.49; P < .000001), but not grade 2-4 acute GVHD (54% v 53%; P = .49). PBSCT was associated with a decrease in relapse (21% v 27% at 3 years; OR = 0.71; 95% CI, 0.54 to 0.93; P = .01) in both late-stage-(33% v 51% at 3 years; OR = 0.59; 95% CI, 0.38 to 0.93; P = .02) and early-stage-disease patients (16% v 20% at 3 years; OR = 0.69; 95% CI, 0.49 to 0.98; P = .04). Nonrelapse mortality was not different between groups. Overall and disease-free survival were only statistically significantly improved in patients with late-stage disease (overall survival: 46% v 31% at 3 years; OR = 0.64; 95% CI, 0.46 to 0.90; P = .01; disease-free survival: 41% v 27% at 3 years; OR = 0.63 95% CI, 0.45 to 0.87; P = .01).nnnCONCLUSIONnPBSCT is associated with a decreased relapse rate in hematologic malignancies and improvement in overall and disease-free survival in patients with late-stage disease. PBSCT is also associated with a significant risk of extensive chronic GVHD.

Prognostic effect of chromosomal abnormalities in childhood B-cell precursor acute lymphoblastic leukaemia: results from the UK Medical Research Council ALL97/99 randomised trial

BACKGROUNDnChromosomal abnormalities in childhood acute lymphoblastic leukaemia are well established disease markers and indicators of outcomes. However, the long-term prognosis and independent prognostic effect of some abnormalities has been questioned. Also, little is known about the association between cytogenetics and the characteristics of relapse (eg, time and site of relapse) that are known to predict outcome after relapse.nnnMETHODSnWe analysed cytogenetic data from 1725 children with B-cell precursor acute lymphoblastic leukaemia who were included in the UK Medical Research Council ALL97/99 study and followed up for a median time of 8.2 years. Univariate and multivariate analysis were done to examine risk of relapse, event-free survival, and overall survival associated with 21 chromosomal abnormalities and three cytogenetic risk groups constructed from these data.nnnFINDINGSnTwo chromosomal abnormalities were associated with a significantly better outcome (ETV6-RUNX1, hazard ratio [HR] 0.51, 95% CI 0.38-0.70 and high hyperdiploidy, 0.60, 0.47-0.78), whereas five abnormalities were associated with an increased risk of relapse (intrachromosomal amplification of chromosome 21 [iAMP21], 6.04, 3.90-9.35; t(9;22), 3.55, 2.21-5.72; MLL translocations, 2.98, 1.71-5.20; abnormal 17p, 2.09, 1.30-3.37; and loss of 13q, 1.87, 1.09-3.20). Multivariate analysis incorporating age, white-cell count, and treatment parameters showed that six cytogenetic abnormalities (ETV6-RUNX1, high hyperdiploidy, iAMP21, t(9;22), loss of 13q, and abnormal 17p) retained their significance for effect on relapse risk. Based on these data, patients were classified into good, intermediate, and poor cytogenetic risk groups. Slow early treatment response correlated with cytogenetic risk group: 34 of 460 (7%) in the good-risk group, 22 of 211 (10%) in the intermediate-risk group, and 27 of 95 (28%) in the poor-risk group had a slow response (p<0.0001). Additionally, the proportion of patients with a very early (<18 months) relapse varied by cytogenetic risk group: eight of 129 (6%) patients in the good-risk group had a very early relapse, compared with 24 of 98 (24%) in the intermediate-risk group, and 37 of 82 (45%) in the poor-risk group (p<0.0001). However, there was no difference in the site of relapse by cytogenetic risk group.nnnINTERPRETATIONnIndividual chromosomal abnormalities are strong independent indicators of outcome, especially risk of relapse. Diagnostic cytogenetics identifies patients with a higher rate of relapse and those who are likely to have a high-risk relapse.nnnFUNDINGnLeukaemia and Lymphoma Research (LLR).

Clinical heterogeneity in childhood acute lymphoblastic leukemia with 11q23 rearrangements.

To assess the clinical heterogeneity among patients with acute lymphoblastic leukemia (ALL) and various 11q23 abnormalities, we analyzed data on 497 infants, children and young adults treated between 1983 and 1995 by 11 cooperative groups and single institutions. The substantial sample size allowed separate analyses according to age younger or older than 12 months for the various cytogenetic subsets. Infants with t(4;11) ALL had an especially dismal prognosis when their disease was characterized by a poor early response to prednisone (P=0.0005 for overall comparison; 5-year event-free survival (EFS), 0 vs 23±12% s.e. for those with good response), or age less than 3 months (P=0.0003, 5-year EFS, 5±5% vs 23.4±4% for those over 3 months). A poor prednisone response also appeared to confer a worse outcome for older children with t(4;11) ALL. Hematopoietic stem cell transplantation failed to improve outcome in either age group. Among patients with t(11;19) ALL, those with a T-lineage immunophenotype, who were all over 1 year of age, had a better outcome than patients over 1 year of age with B-lineage ALL (overall comparison, P=0.065; 5-year EFS, 88±13 vs 46±14%). In the heterogeneous subgroup with del(11)(q23), National Cancer Institute-Rome risk criteria based on age and leukocyte count had prognostic significance (P=0.04 for overall comparison; 5-year EFS, 64±8% (high risk) vs 83±6% (standard risk)). This study illustrates the marked clinical heterogeneity among and within subgroups of infants or older children with ALL and specific 11q23 abnormalities, and identifies patients at particularly high risk of failure who may benefit from innovative therapy.

Mutational Status of the TP53 Gene As a Predictor of Response and Survival in Patients With Chronic Lymphocytic Leukemia: Results From the LRF CLL4 Trial

PURPOSEnTP53 mutations have been described in chronic lymphocytic leukemia (CLL) and have been associated with poor prognosis in retrospective studies. We aimed to address the frequency and prognostic value of TP53 abnormalities in patients with CLL in the context of a prospective randomized trial.nnnPATIENTS AND METHODSnWe analyzed 529 CLL samples from the LRF CLL4 (Leukaemia Research Foundation Chronic Lymphocytic Leukemia 4) trial (chlorambucil v fludarabine with or without cyclophosphamide) at the time of random assignment for mutations in the TP53 gene. TP53 mutation status was correlated with response and survival data.nnnRESULTSnMutations of TP53 were found in 40 patients (7.6%), including 25 (76%) of 33 with 17p deletion and 13 (3%) of 487 without that deletion. There was no significant correlation between TP53 mutations and age, stage, IGHV gene mutations, CD38 and ZAP-70 expression, or any other chromosomal abnormality other than 17p deletion, in which concordance was high (96%). TP53 mutations were significantly associated with poorer overall response rates (27% v 83%; P < .001) and shorter progression-free survival (PFS) and overall survival (OS; 5-year PFS: 5% v 17%; 5-year OS: 20% v 59%; P < .001 for both). Multivariate analysis that included baseline clinical variables, treatment, and known adverse genetic factors confirmed that TP53 mutations have added prognostic value.nnnCONCLUSIONnTP53 mutations are associated with impaired response and shorter survival in patients with CLL. Analysis of TP53 mutations should be performed in patients with CLL who have progressive disease before starting first-line treatment, and those with mutations should be selected for novel experimental therapies.

Adolescents with acute lymphoblastic leukaemia: Outcome on UK national paediatric (ALL97) and adult (UKALLXII/E2993) trials

Adolescents with acute lymphoblastic leukaemia (ALL) have languished in the shadow of success of the outcome of therapy in childhood ALL. Their treatment has always been incorporated into either paediatric or adult clinical trials depending on the mode of referral and hence there is a need to address an age and risk specific strategy for improving the outcome of this neglected group of patients. This article has summarised the recent and updated retrospective comparative analysis of adolescents treated on the Medical Research Council (MRC) trials. This analysis adds further emphasis to the treatment approach and the merits and limitations of treatment of adolescents on paediatric and adult trials.

Treatment reduction for children and young adults with low-risk acute lymphoblastic leukaemia defined by minimal residual disease (UKALL 2003): a randomised controlled trial.

BACKGROUNDnMinimal residual disease (MRD) is the most sensitive and specific predictor of relapse risk in children with acute lymphoblastic leukaemia (ALL) during remission. We assessed whether treatment intensity could be adjusted for children and young adults according to MRD risk stratification.nnnMETHODSnBetween Oct 1, 2003 and June 30, 2011, consecutive children and young adults (aged 1-25 years) with ALL from the UK and Ireland were recruited. Eligible patients were categorised into clinical standard, intermediate, and high risk groups on the basis of a combination of National Cancer Institute (NCI) criteria, cytogenetics, and early response to induction therapy, which was assessed by bone marrow blast counts taken at days 8 (NCI high-risk patients) and 15 (NCI standard-risk patients) after induction began. Clinical standard-risk and intermediate-risk patients were assessed for MRD. Those classified as MRD low risk (undetectable MRD at the end of induction [day 29] or detectable MRD at day 29 that became undetectable by week 11) were randomly assigned to receive one or two delayed intensification courses. Patients had received induction, consolidation, and interim maintenance therapy before they began delayed intensification. Delayed intensification consisted of pegylated asparaginase on day 4; vincristine, dexamethasone (alternate weeks), and doxorubicin for 3 weeks; and 4 weeks of cyclophosphamide and cytarabine. Computer randomisation was done with stratification by MRD result and balancing for sex, age, and white blood cell count at diagnosis by method of minimisation. Patients, clinicians, and data analysts were not masked to treatment allocation. The primary outcome was event-free survival (EFS), which was defined as time to relapse, secondary tumour, or death. Our aim was to rule out a 7% reduction in EFS in the group given one delayed intensification course relative to that given two delayed intensification courses. Analyses were by intention to treat. This trial is registered, number ISRCTN07355119.nnnFINDINGSnOf 3207 patients registered in the trial overall, 521 MRD low-risk patients were randomly assigned to receive one (n=260) or two (n=261) delayed intensification courses. Median follow-up of these patients was 57 months (IQR 42-72). We recorded no significant difference in EFS between the group given one delayed intensification (94·4% at 5 years, 95% CI 91·1-97·7) and that given two delayed intensifications (95·5%, 92·8-98·2; unadjusted odds ratio 1·00, 95% CI 0·43-2·31; two-sided p=0·99). The difference in 5-year EFS between the two groups was 1·1% (95% CI -5·6 to 2·5). 11 patients (actuarial relapse at 5 years 5·6%, 95% CI 2·3-8·9) given one delayed intensification and six (2·4%, 0·2-4·6) given two delayed intensifications relapsed (p=0·23). Three patients (1·2%, 0-2·6) given two delayed intensifications died of treatment-related causes compared with none in the group given one delayed intensification (p=0·08). We recorded no significant difference between groups for serious adverse events and grade 3 or 4 toxic effects; however, the second delayed intensification course was associated with one (<1%) treatment-related death, and 74 episodes of grade 3 or 4 toxic effects in 45 patients (17%).nnnINTERPRETATIONnTreatment reduction is feasible for children and young adults with ALL who are predicted to have a low risk of relapse on the basis of rapid clearance of MRD by the end of induction therapy.nnnFUNDINGnMedical Research Council and Leukaemia and Lymphoma Research.

Long-term follow-up of the United Kingdom medical research council protocols for childhood acute lymphoblastic leukaemia, 1980-2001.

Between 1980 and 2001, the United Kingdom Medical Research Council Childhood Leukemia Working Party conducted four clinical trials in acute lymphoblastic leukaemia (ALL), which recruited a total of 6516 patients. UKALL VIII examined the role of daunorubicin in induction chemotherapy, and UKALL X examined the role of post-induction intensification. Both resulted in major improvement in the outcomes. UKALL XI examined the efficacy of different methods of central nervous system-directed therapy and the effects of an additional intensification. ALL97, which was initially based on the UKALL XD template (two intensification phases), examined the role of different steroids in induction and of different thiopurines through continuing chemotherapy. A reappraisal of results from UKALL XI compared with other cooperative group results led to a redesign in 1999, which subsequently resulted in a major improvement in outcomes. In addition, ALL97 and ALL97/99 showed a significant advantage for the use of dexamethasone rather than prednisolone; although the use of 6-thioguanine resulted in fewer relapses, this advantage was offset by an increased incidence of deaths in remission. Over the era encompassed by these four trials, there has been a major improvement in both event-free and overall survival for children in the United Kingdom with ALL.

Variation in CDKN2A at 9p21.3 influences childhood acute lymphoblastic leukemia risk

Using data from a genome-wide association study of 907 individuals with childhood acute lymphoblastic leukemia (cases) and 2,398 controls and with validation in samples totaling 2,386 cases and 2,419 controls, we have shown that common variation at 9p21.3 (rs3731217, intron 1 of CDKN2A) influences acute lymphoblastic leukemia risk (odds ratio = 0.71, P = 3.01 × 10−11), irrespective of cell lineage.

Outcomes after Induction Failure in Childhood Acute Lymphoblastic Leukemia

BACKGROUNDnFailure of remission-induction therapy is a rare but highly adverse event in children and adolescents with acute lymphoblastic leukemia (ALL).nnnMETHODSnWe identified induction failure, defined by the persistence of leukemic blasts in blood, bone marrow, or any extramedullary site after 4 to 6 weeks of remission-induction therapy, in 1041 of 44,017 patients (2.4%) 0 to 18 years of age with newly diagnosed ALL who were treated by a total of 14 cooperative study groups between 1985 and 2000. We analyzed the relationships among disease characteristics, treatments administered, and outcomes in these patients.nnnRESULTSnPatients with induction failure frequently presented with high-risk features, including older age, high leukocyte count, leukemia with a T-cell phenotype, the Philadelphia chromosome, and 11q23 rearrangement. With a median follow-up period of 8.3 years (range, 1.5 to 22.1), the 10-year survival rate (±SE) was estimated at only 32±1%. An age of 10 years or older, T-cell leukemia, the presence of an 11q23 rearrangement, and 25% or more blasts in the bone marrow at the end of induction therapy were associated with a particularly poor outcome. High hyperdiploidy (a modal chromosome number >50) and an age of 1 to 5 years were associated with a favorable outcome in patients with precursor B-cell leukemia. Allogeneic stem-cell transplantation from matched, related donors was associated with improved outcomes in T-cell leukemia. Children younger than 6 years of age with precursor B-cell leukemia and no adverse genetic features had a 10-year survival rate of 72±5% when treated with chemotherapy only.nnnCONCLUSIONSnPediatric ALL with induction failure is highly heterogeneous. Patients who have T-cell leukemia appear to have a better outcome with allogeneic stem-cell transplantation than with chemotherapy, whereas patients who have precursor B-cell leukemia without other adverse features appear to have a better outcome with chemotherapy. (Funded by Deutsche Krebshilfe and others.).

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, du20038 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 (>u200350 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 8u2003d 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 5u2003years. 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.