The main issue for younger patients with acute myeloid leukemia is the prevention of relapse. About 55% of patients relapse and the risk can partially be predicted by prognostic factors, particularly cytogenetics. A number of strategies can attempt to reduce the relapse risk. Intensification of induction therapy has been attempted but there is as yet no convincing evidence that survival is improved. Transplantation of either allogeneic or autologous stem cells does not seem to offer major survival advantage overall or within risk groups. Improved understanding of resistance mechanisms and the identification of new risk factors may enable the development of a more targeted approach to therapy.
Summary Relapsed or refractory (R/R) diffuse large B‐cell lymphoma ( DLBCL ) in those unfit or ineligible for autologous stem cell transplantation is associated with a poor outcome and new treatment approaches are needed. Pixantrone is a novel aza‐anthracenedione which is structurally similar to anthracyclines and is licenced in R/R DLBCL and National Institute for Health and Care Excellence ( NICE )‐approved following the PIX 301 trial. No data exist post‐ NICE approval. We performed a UK ‐wide retrospective multi‐centre study of 92 R/R DLBCL who received pixantrone. Eighty‐five per cent had refractory disease and 72% had an international prognostic index ( IPI ) 3–5 at commencement of pixantrone. The median progression‐free survival ( PFS ) was 2·0 months (95% confidence interval ( CI ) 1·5–2·4) and the median overall survival was 3·4 months (95% CI 2·7–4·5). The overall response rate was 24% (complete response 10%; partial response 14%). We demonstrate that pixantrone has limited activity in a cohort of high risk, predominantly refractory DLBCL . Multivariate Cox regression revealed that patients who relapsed >12 months after first line treatment, those with fewer prior lines of therapy and relapsed (non‐refractory) DLBCL had improved PFS . The major population of unmet need are those with refractory DLBCL who are poorly represented within trials and in whom pixantrone appears less efficacious compared to relapsed DLBCL .
Chromosome 13q deletion is among the most common cytogenetic abnormalities in chronic lymphocytic leukaemia (CLL). We investigated the 13q14.3 deletion in 44 CLL patients by Southern blotting following purification of clonal B CLL cells to >90%. Two sets of probes were used to investigate the site of clonal deletion, the D13S25 and D13S319 markers (at 13q14.3) and probes for exons 11 and 26–27 of the BRCA2 gene (at 13q12). Homozygous and heterozygous deletion at the 13q14.3 region was found in five and 17 patients, respectively. Despite the recent report of the BRCA2 gene involvement in >80% of CLL patients, we failed to detect a single case of homozygous or heterozygous deletion involving the 13q12 region. Our data support previous findings that the 13q14.3, and not the 13q12 region, is the major site of candidate tumour suppressor gene(s) in CLL.
BackgroundMinimal 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.MethodsBetween Oct 1, 2003 and June 30, 2011, consecutive children and young adults (aged 1–24 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 [less than 0·01%] 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.FindingsOf 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%).InterpretationTreatment 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.FundingMedical Research Council and Leukaemia and Lymphoma Research.