Alan Kenneth Burnett

Placebo-controlled phase III trial of lenograstim in bone-marrow transplantation

Haemopoietic growth factors are accepted as accelerating haemopoietic recovery after bone-marrow grafting, yet no large randomised trials have been published that convincingly show benefit. Lenograstim (glycosylated recombinant human granulocyte colony-stimulating factor) was given to 315 patients after bone-marrow transplantation in a prospective randomised placebo-controlled multicentre trial. 1 day after bone-marrow infusion, 163 patients received lenograstim 5 micrograms/kg per day by 30-min infusion, and 152 patients received placebo daily for 28 days or until neutrophil recovery. 137 patients had lymphoma, 35 myeloma, 85 acute lymphoblastic leukaemia, and 58 a solid tumour. Patients were stratified by age and by type of bone-marrow transplantation (BMT). Neutrophil recovery to above 10(9)/L for 3 consecutive days was seen earlier in lenograstim-treated patients (16 vs 27 days, p < 0.001). Time to neutrophil recovery above 0.5 x 10(9)/L was reduced (14 vs 20 days, p < 0.001). The difference was significant both in autograft (20 vs 14 days, p < 0.001) and allograft (20 vs 14 days, p < 0.01) patients, in children (20 vs 13 days, p < 0.001), and adults. Lenograstim-treated patients had fewer days of infection, and of antibiotic administration, and also spent less time in hospital. However, clinical and microbiological sepsis was similar in both groups. There was no significant toxicity ascribed to lenograstim. Survival was the same at days 100 and 365. In patients undergoing autologous or allogeneic BMT for neoplastic disease, lenograstim significantly reduced duration of neutropenia and led to earlier hospital discharge.

The prognostic significance of IDH1 mutations in younger adult patients with acute myeloid leukemia is dependent on FLT3/ITD status

Mutations in the isocitrate dehydrogenase gene (IDH1) were recently described in patients with acute myeloid leukemia (AML). To investigate their prognostic significance we determined IDH1 status in 1333 young adult patients, excluding acute promyelocytic leukemia, treated in the United Kingdom MRC AML10 and 12 trials. A mutation was detected in 107 patients (8%). Most IDH1(+) patients (91%) had intermediate-risk cytogenetics. Mutations correlated significantly with an NPM1 mutation (P < .0001) but not a FLT3/ITD (P = .9). No difference in outcome between IDH1(+) and IDH1(-) patients was found in univariate or multivariate analysis, or if the results were stratified by NPM1 mutation status. However, when stratified by FLT3/ITD status, an IDH1 mutation was an independent adverse factor for relapse in FLT3/ITD(-) patients (P = .008) and a favorable factor in FLT3/ITD(+) patients (P = .02). These results suggest that metabolic changes induced by an IDH1 mutation may influence chemoresistance in a manner that is context-dependent.

Impact of karyotype on treatment outcome in acute myeloid leukemia.

In aspergillus infections of the central nervous system (CNS) the mortality risk usually exceeds 90%. Data from case-reports and a recent retrospective study suggest that neurosurgical interventions, such as abscess resections, stereotactic drainages, or the use of intraventricular catheters, might improve the outcome in CNS aspergillosis. However, there is a lack of clear evidence supporting an extensive neurosurgical management in these patients. A major reason for the devastating prognosis in CNS aspergillosis is a poor penetration of antifungal drugs into the CNS, with the exception of voriconazole. Treatment with voriconazole results in measurable drug levels in the cerebrospinal fluid, which may exceed the minimal inhibitory concentration for aspergillus. Moreover, voriconazole brain tissue levels exceed those measured for other antifungal drugs. In a recent retrospective study, a complete or partial response occurred in 35% of patients who were treated with voriconazole for CNS aspergillosis with a survival rate of 31%. These data support the use of voriconazole in this clinical setting. An intense neurosurgical management and higher doses of voriconazole might further improve the outcome in CNS aspergillosis, but this needs to be evaluated in future studies.

Defining the landscape of resistance mutations in the context of modern treatment protocols for acute promyelocytic leukaemia

Introduction: An audit was done in the Ulster Hospital in Northern Ireland to assess compliance with local guidelines for giving Intravenous Iron dextran in the year 2007. The Audit also assessed additional points such as Oral Iron Intolerance documentation and Investigation of Iron Deficiency Anaemia in these patients. Methods: 47 patients who had Intravenous Iron dextran were selected for this audit. Patients charts were chosen randomly among all specialities. Patients age ranged between 15 and 90 with median age of 63. Female:Male Ratio is 2.6. Patients were assessed against the Poster Session: General Haematology

hTERT expression in AML is heterogeneous and is of likely prognostic significance

Molecular events in AML (e.g. Flt3-ITD) may be exploited as prognostic indicators or therapeutic targets. The cancer- and stem/ progenitor cell-related enzyme telomerase is central to maintaining the immortal phenotype. We investigated whether levels of telomerase expression are of prognostic value in AML. Following validation of the assay in a range of telomerase positive and negative cell lines and tissues, 300 samples of archived peripheral blood MNC RNA (MRC AML12 study) were analysed blindly by Q-PCR (Light- Cycler) for hTERT (the catalytic component of telomerase). Internal QA utilised Q-PCR for the control gene PBGD. Only samples generating 4103 PBGD transcripts were analysed. Results were expressed as hTERT/PBGD transcripts (%) and as either hTERT positive or negative, or high, intermediate or low (43.2%, 40.7o 3.2, o0.7, respectively, according to levels detected in normal CD341 PBSC and PBL MNC, median of 3.2% and 0.7%, respectively) to facilitate statistical analysis. 1169 samples were analysed, with hTERT transcripts undetectable in 75 (hTERT range 0–255.9%, median 0.17%, mean 4.3%). When analysed on an hTERT-positive or negative basis, there was no correlation between hTERT levels and cytogenetic risk group, FAB subgroups, white cell count or age. Using multivariate regression analysis, adjusted for the known prognostic factors (as previous, plus performance status), there was no evidence of differences in CR rate (OR 1.14, 95%CI 0.43–3.02, p50.8), but borderline evidence of worse overall survival (OS) and disease-free survival (DFS) among hTERT positive patients (5 year OS: 39% vs 53% HR 1.54 (95%CI 0.97–2.45), p50.07; 5 year DFS: 42% vs 54% HR 1.62 (95%CI 0.96–2.74), p50.07). Classifying hTERT as high, intermediate or low, 5 year OS was 34%, 50% and 47% (p50.5 for trend). hTERT expression in AML is heterogeneous and may be of prognostic significance. Larger studies are required to investigate further these findings.