As part of the UK NCRI AML17 trial, adult patients with acute myeloid leukemia in remission could be randomized to receive the mammalian target of rapamycin inhibitor everolimus, sequentially with post-induction chemotherapy. Three hundred and thirty-nine patients were randomised (2:1) to receive everolimus or not for a maximum of 84 days between chemotherapy courses. The primary endpoint was relapse-free survival. At 5 years there was no difference in relapse-free survival [29% versus 40%; odds ratio 1.19 (0.9-1.59) P=0.2], cumulative incidence of relapse [60% versus 54%: odds ratio 1.12 (0.82-1.52): P=0.5] or overall survival [45% versus 58%: odds ratio 1.3 (0.94-1.81): P=0.11]. The independent Data Monitoring Committee advised study termination after randomization of 339 of the intended 600 patients because of excess mortality in the everolimus arm without any evidence of beneficial disease control. The delivery of the everolimus dose was variable, but there was no evidence of clinical benefit in patients with adequate dose delivery compared with no treatment. This study suggests that the addition of mammalian target of rapamycin inhibition to chemotherapy provides no benefit.
Improving or replacing the traditional induction (3 + 7) and consolidation (high-dose cytarabine; Ara-C) as the standard of care for acute myeloid leukemia (AML) has proved disappointing.Recent studies have raised the possibility that daunorubicin dose escalation might have the potential to improve survival. Antibody-directed therapy by means of gemtuzumab ozogamicin as an adjunct to induction chemotherapy may yet be a viable option in older patients, and alternative nucleoside analogues in induction could help higher risk subgroups. In consolidation, the number of courses and dose level of Ara-C required are being clarified. New treatments for older patients who will not be subjected to conventional chemotherapy are an active area, but randomized trials have not yet usurped low-dose Ara-C (LDAC).Recent information in these areas is reviewed.
Summary. Myelodysplastic (MDS) patients at diagnosis ( n = 162) were analysed by the International Prognostic Scoring System (IPSS). The two intermediate groups were not significantly different. The IPSS was of limited value in predicting survival of MDS patients after preliminary separation into subgroups with < 5%, or ≥ 5%, myeloblasts. Cox's proportional hazards analysis of these subgroups enabled discrimination of highly significant prognostic groups. In both subgroups, longer survival was associated with macrocytosis. Mean corpuscular volume (MCV) and marrow myeloblast number were used to define four groups with prognostic significance similar to the IPSS. A low‐risk group was described by macrocytosis associated with < 5% myeloblasts and high risk was related to blast counts ≥ 5% and MCV < 100 fl. Further analysis defined factors identifying very high‐risk patients and those with benign disease, together with many intermediate survival patterns. Results were consistent in two time‐separated patient groups.
RAS mutations arise at high frequency (20–40%) in both acute myeloid leukemia and myelodysplastic syndrome (which is considered to be a manifestation of preleukemic disease). In each case, mutations arise predominantly at the N-RAS locus. These observations suggest a fundamental role for this oncogene in leukemogenesis. However, despite its obvious significance, little is known of how this key oncogene may subvert the process of hematopoiesis in human cells. Using CD34+ progenitor cells, we have modeled the preleukemic state by infecting these cells with amphotropic retrovirus expressing mutant N-RAS together with the selectable marker gene lacZ. Expression of the lacZ gene product, β-galactosidase, allows direct identification and study of N-RAS–expressing cells by incubating infected cultures with a fluorogenic substrate for β-galactosidase, which gives rise to a fluorescent signal within the infected cells. By using multiparameter flow cytometry, we have studied the ability of CD34+ cells expressing mutant N-RAS to undergo erythroid differentiation induced by erythropoietin. By this means, we have found that erythroid progenitor cells expressing mutant N-RAS exhibit a proliferative defect resulting in an increased cell doubling time and a decrease in the proportion of cells in S + G2M phase of the cell cycle. This is linked to a slowing in the rate of differentiation as determined by comparative cell-surface marker analysis and ultimate failure of the differentiation program at the late-erythroblast stage of development. The dyserythropoiesis was also linked to an increased tendency of the RAS-expressing cells to undergo programmed cell death during their differentiation program. This erythroid lineage dysplasia recapitulates one of the most common features of myelodysplastic syndrome, and for the first time provides a causative link between mutational activation of N-RAS and the pathogenesis of preleukemia.
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