Five new pedigrees with inherited RUNX1 mutations causing familial platelet disorder with propensity to myeloid malignancy.

Familial platelet disorder with propensity to myeloid malignancy (FPD/AML) is an autosomal dominant syndrome characterized by platelet abnormalities and a predisposition to myelodysplasia (MDS) and/or acute myeloid leukemia (AML). The disorder, caused by inherited mutations in RUNX1, is uncommon with only 14 pedigrees reported. We screened 10 families with a history of more than one first degree relative with MDS/AML for inherited mutations in RUNX1. Germ- line RUNX1 mutations were identified in 5 pedigrees with a 3:2 predominance of N-terminal mutations. Several affected members had normal platelet counts or platelet function, features not previously reported in FPD/AML. The median incidence of MDS/AML among carriers of RUNX1 mutation was 35%. Individual treatments varied but included hematopoietic stem cell transplantation from siblings before recognition of the inherited leukemogenic mutation. Transplantation was associated with a high incidence of complications including early relapse, failure of engraftment, and posttransplantation lymphoproliferative disorder. Given the small size of modern families and the clinical heterogeneity of this syndrome, the diagnosis of FPD/AML could be easily overlooked and may be more prevalent than previously recognized. Therefore, it would appear prudent to screen young patients with MDS/AML for RUNX1 mutation, before consideration of sibling hematopoietic stem cell transplantation.

Patterns of recruitment into acute myeloid leukaemia (AML) 15 and outcome for young patients with AML at a single referral centre.

This study assessed the recruitment to an acute myeloid leukaemia (AML) trial (AML15) in a single centre, evaluated whether outcome was influenced by trial entry and whether the trial population could be considered representative of all AML patients by retrospective comparison of patient characteristics, trial entry and outcome for 81 consecutive patients (<60 years). All patients were considered for trial entry, however the trial was not offered to 12 (15%) patients. These patients had a worse outcome than the 69 (85%) patients that were invited to participate (P = 0.04). Sixteen patients (23%) invited to participate in the trial declined and were treated on equivalent protocols. These patients had a similar outcome to those who accepted entry into the trial (P = 0.2). These results suggested that physicians exert a selection bias when evaluating patients for trial entry. Thus the overall survival estimates generated from large phase III trials may indicate that the outcome for patients with AML is better than the outcome experienced in the 'real' world. Furthermore, patients who are considered appropriate for randomization into a trial, but decline entry, experience a similar outcome to those treated on trial when treated in an equivalent manner.