Has the prognosis of adult patients with acute myeloid leukemia improved over years? A single institution experience of 784 consecutive patients over a 16-year period.

We reviewed the reports of 784 consecutive patients admitted to our department for newly diagnosed acute myeloid leukemia (AML) over a 16-year period. Median, 5-year and 10-year overall survivals were 9. 5 months, 17.3% and 11.7% respectively. Induction treatment (698 patients) resulted in 50% complete remissions (CR) (from 26.5% in secondary AML to 81.2% in patients <60 years with de novo AML). Period of diagnosis (1980-84/85-89/90-95) demonstrated a major significance for CR achievement and OS in multivariate analysis. In patients >/=60 years (372), CR rate increased (25% to 36.8%, P = 0. 03), and 5-year OS (3.7% to 10.6%, P = 0.022) improved, probably due to an increase in the proportion of patients administered conventional combined chemotherapy (54.5% to 83.8%, P < 0.0001). In younger patients CR rate continuously increased (61.5% to 74.8%, P = 0.028) with an associated improvement of 5-year OS (19.2% to 35.4%). No significant change in DFS and CR durations was observed. This large single center study on a large cohort of unselected AML patients reflects the improvement achieved in the management of AML patients, likely due to improvement of supportive care practices, administration of conventional induction to more elderly patients, and intensification of induction and post-remission treatments in patients <60 years.

Simultaneous activity of MRP1 and Pgp is correlated with in vitro resistance to daunorubicin and with in vivo resistance in adult acute myeloid leukemia.

In adult acute myeloid leukemia (AML), the weight of the contribution of the combined activity of Pgp and MRP1 to drug resistance is not known. To address this question, we compared the activity of these proteins to the in vitro resistance to daunorubicin (DNR), etoposide, and cytosine arabinoside (Ara-C), using the calcein-AM uptake and the 3-[4, 5-di-methyl-thiazol-2, 5-diphenyl] tetrazolium bromide (MTT) assay in 80 adult AML patients. We found no correlation or only a weak correlation between the in vitro drug resistance to DNR and etoposide and MRP1 or Pgp expression or function when tested separately. However, a strong correlation was observed between the simultaneous activity of MRP1 and Pgp (quantified as the modulation of calcein-AM uptake by cyclosporin A and probenecid) and the LC50 of DNR (r =.77, P <.0001). This emphasized the role of these two proteins, not separately, but together in the resistance to DNR. In contrast, Mvp/LRP expression did not correlate with the LC50 of DNR. A high level of simultaneous activity of Pgp and MRP1 was predictive of a poor treatment outcome (for achievement of CR [P =.008], duration of relapse-free survival [RFS; P =.01], and duration of overall survival [OS; P =.02]). In addition, high LC50 of DNR and high LC50 of etoposide together were also predictive of a poor treatment outcome (for duration of RFS [P =.02] and duration of OS [P =.02]). The unfavorable cytogenetic category was more closely associated with the combined activity of both MRP1 and Pgp (P =.002) than with the activity of Pgp or MRP1 separately. This could explain the poor prognosis and the in vitro resistance to daunorubicin in this group of patients. These data suggest that treatment outcome may be improved when cellular DNR and etoposide resistance can be circumvented or modulated. Modulation of not only Pgp but also MRP1 could be essential to attain this aim in adult AML.

Heavy transfusions and presence of an anti-protein 4.2 antibody in 4. 2(-) hereditary spherocytosis (949delG).

BACKGROUND AND OBJECTIVE: A patient with hereditary spherocytosis (HS) was found not to have red cell membrane protein 4.2. This rare form of HS, or 4.2 (-) HS, stems from mutations within the ELB42 or the EPB3 genes. The patient had long suffered from a gastric ulcer and impaired liver function. He had had several dramatic episodes of gastrointestinal tract bleeding and had received numerous transfusions. An antibody against a high frequency, undefined antigen was found, creating a transfusional deadlock. We elucidated the responsible mutation and searched for an anti-protein 4.2 antibody. DESIGN AND METHODS: Red cell membranes were analyzed by SDS-PAGE and by Western blotting. Nucleotide sequencing was performed after reverse transcriptase-polymerase chain reaction (RT-PCR) and nested PCR. RESULTS: The not previously described mutation was a single base deletion: 949delG (CGCAECC, exon 7, codon 317) in the homozygous state. It was called protein 4.2 Nancy. The deletion placed a non-sense codon shortly downstream so that no viable polypeptide could be synthesized. The patient carried a strong antibody against protein 4.2 as shown by Western blotting. INTERPRETATION AND CONCLUSIONS: The manifestations resulting from the mutation described were compared with the picture of HS stemming from other ELB42 gene mutations. We discuss the mechanism through which the anti-protein 4.2 antibody developed. There was no way to establish or to rule out whether the antibody participated in the transfusional deadlock found in our patient.

Suppression of CDA II expression in a homozygote.

The CDAN2 gene, responsible for congenital dyserythropoietic anaemia, type II (CDA II), was recently mapped to 20q11.2. We report data on an additional member of a previously studied CDA II family. This member had always been regarded as haematologically normal. Unexpectedly, she had the same microsatellite assortments around the CDAN2 alleles as her three sisters with CDA II. In particular, she was a homozygote for microsatellites D20S863 and D20S841. This prompted an analysis of all facets of her phenotype. The Ham test was negative. The bone marrow smears contained a normal proportion of binucleate erythroblasts. Electron microscopy revealed the absence of extensive stretches of cisternae beneath and parallel to the inner surface of the erythroblast plasma membrane. Proteins of the endoplasmic reticulum, which contaminate the reticulocyte plasma membrane in CDA II patients, were missing. Only the shape of the band 3 peak appeared slightly altered. This case exemplifies that homozygosity (or compound heterozygosity) for a deleterious gene may be silenced, or almost completely silenced. In recessively inherited diseases, suppressed phenotypes tend to be overlooked in siblings where both patients and unaffected individuals are expected.