[Birgitta-A]

Hi all,
Now the abstracts from the European Hematology Association Congress 2009 are available - just google EHA 2009. Here is a rather complicated report about changes that have been found in patients that transform to AML. Jump to the Summary if you only get confused when you read the abstract.

This kind of results are very important because patients with these changes perhaps should accept SCT because many of them will otherwise get AML. Of cause these findings are still not possible to perform in every clinic but we can hope that the researchers soon will be able to tell us which patients have the best response to the different treatments.

Nucleophosmin is a protein found most frequently in nucleoli. Nucleophosmin acts as a molecular chaperone and is thought to participate in maturation and duplication and in the regulation of the ArF-p53 tumor suppressor pathway.

EXPRESSION OF P53 OR CYTOPLASMIC NUCLEOPHOSMINE ASSOCIATED WITH INCREASED RISK OF DISEASE PROGRESSION IN MYELODYSPLASTIC SYNDROME WITH ISOLATED DEL(5Q)
Martin J, Saft, Leonie G, Hege, Hast R, Nilsson L, Samuelsson J, Porwit A, Hellström-Lindberg, E, Karolinska Institutet, Stockholm, Sweden

Background
Myelodysplastic syndrome with isolated del(5q) and <5% marrow blasts has around 10% cumulative risk of leukemic transformation. Lenalidomide (Revlimid) effectively improves hemoglobin levels in this category of MDS.

However, due to concerns about the observed rate of disease progression the European Medicines Agency refrained from approval of the drug in 2008. It is unclear whether lenalidomide indeed increases the risk of AML or if progression merely reflects the natural course of the disease.

A recent case report indicates that p53 and aberrant cytoplasmic nucleophosmine (NPMc) was present in small subpopulations of marrow progenitors at time of diagnosis, and that these clones evolved in conjunction with disease progression during lenalidomide treatment. Also, recent data demonstrated that 7 of 22 (32%) of 5q- patients treated with lenalidomide developed complex karyotypes and 6 of these 7 patients evolved to AML.

Aims
To evaluate the association of p53 and NPMc expression with outcome in MDS with del(5q).

Methods
We investigated 32 patients with MDS and del(5q) and less than 10% marrow blasts diagnosed at our department. Twenty-five had del(5q) as single abnormality, 5 had del(5q)+1, and 2 had del(5q) as part of a complex karyotype. Immunohistochemistry was used to detect expression of p53 and NPMc on sections of bone marrow biopsies or clots. The Kaplan-Meier estimate and the logrank test were used for analysis of survival and disease progression.

Results
The median age was 79 years (range 38-94). The median follow-up was 47 months (interquartile range 25-63) and the median overall survival was 63 months (range 4-146+).

Fourteen patients (44%) expressed p53 or NPMc in subpopulations of marrow cells at an early stage of the disease (5 only p53, 5 only NPMc, and 4 both). Nine patients (28%) progressed during the observation period, either by blast increase above 10% and/or by the acquisition of a complex karyotype, and 8 of these subsequently evolved to AML. Seven of 9 patients with disease progression expressed p53 or NPMc before transformation. Merely 2 of 9 patients with transformation had complex karyotypes at diagnosis, and none had del(5q)+1.

The 5-year Kaplan-Meier estimate of survival was 63% and 45% (logrank test p=0.52) in patients with or without expression of p53 or NPMc before disease progression, respectively.

The 5-year-risk of AML evolution was 12% and 52% (p=0.060), and of blast or cytogenetic progression 7% and 57% (p=0.019; Figure 1), respectively. The dataset was not powered to assess any potential influence of lenalidomide, however, this is currently being evaluated prospectively in a population-based trial within the Nordic MDS Group.

Summary / Conclusions
The presence of p53 and/or NPMc expression in marrow progenitors at an early stage of MDS with del(5q) significantly correlates with subsequent disease progression in the study cohort.
Kind regards
Birgitta-A