Special changes that can lead to AML

[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

[helen c.]

hi i dont understand abut what chromosones have to do with mds but with bmb in jan.09 my husband husband had 21abnormalty but with last bmb he had 8% blasts and chromosone 3abnormalty and no longer had the 21 dr. said it was no longer there is that good or bad he gets transfusions every week now and platlets about every 3 weeks

[Birgitta-A]

Hi Helen,
In about 50 % of the MDS patients the young blood cells in the bone marrow have chromosome aberrations. Some of these are good, other intermediate and some bad. They prevent the young blood cells from normal development to mature well functioning blood cells. http://www.pubmedcentral.nih.gov/art...?artid=2413090

Different reseachers have found different results. As far as I understand from this article the author reports that chromosome 3 abnormality has an intermediate prognosis. If a chromosome aberration really has disappeared it is a good sign. You know the prognosis depends on many factors like age and other diseases.
Kind regards
Birgitta-A
Chromosome aberrations 12p- and X-

[Helen Robinson]

Dear Birgitta

Firstly I would like to thank you for helping us with such current research information. I have even given some to my husband's haemotologist. I know he attends conferences but I am sure he does nor have many MDS patients.

Am I right in thinking that if you only have a 5q del chromosome change that you are least likely to progress to AML? I know that David's last BMB at the end of the Revlimid treatment showed no other chromosome changes.

Our problem at present is nor getting fresh blood where we live in the countryside. The last two TXs had blood over three weeks old and the cytokines make him feel sick and the time interval is much less. If the next one is as old we will think seriously about travelling the 4 hrs to the city where the haem patients get the freshest blood at our hospital.

Thank you

Helen

[Birgitta-A]

Hi Helen,
Yes, patients with isolated 5q- have the best prognosis of all MDS groups but some of them do transform to AML and in these patients they have found p53 and aberrant cytoplasmic nucleophosmine in the young blood cells in the bone marrow.

Regarding fresh blood you are right - blood that is more than 14 days old can be less effective http://www.newscientist.com/article/...nsfusions.html

I have so much antibodies that it is very difficult to find blood that is OK for me. Obviously they have found that fresh blood suits me better so my blood is never more than 4 days old.
Kind regards
Birgitta-A