Blood Hematopoietic Disease：Bone marrow Dysplasia Syndrome (MDS)

• Disease which is close to the early stage of leukemia.
• May be developed as the complicating disease of cancer radiation treatment.
• Symptoms are anemia, bleeding, and infection disease.
• The case which advances to AML from MDS is a adverse prognosis.
• Diagnosed as MDS with blastogenic in bone marrow is less than 20%.
• The key is to maintain QOL with conserving the number of blood infusion.

Disease which is close to the early stage of leukemia.

Myelodysplastic Syndromes (MDS) is a disease that the abnormality generated stem cell in bone-marrow increases in neoplasm stage so that it holds the normal hematopoiesis under. Blood cell grown and differentiated from these abnormal stem cells shows the variety of abnormal morphology (alloplasia) and most of them turns into apoptosis then becomes ineffective erythropoiesis. As the result, when it becomes as pancytopenia stage, differentiation with aplastic anemia is necessary. On the other hand, gemmule is came up in peripheral blood or bone-marrow, but gemmule growth is not as active as acute leukemia. Its clinical condition, by some way, can be said as preleukemia stage. Pathogenesis increase gradually from age 40s, and is the common disease among aged person, so that along with this country’s aging of society, the numbers of patients are in increasing tendency.

May be developed as the complicating disease of cancer radiation treatment.

Development of MDS is possibly caused by the ambient exposure such as radiation or benzene. Other than that, it is known that the secondary MDS is developed as complicated disease with cancer treatment, normally they are the combination of radiation treatment and alkylating agent (incubation period is 5 to 7 years), or the combination treatment with DNA topoisomerase inhibitor (incubation period is 2 years). Bone-marrow of MDS most likely become to hyper morphosis by the growth of abnormal clones, on the other hand, peripheral blood become to cytopenia stage since apoptosis grow worse. It is said that when abnormality in a gene is further accompanied with these MDS abnormal clones, apoptosis-resistant acquisition clones are produced, and then lead to the development of acute myelocytic leukemia.

Symptoms are anemia, bleeding, and infection disease.

Disease is likely found with no symptoms or unexplained chronic anemia. Or, there is a case where disease is diagnosed when the presence of gemmule in peripheral blood is found at ordinally blood test. Primary symptoms are chronic anemia, bleeding, infection disease. But these symptoms can be seen in aplastic anemia so that they are not the unique symptoms for MDS. Anemia varies from macrocytic to microcytic.

The case which advances to AML from MDS is a adverse prognosis.

It is said that the number of years of life for refractory anemia type with benign prognosis is about 5 years, and for adverse prognosis type it is roughly 1 year. The latter is the cases of acute leukemia. It is classified in high-risk group that the case , among MDS, which has a high risk of possible transition to the acute myelocytic leukemia (AML) in high rate. It is an adverse prognosis for the case which MDS is advanced to AML.

Diagnosed as MDS with blastogenic in bone marrow is less than 20%.

MDS is classified with several disease type, And WHO Classification established in the year 2000 is commonly used. They are classified into; refractory cytopenia of unilineage dysplasia (RCUD, there are RA, RN and RT), refractory Anemia with ringed sideroblasts (RARS, there are RARS and RARS-T), refractory cytopenia with multi-lineage dysplasia (RCMD, there are RCMD and RCMD-RS), refractory anemia with excess blasts-1 (RAEB-I), refractory anemia with excess blasts-2 (RAEB-II), and non-classifiable MDS (MDS-U). Also, 5q-syndrome is separately defined. When blasts in peripheral blood or bone-marrow is less than 19%, it is grouped in MDS, but when it exceeds more than 20%, it is grouped in acute myelocytic leukemia (AML).

Peripheral blood coating smear specimen inspection and Bone marrow coating smear specimen inspection

In bone-marrow, unlike aplastic anemia, hypermorphosis can be seen fundamentally by euplasia or ineffective erythropoiesis. There is a one in which partial hypoplasia is seen so that it is confusable with aplastic anemia. Existence of dysplastic cell in 3 phyletic lines of granulated leukocyte, megakaryocyte and erythroblast is evaluated by peripheral blood or bone-marrow smear. In granulated leukocyte, false Pergel nuclear anomaly/low segmented neutrophil, hypogranular or degranulated neutrophil, and giant neutrophil are seen. Morphological aberration of megakaryocyte in bone-marrow, especially micro megakaryocyte, is checked. Also, in erythroblast, ringed sideroblasts, internuclear bridging erythroblasts, internuclear cross-linked erythroblasts, excess segmented erythroblasts are observed. (fig.1)

Bone-marrow Flowcytometry and Chromosomal Test

Flowcytometry and chromosomal test are conducted at bone puncture. In Flowcytometry, existence or non-existence of subset (CD33+CD34+HLADR+) which indicate the existence of gemmule, and its percentage are compared and evaluated with the configuration percentage of gemmule on smear. In case clonal chromosome abnormalities (5q-, -7/7q, +8, 20q-) exists, certainty of MDS diagnosis becomes higher.

The key is to maintain QOL with conserving the number of blood infusion.

For the case which shows prominent anemia, blood transfusion therapy is necessary. However, in case if concentrated red cell transfusion is conducted for longer time, the risk of iron overload disorder (hemochromatosis) becomes higher, so that how to maintain QOL with conserving the number of blood transfusion becomes as the essential point in the treatment. There is a case where administration of erythropoietin is effective. For neutrophil depletion case, administration of granulocyte colony-stimulating factor (G-CSF) is performed, but the administration of G-CSF has a high risk of stimulating the increase of gemmule, so that combination usage of G-CSF and small amount of Cylocide (AraC) is effective. In MDS, as the result of epigenetic change of DNA structure is figured out at the recent progress, it is found that the uncontrolled cell enhancement and hypocytosis are caused due to the Loss of DNA methylation control. So that in nowadays, DNA methylation inhibitor like azacytidine (Vidasa) is taking the principal role if the treatment. For 5q- syndrome in MDS, it is indicated that lenalidomide (Revlimid) is specifically effective. The long-term survival rate in case for hematopoietic stem cell transplant is conducted for MDS as transplant adaptation, 40 to 60 % for refractory anemia (RA), and 20 to 30% for RAEB.

Fig.1 Image of abnormal blood cell seen at MDS; (A) Erythroblast abnormality, (B) Ringed sideroblasts, (C) Neutrophil abnormality, (D) Micromegakaryocyte