Late Clonal Disorders in Patients with Aplastic Anemia

Long-term survival of AA patients as a result of effective immunosuppressive therapy (IST) is accompanied by an increased risk of MDS / AML development. Clonal evolution of AA in MDS / AML is detected in 2,3-10,6% of cases ( M.G.Afable et al, Hematology ASH Educ Program., 2011; p.90-95).

From 1996 till 2015 385 pts were treated in National Research Center of Hematology, Moscow, Russia. Seventeen (4,4%) pts ( 8 men and 9 women; median age 23 years) with AA (6 severe and 11 moderate AA) were diagnosed with clonal evolution to MDS, AML and CMML.

At the moment of AA diagnostics all those 17 pts had normal cytogenetics and were treated by: ATG+CsA+/-splenectomy (n=8); CsA+/-splenectomy (n=9). G-CSF was not administered in any case. Primary response (hematological response) was registered in all 17 pts with the further development of CR in 13 pts; median response duration till the clonal evolution was 78 (10-360) months. Three pts at the time of progression are conducted IST (CsA).

Clonal disorders developed at a median of 80 (47-408) months from the time of AA diagnosis. The median age at the moment of clonal evolution was 34 (27-60) years. Abnormalities of chromosome 7 were found in 8 pts (44%). In pts with monosomy 7 the median time response duration till the clonal evolution was twice less than in pts with another abnormalities of karyotype (70 (47-209) months vs 145 (70-408) months).

At the moment the clonal expansion was detected all the 17 pts had morphological characteristics of dismyelopoesis, however, bone marrow was hypercellular in 7 cases, hypocellular - in 4; mixed (hyper- or hypoplasia) - in 4 cases. Fibrosis was found in 2 pts, it was difficult to detect karyotype in these cases (not mitosis).

The therapy was conducted in accordance to the type of disease and bone marrow cellularity (IST, hypomethylating agents, chemotherapy). Five pts were transplanted from allogeneic donors. The median life duration since clonal evolution was 22 (2-203) months. Five of the 17 pts are alive ( the median - 64(5 -203) months): after allo- HSST (n=3); IST (n=1); "watch and wait" strategy (n=1).

Conclusion: Our 20 years study of a big cohort of AA pts has demonstrated low frequence of clonal evolution to myeloid disorders - 4,4%. We suggest that the absence of G-CSF in our IST programs may contribute to this fact. Almost half of AL/MDS cases harboured monosomy 7 and the median time to clonal evolution was twice less to this pts (70 vs 145 months). The only curative approach in case of clonal evolution to AL/MDS in pts with AA is allo-HSST.