Rearrangement of the myeloid/lymphoid leukemia gene in therapy-related myelodysplastic syndrome in patients previously treated with agents targeting DNA topoisomerase II.
BACKGROUND
Therapy-related acute myeloid leukemias (t-AML), with balanced translocations affecting the 11q23 point in the myeloid/lymphoid leukemia (MLL) gene, are one of the most serious complications of treatments with topoisomerase II inhibitors. However, only a few reports of t-AML exist. We aimed to study if these translocations are cumulative-dose-dependent, their frequency in therapy-related myelodysplastic syndrome and the relationship between their presence, the type of therapy and the response criteria.


METHODS
This retrospective study included 120 patients with various malignancies (108 non-Hodgkin's lymphoma, 8 Hodgkin's disease and 4 neuroblastoma) in remission, being treated with topoisomerase 2 inhibitors; 74 had been diagnosed with therapy-related myelodysplasia and 46 did not have dysplasia. All bone marrow biopsy samples were evaluated by fluorescence in situ hybridization for 11q23 point breakage in the MLL gene.


RESULTS
MLL gene rearrangement frequency was 6% in dysplastic versus 2% in nondysplastic groups; p < 0.001. It was associated with a worse overall survival (mean 13 ± 2 vs. 39 ± 3 months, log-rank p value <0.0001). It was dose-dependent with a cut-off value of 290 mg/kg of topoisomerase II inhibitors as assessed by ROC curve (area under the curve 0.84 ± 0.05, p < 0.0001).


CONCLUSIONS
It is proposed that the MLL gene is etiopathogenetically relevant for hematological neoplasias transformation and survival.
Department of Clinical Pathology, South Egypt Cancer Institute, Assiut, Egypt.
Eman
E
Mosad
Madleen
M
Abdou
Amen Hamdy
AH
Zaky
D000328:Adult; D000368:Aged; D005260:Female; D015321:Gene Rearrangement; D011495:Histone-Lysine N-Methyltransferase; D006689:Hodgkin Disease / Q000188:drug therapy / Q000235:genetics; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D009447:Neuroblastoma / Q000235:genetics; D012189:Retrospective Studies; D059005:Topoisomerase II Inhibitors / Q000627:therapeutic use*; D014178:Translocation, Genetic; D016896:Treatment Outcome
C497422:KMT2A protein, human; D059005:Topoisomerase II Inhibitors; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase