Therapy-Related Chronic Myeloid Leukemia and Myelodysplastic Syndrome with -7, t(9;22), and 5q-, t(9;22).

Therapy-related hematologic diseases are known to include acute myelocytic leukemia (AML) and myelodysplastic syndromes (MDS), but reports of therapy-related chronic myeloid leukemia (CML) are rare. Philadelphia chromosome-positive (Ph+) CML has been described in patients who were previously exposed to alkylating agents or topoisomerase II inhibitors. Below, we present a patient with Ph+ CML and MDS with both monosomy 7 (-7) and deletion of the long arm of chromosome 5 (5q-) following chemotherapy and radiation for pleomorphic liposarcoma.

An 80 year old African American man was diagnosed with pleomorphic liposarcoma involving his right thigh fourteen years ago. He received six cycles of peri-operative chemotherapy with cyclophosphamide, doxorubicin and dacarbazine, and adjuvant radiation therapy. Six years later, he received seven cycles of dacarbazine, ifosfamide/mesna and etoposide peri-operatively for a recurrence in the abdomen. Twelve years later, he received sixteen cycles of gemcitabine and docetaxel for another intra-abdominal recurrence, with disease progression. He then received a study drug, ANG (1-7) for a year, with disease progression. This was treated with radiation therapy to the abdominal site, completed three months ago. On routine follow up, he was doing well and had an unremarkable physical examination. A CT scan of his abdomen revealed stable disease. He was noted to have a WBC count of 30,000/microliter with 61% segmented neutrophils, 5% band neutrophils, 6% metamyelocytes, 4% myelocytes, 2% basophils, 1% eosinophils, 14% monocytes and 7% lymphocytes. Hemoglobin was 12.6 grams/deciliter and platelets 129,000/microliter. A bone marrow biopsy showed marked granulocyte hyperplasia with large paratrabecular aggregates of immature myeloid precursors. Megakaryocytes were increased in number with dysplastic features including small, hyperchromatic and hypolobated forms. There was frequent clustering. There were no dysplastic features in the erythroid cell line. Background hematopoiesis was decreased. There was no increase in blasts. 11 cells were karyotyped with a band resolution of 450, revealing 2 cell lines. One was an abnormal clonal male cell line with t(9;22) and monosomy 7. The other, had t(9;22) and deletion of the long arm of chromosome 5. Peripheral blood RT-PCR for BCR-ABL gene rearrangement quantitation showed a ratio of 1.607 of fusion transcript to control. A diagnosis of therapy-related CML in chronic phase and MDS was thus made. His IPSS score is intermediate-1. He is currently on imatinib mesylate, which he is tolerating well. After 2 weeks of therapy, his WBC count was 7,800/microliter with a normal differential count, hemoglobin 10.7 grams/deciliter and platelets 86,000/microliter.

The presence of -7 and t(9;22) in one cell line, and 5q- and t(9;22) in the other implies that the t(9;22) may have been an earlier event. Abnormalities in chromosome 5 and 7 are typically associated with therapy-related MDS and AML following exposure to alkylating agents, and carry a poor prognosis. The abnormalities involving chromosomes 5 and 7 affecting the cells carrying the t(9;22) overwhelmingly support a diagnosis of therapy-related CML. Topoisomerase II inhibitors have been associated with therapy-related AML with balanced translocations involving the chromosome bands 11q23 and 21q22. The t(9;22) could have arisen as a result of mitotic, non-homologous chromosomal recombination of topoisomerase II-induced double-strand breaks of DNA. In this case, CML is the presenting diagnosis of therapy-related malignant hematologic disease. This patient was initiated on treatment for CML, but close follow up will be maintained regarding his MDS.

Therapy-related CML should be considered in patients who have had chemotherapy and/or radiation. It may present prior to the onset of other more fatal therapy-related hematologic disorders, and therefore has implications on treatment and long term follow up.

Powell:Novartis Pharmaceuticals: Research Funding.