Correspondence

Chromosomal Translocations in Secondary Acute Myeloid Leukemia

N Engl J Med 1996; 334:601-603February 29, 1996

Article

To the Editor:

Acute myeloid leukemia (AML) occurs in up to 15 percent of patients treated with cytotoxic drugs, radiation, or both.1 In the leukemic cells of these patients, losses of chromosome 5, 7, or both are most common; a balanced translocation involving chromosome band 11q23 and the MLL gene is closely associated with prior treatment with drugs that inhibit topoisomerase II.2-6

The Clinical Investigations Branch of the National Cancer Institute has compiled eight cases of chemotherapy-related AML among the 2548 patients with node-positive breast cancer who were enrolled in Protocol B25 of the National Surgical Adjuvant Breast and Bowel Project (NSABP). These patients were treated with cyclophosphamide, doxorubicin, and granulocyte colony-stimulating factor. Several patients had 11q23 abnormalities in leukemic cells. One of them, a 64-year-old woman, had received four cycles of doxorubicin and cyclophosphamide every 21 days as well as granulocyte colony-stimulating factor 1 week per cycle. AML was diagnosed 10 months later. A karyotypic analysis of this woman's leukemic cells was done. In 25 cells in metaphase obtained from bone marrow cells cultured for 24 hours the karyotype was 46,XX,del(11)(q23),16p+[23]/45,XX,idem,-18[2] (Figure 1AFigure 1Analysis of Bone Marrow Cells.). In further studies, marrow cells were hybridized with a digoxigenin-labeled probe derived from CD3 yeast artificial-chromosome clone (B22B2; Oncor, Gaithersburg, Md.). The probe hybridized to the del(11q), the 16p+, and the normal 11 chromosomes (Figure 1B). Thus, the cells contained a t(11;16)(q23;p13) that probably involved the MLL gene. These results again show the usefulness of fluorescence in situ hybridization as an adjunct to karyotypic analysis.

Why does acute leukemia develop in up to 15 percent of patients receiving cytotoxic treatment and not in the other 85 percent? The difference may be due to chance or to genetic susceptibility. To investigate these possibilities, clinicians should obtain bone marrow with chemotherapy-related myelodysplastic syndrome or AML from every patient for cytogenetic and DNA analysis. Karyotypic analysis will establish whether the leukemic cells show losses of chromosome 5, 7, or both or a balanced translocation. These different karyotypic changes may reflect underlying inherent differences in germ-line genes. Of the eight patients with chemotherapy-related AML in NSABP Protocol B25, only five underwent cytogenetic studies, and only two underwent molecular studies. Therefore, a valuable opportunity for identifying patients who might have a genetic predisposition to this disease has been lost.

Newer drugs — for example, the epipodophyllotoxins — affect cellular pathways that have not previously been targets of therapy; patients with an inherent genetic susceptibility to the action of these drugs may be at increased risk for chemotherapy-related AML. Physicians should therefore obtain bone marrow to be used for the precise identification of the genetic (cytogenetic) changes in leukemic cells. DNA should be available for use in screening for mutations in genes involved in the replication, repair, and recombination of DNA.

Janet D. Rowley, M.D.
Christine Vignon
University of Chicago, Chicago, IL 60637

Susanne M. Gollin, Ph.D.
University of Pittsburgh, Pittsburgh, PA 15261

Carol L. Rosenberg, M.D.
Herman E. Wyandt, Ph.D.
Aubrey Milunsky, M.B., B.Ch.
Boston University, Boston, MA 02118

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Citing Articles (5)

Citing Articles

1. 1

   Feyruz Virgilia Rassool. (2003) DNA double strand breaks (DSB) and non-homologous end joining (NHEJ) pathways in human leukemia. Cancer Letters 193:1, 1-9
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2. 2

   Carolyn A. Felix. (2001) Leukemias related to treatment with DNA topoisomerase II inhibitors. Medical and Pediatric Oncology 36:5, 525-535
   CrossRef

3. 3

   Susan Mathew, David Head, Jeffrey E. Rubnitz, Susana C. Raimondi. (2000) Concurrent translocations ofMLL andCBFA2 (AML1) genes with new partner breakpoints in a child with secondary myelodysplastic syndrome after treatment of acute lymphoblastic leukemia. Genes, Chromosomes and Cancer 28:2, 227-232
   CrossRef

4. 4

   Robert D. Legare, John G. Gribben, Marlon Maragh, Anne Hermanowski-Vosatka, Sheila Roach, Ramana Tantravahi, Lee M. Nadler, D. Gary Gilliland. (1997) Prediction of therapy-related acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) after autologous bone marrow transplant (ABMT) for lymphoma. American Journal of Hematology 56:1, 45-51
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5. 5

   Noriko Satake, Yasushi Ishida, Yoshiko Otoh, Shin-ichi Hinohara, Hirofumi Kobayashi, Akiko Sakashita, Nobuo Maseki, Yasuhiko Kaneko. (1997) NovelMLL-CBP fusion transcript in therapy-related chronic myelomonocytic leukemia with a t(11;16) (q23;p13) chromosome translocation. Genes, Chromosomes and Cancer 20:1, 60-63
   CrossRef