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Acute Myeloid Leukemia Following 3M (Mitoxantrone, Mitomycin and Methotrexate) Chemotherapy for Advanced Breast Cancer

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Acute Myeloid Leukemia Following 3M (Mitoxantrone, Mitomycin and Methotrexate) Chemotherapy for Advanced Breast Cancer Correspondence 2211 S Savas¸an1 Barbara Ann Karmanos Cancer Ginsberg C, Trujillo J, Stass S, Champlin RE. Preliminary results of E Abella1,2 Institute and 1Children’s Hospital treatment with filgrastim for relapse of leukemia and myelodyspla- AJ Akhtar2 of Michigan, Division of sia after allogeneic bone marrow transplantation. New Engl J Med 1 2 1993; 329: 757–761. Y Ravindranath Hematology/Oncology and Bone 4 Shinohara K, Oeda E, Nomiyama J, Inoue H, Kamei S, Tajiri M, Marrow Transplantation Unit, Ichikawa T, Kuwaki T, Tachibana K. The levels of granulocyte col- Harper Hospital, Wayne State ony-stimulating factor in the plasma of the bone marrow aspirate University, Detroit, MI, USA in various hematological disorders. Stem Cells 1995; 13: 421–427. 5 Gabrilove JL, Jakubowski A. Granulocyte colony-stimulating fac- tor: preclinical and clinical studies. Hematol Oncol Clin North Am 1989; 3: 427–440. References 6 Keil F, Kalhs P, Haas OA, Fritsch G, Lechner K, Mannhalter C, Greinix HT. G-CSF stimulation of donor myelopoiesis prolongs ¨ 1 Terpstra W, Lowenberg B. Application of myeloid growth factors survival of relapsed BCR-ABL-positive acute lymphoblastic leuke- in the treatment of acute myeloid leukemia. Leukemia 1997; 11: mia after allogeneic marrow transplantation. Bone Marrow Trans- 315–327. plant 1996; 18: 655–657. 2 Rowe JM, Liesveld JL. Hematopoietic growth factors in acute leu- 7 Savas¸an S, Abella E, Karanes C, Ravindranath Y. Recurrent breast kemia. Leukemia 1997; 11: 328–341. relapses in a patient with acute lymphoblastic leukaemia following 3 Giralt S, Escudier S, Kantarjian H, Deisseroth A, Freireich EJ, And- allogeneic bone marrow transplantation. Acta Haematol 1997; ersson BS, O’Brien S, Andreeff M, Fisher H, Cork A, Hirsch- 871. Acute myeloid leukemia following 3M (mitoxantrone, mitomycin and methotrexate) chemotherapy for advanced breast cancer TO THE EDITOR were admitted in 1996 to our Department for acute leukemia. Clinical characteristics of the patients are shown in Table 1. The risk of secondary acute myeloid leukemia (AML) among Patient No. 1, a 44-year-old woman, was well until 4 years subjects with breast cancer receiving standard-dose cyclopho- earlier, when breast cancer occurred. She was treated with sphamide and doxorubicin has been reported equivalent to radical surgery plus six courses of cyclophosphamide, metho- that of the general population.1 Recently an increased fre- trexate and 5-fluorouracil (CMF). One year after the initial quency of therapy-related leukemias has been documented, diagnosis, she had recurrence of the disease with bone metast- paralleling the more widespread use of dose-intensive ther- ases and was treated with six courses of 3M followed by med- apies and the longer survival of cancer patients.2 roxyprogesteron acetate (MAP) and radiation therapy (RT) on Alkylating agents3 or more recently, epidophyllotoxins- the bone lesions. About 6 months from the start of 3M a related4 secondary AML have been described, but also decrease of white blood cells and platelets count was noted. growth factors or different drug combinations seem to affect Eighteen months later she was admitted to our Department cellular proliferation, especially in subjects with genetic because of a hemorrhagic syndrome: the bone marrow exam- susceptibility.5 ination revealed AML M0 according to FAB criteria. The Because of the effectiveness of chemotherapeutic agents patient died 4 days later. such as topoisomerase II inhibitors (epidophyllotoxins, anthra- Patient No. 2, a 60-year-old woman, had a history of breast cyclines and their derivates) it is important to define their leu- cancer treated with radical surgery at 50 years. Six years later, kemogenic potential in patients with advanced diseases and bone metastases developed and she was treated with eight mainly in adjuvant regimens for early cancer. courses of CMF and RT to lesions of the skeleton. At the age We describe three cases of secondary AML observed in the of 58, the disease progressed and she was therefore treated last year in our Institution, which occurred in women treated with seven courses of 3M followed by MAP. One year after with 3M (methotrexate, mitoxantrone, mitomycin) regimen for the end of the therapy, piastrinopenia and hemorrhagic syn- advanced breast cancer. drome occurred: bone marrow examination disclosed acute Clinical and biologic features are described and the poss- promyelocytic leukemia. All-trans retinoic acid therapy was ible relationship between these drugs and the onset of acute started and at +10 months from diagnosis the patient is alive leukemia is discussed. and well. Three women with a history of advanced breast cancer Patient No. 3 was a 52-year-old woman. She was well until treated with mitoxantrone (8 mg/m2 intravenously every 3 10 years earlier when she underwent radical surgery and weeks), mitomycin (8 mg/m2 intravenously every 6 weeks) and breast RT for breast cancer. Thirty months before admission, methotrexate (30 mg/m2 intravenously every 3 weeks) (3M) the patient received five courses of 3M followed by tamoxifen for disease recurrence to skeleton and skin. After that a pro- gressive anemia and leucopenia developed: bone marrow examination revealed refractory anemia. Transfusional ther- Correspondence: LMA Melillo apy was prescribed. Two weeks before admission acute mon- Received 20 February 1997; accepted 5 September 1997 ocytic leukemia developed; the patient was treated with Correspondence 2212 Table 1 Clinical and laboratory features at diagnosis of breast cancer patients developing acute myeloid leukemia Patient No. Age FAB Latent period from 3M Previous treatment WBC Organomegaly or (months) for breast cancer (× 109/l) adenopathy 1 44 M0 24 Radical mastectomy + 6CMF 0.5 No 2 60 M3 12 Radical mastectomy + Tamoxifen 21.3 No 8CMF + RT 3 52 M5 30 Radical mastectomy + RT 43.4 No mitoxantrone and intermediate doses of cytosine arabinoside, genetic abnormalities, but molecular analysis was not but she died a few days later. reported. In our series, however, Southern blot analysis Chromosome investigations were carried out at diagnosis detected a germline configuration of MLL gene. on bone marrow samples using direct or short term (24–48 h) Since methotrexate seems to have little leukemogenic poten- culturing techniques. Twenty well-spread GTG banded meta- tial,12 the increased risk of AML appears to be probably related phases were analyzed for each patient. to mitoxantrone, alone or by an interaction with mitomycin or Patient 1 had normal karyotype; patient 2 was found to methotrexate and/or previous therapies, including RT. have 46,XX,t(15;17)(q22;q12). In patient 3, cytogenetic In conclusion, the clinical features of our cases resemble analysis revealed a complex karyotype interpreted as those of secondary AML occurring after treatment with topo- 45,XX,del(3)(q12.q25), −7,−19,+mar. The chromosome 3 isomerase II agents: nevertheless, the lack of MLL rearrange- interstitial deletion was confirmed by whole chromosome ments in our series suggests a different pathway by which painting with a digoxygenin-labelled probe specific for chro- cytotoxic drugs and radiations interfere with the genetic pro- mosome 3 (Oncor, Gaithersburg, MD, USA) that did not show gram of hemopoietic cells. any translocation. Molecular analysis by RT-PCR assay was able to detect fusion transcript PML/RAR alpha (bcr3) in case 2. Southern blot analysis with 0.74 kb MLL cDNA probe to Acknowledgements detect MLL gene rearrangements revealed a germline con- figuration in all three examined cases. We wish to thank Dr Daniela Diverio and Dr MC Rapanotti, AML occurs in up to 15% of patients treated with cytotoxic Cattedra di Ematologia, Dipartimento di Biopatologia Umana, 3 ` drugs, radiation or both. Two different forms of secondary Universita La Sapienza, Rome for performing the molecular AML are described. The classic one, in patients treated with analysis. alkylating agents and/or RT, is characterized by a long latency period (3–5 years), a high incidence of preleukemic phase, LMA Melillo Divisione di Ematologia, frequent cytogenetic abnormalities involving chromosomes 5 MR Sajeva Ospedale ‘Casa Sollievo della Sofferenza’ 5 and 7 and an extremely poor prognosis. The second form, P Musto IRCCS, that occurs in patients who have received agents targeting G Perla S Giovanni Rotondo, DNA topoisomerase II, such as epidophyllotoxin derivates N Cascavilla Italy 4 (etoposide, teniposide) or anthracyclines and their derivates MM Minervini 6 (such as mitoxantrone) develops after a short latency period G D’Arena (2–3 years), a brief myelodysplastic phase and is associated M Carotenuto with myelomonocytic or monocytic morphology. In this form, most cases show a balanced translocation involving chromo- some 11q23 leading to rearrangement of MLL gene. This gene References encodes a transcription factor with extensive homology to the Drosophila homeotic regulator trithorax and is probably 1 Tallman MS, Gray R, Bennet JM, Variakojis D, Robert N, Wood involved in the regulation of differentiation pathway through WC, Rowe JM, Wiernik PH. Leukemogenic potential of adjuvant DNA interaction.7 Many different mechanisms (aberrant V-D- chemotherapy for early breast cancer: the Eastern Cooperative J recombination, homologous recombination between Alu- Oncology Group experience. J Clin Oncol 1995; 13: 1557–1563. repeats, and topoisomerase II-mediated non-homologous 2 Shepherd L, Ottaway J, Miles J, Levine M. Therapy related leuke- 8 mia associated with high-dose 4-epi-doxorubicin
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