TO THE EDITOR. We read with interest the letter by Andersen et al1 reporting three cases of chronic myeloid leukemia (CML) with clonal. Philadelphia negative ...
Leukemia (2003) 17, 634–635 r 2003 Nature Publishing Group All rights reserved 0887-6924/03 $25.00 www.nature.com/leu
SPOTLIGHT CORRESPONDENCE Fatal myelodysplastic syndrome developing during therapy with imatinib mesylate and characterised by the emergence of complex Philadelphia negative clones
Leukemia (2003) 17, 634–635. doi:10.1038/sj.leu.2402842
TO THE EDITOR
SPOTLIGHT
We read with interest the letter by Andersen et al1 reporting three cases of chronic myeloid leukemia (CML) with clonal Philadelphia negative (Ph ) hematopoiesis arising after treatment with imatinib mesylate and would like to describe a further interesting patient with some similar features, but a fatal outcome. The patient was a 42-year-old man who first presented in March 1995 with Philadelphia positive (Ph+) chronic phase CML. Karyotyping at presentation showed 46,XY,t(9;22)(q34;q11) as the sole abnormality in eight metaphases analysed. He was initially treated with hydroxyurea and interferon, and 4 months later underwent an HLA-identical sibling bone marrow transplant from his brother, conditioned with TBI and cyclophosphamide. He suffered cytogenetic relapse 10 months after transplantation and failed to respond to two donor lymphocyte infusions (DLIs). His counts were controlled over the next 42 months with interferon and cytarabine. However, throughout this period he remained 100% Ph+, with up to four new Ph+ related clones detected, suggesting acceleration: (46XY,t(9;22)(q34;q11)[1]/46XY,t(9;22) (q34;q11),(t11;14)(q23;q11)[3]/46XY,t(4;der(9)t(9;22)(q34;q11);14) (q31?.3;q32;q11),der(22)t(9;22)(q34;q11)[9]/46XY,t(1;19)(q3?2;q13), t(9;22)(q34;q11)[3]/46XY[1]). In December 2000, he was entered into the Novartis expanded access accelerated phase imatinib mesylate (Glivec) trial (protocol 0114). Following 9 months of therapy with imatinib mesylate his marrow was shown to have become 100% Ph (10 metaphases including three cells with unrelated nonclonal abnormalities). After 15 months of treatment with imatinib mesylate, he developed pancytopenia with marked trilineage dysplasia, 15% blasts and multiple, related, cytogenetic clonal abnormalities including monosomies 5, 7 and 16 (42–45,XY, 5, 7,?psudic (12;8) (p13;q10), 16,psudic(17;8)(p13;?q10),+mar[cp5]/42–43,XY, 5, 7,add(12)(p12–13), 16, psudic (17;8)(p13;?q10), +3mar[cp3] / 46XY[1],). Interestingly, these clones remained 100% Ph with low ratios of bcr-abl/abl(0.1–0.895) consistent with a Ph karyotype . None of these clones was related to the previously identified Ph+ clones. He progressed rapidly to secondary acute myeloid leukemia (AML) and died having declined further therapy. Our patient shared some features similar to those reported and reviewed by Andersen et al.1 Most importantly, he developed new Ph cytogenetically unrelated clones during treatment with imatinib mesylate. However, we believe that this is the first time clinical myelodysplasia (MDS) has been described in association with this phenomenon. This case is complicated by the
Correspondence: DJ Culligan, Department of Haematology, Ward 16, ANCHOR Unit, Aberdeen Royal infirmary, Foresterhill Road, Aberdeen AB25 2ZN, UK; Fax: 44 1224 550714 Received 10 October 2002; accepted 31 October 2002
history of allogeneic transplantation. Features supporting the development of straightforward treatment-related myelodysplasia (t-MDS) include exposure to alkylating agent, the time period to development of MDS and complex cytogenetic abnormalities involving monosomy for 5 and 7. However, this diagnosis is rare after allogeneic transplantion.2 We, therefore, suggest two alternative scenarios. Firstly, as proposed by Andersen et al,1 the new Ph clones may represent a preleukemic stage of CML and treatment with imatinib mesylate, which specifically targets the Ph+ clone, conferred a growth advantage on these otherwise silent clones. Secondly, previous chemotherapy and radiotherapy may have caused or added further damage to normal or abnormal Ph stem cells. The clinical emergence of these clones was then selected for by treatment with imatinib mesylate. If so, this would have implications for the use of imatinib mesylate in combination treatment or as maintenance treatment post-transplantation. This might be especially relevant after autografting when t-MDS is more frequently recognised. The Ph clone in our case was typical of t-MDS and, unlike the cases described by Andersen et al, did not include trisomy 8. Unfortunately, the allogeneic transplant was not sex mismatched and we were unable to ascertain if the MDS clone was of host or donor origin. We accept that this case may simply represent a rare example of t-MDS post allografting. However, the onset in relation to the introduction of imatinib mesylate therapy, the emergence of the Ph unrelated clones on the background of a complete cytogenetic response of CML and the aggressive, rapidly fatal phenotype of the resultant MDS is of concern in the light of the observations of Andersen et al1 and others,3,4 including an abstract by Marktel et al (The Haematology Journal 2002, 3, Suppl 1, 175). To date these reports have described the development of new Ph clones, including monosomy 7,4 but not the development of clinical MDS. We welcome further reports and suggest careful monitoring of patients when imatinib mesylate is used after previous leukemogenic therapy.
YL Chee1 MA Vickers1 D Stevenson1 TL Holyoake2 DJ Culligan1
1 Departments of Haematology and Cytogenetics, Aberdeen Royal Infirmary, Foresterhill, Aberdeen AB25 2ZN, UK; 2 Division of Cancer Sciences and Molecular Pathology, University of Glasgow, Royal Infirmary, Glasgow G31 2ER, UK
References 1 Andersen MK, Pedersen-Bjergaard J, Kjeldsen L, Dufva IH, Brondum-Nielsen K. Clonal Ph-negative hematopoiesis in CML after therapy with imatinib mesylate is frequently characterised by trisomy 8. Leukemia 2002; 16: 1390–1393. 2 Socie G, Deeg JC. Malignancies after haematopoietic stem cell transplantation. Many questions, some answers. Blood 1998; 91: 1833–1844.
Correspondence
635 4 Meeus P, Demuynck H, Martiat PH, Michaux L, Wouters E, Hagemeijer A. Sustained, clonal karyotype abnormalities in the Philadelphia chromosome negative cells of CML patients successfully treated with imatinib. Leukaemia 2003; 17: 465–467.
SPOTLIGHT
3 Braziel RM, Launder TM, Druker B, Olson SB, Magenis RE, Mauro MJ et al. Hematopathologic and cytogenetic findings in imatinib mesylate-treated chronic myelogenous leukemia patients: 14 months’ experience. Blood 2002; 100: 435–441.
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