Myelodysplastic subclones in chronic myeloid leukemia: implications for imatinib mesylate therapy

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Abstract
Short-term results with imatinib mesylate (Gleevec; Novartis Pharmaceuticals, Hanover, NJ) for chronic-phase chronic myelog- enous leukemia (CML) are extremely encouraging, with greater than 95% hematologic and 83% major cytogenetic responses in previously untreated patients. 1 Long-term experience with inter- feron- therapy suggests that only those patients achieving major cytogenetic responses experience significant survival benefits.2 Therefore, serial cytogenetic monitoring of imatinib mesylate- treated patients is imperative so that individuals not attaining major cytogenetic responses may be referred for potentially curative allogeneic marrow transplantation or investigative therapies before progressing to accelerated or blastic phases. Although repetitive bone marrow aspirations for cytogenetics are an effective tech- nique to evaluate response, this method is time consuming, costly, and unpleasant for patients. Several investigators have reported that peripheral blood fluorescence in situ hybridization (FISH) for the BCR-ABL translocation, with its ease of procurement, sensitivity, and quantifiable nature may be a more convenient, yet accurate, method of serial monitoring. 3,4 The specificity of peripheral blood FISH, however, results in its major limitation; an inability to detect acquisition of additional cytogenetic abnormalities. We report a case where FISH could have led to false reassurances of successful imatinib mesylate treatment. A 55-year-old man presented with leukocytosis and a hypercel- lular marrow without dysplasia or blast forms. Peripheral blood karyotype analysis revealed 46, XY,-5, del(6)(q23), t(9;22)(q34; q11.2), mar and FISH for the BCR-ABL translocation was positive. Interferon therapy for one year yielded only a partial hematologic response. Imatinib mesylate resulted in a rapid complete hematologic response. Marrow FISH at 6 and 10 months demonstrated no evidence of the BCR-ABL translocation in 500 examined cells each time, suggesting a complete cytogenetic response. In contrast, marrow karyotyping yielded 46, XY, der(5)ins(5;5)(p15;q22q12)del(5)(q31q35), del(6)(q23) in 2 of 21 metaphases (6 months) and 7 of 20 metaphases (10 months), with the remaining cells normal. No Philadelphia chromosome-positive (Ph) clones were identified.