The Philadelphia-Chromosome Is Unmasked as the Secondary Genetic Change in Acute Myeloid Leukemia on Imatinib Treatment.

The Philadelphia chromosome (Ph) is present in less than 3% of the acute myeloid leukemia (AML) and associated with poor prognosis. There are only few reports on the use of imatinib in Ph+ AML. We describe an adult female patient presenting with AML (Hb 3.6 g/dl, Wbc 137×10⁹/L, Plt 295,000/uL and marrow blast 74%, with no basophilia or splenomegaly). Cytogenetic studies showed 45,XX,inv(3)(q21q26),-7,t(9;22)(q34;q11.2) [12] and RT-PCR showed p190^BCR-ABL transcripts. The leukemia failed to respond to 2 cycles of daunorubicin and ara-C and imatinib 600mg daily was then started. Fluorescence in-situ hybridization (FISH) analysis of 300 marrow cells using dual fusion BCR-ABL translocation probes (D-FISH, Vysis, Downers Grove, IL, USA) showed that before imatinib, 78% of the cells were positive for BCR-ABL (at diagnosis, it was 83%), which after 6 weeks of imatinib treatment, became BCR-ABL negative (sensitivity 0.3%). However, marrow biopsy still showed 15% blasts. Repeated cytogenetics showed poor growth, but one metaphase showed 45,XX,inv(3)(q21q26),-7. With FISH, 39% of the marrow cells, including neutrophils, were positive for monosomy 7. At 4 months of imatinib, when the marrow blasts count increased to 40%, BCR-ABL remained negative by FISH, whereas monosomy 7 positive cells had risen to 82%. However, by nested RT-PCR with sets of BIOMED primers (sensitivity of 10⁻⁵), the p190^BCR-ABL transcript was still present, suggesting persistence of a small and quiescent population of BCR-ABL positive leukemic stem cells. In summary, our case study demonstrates the need for careful cytogenetic and molecular analysis in cases of acute leukaemia with Ph chromosome to exclude the possibility of Ph chromosome being a secondary event, in which case durable leukemia remission will be unlikely if treatment is by BCR-ABL inhibition alone.