Monitoring of Chronic Myeloid Leukemia (CML) Imatinib Response by Fluorescence-In-Situ-Hybridization (FISH).

Abstract

Abstract Glivec, a tyosine kinase inhibitor is the drug of choice for newly diagnosed chronic phase CML. Whilst Q-PCR is the most sensitive method to monitor response; cytogenetic analysis as well as FISH is routinely used in many laboratories. FISH has the advantage over marrow cytogenetic by allowing analysis of more cells, and cells in interphase, obviating necessity for an invasive marrow procedure. We performed 126 FISH studies using BCR-ABL dual color dual fusion translocation probe for 69 CML patients on imatinib. For each samples, 300 nucleated cells were counted. Clinical information was available from 57 patients (34 chronic-phase (CP), 7 accelerated phase (AP), 8 blastic phase (BT) and 8 post-BMT relapses). Most CP patients (94%) could achieve sustained complete hematological responses (CHR), including 14 of the 15 patients pre-treated with IFN. IFN pre-treated patients received imatinib generally late in the course of CP compared to those without (median 19M vs 0.8M, p<0.001). At 12–15 months, 61% CP patients were FISH-ve. Fewer IFN-pretreated patients achieved FISH-ve responses (41.7% vs 90%, p=0.03). With a mean follow-up of 25 months (4–55M), none of the FISH-ve patients had disease transformation while AP/BT developed in 2 FISH+ patients (0% vs 22%, p=0.14). In CML-AP, early institution of imatinib (1–10M) achieved more FISH-ve responses than late treatment (30–36M) and degree of FISH response after 6–12 months of imatinib in CML-AP appeared to predict prognosis. For patients treated in BT, 4 received imatinib upfront and 4 after remissions or reversion to CP after chemotherapy. FISH negativity in the first few months of imatinib treatment, however, did not predict better prognosis. Two patients remained FISH-ve and disease-free 52 months without transplant, suggesting imatinib may be useful as maintenance after chemotherapy induction for BT patients not eligible for transplant. The observation that imatinib after chemotherapy induction has better prognosis than imatinib upfront requires confirmation by larger studies. In post-BMT relapses (8 patients: 1 cytogenetic relapse, 4 CP relapses, 1 blastic relapse, 2 AP relapses), hematological response could be achieved in all. Half became FISH-ve at 6–9 months and remained so at latest follow-up (44–56M). Three patients (1 CP, all 2 AP) were FISH+ at 6–9 months (42–90% Ph+ cells) and remained FISH+ thereafter, with one progressed to blastic disease at 24 months. FISH response at 6–9 months, thus, appears to carry prognostic significance in post-transplant CML relapses. In summary, our initial experience suggests monitoring of imatinib response by FISH provides useful prognostic information in different stages of CML.