Landmark Analysis of Imatinib Treatment in CML Chronic Phase: ES-FISH <10% Ph+ At 3 Months Associated with Better Cytogenetic Response and Improved Long-Term Event-Free Survival

Abstract 1702

The use of imatinib (ima) and other tyrosine kinase inhibitors (TKI) has dramatically improved the clinical outcome for patients (pts) with chronic myeloid leukemia in chronic phase (CMLcp). Although most pts respond well, there is a subpopulation that fails to reach internationally defined clinical treatment goals, as assessed by techniques such as cytogenetics (CG) and quantitative polymerase chain reaction (PCR). Pts with a poor initial treatment response appear to have an increased risk of subsequent disease progression to accelerated phase or blast crisis, which still constitute a serious medical challenge. It was recently shown that landmark analysis assessing PCR levels after 3 months (mo) of ima treatment was linked to major cytogenetic response (mCyR) at 12 mo and risk of long-term progression (Hanfstein ASH2010 abstract 360). Similar data based on fluorescence in-situ hybridization (FISH) landmark assessment of larger CMLcp pt groups are still lacking.

We have followed a cohort of 45 newly diagnosed CMLcp pts, all initiated on ima (400mg qd), by sequentially assessing their treatment responses by CG, PCR and interphase ES-FISH and relating early BCR-ABL expression levels to subsequent clinical response. A complete cytogenetic response (CCyR) was observed in 56% of evaluable pts after 6 mo, 80% after 12 mo and 94% after 24 mo of treatment. Corresponding figures for major molecular response (MMR) were 9%, 47% and 71%, respectively. Early levels of BCR-ABL as assessed by FISH could predict subsequent response. Thus, of patients with FISH-pos ≤10% at 3 mo 95% achieved CCyR at 12 mo, while this response was noted in only 67% of pts with FISH-pos >10% at 3 mo (p=0.042; Fisher's exact test, n=37). Similarly, all evaluable pts with FISH-pos ≤10% at 3 mo were alive and event-free (EFS) at 36 mo, as compared to 67% EFS at 36 mo among pts with FISH-pos >10% at 3 mo (p=0.008, n=37). Performing similar landmark analyses with FISH ≤ or >10% at 6 and 12 mo also yielded significant differences regarding EFS at 36 mo (p=0.046 and p=0.003, respectively). Employing corresponding landmark analyses with PCR at 3 mo and 6 mo, no significant association to EFS at 36 mo could be detected.

In conclusion, our landmark analysis data indicate that ES-FISH can be used effectively already after 3 mo of ima treatment in order to identify a patient cohort with inferior long-term survival and with a higher risk for disease progression. FISH can unlike CG, be efficiently performed on peripheral blood cells which facilitates its clinical use. In comparison to PCR earlier data have shown that FISH, although less sensitive, may be more reliable and reproducible at higher BCR-ABL expression levels, typically seen in the early treatment phase. This may explain the superior outcome of early landmark analysis using FISH, as compared to PCR, in our study. Expanded trials on larger CMLcp pt cohorts are warranted to further clarify the prognostic value, and possible impact on early treatment alterations, of early FISH analyses during TKI treatment.