Chronic myeloid leukemia (CML) is a clonal stem cell malignancy associated with the Philadelphia chromosome, t(9;22)(q34q31)/BCR-ABL gene fusion. Additional cytogenetic abnormalities have been known to emerge in Philadelphia (Ph) positive cells (additional Ph+ clones) or Ph negative cells (Ph- clones) at diagnosis, or during or post tyrosine kinase inhibitor (TKI) therapy. Many studies have elucidated that the presence of some Ph+ clones were frequently associated with disease progression, while presence of Ph- clones were unrelated to disease outcome. A majority of studies have shown a waxing and waning of Ph- clonality in response to therapy. However, there remains no solid data regarding overall survival comparing Ph+ and Ph- clones over a long term period. This study focuses on the observation of clonal evolution in various phases of CML, and the relationship to overall survival, disease resistance, kinase domain mutation (KDM) and progression to accelerated or blast phase in patients with CML.
Materials and Methods: Data from 318 patients who were diagnosed with CML was retrieved from Moffitt Cancer Center during January 1990-December 2010. Patients are divided into three groups based on the presence of additional ph+ clone (A), ph- clone (B) and absence of both (C). Clinicopathologic results including initial diagnosis date, nature and frequency of clone, copy of clone at karyotyping, disease status in response to treatment and overall outcome were documented and statistically analyzed. All patients with Ph- and Ph+ clones have been treated with TKIs since 2001. Median overall survival and median disease progression survival were compared between conal ph- and clonal ph+ group by the log-rank test. Survival curves were generated using the Kaplan–Meier method. All reported P values are two-sided. Cox Regression (multivariate analysis) was also performed for time to progression.
Of 318 (average age 57, range: 19 to 89, M:F=1:1), 17 carried ph- clones (5.3%) and 41 showed additional ph+ clones (12.9%) and the rest (258) lacked additional ph+ or ph- clones. Additional clonal cytogenetic aberrations were random with the most frequent occurrence of trisomy 8 (7 of 17 ph- and 14 of 41 ph+ clones, respectively) and isochromosome 17q (4 in ph+ clone only). There is a higher rate of transformation to accelerated/blast phase in Ph+ additional clones (36.6%,15 of 41) as compared to Ph- additional clone (17.6%, 3 of 17) and Ph+ without additional clones(11.1%, 29 of 260) (p=0.015). The overall median survival is shorter in patients with ph+ clones (133.4 months) than in those with ph- clones (172 months) (p<0.005). KDM were observed in 27 of 110 tested patients (24.5%), and many of them fell into the Ph+ clone group (10 of 22 tested) and fewer into ph- clone group (3 of 10 tested) (p<0.005). Statistical analysis proved that there is a higher rate of transformation to accelerated/blast phase in the presence of a KDM (p<0.005). Of note, most of those with ph- clones had only one episode (59%) with 41% having more than one occurrence and lasting from 6–58 months (average 21.1 months), while in those 41 patients with Ph+ clone; a subset (18 of 41, 43.9%) showed a long-lasting ph+ clone over months (ranging from 2 months to 70 months, average 14.5 months) and the remaining only occurred one occasion (23 of 41, 56.1%). Multivariate analysis for disease progression demonstrated statistical significance with regards to both the ph+ clone and kinase mutation categories (p=0.003 and 0.034).
Most Ph+ or Ph- clones are occasionally observed during the long course of CML, with a minor subset of clones showing persistency, especially in Ph- ones. The presence of an additional Ph+ clone is correlated with disease progression, drug resistance and shorter overall survival in comparison to a Ph- clone. A relatively long overall survival is observed in patients with ph- clones. Ph- clones were often identified during disease remission regardless of frequency of clonal copy or clonal persistence. The outcome of patients with concurrent Ph+ and Ph- clones was dictated by the Ph+ clone.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.