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BACKGROUND Chronic myeloid leukemia (CML) is a clonal disease with specific cytogenetic changes involving the Philadelphia (Ph) translocation. The authors examined the relationship between telomere length (terminal restriction fragment [TRF]) and therapy-associated cytogenetic responses in CML patients. METHODS The authors examined the telomere length and telomerase activity in 44 patients with Ph-positive CML in the chronic phase. TRF was determined by Southern blot analysis using the (TTAGGG)4 probe and telomerase activity was assessed by the telomeric repeat amplification protocol and fluorescent-labeled primers. RESULTS At the time of CML diagnosis, 19 patients had TRFs within the age-matched normal range (mean ± 2 × standard deviation [SD]) and the remaining 25 patients had TRFs shorter than the age-matched normal range (< mean ± 2 × SD). Hematologic findings, including leukocyte count, hemoglobin level, platelet count, and percentage of bone marrow blasts at the time of diagnosis did not significantly differ between patients with normal and shortened TRFs; however, those with shortened TRFs had high levels of telomerase activity (P = 0.045). In a group of patients treated with alpha-interferon (n = 32), those with normal TRFs had a significantly lower frequency of blast crises (P = 0.0328), a significantly higher incidence of cytogenetic responses (P = 0.0185), and a favorable prognosis (P < 0.01) compared with those with shortened TRFs. CONCLUSIONS These findings suggest that normal TRFs in a small number of CML patients at the time of diagnosis may have a significant amount of normal stem cells remaining. The authors suggest that normal TRFs at the time of diagnosis indicate a subset of CML patients who may respond favorably to alpha-interferon therapy. Cancer 1997; 79:1552-60. © 1997 American Cancer Society.