Correlation of Molecular Response At 18 Month with Survival Benefits As Response-Related Prognostic Factor

Abstract 2766

Superior efficacy of Bcr-Abl tyrosine kinase inhibitors in chronic myeloid leukemia (CML) therapy has increased the demand for more sensitive monitoring system in checking clinical response from CML patients. Molecular response measuring Bcr-Abl transcript level by quantitative real-time PCR has been introduced and then widely used as important routine monitoring methodology (Müller et al. Leukemia 2009; 23: 1957–19633; Nick Best Pract Res Clin Haematol 2009; 22:355–65). European LeukemiaNet 2009 guide line recommended achievement of major molecular response (MMR) as optimal response at 18 months after initiation of imatinib (Baccarani et al. J Clin Oncol 2009; 27: 6041–6051).

However, several studies have reported different clinical implications of MMR at specific time points to long-term survival outcomes. IRIS study proved MMR at 12 and 18 months can predict significantly better progression free survival (Hughes et al. N Engl J Med 2003; 349: 1423–1432; Druker et al. N Engl J Med 2006; 355: 2408–17). However, other studies reported that such differences may not be clinically relevant and only achievement of CCyR was significant to anticipate survival (de Lavallade et al. J Clin Oncol 2008; 26: 3358–3363, Kantarjian et al. Cancer 2008; 112: 837–84511).

To find the level of molecular response (MR) at 18 months which can provide survival benefits, we selected newly diagnosed CP CML patients who registered at Seoul St. Mary's Hospital between January 2001 and June 2011. Selection conditions included initiation of imatinib therapy (400mg/d) within 6 months of diagnosis without prior treatment for leukemia (except for hydroxyurea or anagrelide), treatment with imatinib for more than 18 months and available molecular response record at 18 months. Total 237 patients met the above conditions. Their median age was 40 years (range; 18–74 years) and median duration of imatinib treatment was 44 months (range; 18–119 months).We investigate effect of different levels of MR (0.1%, 0.2%, 0.4% and 0.8% in Bcr-Abl transcript level) at 18 months on survivals including overall survival (OS), progression free survival (PFS) and event free survival (EFS) with these patients.

Achievement of MMR did not provide survival benefits in OS, PFS and EFS. However other level of MR showed significant survival benefits in PFS and EFS between patients who achieved the level and patients who did not achieve the level. In achievement of 0.2% in Bcr-Abl transcript level, patients with MR level of 0.2 or less % showed better survival benefit than patients with MR level of more than 0.2% in PFS (98.0% vs.91.1%; P=0.017) and in EFS (94.2% vs. 85.5%; P=0.009) at 84 months. Bcr-Abl transcript level of 0.4% also showed survival benefits at 84 months between the patients with 0.4% or less and patients with more than 0.4% in PFS (97.7 vs. 88.9, P=0.007) and EFS (94.6 vs. 80.8, P=0.005). Similar results were observed in Bcr-Abl transcript level of 0.8%. However, achievement of all the levels of MR investigated in this study failed to provide clear benefit in OS. It may be due to extremely low portion of death (2.5%; 6 of 237 patients).

The 0.2% of Bcr-Abl transcript at 18 months was the lowest value which showed clear correlation with survival benefits. MMR is defined as a Bcr-Abl transcript level of 0.1% or lower on international scale (IS), which is equivalent to a reduction in the Bcr-Abl transcript level by at least 3 log from the baseline level. The baseline level was determined as a median ratio of Bcr-Abl to Abl obtained from 116 untreated CP-CML patients in our institution.

Survivals according to different level of molecular response (MR)