No Differences in Outcomes Between Patients Achieving Early Molecular Response at 3 Months and Those Achieving Optimal Response at 6 or 12 Months in Chronic Phase of Chronic Myeloid Leukemia Treated with Front-Line Imatinib: Taiwan CML Study

Introduction and Aims: Recent reports demonstrated the importance of early molecular response (EMR) in chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitors. However, there were rare reports focusing on the clinical outcomes if patients did not meet EMR at 3 months but achieved optimal response later. We aimed to compare the cumulative incidence (CI) of major molecular response (MMR), MR^4.5, and progression-free survival (PFS) and overall survival (OS) in front-line imatinib (IM)-treated CML-CP patients who achieved EMR at 3 months with those who achieved optimal response later on at 6 or 12 months.

Methods: Newly diagnosed CML-CP patients enrolled in Taiwan CML Study from Jun-2004 to Jun-2013 who had available BCR-ABL1 levels at 3, 6, or 12 months and had been followed for at least 12 months were included. Peripheral blood BCR-ABL1 levels were measured every 3 months by RQ-PCR assay expressed as International Scale (IS) in a central laboratory. Patients were divided according to the IS levels: Group I (IS ≤ 10% at 3 months), Group II (IS > 10% at 3 months, but IS ≤ 1% at 6 months), Group III (IS >10% at 3 months, IS >1% at 6 months, but IS ≤ 0.1% at 12M), and Group IV (IS > 10% at 3 months, IS > 1 % at 6 months, and IS > 1% at 12 months). CI of MMR, MR^4.5, disease progression, PFS and OS were compared between Group I and other group.

Results: Four hundred and twenty-five newly diagnosed CML-CP patients (males 255), with a median age of 45.6 years and median follow-up time of 45.6 months, were included. In total, 250 patients achieved MMR (58.9%, median time to MMR 12.7 months) and 107 patients achieved MR^4.5 (25.2%, median time to MR^4.5 31.5 months). Accelerated phase (AP, N=10)/Blastic crisis (BC, N=12) occurred in 22 (5.2%) patients with 7 acute lymphoblastic leukemia (ALL)-BC and 5 acute myeloid leukemia (AML)-BC. Four of 7 patients with ALL-BC occurred within 6 months (1.8, 2.3, 3.4, and 4.8 months, respectively). The median time from IM treatment to ALL-BC was 4.6 months (range 1.8 - 35.6 months) which occurred more rapidly than patients with AML-BC (22.9 months, range 14.9 - 43.0 months). CML-related death occurred in 12 (2.8%) patients. Two hundred and thirty-five patients were classified as Group I, 38 Group II, 24 Group III, and 128 Group IV. Outcomes following IM treatment according to group stratification are summarized in Table 1. Group IV patients had a higher incidence of disease progression than Group I (P<0.0001). None of patients in Groups II and III had disease progression. There was no significant difference in the incidence of disease progression between Group I and Group II or III. Eleven of 12 patients with CML-BC were allocated in Group IV. Group I patients had significantly higher CI of MMR at 3 years (P<0.0001), MR^4.5 at 4 years (P< 0.0001), PFS at 9 years (P< 0.0001) and OS (P< 0.0001) than Group IV. When comparing Group I with Group II or Group III, no statistical difference was observed between the two groups in MMR at 3 years (P=0.884 and P=0.614, respectively), PFS at 9 years (P=0.469 and P=0.564, respectively) and OS (P=0.702 and P=0.794, respectively). There was also no significant difference in MR^4.5 at 4 years (50.3% vs. 34.8%, P=0.455) between Group I and Group II, whereas Group III had an inferior MR^4.5 at 4 years than Group I (20.5% vs. 50.3%, P=0.015).

Conclusions: Our results showed that CML-CP patients treated with front-line IM who failed to achieve EMR at 3 months had comparable MMR at 3 years, PFS and OS if they were able to achieve optimal molecular responses at 6 or 12 months. Most cases with ALL-BC occurred very early and unpredictably in whom early switch to 2^nd generation tyrosine kinase inhibitors might not be possible.

MMR: major molecular response; PFS: progression-free survival; OS: overall survival.

Grant support: XMRPG1A0083