CHRONIC MYELOID LEUKEMIA: IS THE REAL PROGNOSIS OF NEWLY DIAGNOSED PATIENTS REALLY SO GOOD?

Background
Precise, mature data about real-world treatment efficacy in modern era of chronic myeloid leukemia (CML) are still missing. Moreover, true incidence of persistent side effects of tyrosine kinase inhibitors (TKI) is rarely reported in clinical trials.

Aims
To give a real picture of TKI treatment by analyzing detailed, prospective database of all consecutive CML cases.

Methods
Data regarding all patients treated in the academic institution with the catchment area of about 2 million people were analyzed according to the European LeukemiaNet recommendations (Guilhot, Blood 2012). Diagnostic and treatment protocols follow ELN and EUTOS recommendation/standardization. TKI side effects were assessed according to CTCAEv4. 

Results
Two hundred and fourteen patients (median age 58 years, range 18-92; 53.7% of males) with newly diagnosed CML in 2005 – 2014 underwent the analysis: 194 patients (90.7%) in chronic phase (CP), 11 (5.1%) in accelerated phase, 8 (3.7%) in blast crisis, and in 1 (0.5%) case the phase was unknown. In total, 41 (19.2%) patients died during the follow-up (median 3.8 years, range 0.1-9.8): 22 patients due to CML activity, 13 patients due to causes probably not related to CML, and in 6 cases the reason was unknown. The first line therapy given to patients diagnosed in CP (Sokal high risk in 29.9%) was as follows: imatinib, N=152 (78.4%); nilotinib, N=24 (12.4%); dasatinib, N=6 (3.1%); other, N=7 (3.6%); none, N=5 (2.5%) due to death (N=3) and lost to follow-up (N=2) before the treatment start. The median follow-up of 182 patients in CP treated with 1^st line TKI was 45.3 months (range, 5.2-115.8). Estimated cumulative incidences of complete cytogenetic responses and major molecular responses at 48 months were 92.2% and 89.2%, respectively. Estimated OS (defined as the time from the start of TKI therapy to the death, with no censoring at the time of therapy change) at 48 months was 89%. Estimated PFS, FFS, EFS, and ATFS at the same time point were 89.9%, 74.5%, 67.4%, and 66.7%, respectively. In total, 38.5% of patients permanently discontinued the first line TKI. The reasons for discontinuation in group treated with imatinib (N=61/152; 40.1%) were resistance in 32/61 patients (52.4%), intolerance (13/61; 21.3%), and other reasons (16/61; 26.2%; in 9 cases the reason was participation in discontinuation trials, and in 5 patients non-CML related deaths). Reasons for nilotinib discontinuation (6/24; 25%) were as follows: resistance (N=1), intolerance (N=3), and other (N=2). Subsequent therapy after imatinib discontinuation included dasatinib (N=19), nilotinib (N=16), and other (N=15). After cessation of nilotinib, patients were treated with dasatinib (N=2), imatinib (N=2), and other therapy (N=2). Analysis of imatinib and nilotinib clinical non-hematological toxicity incidence during the time revealed significant proportion of clinically relevant events of grade 2-4, and their persistence during the whole follow-up (Tab. 1).     

Summary
About 10% of CML patients is diagnosed in advanced disease and many newly diagnosed patients still die from leukemia. Moreover, more than one third of patients in CP have changed the first line therapy, mainly due to resistance, or intolerance. ATFS is a valuable parameter covering all situations of treatment change. In patients who continue on originally chosen TKI, there is the evidence of clinically relevant adverse events persistence in many of them, which can influence quality of life and can contribute to drug non-compliance. More detailed analysis will be presented.

Keyword(s): Chronic myeloid leukemia, Imatinib, Tyrosine kinase inhibitor

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