Chronic Myeloid Leukemia in Chronic Phase: Survival in the Era of Tyrosine Kinase Inhibitors Is Similar to That of the General Population in All Age Groups
Authors: Sasaki Koji , Strom Sara S. , O'Brien Susan , Jabbour Elias , Ravandi Farhad , Konopleva Marina , Borthakur Gautam , Pemmaraju Naveen , Daver Naval , Pierce Sherry R. , Kantarjian Hagop M. , Cortes Jorge E. 
Published: October 2019

Abstract
Introduction
Tyrosine kinase inhibitors (TKIs) are effective treatments for chronic myeloid leukemia in chronic phase (CML-CP) in terms of response rates and clinical outcomes including overall survival (OS). The purpose of this study was to compare OS in each age group with newly diagnosed CML-CP compared to that of general population in the same age group in the era of multiple TKIs.
Methods
Response and survival data for 483 patients (pts) with newly diagnosed CML-CP who enrolled in five consecutive or parallel prospective clinical trials of imatinib at a dose of 400 mg or 800 mg daily, imatinib at a dose of 800 mg with pegylated interferon, dasatinib, or nilotinib were analyzed. The pts were divided into groups by age at diagnosis, as follows: 15-45 years; 45-65 years; 65-85 years; over 65 years. All pts, regardless of age, were divided into the following response groups within 1 year of treatment: complete cytogenetic response (CCyR); major molecular response (MMR); MR4.5 defined as more than or equal to 4.5 log reduction of BCR-ABL on the international scale; or complete molecular response (CMR). Pts also were assessed for OS, event-free survival (EFS), transformation-free survival (TFS), and failure-free survival (FFS). OS was dated from the start of therapy until death from any cause at any time. EFS was calculated from the start of therapy to loss of complete hematologic response, loss of major cytogenetic response, transformation to accelerated (AP) or blast phase (BP), or death from any cause during study therapy. TFS was calculated from the start of therapy to transformation to AP or BP, or death during study therapy. FFS was calculated from the start of imatinib, dasatinib or nilotinib to an event (as defined above), discontinuation for any reason, or death. The Kaplan-Meier method was used to calculate OS, EFS, TFS, and FFS. A log-rank test was used for univariate comparisons. Pvalues of less than 0.05 were considered statistically significant. Five-year relative survival rates were calculated from the five-year absolute OS divided by the estimated five-year OS in the general population. Estimated OS rates in the U.S. general population were obtained from national vital statistics reports for the year 2009.
Results
Of the 483 pts analyzed in the study, 271 were treated with imatinib, 101 with nilotinib, and 111 with dasatinib. The age breakdown was as follows: 15-45 years, 197 pts; 45-65 years, 222 pts; 65-85 years, 64 pts; over 65 years, 64 pts. No pts older than 85 years were enrolled in this study. Sokal risk score at diagnosis, and type of TKI treatment were analyzed by age group, cumulative best response, and five-year OS, EFS, TFS, and FFS, and the results are summarized in Table 1. Five-year OS in the general population, relative five-year OS in all age groups, and relative five-year OS by response group are also described in Table 1. As expected, 5-year OS decreased with increasing age groups, but for all age groups OS was similar to 5-year OS in the corresponding age group in the general population. 5-year OS in pts of ages 15-85 who achieved CCyR or better was similar to that in the general population.
Conclusion
In the era of TKIs, the OS rates in pts with newly diagnosed CML-CP in all age groups are only slightly lower to that of general population. However, the OS rates in pts who achieved CCyR or better within 1 year of treatment is similar to that of general population.
Table 1. Patient Characteristics and Outcomes by Age Group Age 15-45 [n= 197] No. (%) Age 45-65 [n= 222] No. (%) Age 65-85 [n= 64] No. (%) P Sokal Risk Score .419 Low 129 (65) 158 (71) 48 (75) Intermediate 56 (28) 48 (22) 12 (19) High 12 (6) 16 (7) 4 (6) Type of TKIs .364 Imatinib 113 (57) 116 (52) 42 (66) Nilotinib 42 (21) 50 (23) 9 (14) Dasatinib 42 (21) 56 (25) 13 (20) Cumulative Best Response CMR 91 (46) 124 (56) 33 (52) .142 MR4.5 127 (64) 158 (71) 47 (73) .230 MMR 162 (82) 197 (89) 54 (84) .162 CCyR 171 (87) 208 (94) 59 (92) .048 5-y Outcome (%) FFS 77.9 74.5 60.6 .043 TFS 93.8 93.4 87.4 .224 EFS 81.0 89.2 78.9 .094 OS 96.2 93.5 80.1 < .001 5-y Absolute OS 5-y Relative OS 5-y OS in General Population Age Group (%) Ages 15-45 96.2 96.9 99.3 Ages 45-65 93.5 97.1 96.3 Ages 65-85 80.1 97.1 82.5 Ages 15-85 92.7 98.2 94.4 Ages 15-85 by Response (%) CCyR within 1 year 97.3 103.1 94.4 MMR within 1 year 97.9 103.7 94.4 MR4.5 within 1 year 97.1 102.9 94.4 CMR within 1 year 96.7 102.4 94.4

Disclosures
Jabbour: Ariad, Novartis, BMS, Pfizer, and Teva : Consultancy. Kantarjian:ARIAD, Pfizer, Amgen: Research Funding.