A Single Institution Respective Study of Tyrosine Kinase Inhibitor Cessation in Patients with Chronic Phase CML in MMR
Authors: McCloskey James K. , Koprivnikar Jamie L. , Goldberg Stuart L. , Nyirenda Themba L , Stanislaus Genique , Howlett Christina , Faderl Stefan 
Published: November 2019

Abstract

Background: Imatinib revolutionized the treatment of chronic myelogenous leukemia (CML) demonstrating improved survival and durable response to treatment. Earlier and deeper response rates were observed with dasatinib and nilotinib in the front line setting compared to imatinib. Multiple clinical trials have revealed that carefully selected patients may safely discontinue TKI therapy. However, lifelong TKI therapy remains the standard of care outside of clinical trial.
Methods: We reviewed the charts of patients with chronic phase CML treated with imatinib, dasatinib or nilotinib for chronic phase CML between January 2010 and April 2015 and identified 29 patients that had discontinued therapy. We collected data on their treatment history, response to therapy, and outcomes following TKI withdrawal.
Results: At the time of TKI cessation all the patients had achieved an MMR (MR4) for at least 2 years. The median time in MMR prior to treatment withdrawal was 64 months. Twelve patients (41%) were treated with imatinib, 7 (24%) were treated with dasatinib, and 10 (35%) were treated with nilotinib. More than half of the patients had received prior treatment with an alternative TKI. At the time of data collection, 16 patients (55%) remained in MMR off therapy. The median time off treatment was 7 months (range: 3-24 months). The median time to loss of MMR was 5 months (range: 2-11 months). No significant difference was observed between TKI and time to loss of MMR (Table 1). Of those patients who lost MRR while off therapy, all achieved a second MMR upon resuming TKI therapy. Based on the average wholesale price, $3,149,576 was saved by cessation of TKI therapy during the observed period. The required follow up and PCR testing accounted for an additional cost of $84,200 for a net savings of $3,065,376.
Conclusions: TKI therapy can be safely discontinued in patients with an MMR duration more than two years with close follow up. While this is a small retrospective study, the results are in keeping with those observed in larger trials. With the life expectancy of patients with chronic phase CML now approaching that of the healthy population, lifelong use of TKI has important implications for patients in terms of medical costs and quality of life.
Table 1. Comparison of Patient Characteristics and Outcomes Off Treatment Variable Imatinib (n=12) Dastanib (n=7) Nilotinib (n=10) P-Value Age (years) Median (IQR) 55.5 (53.0 - 61.5) 68.0 (50.0 -72.0) 63.5 (51.0 - 72.0) 0.3811 Range 42.0 - 75.0 48.0 - 72.0 42.0 - 76.0 Gender Male n= 6 (50.0) n= 4 (57.1) n= 2 (20.0) 0.2266 Female n= 6 (50.0) n= 3 (42.9) n= 8 (80.0) Time on treatment prior to discontinuation Median (IQR) 98.0 (64.0- 110.5) 49.0 (39.0 - 69.0) 37.5 (27.0 - 60.0) 0.0016 Range 52.0 - 155.0 33.0 - 115.0 6.0 - 92.0 Time in MMR prior to stopping TKI Median (IQR) 52.5 (39.0 - 96.0) 37.0 (30.0 - 92.0) 71.0 (56.0 - 91.0) 0.6707 Minimum - Maximum 8.0 - 126.0 17.0 - 109.0 19.0 - 108.0 Time off treatment Median (IQR) 7.5 (3.0 - 12.0) 5.0 (2.0 - 9.0) 10.0 (6.0 - 12.0) 0.1599 Range 2.0 - 24.0 2.0 - 11.0 2.0 - 16.0 MMR status off treatment Remain in MMR N= 5 (41.7) N= 4 (57.1) N= 4 (40.0) 0.7970 Loss of MMR N= 7 (58.3) N= 3 (42.9) N= 6 (60.0) Time measured in months. Unless specified otherwise, data are presented as counts (percentages). Categorical variables were examined using Pearson's Chi-square test or Fisher's exact test, as appropriate. Continuous variables were examined using Kruskal-Wallis test or Proc mixed for one-way models, as appropriate. Any P<0.05 was considered statistically significant.

Disclosures
McCloskey: Novartis: Consultancy; Pfizer: Consultancy. Koprivnikar:Alexion: Consultancy. Goldberg:Novartis: Research Funding, Speakers Bureau; COTA: Employment, Equity Ownership, Other: Leadership, Stock; Pfizer: Research Funding; BMS: Research Funding, Speakers Bureau; Ariad: Research Funding, Speakers Bureau. Howlett:Teva: Speakers Bureau.