Contemporary Practice Patterns of Tyrosine Kinase Inhibitor Use Among Older Patients with Chronic Myeloid Leukemia in the United States
Authors: Shallis Rory M. , Wang Rong , Bewersdorf Jan Philipp , Zeidan Amer M. , Huntington Scott F. , Davidoff Amy J , Ma Xiaomei , Podoltsev Nikolai A. 
Published: February 2021

Introduction: BCR-ABL1-directed tyrosine kinase inhibitor (TKI) therapy is the standard of care for patients (pts) with chronic-phase chronic myeloid leukemia (CML). Several TKI agents are available and approved for use in the frontline (1L) setting, specifically imatinib and the second-generation TKIs dasatinib, nilotinib, bosutinib. No prospective study has compared the efficacy of the second-generation TKIs, so the choice of 1L TKI may be tailored to disease risk as well as patient characteristics such as age and comorbidity. As many CML pts are older, they have a greater burden of comorbidities that may be relevant to the initial TKI choice and sequence of additional TKI lines of therapy (LOT). We sought to describe the patterns of TKI use in older CML pts in the United States. We expected imatinib to be the most common 1L TKI for older pts, but that switching to another TKI within 12 months of diagnosis would be common.
Methods: We assembled a population-based cohort of older CML pts diagnosed during 2007-15 and included in the Surveillance, Epidemiology, and End Results (SEER) database who: 1) were age 66-99 years at diagnosis, 2) had continuous Medicare Parts A/B and D coverage from 1 year and 3 months, respectively, before diagnosis to end of follow-up and 3) did not receive a TKI within 3 months before diagnosis. Pts were followed from diagnosis to change in Medicare status, death, or 12/31/2016, whichever came first. We identified 5 available TKIs (imbatinib, bosutinib, dasatinib, nilotinib, and ponatinib) for the treatment of CML from diagnosis to the end of follow-up. A switch from one TKI to another was defined as a new TKI LOT.
Results: We identified 828 pts with newly-diagnosed CML initiating a TKI. The median time from diagnosis to TKI initiation was 45 (IQR 29-81.5) days and median follow-up for the cohort was 2.2 years. The median age of pts was 75 (interquartile range [IQR] 70-81) years; 50.8% were female and 88.2% were white. A total of 241 (29.1%) TKI users also received hydroxyurea after diagnosis.
The proportion of pts ever receiving a TKI increased over time from 50.0% among pts diagnosed in 2007 to 69.5% among pts diagnosed in 2015 (Figure 1). TKI users received up to 5 available TKIs, with 66.1%, 24.4% and 7.7% pts having ever used 1, 2 and 3 TKIs, respectively. Only 15 (1.8%) pts used &gt;4 different TKIs. Imatinib was the most common ever-used TKI (72.6%) followed by dasatinib (38.3%) and nilotinib (28.1%); bosutinib, the latest available during the study timeframe, was used in only 38 (4.6%) pts. Only 16 pts (1.9%) ever-used ponatinib with nearly all pts using it as &gt;2nd LOT.
Imatinib (65.3%) was the most used 1L TKI. With increasing availability and use of dasatinib and nilotinib during the study period, the use of imatinib as 1L decreased during 2009-2015 (Figure 1). The median duration of the 1L treatment was 17.8 (IQR 4.5-37.8) months. At 360 days after TKI initiation, among 689 alive pts, 507 (73.6%) were still on the 1L TKI and 129 (18.7%) already switched to another TKI LOT. Among 281 TKI users who eventually switched to another TKI LOT, only 35 (12.5%) pts had received ≥4 LOT with a maximum of 7 LOT as pts may return to a previously abandoned TKI as a subsequent LOT. Median time on post-1L TKI LOT progressively decreased with each additional TKI LOT (10.5, 8.0, and 4.5 months for 2nd, 3rd, and 4th LOT, respectively). The most common 2nd LOT TKI was dasatinib (38.4%) and nilotinib (32.0%). However, imatinib (30.9%) was the most common choice as 3rd LOT among 110 pts receiving &gt;3 TKI LOT (Table 1). Of the 110 pts that switched from 1L imatinib therapy, 31 (28.2%) eventually returned to imatinib with nearly all returning to it as the 3rd TKI LOT. Only 4.2% and 2.7% of pts treated with 1L dasatinib and nilotinib returned to it after 2nd TKI LOT.
Conclusions: We report a large, contemporary analysis of TKI use in older CML pts which showed imatinib to be the preferred 1L TKI with a majority of patients remianing on it after 1 year of treatment. Despite the associated pulmonary toxicity and vaso-occlusive complications of dasatinib and nilotinib, respetively, these TKIs were used in a substantial proportion of older pts with the number of users increasing over time. One-third of 1L TKI users switched to another TKI LOT with one-quarter of pts switching from 1L imatinib eventually returning to imatinib, suggesting that the toxicity of imatinib is likely tolerable among those older CML pts. This work was supported by the Frederick A. DeLuca Foundation.

Disclosures
Wang: Celgene/BMS: Research Funding. Zeidan:Leukemia and Lymphoma Society: Other; CCITLA: Other; Celgene / BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Astex: Research Funding; MedImmune/Astrazeneca: Research Funding; ADC Therapeutics: Research Funding; Aprea: Research Funding; Epizyme: Consultancy, Honoraria; Ionis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Cardiff Oncology: Consultancy, Honoraria, Other; BeyondSpring: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Incyte: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Acceleron: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Cardinal Health: Consultancy, Honoraria; Taiho: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Trovagene: Consultancy, Honoraria, Research Funding. Huntington:DTRM: Research Funding; Genentech: Consultancy; Pharmacyclics: Honoraria; Novartis: Consultancy; AbbVie: Consultancy; Astrazeneca: Honoraria; Bayer: Consultancy, Honoraria; Celgene: Consultancy, Research Funding; TG Therapeutics: Research Funding. Davidoff:Celgene: Research Funding. Ma:Celgene: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Podoltsev:Samus Therapeutics: Research Funding; Kartos Therapeutics: Research Funding; Sunesis Pharmaceuticals: Research Funding; Daiichi Sankyo: Research Funding; Astellas Pharma: Research Funding; Boehringer Ingelheim: Research Funding; CTI biopharma: Consultancy, Honoraria, Research Funding; Bristol-Myers Squib: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Blueprint Medicines: Consultancy, Honoraria; Agios Pharmaceuticals: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Alexion: Consultancy, Honoraria; Astex Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Research Funding; Genentech: Research Funding; AI Therapeutics: Research Funding; Arog Pharmaceuticals: Research Funding.