Correlation between Duration of Concomitant Exposure to Acid Reduction Agents and Remission Rates in Newly Diagnosed CML Patients on TKI's
Authors: Kilcyone Adrian , Russo Pierantonio , Liljebris Charlotta , Nathan Ramaa , Anderson Carlton , Sicilia Michael , Moore Alex , Prasad Sudarshan , Andersson Per 
Published: December 2024

Objectives: Tyrosine Kinase Inhibitors (TKI's) have revolutionized outcomes for CML patients. However, pH dependent solubility and reduced bioavailability when co-administered with acid reducing agents (ARAs) may impact outcomes. While evidence suggests an association between concomitant use of ARAs with TKIs and poorer outcomes, registry data demonstrated that half of CML patients on TKI's are in need of and are co-prescribed PPI's. To date, no data has assessed the correlation between duration of concomitant exposure to ARA, remission rates and survival. The objective of this analysis was to understand the impact of duration of concomitancy on these outcome measures.

Methods: The Merative closed claims database from 2006-2023 was used to analyze CML patients new to TKI's with a label recommendation to avoid concomitant ARA's. Patients with at least one ICD-10 code of “not having achieved remission” and with a subsequent ICD-10 code of “achieved remission” were included. Concomitancy duration was measured as the percentage of TKI-treatment time when ARAs were co-prescribed. Cox proportional hazard regressions were performed, using both multivariate analysis (adjusting for covariates directly) and univariate analysis adjusted via entropy balancing weighted for sex, insurance type, region, age at index, baseline Elixhauser Comorbidity Index (ECI) and first/second generation TKI. An additional weighted analysis of remission code rates at 60 months was conducted for &gt;50% and &lt;50% concomitancy.

Results: 6,028 patients with CML were identified as having received TKI treatment with a recommendation against concomitant ARA use and with at least 12 months of history prior to TKI initiation. Of those, 1,625 (27%) of patients received an ARA concomitantly with TKI treatment at least once. In the Multivariate Cox Proportional Hazard analysis for remission, concomitancy duration was shown to exhibit a Hazard Ratio of 0.448 (p-value &lt;0.0005) indicating a 55.2% decrease in remission likelihood with 100% concomitancy. In the survival analysis, ARA concomitancy curation had a Hazard Ratio of 1.215 (p=NS), suggesting a trend towards an increased risk of mortality with 100% concomitancy. The adjusted univariate analysis for remission exhibited Hazard Ratio of 0.436 (p&lt;0.0005), indicating that a patient with 100% concomitancy is 56.4% less likely to achieve remission compared to a patient with no concomitancy. The survival analysis exhibited a Hazard Ratio of 1.461 (p=NS), indicating a trend toward a 46.1% increased risk of mortality compared to a patient with no concomitancy.

The remission code rate at 60 months was 55.9% for patients on TKI's alone vs 43.6% for patients with &lt;50% concomitancy (p&lt;0.00001) and vs 35.9% for patients with &gt;50% concomitancy (p&lt;0.00001).

Conclusion: Despite recommendations to the contrary, many patients are prescribed concomitant ARAs with their TKI. Our analyses suggest a correlation between duration of concomitancy and failing to achieve a remission code. Given that the key confounding factors were controlled through entropy balancing, the observed differences are likely due to lower bioavailability of the TKIs when gastric pH is increased. There is a need for therapeutic options whose bioavailability is less pH dependent and allows for concomitant use of ARA's without impacting bioavailability and remission rates.