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\begin{document}

\title{The Application of Therapeutic Drug Monitoring of Imatinib in the
Patients with Gastrointestinal Stromal Tumors (GISTs): A Retrospective
Cross-Sectional Study}



\author[1]{Jian Wang}%
\author[2]{Jin Xiang}%
\author[1]{Tao Wang}%
\author[1]{Wentao Wang}%
\author[1]{Bo Zhang}%
\author[1]{Yuan Yin}%
\affil[1]{Affiliation not available}%
\affil[2]{Institute of Clinical pharmacology}%


\vspace{-1em}



  
  \date{May 27, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Aims: The optimal dose of imatinib on survival in the adjuvant treatment
of patients with resected GISTs remains unsettled. Therefore, this study
aimed to assess the impact of the adjustment of dose based on imatinib
plasma trough concentrations (Cmin) on the prognosis of GIST based in
the adjuvant setting. Methods: We conducted a retrospective
cross-sectional study of GIST patients treated with imatinib.
Simultaneously, the blood samples at steady-state of the aforementioned
patients were obtained for the determination of imatinib Cmin. Inverse
probability of treatment weighting (IPTW) was used for reducing
selection bias in baseline characteristics. Kaplan--Meier analyses and
multivariate Cox proportional hazards were used to evaluate the
association of the different dosages of imatinib with recurrence-free
survival (RFS). Results: A total of 79 patients were identified in this
study. Of these patients treated with imatinib 200 mg/d (n=8), 300 mg/d
(n=33), 400 mg/d (n=37), and 600 mg/d (n=1)the mean\selectlanguage{ngerman}±standard deviation
(SD) imatinib Cmin was 704±299ng/mL, 1153±473.3ng/mL, and
1246±491.3ng/mL, respectively. Additionally, imatinib Cmin of 200-mg/day
group was significantly lower than groups of 300- (P=0.036) and
400-mg/day (P=0.016), no significant difference in the Cmin of 300- and
400 -mg/day group (P=0.427) (Fig 3). Before and after adjustment by
propensity score-based IPTW, no significant difference in
recurrence-free survival between the Conclusions: Our findings provide a
new insight that imatinib Cmin may be used as a potential biomarker, to
assist in the evaluation of the safety, and efficacy of individualized
dosage adjustments in the adjuvant setting.%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


\textbf{1 INTRODUCTION}

Gastrointestinal stromal tumors (GIST) are the most common type of
sarcoma derived from the digestive tract and are characterized by the
common presence of oncogenic mutations in genes encoding the KIT or
PDGFRA receptor tyrosine kinases.1 The advent of imatinib, a tyrosine
kinase inhibitor (TKI), has greatly improved the oncological outcomes of
GISTs. \textsuperscript{1,2} It has been widely validated that the
patients with resected GIST at intermediate-, high-risk could benefit
from the imatinib adjuvant setting, especially recurrence-free survival
(RFS).\textsuperscript{3-13} A randomized clinical trial (SSG XVIII/AIO)
reported that RFS was significantly better in 3 years of imatinib when
compared with 1-year arm, indicating that prolonged the duration of
imatinib adjuvant therapy leading to improving the prognosis of these
patients.\textsuperscript{10} Furthermore, it has been reported that
about 50\% of deaths may be avoided during the first 10 years of
follow-up following surgical resection with longer adjuvant imatinib
treatment.\textsuperscript{13}

However, it is noted that approximately 50\% of the patients
discontinued imatinib treatment early. Of these, quite a proportion of
patients are intolerant to imatinib-related adverse
reactions.\textsuperscript{10} In real clinical practice, physician
usually consider dose reduction for the above patients with GISTs to
alleviate drug toxic effects and the maintenance of imatinib
treatment.\textsuperscript{14-18}So far, the feasibility of low-dose
imatinib adjuvant therapy remains unknown. Generally, imatinib is
initiated at a fixed dose of 400mg/d in the patients regardless of body,
which is thought to be a potential contributor to variability in
imatinib systemic exposure.

On the other hand, numerous studies have shown that imatinib plasma
trough concentration (C\textsubscript{min}) is significantly associated
with the prognosis of GISTs and chronic myelogenous leukemia
(CML).\textsuperscript{19-21}Furthermore, the patients with a threshold
of C\textsubscript{min} [?] 1100ng/mL have a favorable prognosis when
compared to those with C\textsubscript{min} less than
1100ng/mL.\textsuperscript{19} Another real-world study demonstrated
that the correlation of threshold of C\textsubscript{min} 760 ng/mL in
patients with prolonged progression-free survival
(PFS).\textsuperscript{20} Thus, it is necessary to underscore the
significance of close clinical monitoring to continue imatinib treatment
for patients at intermediate and high risk.

In this case, we conducted a retrospectively cross-sectional study, and
collected and analyzed data on patients with resected GIST treated in
our institute with imatinib at either 200 mg daily, 300 mg daily, 400 mg
daily, or 600 mg daily, to elucidate the impact of different dosages of
imatinib on these patients. In addition, the distribution of the
imatinib C\textsubscript{min} at different levels of doses in patients
was evaluated in this study. Collectively, the main objective of this
study was to explore that imatinib C\textsubscript{min}, as a biomarker,
is used to evaluate the feasibility, safety, and efficacy of the
different levels of imatinib doses in the adjuvant treatment setting.

\textbf{2 MATERIALS}

From 2019 to 2020, the patients with histologically confirmed GIST in
Sichuan University Gastrointestinal Surgery Center in Chengdu, China,
actively participated in this study. Inclusion criteria are as follows:
(1) [?]18year-olds with hepatic and renal functions, adequate
hematological, histologically proven GIST; (2) Eastern Cooperative
Oncology Group performance status (ECOG PS) [?]2; (3) The duration of
imatinib adjuvant therapy at least 29days. The study protocol was
approved by the medical ethics review boards and performed following the
Declaration of Helsinki. All patients provided written informed consent
before registration. This trial was registered with the Chinese Clinical
Trial Registry and the registration number was ChiCTR1900020854
(\emph{http://www.chictr.org.cn}.). Patients underwent follow-up with
enhanced computed tomography or magnetic resonance imaging scans every 6
months for the first 2 years, every 1 year for the next 5 years in the
process of imatinib adjuvant therapy. Hematological and
non-hematological adverse events were documented and graded in light of
CTCAE (Common Terminology Criteria for Adverse Events Version 5.0) v5.0.
Moreover, patient medical records were reviewed
retrospectively.\textsuperscript{22}

Clinical data of patients with GIST, who had been treated with various
doses of imatinib (200--600 mg/day) for at least 29 days were collected
between December 2019 and November 2020. Within 24\selectlanguage{ngerman}±2 h after the last
dosage of imatinib, blood samples (at least 3 mL) were collected into
heparinized tubes, centrifuged at 3,000 rpm for 10 min at room
temperature, and stored at \selectlanguage{english}-80degC until analysis. C\textsubscript{min}was
measured by a validated liquid chromatography-tandem mass spectrometry
(LC-MS/MS) method, specific methods have been previously
reported.\textsuperscript{23} All samples were detected in the
Laboratory of Clinical Pharmacology, West China Hospital of Sichuan
University (Chengdu, China). In addition, to evaluate the correlations
between imatinib C\textsubscript{min} and different dosages, the
patients were divided into four groups according to the imatinib
C\textsubscript{min} quartiles. The lower quartile (Q1) included the
25\% of patients with the lowest imatinib C\textsubscript{min}; Q2 and
Q3 indicated the 25 \% below and above the median concentration,
respectively; Q4 included the 25\% of patients with the highest imatinib
C\textsubscript{min}.

Statistical analysis

Pearson \selectlanguage{greek}χ\selectlanguage{english}\textsuperscript{2} or Fisher's exact test was used for the
comparison of categorical variables, while the Wilcoxon rank-sum test
was used for ordinal and continuous variables. Recurrence-free survival
(RFS) was the primary endpoint of this study, which was defined as the
time from the date of the first dose of imatinib to the date of the
first documented tumor recurrence assessed by radiographic imaging or
mortality resulting from any cause. Patients who were alive and without
the disease-specific recurrence were censored at the last follow-up.

We calculated the inverse probability of treatment weighting (IPTW)
method using the propensity scores for eliminating the effects of
confounding and selection bias by creating a pseudo-sample with the
method as reported previously. \textsuperscript{24,25} To estimate the
IP weights, we calculated each patient's probability of imatinib dosage
adjustment via application of multivariate logistic regression model,
with dosage adjustment of imatinib as the outcome and BSA, age, gender,
risk stratification, mutation status, primary tumor site, and imatinib
trough concentration (C\textsubscript{min}) as covariates. The IP
weights were then calculated based on each patient's estimated
probability of whether dose reduction of imatinib, given their actual
regimen of imatinib therapy.

To study the effect of dosage of imatinib adjustment on RFS of resected
GISTs, weighted Cox proportional hazard regression models were
estimated. Hazard ratios (HRs) along with their 95\% confidence
intervals (CI) were reported. RFS was calculated by the Kaplan--Meier
method and compared by log-rank test. Cox proportional hazard model was
used to assess the prognostic factors for the IPTW-matched patients. All
statistical analyses were performed by using RStudio
(\emph{https://www.rstudio.com/}) in the text of R, version 4.1.2 (R
Core Team 2021, Vienna, Austria) (\emph{https://www.r-project.org/}).
All tests were two-sided, P-values less than .05 were considered
statistically significant.

\textbf{3 RESULTS}

To determine the therapeutic outcomes and safety of adjuvant therapy in
the setting, and eventually, a total of 79 GIST patients fulfilling the
inclusion criteria were included in this study (Figure 1). As shown in
Figure 2, distribution of steady-state imatinib C\textsubscript{min} of
postoperative patients with following imatinib adjuvant therapy at least
day 29. Of these patients treated with imatinib 200 mg/d (n=8), 300 mg/d
(n=33), 400 mg/d (n=37) and 600 mg/d (n=1), the mean\selectlanguage{ngerman}±standard deviation
(SD) imatinib C\textsubscript{min} was 704±299ng/mL, 1153±473.3ng/mL,
1246±491.3ng/mL, and 1621ng/mL, respectively. Furthermore, these
patients were divided into four groups four groups based on the levels
of imatinib C\textsubscript{min}. The Q1 (335 to 807 ng/mL; n=20), Q2-Q3
(807 to 1347 ng/mL; n=40), and Q4 (1347 to 2919 ng/mL; n =20). The 8
patients in the 200-mg dose group, five were in Q1, three were in Q2-Q3;
for the 33 patients in the 300-mg dose group, 12 patients were in
quartile 1 (Q1), 17 were in Q2-Q3, and seven were in Q4; for the 37
patients in the 400-mg dose group, six were in Q1, 19 were in Q2-Q3, and
12 were in Q4. It is noteworthy that the proportion of patients reaching
the predefined target C\textsubscript{min} (1100ng/mL) was comparable
between both different dose groups, with 54.1\% (20/37) of 400-mg dose
group and 48.5\% (16/33) of 300-mg dose group reaching the target (P =
0.82). Furthermore, when the predefined target imatinib
C\textsubscript{min} was defined as 760ng/mL, no significant difference
was observed between the above-mentioned two groups (55.9\% (33/37) vs.
44.7\% (26/33), P=0.33). In addition, the steady-state imatinib
C\textsubscript{min} of 200-mg/day group was significantly lower than
groups of 300- (P=0.036) and 400-mg/day (P=0.013), no significant
difference in the C\textsubscript{min} of 300- and 400 -mg/day group
(P=0.427) (Fig 3A). Additionally, the higher imatinib
C\textsubscript{min} levels in women were observed in the 300 and 400-mg
daily groups when compared with males (Fig 3B). On the other hand, we
excluded the patients with 200mg/d and 600mg/d because of the limited
patients in this study, and eventually, 79 patients were identified for
further analysis. The baseline clinical characteristics of the
aforementioned patients were shown in Table 1. With regard to the
adverse drug reactions (ADRs), as shown in Table 2, the most common mild
adverse reactions were periorbital edema (71.4\%), followed by muscle
cramps (59.5\%), nausea and vomiting diarrhea (53.2\%), fatigue
(35.4\%), and et al. Generally, imatinib was well tolerated, while
mild-to-moderate ADRs (grade 1 and 2) were found in these patients. The
median follow-up for the entire cohort was 51.1 months (interquartile
range (IQR), 33.4 to 65.0 months). A comparison of prognostic outcomes
in the PTW-adjusted cohort showed no significant difference in RFS
between the 300-mg and 400-mg daily groups (Figure4). The median RFS in
the 400-mg daily group was 130 months (95\% CI 130--not reached) versus
not reached for those in the 300-mg daily group (p = 0.47).
Additionally, the result of multivariate Cox proportional hazards
regression analysis showed that a dose of 300-mg daily has no
significant impact on RFS (hazard ratio {[}HR{]} 3.5; 95\% confidence
interval {[}CI{]} 0.3-44.1). This is consistent with the result (HR 2.3;
95\% CI, 0.2-30.4) after the IPTW-adjusted.

\textbf{4 DISCUSSION}

It is widely acknowledged that measuring the steady-state imatinib
C\textsubscript{min} level of imatinib is of important guiding
significance for medication instructions and dosage individualization
for GIST patients.\textsuperscript{14-17,19,20} The study conducted by
Demetri and colleagues found out that patients with advanced GIST with
the threshold of imatinib C\textsubscript{min} more than 1100 ng/mL have
a favorable progression-free survival (PFS) compared to these less than
1100 ng/mL.\textsuperscript{19} In this study, the imatinib
C\textsubscript{min} in 51.4 \% of patients with GIST was more than
1,100 ng/mL. This outcome is superior to a study in Holland, where only
33.3\% of patients had imatinib C\textsubscript{min} values of 1,000
mg/L in all samples of 180 patients.\textsuperscript{26}Additionally,
Bouchet et al found a significant correlation between the imatinib
C\textsubscript{min} threshold of 760 ng/mL and longer PFS for patients
with advanced GIST.\textsuperscript{20}An increasing number of studies
have demonstrated that imatinib increases the RFS of GIST patients,
while retaining patients on therapy following a radical resection
remains challenging because of discontinuation of imatinib therapy
occurring in a percentage of patients owing to drug-related adverse
events (AEs).\textsuperscript{10,16} In addition, the study conducted by
Chandrajit P and colleagues reported that women were prone to
discontinuation of fixed-dose imatinib of 400mg/d, and had higher
imatinib C\textsubscript{min} levels compared with men, indicating that
lower doses could be considered. \textsuperscript{9}Although the
C\textsubscript{min} level of imatinib is associated with the prognosis
of GIST, it is still undefined that whether individualized dosage
adjustments based on the C\textsubscript{min} level would provide
clinical benefits to GIST patients, such as improving the long-term
prognosis and reducing imatinib-related toxicity. Additionally, the
findings of our study show patients in low-dose arms usually are
characterized by elderly female predominance and lower BSA. This is
consistent with the research conducted by Yuichi et
al.\textsuperscript{17} Moreover, no significant differences in RFS and
C\textsubscript{min} levels of 300- and 400-mg daily groups were
observed in our study, suggesting that it may be feasible to apply
individualized dosage adjustments based on the imatinib
C\textsubscript{min} level. On the other hand, numerous studies have
been shown that higher imatinib C\textsubscript{min} levels are
associated with imatinib-related toxicity.\textsuperscript{14,16,18} But
pharmacokinetic data were too limited to draw any significant
correlation of C\textsubscript{min} with drug toxicity in this study. It
is noteworthy that the Chinese and Japanese populations were prone to
experience imatinib treatment-related serious adverse events compared
with that in the population of European ancestry when with standard dose
of imatinib is 400 mg once daily.\textsuperscript{17,26,27}

There are still several shortcomings in this study, the mutation
information of patients was limited because of economic status and their
wills. Therefore, we cannot further investigate the impact of tumor
mutational status on long-term oncological outcomes of resected GIST
patients with imatinib adjuvant therapy. However, a multi-institutional
European retrospective study conducted by Bruno et al found that a daily
dose of 800 mg versus 400mg for GIST patients with harboring exon 9 kit
mutations did not demonstrate better outcomes in terms of survival
results in the post-operative setting, in agreement with the result of a
study conducted by Almudena and colleagues.\textsuperscript{12} In
addition, the result of the ACOSOG Z9001 trial shows that tumor genotype
seems did not have a significant impact on the RFS of resected patients
at high risk.\textsuperscript{5} Besides, the sample of our study was
small, and large sample, prospective multicenter research is warranted.
Furthermore, it is mandatory to establish the effective threshold of
imatinib C\textsubscript{min} of the Chinese population of GIST
patients.

\textbf{5 CONCLUSIONS}

In conclusion, considering the limitations of the retrospective analysis
and the small size of the sample, an additional effort should be
supported on an international basis to clarify the role of adjuvant
therapy in this setting. Even though our study is limited by the
selection bias and small size of the sample, we believe that our results
should be considered when adjusting the regimen of imatinib for patients
who are intolerant to standard-dose imatinib therapy in the absence of a
randomized clinical trial.

Figure1. The flow diagram of research cohort inclusion and exclusion.

Figure2. The distribution of C\textsubscript{min} in different dose
groups. The horizontal line represents C\textsubscript{min} =1100 ng/mL,
and the two vertical lines represent 25\% and 75\% percentiles (1,100
and 2,040 ng/mL), respectively.

Figure3. Association of different doses of imatinib and imatinib plasm
trough concentration (C\textsubscript{min})(A). The group of 600-mg/d
was only one patient and thus was excluded. Correlations between
imatinib C\textsubscript{min} and gender in 300-, and 400-mg/d
groups(B).

Figure4. Recurrence-free survival in the unmatched (A), and the inverse
probability of treatment weight-adjusted analysis (B) in groups of
patients with different doses.

\textbf{ACKNOWLEDGEMENTS}

Funding: This work was supported by the 1.3.5 project for disciplines of
Excellence-Clinical

Research Incubation Project, West China Hospital, Sichuan University
(19HXFH054), and the Sichuan Provincial Health and Family Planning
Commission key research project (20ZD007).

\textbf{CONTRIBUTORS}

B.Z. and Y.Y. designed the study. J.X. performed the imatinib
quantification in plasma. T.W. and J.W. performed the pharmacokinetic
and statistical analysis, interpreted the data, and wrote the
manuscript. W.W. and J.X. critically reviewed the manuscript. All
authors approved the final version of the manuscript.

\textbf{CONFLICT OF INTEREST}

The authors declare that they have no competing interests

DATA AVAILABILITY STATEMENT

Research data are not shared.

ORCID

Jian Wang\emph{https://orcid.org/0000-0001-7280-0566}

Tao Wang\emph{https://orcid.org/0000-0002-0699-5921}

Wentao Wang\emph{https://orcid.org/0000-0002-6966-2665}

Bo Zhang\emph{https://orcid.org/0000-0002-0254-5843}

Yuan Yin\emph{https://orcid.org/0000-0001-9654-7374}

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\textbf{Hosted file}

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\includegraphics[width=0.70\columnwidth]{figures/Figure-2/Figure-2}

\end{center}
\end{figure}

\textbf{Hosted file}

\verb`Figure 3.pptx`  available at \url{https://authorea.com/users/739897/articles/713180-the-application-of-therapeutic-drug-monitoring-of-imatinib-in-the-patients-with-gastrointestinal-stromal-tumors-gists-a-retrospective-cross-sectional-study}

\textbf{Hosted file}

\verb`Figure 4.pptx`  available at \url{https://authorea.com/users/739897/articles/713180-the-application-of-therapeutic-drug-monitoring-of-imatinib-in-the-patients-with-gastrointestinal-stromal-tumors-gists-a-retrospective-cross-sectional-study}

\textbf{Hosted file}

\verb`Tbele 1.docx`  available at \url{https://authorea.com/users/739897/articles/713180-the-application-of-therapeutic-drug-monitoring-of-imatinib-in-the-patients-with-gastrointestinal-stromal-tumors-gists-a-retrospective-cross-sectional-study}

\textbf{Hosted file}

\verb`Table 2.docx`  available at \url{https://authorea.com/users/739897/articles/713180-the-application-of-therapeutic-drug-monitoring-of-imatinib-in-the-patients-with-gastrointestinal-stromal-tumors-gists-a-retrospective-cross-sectional-study}

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