The management of imatinib-associated severe skin rash in gastrointestinal stromal tumor: desensitization therapy and pharmacogenetic investigation

Abstract

Background

Skin rash is one of the most common imatinib-associated adverse events in patients with gastrointestinal stromal tumors (GISTs), potentially compromising treatment adherence and therapeutic efficacy. This study presents a personalized desensitization management of imatinib-associated severe rash with therapeutic drug monitoring (TDM) and pharmacogenetic investigation.

Methods

Among 712 patients with GIST receiving imatinib, 54 patients (7.6%) developed severe skin rash (grade 3: 37 patients, recurrent grade 2: 17 patients) and underwent personalized desensitization treatment. This approach involved a temporary cessation of imatinib and initiation of systemic steroids, followed by reintroduction of imatinib with TDM-assisted gradual dose escalation, while steroids were tapered until discontinuation. Pharmacogenetic analysis was conducted to explore potential genetic susceptibility.

Results

Following desensitization therapy for severe rash, the majority of patients (92.6%) successfully resumed imatinib treatment at personalized maintenance doses. Grade 3 rash occurred earlier than recurrent grade 2 rash before desensitization therapy (P = .004) and was associated with lower final maintenance doses of imatinib after desensitization (P = .010). The final imatinib trough concentrations postdesensitization were significantly lower than those at rash onset (P < .001). Pharmacogenetic analysis identified IL-6R rs4129267 as significantly associated with imatinib-associated severe skin rash (odds ratio [OR] 1.966, 95% CI, 1.143-3.380, P = .015).

Conclusions

Personalized desensitization therapy assisted by TDM could effectively manage imatinib-associated severe skin rash. The early onset of grade 3 rash underscored the importance of vigilant monitoring during the initial phase of imatinib treatment. Genetic variant in IL-6R may be involved in rash pathogenesis.

Implications for Practice.

Imatinib-associated severe skin rash poses a challenge in the management of gastrointestinal stromal tumors, potentially leading to treatment discontinuation. This study demonstrates that personalized desensitization therapy assisted with therapeutic drug monitoring effectively enables most patients to resume imatinib. The early onset of grade 3 rash before desensitization highlights the need for close monitoring during initial imatinib treatment. Furthermore, the identification of IL-6R genetic variant associated with rash susceptibility suggests the potential for pharmacogenetic testing in guiding patient management strategy.

Introduction

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract, with an annual incidence of 10-20 cases per million.^1-4 Imatinib, a selective tyrosine kinase inhibitor targeting breakpoint cluster region-abelson (BCR-ABL) and platelet-derived growth factor receptor α (PDGFRA), is the standard treatment for advanced and adjuvant GIST, significantly improving survival outcomes.^5-10 Most imatinib adverse events (AEs) are mild and generally well-tolerated, but some patients may experience severe AEs.^11-13 Skin rash is one of the most prevalent imatinib-associated AEs, affecting one-third of patients with GIST.^12-17 It typically manifests as erythematous and maculopapular lesions on the forearms and trunk, often accompanied by pruritus and desquamation.^18,19 While mild to moderate imatinib-associated skin rash could be managed with symptomatic treatment,²⁰ severe cases occur in 3%-6.8% of patients, potentially compromising treatment compliance and efficacy.^12,14,15

Systemic steroids have been used for the management of imatinib-associated severe skin rash, with reported effective rates of 66.8%-75.8%,^15,21 and further exploration of desensitization strategies may provide further benefits. Therapeutic drug monitoring (TDM) could be used for monitoring drug efficacy and safety. Our previous research indicated that maintaining imatinib trough concentration over 738 ng/mL led to improved clinical outcomes in advanced GIST.²² Given the risk of subtherapeutic drug exposure due to dose modifications during desensitization, TDM may help mitigate underdosing risks. In addition, the underlying mechanism of imatinib-associated skin rash remains to be elucidated, and identifying genetic susceptibility may aid in risk stratification and personalized management approaches.

In this study, we evaluated a desensitization strategy for imatinib-associated severe skin rash in patients with GIST, incorporating TDM and pharmacogenetic analysis for personalized medicine.

Methods

Study population

This retrospective study enrolled 712 patients between 2017 and 2021. Eligibility criteria included having histologically confirmed GIST, receiving imatinib treatment, and age ≥ 18 years. Skin rash was graded according to the Common Terminology Criteria for Adverse Events version 5.0 (Table S1),²³ and imatinib-associated severe skin rash was defined as grade 3 or recurrent grade 2 rash. The study was approved by the Ethics Committee of the First Affiliated Hospital of Sun Yat-sen University (No. [2019] 59) and was conducted in accordance with the Declaration of Helsinki. All participants provided written informed consent for the study.

Desensitization therapy

In accordance with the management protocol for imatinib-associated severe skin rash at our center, recurrent grade 2 rash (2 occurrences) was managed with topical steroids ± H₁ receptor antagonists. For grade 3 rash or recurrent grade 2 rash (≥3 occurrences), a 7-9 week desensitization regimen was implemented (Figure 1). This approach involved a temporary cessation of imatinib and initiation of systemic steroids, followed by reintroduction of imatinib with TDM-assisted gradual dose escalation, while steroids were tapered until discontinuation. Specifically, imatinib was interrupted for 1-2 weeks, and patients received oral steroids (prednisone 30 mg/day or equivalent) along with H₁ receptor antagonists when pruritus was present. If skin rash resolved within 1-2 weeks, imatinib was reintroduced starting at 100 mg/day for 1 week, followed by weekly increments of 100 mg, with TDM monitoring to achieve the target therapeutic dose, specifically maintaining trough levels above 738 ng/mL in advanced settings while avoiding excessively high concentrations.²² One week after reaching the target dose, prednisone was tapered (20 mg/day for 1 week, 10 mg/day for 1 week, and 5 mg/day for 1 week) until discontinuation. Proton pump inhibitors were co-administered alongside systemic steroids for gastroprotection. In the event of rash recurrence during desensitization, the management approach was adjusted based on severity. Recurrence of grade 3 rash necessitated permanent discontinuation of imatinib treatment, while grade 2 rash recurrence was managed by modifying steroid dosage, generally increasing daily prednisone by 10-20 mg. Desensitization was considered successful if imatinib treatment could be continued without rash recurrence exceeding grade 1 that required further intervention within 16 weeks of completing the regimen.

Figure 1.

The desensitization therapy for imatinib-associated severe skin rash. Abbreviations: IM, imatinib; PPI, proton pump inhibitor; TDM, therapeutic drug monitoring; Q.M., every morning.

Genetic analysis

Genomic DNA was extracted from the whole blood samples of 528 patients with GIST receiving imatinib treatment (39 severe skin rash cases and 489 controls without rash occurrence). interleukin-6 (IL-6) genetic polymorphisms rs4129267, rs4537545, and rs4845625, selected according to the literature, were genotyped by Illumina ASA chip.

Statistical analysis

Descriptive statistics were conducted for all study variables. Continuous variables were reported as median (range), and categorical variables were represented as percentages. Nonparametric comparisons between 2 groups were performed using the Mann–Whitney U test. Categorical variables were analyzed using Pearson’s chi-square test or Fisher’s exact test, as appropriate. Logistic regression was performed to evaluate the associations between genetic polymorphisms and imatinib-associated severe skin rash. A 2-tailed P < .05 was considered statistically significant. To account for multiple comparisons in genetic analysis, Bonferroni correction was applied, setting the significance threshold at 0.017 (0.05/3).

Results

Frequency and characteristics of severe skin rash

Among 712 patients receiving imatinib, 54 (7.6%) patients developed severe skin rash and were further investigated in this study, with baseline characteristics summarized in Table 1. Severe skin rash manifested as recurrent grade 2 in 17 patients (31.5%) and grade 3 in 37 patients (68.5%). The predominant skin manifestations included maculopapular (79.6%) and lichenoid reaction (14.8%). Imatinib was administered as adjuvant therapy in 33 patients (61.1%) and for metastatic/recurrent disease in 21 patients (38.9%). Eosinophil elevation was observed in 61.1% of patients, with no significant correlation between eosinophil levels and rash gradings.

Table 1.

Demographic and clinical characteristics of GIST patients with imatinib-associated severe skin rash.

Characteristic	Value
Sex, N (%)
Male	30 (55.6)
Female	24 (44.4)
Age, median (range), years	57 (28-78)
Indication for therapy, N (%)
Adjuvant	33 (61.1)
Metastatic or recurrent	21 (38.9)
Primary site of tumor, N (%)
Stomach	26 (48.1)
Duodenum	8 (14.8)
Small bowel	18 (33.3)
Rectum	1 (1.9)
Other	1 (1.9)
KIT genotype, N (%)
KIT exon 9 mutation	4 (7.4)
KIT exon 11 mutation	44 (81.5)
KIT exon 13 mutation	1 (1.9)
Unknown	5 (9.2)
Imatinib treatment
Imatinib brand, N (%)
Glivec	29 (53.7)
Generic formulation	25 (46.3)
Time from imatinib initiation to the onset of skin rash, median (range), months	1.8 (0.1-64.0)
Initial dose of imatiniba, median (range), mg/d	400 (250-600)
Initial concentration of imatinibb, median (range), ng/mL	1395 (724-3743)
Morphology of skin lesions, N (%)
Maculopapular	43 (79.6)
Lichenoid reaction	8 (14.8)
Others	3 (5.6)
Grade of skin rash, N (%)
2c	17 (31.5)
3	37 (68.5)
Concurrent impairment of other organ functions, N (%)	6 (11.1)
Eosinophil elevationd, N (%)	22 (61.1)

^aInitial dose of imatinib at rash onset.

^bInitial concentration of imatinib at rash onset.

^cRecurrent grade 2 skin rash.

^dEosinophil levels were measured in 36 patients with severe skin rashes.

Effectiveness of desensitization therapy and correlation analysis

Among the 54 patients undergoing desensitization therapy, systemic steroids were administered to 42 patients with recurrent grade 2 rash (≥3 occurrences) or grade 3 rash, and 12 patients experiencing recurrent grade 2 rash (2 occurrences) received topical steroids (Figure 2). Following desensitization, 50 patients (92.6%) successfully resumed imatinib treatment, whereas 2 patients required permanent discontinuation of imatinib, and 2 others were lost to follow-up (Table 2). Steroid-related AEs were observed in 4 patients (9.5%). Soft tissue infections were reported in 3 cases, with one accompanied by hyperglycemia and another with fever requiring oral antibiotics. Additionally, one patient who underwent prolonged steroid therapy due to multiple rash recurrences developed duodenal ulcer.

Figure 2.

Desensitization strategy for imatinib-associated severe skin rash and outcomes in GIST patients.

Table 2.

Comparison of clinical characteristics in GIST patients with different gradings of imatinib-associated severe skin rash.

Characteristic	Grading of severe skin rash		P-value
	Grade 2a (N = 17)	Grade 3 (N = 37)
Initial dose of imatinibb, median (range), mg	400 (250-600)	400 (300-400)	.393
Initial concentration of imatinibc, median (range), ng/mL	1278 (724-2134)	1401 (776-3743)	.524
Time to the onset of skin rashd, median (range), months	3.3 (0.4-64.0)	1.0 (0.1-7.0)	.004
Final maintenance dose of imatinibe, median (range), mg	400 (200-600)	300 (150-400)	.010
Final concentration of imatinibf, median (range), ng/mL	1152 (383-2169)	1038 (484-2636)	.280
Treatment outcomes of skin rash, N (%)			.222
Cure	16 (94.1)	26 (70.3)
Alleviationg	1 (5.9)	7 (18.9)
Failure	0	2 (5.5)
Lost to follow-up	0	2 (5.5)

^aRecurrent grade 2 skin rash.

^bInitial dose of imatinib at rash onset.

^cInitial concentration of imatinib at rash onset.

^dTime from imatinib initiation to the onset of skin rash before desensitization.

^eFinal maintenance dose of imatinib after desensitization.

^fFinal maintenance concentration of imatinib after desensitization.

^gThe severity of skin rash reduced to grade 1.

The onset of grade 3 rash occurred significantly earlier than recurrent grade 2 rash prior to desensitization therapy (1.0 vs 3.3 months, P = .004) (Table 2; Figure 3A). The initial dose of imatinib at the time of rash onset, which ranged from 250 to 600 mg/day, showed no significant association with rash gradings. Similarly, the initial trough concentrations of imatinib measured at rash onset did not differ significantly between patients with recurrent grade 2 rash (median 1278 ng/mL) and those with grade 3 rash (median 1401 ng/mL).

Figure 3.

The analysis of imatinib-associated severe skin rash. (A) The association between the time from imatinib initiation to rash onset (before desensitization) and rash gradings. (B) The association between the final maintenance dose of imatinib (after desensitization) and rash gradings. (C) The comparison of imatinib concentrations at rash onset (before desensitization) and after desensitization therapy in patients with severe rash. Initial concentration: measured at rash onset before desensitization; final maintenance concentration: measured when receiving the final maintenance dose of imatinib after desensitization therapy. Grade 2 as recurrent grade 2 skin rash.

At the completion of desensitization, the final maintenance dose of imatinib ranged from 150 to 600 mg/day and was significantly associated with rash gradings (P = .010) (Figure 3B). The median final maintenance trough concentrations of imatinib were 1152 ng/mL in recurrent grade 2 rash and 1038 ng/mL in grade 3 rash, with no significant difference between the groups. Across all cases with severe rash, the final maintenance trough concentrations of imatinib after desensitization were significantly lower than the initial imatinib levels at rash onset (1068 ng/mL vs 1395 ng/mL, P < .001) (Figure 3C).

Pharmacogenetic analysis of IL-6R with skin rash

Logistic regression analysis identified rs4129267 in IL-6R as significantly associated with severe imatinib-induced skin rash (odds ratio [OR] 1.966, 95% CI, 1.143-3.380, P = .015) (Table 3). Genetic variants rs4537545 and rs4845625 were not statistically associated with skin rash after multiple testing correction (P > .017).

Table 3.

The association of IL-6R SNPs with imatinib-associated severe skin rash.

Gene	SNP	A1	A2	A1 freq., Cases	A1 freq., Controls	P-value	OR	L95	U95
IL-6R	rs4129267	C	T	0.782	0.637	.015	1.966	1.143	3.380
	rs4537545	C	T	0.769	0.637	.025	1.843	1.081	3.141
	rs4845625	T	C	0.641	0.508	.029	1.688	1.054	2.705

Abbreviations: A1, risk allele; A1 freq., cases, frequency of the risk allele in cases; A1 freq., controls, frequency of the risk allele in control; A2, reference allele; L95, lower 95% confidence interval; OR, odds ratio with reference to the corresponding A2 allele; SNP, single-nucleotide polymorphism; U95, upper 95% confidence interval.

Discussion

Effective management of imatinib-related AEs is essential for improving patient adherence and clinical outcomes. This study demonstrates the efficacy of a personalized desensitization therapy for imatinib-associated severe rash, achieving a success rate of 92.6%.

Systemic steroids have been utilized in the desensitization management of severe skin rash.²⁴ Park et al. reported that 66.8% of severe rash cases could be controlled with oral steroids and/or imatinib dose modifications.¹⁵ Furthermore, in a subsequent phase II clinical trial, they demonstrated that a 15-week systemic steroid desensitization strategy effectively managed 75.8% of severe rash cases without requiring imatinib dose adjustment.²¹ In the present study, a personalized desensitization protocol was employed, integrating systemic steroids, a brief imatinib discontinuation, and TDM, resulting in a 92.6% treatment success rate. Moreover, a lower incidence (9.5%) of steroid-associated AEs was observed than previously reported.²¹ Overall, the effectiveness and safety of this approach were evident.

The time to rash onset was associated with rash gradings, consistent with the previous study.²⁵ Considering the early onset of grade 3 rash before desensitization, proactive monitoring and early identification are imperative. Imatinib concentrations have been shown to correlate with both therapeutic efficacy and AEs.^26-28 Our previous research indicated that maintaining imatinib levels above 738 ng/mL was associated with improved treatment outcomes in advanced GIST.²² For patients in the adjuvant setting, while a therapeutic window has not been established, monitoring imatinib levels remained valuable. Given the lack of a well-defined upper therapeutic limit for imatinib, TDM served primarily to ensure that imatinib levels remained adequate to provide therapeutic effects in patients undergoing desensitization therapy.

Eosinophil elevation has been correlated with imatinib-associated rash severity, implicating inflammatory and immune-mediated responses.^15,29 Eosinophils contribute to inflammatory responses through cytokines such as IL-6, a pro-inflammatory mediator in skin pathology.^30-37 Genetic variants in IL-6R have been linked to cutaneous and inflammatory disorders,^38-45 and our study identified IL-6R rs4129267 as a risk factor for severe rash, suggesting its involvement in rash pathogenesis.

While our study presents an effective desensitization management of imatinib-associated severe rash, further exploration of its long-term impact on patient survival would strengthen this study. Additionally, TDM analysis was not performed in patients with mild rash or without rash, precluding comparisons of imatinib levels across these groups, and pharmacogenetic analysis was restricted to a subset of patients. Therefore, further investigation with multicenter, independent larger cohorts is needed to strengthen the findings.

Conclusion

In patients with GIST experiencing imatinib-associated severe skin rash, personalized desensitization therapy assisted by TDM demonstrated efficacy with a success rate of 92.6%. Grade 3 rash occurred earlier and required a lower final maintenance dose of imatinib after desensitization therapy, emphasizing the importance of close monitoring during the early phase of imatinib treatment. IL-6R genetic variant rs4129267 has been implicated in imatinib-associated skin rash development, suggesting a potential role for pharmacogenetic testing in predicting this adverse event.

Author contributions

Conceptualization and methodology: Xiaoman Liu, Yanzhe Xia, Xinhua Zhang, and Ke-Jing Tang. Data curation, investigation, formal analysis, and writing—original draft: Xiaoman Liu and Mengying Pi. Project administration and resources: Yanzhe Xia, Xinhua Zhang, and Ke-Jing Tang. Funding acquisition: Xiaoman Liu. Writing—review and editing: Yanzhe Xia, Xinhua Zhang, Ke-Jing Tang, Mukai Chen, Shirong Cai, and Yulong He. Final approval of manuscript: All authors.

Funding

This publication is based upon work from the National Natural Science Foundation of China, Grant/Award Numbers: 82104291; the Guangzhou Basic and Applied Basic Research Foundation, Grant/Award Numbers: SL2023A04J02117; the China International Medical Foundation, Grant/Award Numbers: Z-2021-46-2101-2023.

Conflicts of interest

None declared.

Data availability

The data underlying this article are available upon reasonable request to the corresponding authors.