Abstract
Background
To achieve optimal clinical outcomes in patients with gastrointestinal stromal tumor (GIST), it is crucial to maintain sufficient dosing of imatinib. Skin rash is a common imatinib‐associated adverse event and may affect compliance. This phase II study was conducted to evaluate whether imatinib‐associated severe skin rash can be managed with systemic steroids without dose reduction or interruption of imatinib. This study is registered at ClinicalTrials.gov, number NCT03440515.
Patients and Methods
Between 2014 and 2016, 29 patients with imatinib‐associated severe skin rash were enrolled. Skin rash of grade 2 with grade ≥2 pruritus or of grade 3 was considered severe. Oral prednisolone was administered 30 mg/day for 3 weeks, then tapered off over 12 weeks. The primary endpoint was treatment success rate (TSR). Treatment success was defined as maintaining imatinib for more than 15 weeks after completion of the steroid administration schedule without skin rash that led to additional steroid treatment or dose reduction or interruption of imatinib.
Results
Of the 29 patients enrolled, 22 patients with skin rash were treated successfully (TSR, 75.8%), 2 (6.9%) were evaluated as treatment failures, and 5 (17.2%) were not evaluable. The 2‐year rash‐free and imatinib reduction‐free interval rate was 67.2% with median follow‐up of 22.0 months (range, 0.4–30.3). Recurrence of severe skin rash occurred in seven patients (24.1%). Systemic steroids were well tolerated except in one patient who experienced pneumocystis pneumonia.
Conclusion
This study demonstrated that imatinib‐associated severe skin rash can be effectively controlled by systemic steroid treatment without interruption or dose reduction of imatinib in patients with GIST.
Implications for Practice
Imatinib has been the standard treatment of gastrointestinal stromal tumor in both adjuvant and palliative settings. It is crucial to maintain sufficient dosing of imatinib to achieve optimal clinical outcomes. Imatinib commonly causes imatinib‐associated skin rash, which may worsen drug compliance. This phase II study demonstrated that systemic steroids could help maintaining the efficacy of imatinib by preventing interruption or dose reduction of imatinib. The present study provides a new administration strategy of systemic steroids and its efficacy and safety data. Thus, this study can be a cornerstone to establish treatment guidelines for imatinib‐associated skin rash.
Keywords: Prednisolone, Exanthema, Imatinib, Gastrointestinal stromal tumors
Short abstract
Skin rash is a common imatinib‐associated adverse event and may affect compliance. This phase II study was conducted to evaluate whether imatinib‐associated severe skin rash can be managed with systemic steroids without dose reduction or interruption of imatinib.
Introduction
Gastrointestinal stromal tumor (GIST) is the most common gastrointestinal (GI) mesenchymal tumor of the GI tract. GIST harbors mutations in the KIT and platelet‐derived growth factor receptor alpha (PDGFRA) genes as the main oncogenic drivers in about 80% and 10% of patients with GIST, respectively [1, 2, 3]. Imatinib mesylate is a selective tyrosine kinase inhibitor (TKI) of KIT, BCR‐ABL, and PDGFRA [4]. Imatinib has been the standard treatment of GIST with improvement of survival outcomes in both adjuvant and palliative settings [5, 6]. Several studies demonstrated that long‐term use of adequate dose of imatinib is crucial to achieve better clinical outcomes. Long‐term use of imatinib (at least 3 years) is recommended for high‐risk patients with GIST in the adjuvant setting [7]. For metastatic or unresectable GIST, continuous use of imatinib is recommended by current treatment guidelines because rapid disease progression often occurs after treatment interruption. [8, 9]. Moreover, imatinib plasma level is correlated with clinical benefit [10].
Generally, imatinib is well tolerated [11]. However, some patients experience severe adverse events that may result in reduced compliance and dose intensity [12]. Skin rash is one of the common imatinib‐associated adverse events, occurring in 11%–67% of patients, with grade ≥ 3 rashes in up to 10% [13]. Of the cutaneous reactions, erythematous maculopapular rash on the extremities, trunk, and occasionally the face is the most common [14].
Mild to moderate imatinib‐associated skin rash is managed with antihistamines, topical lotions, or topical steroids [15]. In contrast, severe skin rash has been managed with imatinib dose reduction or interruption [16]. Because the skin rash usually occurs within the first few months of imatinib treatment, according to previous studies [17], imatinib dose reduction or interruption due to skin rash can result in a substantial decrease in overall dose intensity, which leads to poorer treatment outcomes. Therefore, other strategies to manage imatinib‐associated skin rash are needed [15]. Small case reports have suggested that systemic steroids may relieve severe skin rash [16]. Based on those reports, we conducted a retrospective study to evaluate the incidence of skin rash in patients with GIST who were administered imatinib and therapeutic interventions for severe skin rash and outcomes [17]. Of the 620 patients treated with imatinib, 42 (6.8%) developed grade ≥ 3 skin rash requiring major intervention, which was defined as dose reduction or interruption of imatinib and/or systemic steroid use. Twenty‐two patients (55.0%) successfully continued imatinib with the first interventions.
Thus, we conducted this phase II study to clarify the effects of systemic steroids alone to maintain higher imatinib dose intensity and treatment outcome. We prospectively evaluated the efficacy and safety of systemic steroid in patients with GIST with imatinib‐associated severe skin rash. This study is registered at ClinicalTrials.gov, number NCT03440515.
Materials and Methods
Phase II Study Design
This was an open‐label, single‐arm, phase II study conducted at a single center (Asan Medical Center, Seoul, South Korea). The primary endpoint was treatment success rate (TSR). Treatment success was defined as maintenance of imatinib for more than 15 weeks after completion of the 15‐week schedule of steroid treatment without persistent/recurrent severe skin rash that led to (a) additional steroid treatment beyond the preplanned schedule or (b) dose reduction or interruption of imatinib. Secondary endpoints were rash‐free, imatinib reduction‐free survival, skin rash recurrence rate, and safety of systemic steroid.
The study was conducted according to the World Medical Association Declaration of Helsinki and the Ethical Guidelines for Clinical Studies. All patients gave their written informed consent, conforming to institutional guidelines, indicating that they were aware of the investigational nature of the study. This study was reviewed and approved by the institutional review board of Asan Medical Center (2014‐0771).
Study Population
Between October 2014 and March 2016, 29 patients who met the following eligibility criteria were enrolled: having histologically confirmed GIST, having imatinib‐associated severe skin rash in either a palliative or adjuvant setting, and age ≥ 18 years with informed consent.
Imatinib‐associated severe skin rash was defined as grade 2 skin rash with pruritus grade ≥ 2 or grade ≥ 3 skin rash that occurred after imatinib administration. The U.S. National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 was used to grade skin rashes (supplemental online Table 1) [18].
Treatment and Follow‐Up
Twenty‐nine patients were treated with oral prednisolone (Pd). Pd was initiated at 30 mg/day for 3 weeks. Then, if skin rash was controlled, Pd was tapered off at 3‐week intervals over 12 weeks following the schedule in Figure 1. If grade 1 skin rash or grade 2 rash without grade ≥ 2 pruritus recurred at any step during the tapering schedule, Pd was readministered for 3 additional weeks at the dose of the prior step. If severe skin rash was not controlled or recurred during the tapering or follow‐up period, a second course, which repeated the whole schedule beginning from step 1, was allowed once. Antihistamines could be used in combination with systemic steroids.
Figure 1.
Prednisolone dosing and tapering schedule.
During the steroid administration period, patients visited both oncology and dermatology outpatient clinics every 3 weeks to evaluate skin rash. Compliance, dosage, efficacy, and adverse events of imatinib and the steroids were recorded. Performance status, additional medications for skin rash, and laboratory data (complete blood counts, eosinophil count, and chemistry) were also checked. GIST disease status, including tumor response, recurrence, and survival, was evaluated until the data cutoff date of this study (November 2017).
Steroids were continued until treatment failure or completion, intolerable adverse event, alteration of GIST treatment due to disease progression, or patient refusal.
Adverse Events
Adverse events associated with systemic steroid or imatinib were monitored and graded by physicians according to CTCAE version 4.03 on every visit. The adverse events were classified as either imatinib‐ or systemic steroid–associated events by the investigators.
Statistical Analysis
Fleming's one stage design was used in sample size calculation (PASS statistical software [NCSS LLC., Kaysville, Utah]) [19]. We estimated that with 26 patients, the study would have 80% power to detect 20% improvement in TSR with systemic steroids in this study (P 1 = 0.75) than our previous retrospective study (P 0 = 0.55), at a one‐sided alpha level of .05 [17]. Taking into consideration a 10% dropout rate, a total of 29 patients were needed. All analyses were performed using the intention‐to‐treat population.
Descriptive statistics were used for the baseline characteristics of the patients. Pearson's chi‐square and Fisher's exact tests were used for comparison of discrete data, and the Mann‐Whitney U test was used for comparison of nonparametric variables. Rash‐free, imatinib reduction‐free survival was calculated from the date of steroid administration to the date of recurrence of severe skin rash or imatinib reduction or discontinuation, whichever occurred first. The survival was estimated using the Kaplan‐Meier method, and the log‐rank test was used to determine the significance of any differences in the survival curves. All tests were two‐sided, and p < .05 was considered statistically significant. The SPSS 25.0 software (IBM SPSS Inc., Chicago, IL) was used for analyses.
Results
Baseline Characteristics
A total of 29 patients (11 male and 18 female) were enrolled. The baseline characteristics are summarized in Table 1. The median age was 61 years (range, 31–77). Sixteen patients (55.2%) were in the adjuvant setting, and 13 (44.8%) were in the palliative setting. The dose of imatinib was 400 mg/day (standard dose) in 26 patients, 300 mg/day in 2 patients, and 600 mg/day in the remaining 1 patient. The median trough plasma level of imatinib was 1,270 ng/mL (range, 712–4,790). The median blood eosinophil count was 1,059/μL (range, 10–4,025/μL), and 22 patients (75.9%) had eosinophilia (blood eosinophil count ≥500/μL) at enrollment.
Table 1.
Baseline characteristics of study patients at enrollment (n = 29)
| Characteristics | n (%) |
|---|---|
| Age, median (range), years | 61 (31–77) |
| Gender | |
| Male | 11 (37.9) |
| Female | 18 (62.1) |
| ECOG performance status | |
| 0 | 6 (20.7) |
| 1 | 22 (75.9) |
| 2 | 1 (3.4) |
| History of dermatologic disease | 0 (0) |
| History of allergic disease | |
| Asthma | 0 (0) |
| Allergic rhinitis | 2 (6.9) |
| History of diabetes mellitus | 2 (6.9) |
| Treatment setting | |
| Adjuvant | 16 (55.2) |
| Palliative | 13 (44.8) |
| Localized unresectable | 4 (13.8) |
| Metastatic | 8 (27.6) |
| Recurrent | 1 (3.4) |
| Primary tumor site | |
| Stomach | 14 (48.3) |
| Small bowel | 9 (31.0) |
| Rectum | 4 (13.8) |
| Other (esophagus, pelvis) | 2 (6.9) |
| Dose of imatinib | |
| 300 mg/day a | 2 (6.9) |
| 400 mg/day | 26 (89.7) |
| 600 mg/day b | 1 (3.4) |
| Plasma level of imatinib, median (range), ng/mL | 1,270 (712–4,790) |
| Grade of skin rash before enrollment | |
| 2 | 6 (20.7) |
| 3 | 23 (79.3) |
| Blood eosinophil count | |
| Median (range), /μL | 1,059 (10–4,025) |
| <500/μL | 7 (24.1) |
| ≥500/μL | 22 (75.9) |
| Mild eosinophilia (≥500 /μL, <1,500 /μL) | 13 (44.8) |
| Moderate eosinophilia (≥1,500 /μL, <5,000 / μL) | 9 (31.0) |
| Severe eosinophilia (≥5,000 /μL) | 0 (0) |
| KIT or PDGFRA genotype | |
| Wild type or PDGFRA mutation | 2 (6.9) |
| KIT exon 9 mutation | 5 (17.2) |
| KIT exon 11 mutation | 20 (69.0) |
| Duration of imatinib treatment before skin rash development, median (range), days | |
| All grades | 41 (0–330) |
| Grade 2 | 80 (35–103) |
| Grade 3 | 31 (0–330) |
| Duration of skin rash before starting Pd administration, median (range), days | 21 (3–86) |
Two patients were administered 300 mg of imatinib because of previous grade 3 and grade 4 neutropenia, respectively.
One patient was administered 600 mg of imatinib at enrollment as she was participating in a clinical study of escalating dose of imatinib (NCT01541709).
Abbreviations: ECOG, Eastern Cooperative Oncology Group; Pd, prednisolone; PDGFRA, platelet‐derived growth factor receptor A.
Imatinib‐associated severe skin rash appeared a median of 41 days (range, 0–330 days) after initiation of imatinib treatment. The patients were enrolled to the study and began steroid administration a median of 21 days after the skin rash appeared (range, 3–86 days). Six patients had grade 2 skin rash with pruritus, and 23 had grade 3 rash. After starting imatinib treatment, grade 3 skin rash tended to develop faster than grade 2 skin rash. The median duration of imatinib treatment before skin rash development was 80 days (range, 35–103) for grade 2 and 31 days (range, 0–330) for grade 3 rash (p = .01; Fig. 2A). Of the 15 patients who developed skin rash after 6 weeks of the imatinib initiation, 14 (93.3%) had grade 3, and 1 (6.7%) had grade 2 skin rash (Fig. 2B). Dose and plasma level of imatinib and eosinophil count at enrollment did not show significant association with the grade of skin rash.
Figure 2.
The time until onset of skin rash differed significantly in relation to severity of skin rash. (A): The median time to onset of grade 3 rash was shorter than that of grade 2 skin rash. (B): In patients who developed skin rash within 6 weeks after the initiation of imatinib, the majority developed grade 3 rash.
Efficacy of Systemic Steroids
Of the 29 patients, 22 (75.8%, TSR) were treated successfully with steroids, 2 (6.9%) had treatment failure, and 5 (17.2%) were not evaluable (Fig. 3). Of the two patients whose treatment failed, one stopped Pd after 7 weeks because of a severe steroid‐associated adverse event (pneumocystis pneumonia). The other patient experienced recurrence of severe skin rash 8 weeks after completion of a second course of Pd. The not‐evaluable patients stopped both Pd and imatinib because of imatinib‐associated adverse events within a median of 4 months (range, 1.4–7.1) of steroid treatment (n = 4) and lower GI bleeding from anal GIST at week 3 of steroid treatment (n = 1).
Figure 3.
Results of steroid treatment. Abbreviation: Pd, prednisolone.
Figure 4 shows the rash‐free and imatinib reduction‐free interval curve. The median rash‐free and imatinib reduction‐free interval was not reached. The 2‐year rash‐free and imatinib reduction‐free interval rate was 67.2% with a median follow‐up of 22.0 months (range, 0.4–30.3).
Figure 4.
Rash‐free and imatinib reduction‐free interval curve.
Recurrence of severe skin rash occurred in seven patients (Fig. 3). Most of them (n = 5) experienced recurrence within 3 weeks after completion of the first course of systemic steroids. Most of the recurrences were successfully treated with a second course of steroids (n = 4). One patient experienced the recurrence during the first course of steroids. This patient had poor compliance with both imatinib and Pd because of imatinib‐associated GI toxicity.
A total of 1,522.5 mg of Pd is administered over the planned treatment schedule. In cases of treatment success, a median of 1,522.5 mg (range, 1,472.5–3,945) of Pd was administered over a median of 15 weeks (range, 15–39). In contrast, a median of 1,695 mg (range, 750–3,607.5) of Pd was administered over a median of 11 weeks (range, 4–72) in unsuccessful cases.
Imatinib was discontinued in 9 (31.0%) patients during the study for following reasons: imatinib‐associated adverse events (n = 4), follow‐up loss (n = 2), a steroid‐associated adverse event (n = 1), curative surgery (n = 1), and GI bleeding from anal GIST (n = 1).
Safety
All toxicities associated with systemic steroids or imatinib are reported in Table 2. Hyperglycemia was the most common steroid‐associated adverse event (n = 17, 58.6%). Regarding severe adverse events (grade ≥3, n = 4), only one case was associated with steroids. The other three cases were associated with imatinib. Steroid‐associated pneumocystis pneumonia (PCP) occurred in a patient (3.4%) with suspected myelodysplastic syndrome. The PCP developed after 7 weeks of steroid administration and was confirmed by bronchoalveolar lavage, which revealed positive immunohistochemistry and DNA polymerase chain reaction results consistent with PCP. Mean daily steroid dose was 24 mg of Pd in the patient. It was the only case of steroid‐associated serious adverse event that resulted in treatment failure. The PCP was treated with intravenous antibiotics. Otherwise, systemic steroids were well tolerated. There were no patients who developed hypertension or symptoms suggestive of cardiovascular events, adrenal insufficiency, myopathy, aseptic necrosis, pancreatitis, or viral infections associated with the steroids.
Table 2.
Imatinib‐ and steroid‐associated adverse events during the trial
| Type of adverse event | All grades, n (%) | Grade 3, 4, n (%) |
|---|---|---|
| Any toxicity | 29 (100) | 5 (17.2) |
| Hematologic | ||
| Neutropenia* | 6 (20.7) | 0 |
| Febrile neutropenia* | 0 | 0 |
| Anemia* | 19 (65.5) | 0 |
| Thrombocytopenia* | 2 (6.9) | 0 |
| Generalized: fatigue | 7 (24.1) | 0 |
| Cardiovascular | ||
| Hypertension† | 0 | 0 |
| Cardiovascular event† | 0 | 0 |
| Gastrointestinal | ||
| Anorexia | 8 (27.6) | 0 |
| Nausea | 6 (20.7) | 0 |
| Vomiting | 6 (20.7) | 0 |
| Dyspepsia | 4 (10.3) | 0 |
| Constipation* | 1 (3.4) | 0 |
| Diarrhea | 7 (24.1) | 0 |
| Abdominal pain | 3 (10.3) | 0 |
| Gastrointestinal bleeding† | 0 | 0 |
| Elevated AST or ALT | 9 (31.0) | 0 |
| Hyperbilirubinemia | 0 | 0 |
| Pancreatitis† | 0 | 0 |
| Musculoskeletal | ||
| Edema | 9 (31.0) | 0 |
| Muscle cramp* | 11 (39.9) | 0 |
| Aseptic necrosis† | 0 | 0 |
| Renal: Elevated creatinine | 2 (6.9) | 0 |
| Dermatologic: alopecia | 3 (10.3) | 0 |
| Infectious | ||
| Pneumonia | 4 (10.3) | 4 (10.3) |
| Imatinib‐related interstitial pneumonitis* | 3 (10.3) | 3 (10.3) |
| Steroid‐related pneumocystis pneumonia† | 1 (3.4) | 1 (3.4) |
| Viral infections† | 0 | 0 |
| Endocrine | ||
| Hyperglycemia† | 17 (58.6) | 0 |
| Adrenal insufficiency† | 0 | 0 |
Those were evaluated to be imatinib‐associated adverse events.
Those were evaluated to be steroid‐associated adverse events. The remaining adverse events could not be classified.
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.
All three imatinib‐associated severe adverse events were drug‐induced interstitial pneumonitis. Because both imatinib and steroids were administered simultaneously, it was difficult to distinguish between imatinib‐ and steroid‐associated adverse events, especially in cases with mild and nonspecific symptoms. Therefore, these adverse events were reported without classification.
Compliance (Dose Intensity) with Prednisolone and Imatinib
Median compliances (dose intensity) with Pd and imatinib were 100% in both groups (range, 36.1%–100% and 65.6%–100%, respectively; Table 3). Compliance was associated with treatment success and the occurrence of severe (grade ≥3) adverse events. Median compliances with Pd and imatinib were significantly higher in patients who were successfully treated with Pd than in those who were not (median compliance with Pd, 100% vs. 88%; p = .03 and median compliance with imatinib, 100% vs. 86.2%; p = .01) and in patients who did not experience severe adverse event than in those who did (median compliance with Pd, 82% vs. 100%; p = .007 and median compliance with imatinib, 86.2% vs. 100%; p = .02). Compliances were also higher in patients without recurrence of skin rash than those with, but the difference was not statistically significant (median compliance with Pd, 98% vs. 100%; p = .09 and median compliance with imatinib, 99.6% vs. 100%; p = .3). The lowest compliance was seen in the patients with severe imatinib‐associated adverse events (drug‐induced pneumonitis).
Table 3.
Compliance (dose intensity) with prednisolone and imatinib
| Compliance | Prednisolone | Imatinib | ||
|---|---|---|---|---|
| Median compliance, % | p value | Median compliance, % | p value | |
| Median compliance (range) | 100 (36.1–100) | 100 (65.6–100) | ||
| Patients whose treatment with Pd succeeded | 100 | .03 | 100 | .01 |
| Patients whose treatment did not succeed | 88 | 86.2 | ||
| Patients whose skin rash recurred | 98 | .09 | 99.6 | .3 |
| Patients whose skin rash did not recur | 100 | 100 | ||
| Patients who experienced adverse event grade ≥3 | 82 | .007 | 86.2 | .02 |
| Patients who did not experience adverse event grade ≥3 | 100 | 100 | ||
Abbreviation: Pd, prednisolone.
Factors Associated with Treatment Outcome and Recurrence of Skin Rash
We analyzed various clinical factors (age, sex, treatment setting [adjuvant or palliative], KIT or PDGFRA genotype, dose and plasma level of imatinib, eosinophil count and grade of skin rash at enrollment, increasing and decreasing rate of eosinophil count at the beginning of steroid administration, and duration of skin rash before the beginning of steroid administration) and their association with skin rash treatment outcome. None of these factors showed significant association with treatment outcome because of the small number of patients (data not shown). However, patients aged <65 years tended to have higher TSR (87.5% vs. 66.2%; odds ratio, 4.38; p = .19).
We also analyzed the association between those factors and recurrence of skin rash (supplemental online Table 2). An interval between beginning of imatinib and development of skin rash shorter than 2 months was significantly associated with recurrence of skin rash compared with a longer interval (recurrence rate, 38.9% vs. 0%; relative risk, 1.64; p = .03). The other factors did not show significant association.
Skin rash preceded eosinophilia in most of patients (84.2%). Eosinophilia peaked at enrollment then rapidly declined after steroid administration, normalizing for all patients (supplemental online Fig. 1). Thus, the relationship between eosinophil count and skin rash recurrence was hard to elucidate. Six patients experienced recurrence of eosinophilia, and the skin rash recurred in three of them (50%). Among the seven patients with skin rash recurrence, the median eosinophil count was 350/μL (range, 2–3,780/μL), and three patients had eosinophilia at the time of skin rash recurrence.
Efficacy of Imatinib
In the adjuvant setting (n = 16), there were no cases of GIST recurrence over a median follow‐up time of 24.3 months after surgery (range, 4.3–37.1 months).
In palliative setting (n = 13), the best response was complete response in one patient (7.7%), partial response in seven patients (53.8%), and stable disease in five patients (38.4%). No one experienced disease progression over a median follow‐up of 19.8 month (range, 2.8–31.7 month).
Discussion
Strategies to improve the management of imatinib‐related adverse events such as skin rash are important to achieve better compliance, clinical outcomes, and quality of life for patients with GIST. This was the first clinical trial evaluating the efficacy and safety of systemic steroids for imatinib‐associated severe skin rash. This was also the first steroid administration schedule proposed to manage severe skin rash. The trial was a phase II study that was conducted at Asan Medical Center, the largest GIST center in Korea.
In this trial, oral Pd was effective with a TSR of 75.8%, which met the primary endpoint. The definition of treatment success included not only disappearance of skin rash but also maintenance of imatinib dose. In addition, TSR was defined as no recurrence of skin rash within 15 weeks after completion of steroid administration to evaluate whether systemic steroids could help long‐term maintenance of imatinib.
In this study, skin rash recurred in 7 of 29 patients (24.1%) during follow‐up. Most of recurrent skin rashes occurred within 1–3 weeks after completion of steroid administration. Thus, even if skin rash resolves, close monitoring for recurrence is required for at least 3 weeks after discontinuation of steroids. Also, maintaining a longer tapering schedule, such as 5 mg/day of Pd for more than 3 weeks beyond step 5, may help to reduce the recurrence of skin rash. Further research is required to determine if this modified schedule would have advantage.
Typical adverse events known to be associated with steroids include hypertension, infections, and hyperglycemia [20]. Their frequency depends on the duration of treatment, dosage, and the studied populations. In this study, a total of 1,522.5 mg of Pd was administered over 15 weeks according to the schedule. PCP occurred in one patient, which was the only (3.4%) severe (grade ≥3) steroid‐associated adverse event. This is in line with a previous study, which showed that cumulative PCP‐free rate at 120 days in patients with rheumatic disease receiving ≥15 to <30 mg/day of Pd was 0.96 [21]. According to a guideline, patients with solid tumors undergoing chemotherapy regimens containing high‐dose steroids (16–25 mg Pd for ≥4 weeks) need prophylaxis for PCP with co‐trimoxazole (grade C recommendation) [22]. However, the research underlying the guideline included patients mainly undergoing dose‐intensive chemotherapy [23]. Moreover, the patient who experienced PCP in that study had been following up at a hematology outpatient clinic with suspicion of myelodysplastic syndrome caused by bicytopenia. Thus, we cannot recommend routine prophylaxis for patients undergoing steroid treatment for imatinib‐associated severe skin rash by the present study.
Grade 1–2 hyperglycemia was the most common (58.6%) steroid‐associated adverse event in this study. This is in line with a previous study, in which the relative risk of developing hyperglycemia requiring hypoglycemic therapy after oral glucocorticoid use was as high as 2.23 [24]. On the other hand, there were no cases of steroid‐induced hypertension in this trial. Some authors previously reported that the risk of steroid‐induced hypertension is dose dependent and only develops in patients receiving a dose equivalent of >20 mg/day of Pd [25]. In this trial, however, Pd >20 mg/day was administered for a duration as short as 3 weeks. This could explain the absence of steroid‐induced hypertension in this study.
In the present study, imatinib‐associated skin rash developed at 0–47 weeks (median onset, 6 weeks) after imatinib administration. After initiating imatinib, grade 3 skin rash developed more rapidly than grade 2 rash. This result was similar to that of a previous study (median onset, 8 weeks; high‐severity imatinib‐associated skin rash developed faster than low‐severity rash) [26]. Because the study only included severe skin rashes, whereas the previous study included all grades of rashes, the relatively earlier median onset of rash can be explained. Likewise, earlier development of skin rash after imatinib administration was the only significant factor associated with recurrence. These results suggest that we should pay more attention to patients who experience rapid development (<2 months) of skin rash because the rash is more likely to be severe and recur in these patients. Further studies are needed to determine whether a higher dose or longer duration of steroid treatment in these patients improves treatment outcomes. Compliance with Pd and imatinib was associated with success of treatment and the occurrence of severe adverse events.
The mechanism of imatinib‐associated skin rash is not fully known. Both pharmacological and hypersensitivity reactions may play a role. PDGFR, which is abundant in keratinocytes, and KIT in basal cells of skin are inhibited by imatinib, and their inhibition may influence skin reactions [27, 28, 29]. In previous studies analyzing the pathologic findings of imatinib‐associated skin rash, the predominance of dermal lymphohistiocytic infiltration over eosinophilic infiltration supports this hypothesis [26, 30]. Imatinib‐induced PDGFR inhibition disturbs transcapillary transport, and it may subsequently increase dermal interstitial fluid pressure, resulting in erythema, desquamation, and papillary dermal edema in imatinib‐associated skin rash [26, 31]. However, it is not clear why imatinib‐associated severe skin rash only occurs in a small proportion of the patients taking imatinib. Hypersensitivity to imatinib cannot be excluded from the pathogenesis because the pathological findings of imatinib‐associated skin rash showed eosinophilic infiltration in a significant number of patients (37.8%) [26, 30]. Previous reports suggest that immune reactions other than hypersensitivity also accompany imatinib‐associated rash [26, 30]. Immune reactions can accompany both, and systemic steroids can be effective for skin rash with immune reactions whether the rash is primarily caused by pharmacological effect or hypersensitivity. Further studies are needed to explain the detailed mechanism of imatinib‐associated skin rash, including pharmacological and hypersensitivity reactions and the accompanying immune reactions.
In addition, it is thought that there is a close relationship between blood eosinophil count and imatinib‐associated skin rash. In our previous retrospective study, eosinophil counts during imatinib treatment were associated with the development of skin rash and its severity and the outcomes of major interventions for severe rash [17]. In the present study, median eosinophil count was high (1,059/μL), and 75.9% of patients had eosinophilia at enrollment. Because peripheral eosinophilia characterizes drug hypersensitivity, frequent presentation of eosinophilia may support the role of hypersensitivity in imatinib‐associated severe skin rash [32]. In addition, although no significant association was found between eosinophil count at enrollment and treatment success or recurrence of skin rash in this study, monitoring eosinophil levels is recommended in patients with imatinib‐associated skin rash to predict progression of rash and determine dose and duration of treatment.
It is reported that 2‐year progression‐free survival (PFS) rate is around 40% in patients with GIST taking imatinib 400 mg/day in the palliative setting [33]. In the adjuvant setting, 2‐year recurrence‐free survival rate is around 90% [7]. In this study, no patients experienced disease progression or recurrence over a median follow‐up of 20 months in the palliative setting and 24 months in the adjuvant setting. Severe skin rash can lead to poor compliance and thus decrease efficacy of imatinib. In our previous retrospective study, the patients with severe skin rash tended to show a poorer PFS than those with mild skin rash or without skin rash [17]. In that study, the median imatinib dose intensity was significantly lower in patients with severe skin rash. In the present study, the efficacy of imatinib was not worse than in previous studies. This may be because the patients maintained high compliance with imatinib (median compliance, 100%), even with severe imatinib‐associated skin rash. It can be postulated that proper management of skin rash through steroid administration could maintain the efficacy of imatinib by improving compliance.
There were some limitations in this study. First, as this was a phase II study, it had no control arm to compare the efficacy of steroids or survival outcomes. According to the previous literature, epidermal growth factor receptor (EGFR) TKIs are also known to induce skin rash, and EGFR TKI–associated rash may improve spontaneously without modification of TKI dose [34, 35, 36]. In the case of imatinib, there are a few reports of spontaneous regression of imatinib‐associated low grade skin rash [14, 37]. However, there have been no reports of spontaneous regression of imatinib‐associated severe rash without dose reduction or interruption of imatinib. Also, we have had no clinical experiences of such cases over more than 20 years at our center, a tertiary cancer center in South Korea. Nevertheless, this study cannot completely exclude the possibility of spontaneous regression of rash because there was no control arm. Second, although the number of patients was enough for primary endpoint analysis, it was too small for other analyses to reach statistical significance. To establish detailed dose control guideline according to the rate of skin rash development and eosinophil count, a study with a larger number of patients is needed.
This study provides a cornerstone to establish evidence‐based treatment guidelines for imatinib‐associated severe skin rash, with a new administration strategy and efficacy and safety data on systemic steroids. It will help in maintaining imatinib dosing and in achieving optimal treatment outcomes in patients with GIST with severe skin rash. Moreover, as far as we know, this is not only the first clinical trial of systemic steroids for the treatment of imatinib‐associated skin rash, but also the first for any TKI‐associated skin rashes. Thus, the present study will be a meaningful resource for the treatment of TKI‐associated severe skin rashes across a variety of cancer treatments.
Conclusion
This study demonstrated that systemic steroid treatment can effectively control severe skin rash and minimize interruption or dose reduction of imatinib in patients with GIST with imatinib‐associated severe skin rash. Systemic steroids were well tolerated in most patients. Further studies are needed with a large population.
Author Contributions
Conception/design: Sook Ryun Park, Min‐Hee Ryu, Yoon‐Koo Kang
Provision of study material or patients: Min‐Hee Ryu, Sook Ryun Park, Woo Jin Lee, Mi Woo Lee, Yoon‐Koo Kang
Collection and/or assembly of data: Mo Youl Beck, Eo Jin Kim, Min‐Hee Ryu, Yoon‐Koo Kang
Data analysis and interpretation: Eo Jin Kim, Yoon‐Koo Kang
Manuscript writing: Eo Jin Kim, Min‐Hee Ryu, Yoon‐Koo Kang
Final approval of manuscript: Eo Jin Kim, Min‐Hee Ryu, Sook Ryun Park, Mo Youl Beck, Woo Jin Lee, Mi Woo Lee, Yoon‐Koo Kang
Disclosures
The authors indicated no financial relationships.
Supporting information
See http://www.TheOncologist.com for supplemental material available online.
Supplemental Tables
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Disclosures of potential conflicts of interest may be found at the end of this article.
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