(P 111) PLASMA CONCENTRATION MONITORING AND PERSONALIZED DESENSITIZATION THERAPY IN PATIENTS OF GASTROINTESTINAL STROMAL TUMORS WITH IMATINIB-ASSOCIATED SKIN RASH

Objective: Imatinib mesylate is the first-line drug for recurrent/metastatic gastrointestinal stromal tumors (GISTs), as well as the only medication for adjuvant therapy after resection of high-risk tumors. Imatinib has significantly improved patient’s prognosis, and is generally well tolerated. The incidence of imatinib related severe adverse events was approximately 38%. Skin rash was one of the most common adverse effects, occurring in 11%-67% of patients, with 3-4 grade up to 10%. It might result in reduced compliance and dose intensity even affecting efficacy. Identification and effective management of imatinib-associated rash is needed. Therefore, we conducted this single center study to summarized the incidence and clinical characteristics including imatinib trough plasma concentrations of rash in patients of GIST treated with imatinib, and to introduce the personalized desensitization management and outcomes of rash therapy.

Methods: From July 2017 to November 2021, a total of 712 GIST patients (pts) received imatinib were screened. Forty-three pts with grade ≥2 rash considered moderate to severe requiring other drugs treatment were included. Clinical data including age, sex, skin lesion morphology, severity of rash, imatinib therapy parameters and desensitization process were collected. The desensitization process in brief, imatinib was interrupted and oral prednisone 30mg/d was administered until rash disappeared in patients with rash in grade 3 or with recurrent rash in grade 2, then imatinib was reintroduced with beginning of 50-100mg/d and modified under plasma concentration monitoring, prednisone was tapered off over 4 weeks.

Results: Of 43 pts, imatinib was administered in setting of adjuvant therapy and maintenance therapy of recurrent/metastatic state in 24 (55.8%) and 19 (44.2%), respectively. Thirty-two pts were of KIT exon 11 mutation, 4 of KIT exon 9 mutation. The doses of imatinib were 600 mg/d in 2 pts, 400 mg/d in 34, 300 mg/d in 6 and 250 mg/d in one patient. Skin lesions were characterized by maculopapule in 34 pts (79.1%), lichenoid reaction in 7 (16.3%) and other reactions in 2 (4.6%). Twelve pts (27.9%) developed rash in grade 2 and 31 (72.1%) in grade 3, with 6 (13.9%) accompanying by alopecia or liver injury. Severe rash develop earlier than moderate, the median duration from beginning of imatinib to diagnosis was 1.5 (0.5-7.0) months in patients with grade 3 and 3.2 (0.4-64.0) months with grade 2 (p=0.04). The median trough plasma concentrations of imatinib at onset of rash were 1400 (777-2134) ng/ml and 1676 (776-3473) ng/ml in patients with grade 2 and grade 3, respectively. Prednisone was administered in 34 pts (79.1%). Patients with grade 3 rash needed longer period of prednisone use and more times of desensitization, compared with grade 2 (both p< 0.01). Of 43 pts, 41 (95.3%) were successfully continued on imatinib through the intervention. The doses of well-tolerant imatinib were 600 mg/d in one patient, 400 mg/d in 5, 350 mg/d in one, 300 mg/d in 23, 250 mg/d in 4, 200 mg/d in 5 and 150 mg/day in one. The median trough plasma concentrations after desensitization therapy from original grade 2 and grade 3 were 1143 (698-2134) ng/ml and 1029 (570-2636) ng/ml, respectively.

Conclusion: The majority of patients with imatinib-associated skin rash in GIST could resume imatinib in well toleration in a personalized dosage, after active management by desensitization therapy under plasma concentration monitoring. Compared with moderate rash, severe rash appeared earlier. Prednisone period should be appropriately extended to avoid rash recurrence. In the early stage of imatinib treatment, special attention should be paid to the occurrence of rash. Monitoring plasma concentration was useful in balance between the dose modification and the recurrence of rash.