Introduction

Dasatinib is a medication that inhibits the protein kinase activity of BCR-ABL chimeric protein and is used to treat chronic myeloid leukemia. However, reports of bleeding complications such as gastrointestinal bleeding have been reported despite its therapeutic effects.

Aims & Methods

To investigate the gastrointestinal symptoms and endoscopic findings associated with dasatinib administration.
We retrospectively reviewed medical records of 26 patients who received dasatinib for chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphocytic leukemia at our hospital from July 2017 to June 2022. Patients with a history of dasatinib treatment for less than 1 year or bacterial or cytomegalovirus enteritis were excluded. We examined the duration of dasatinib treatment, adverse events including bloody stools, and endoscopic findings in 13 patients who underwent colonoscopy.

Results

The male-to-female ratio was 19:7, and the median age was 54.5 years (4-84). The median duration of dasatinib treatment was 48 months (12-132). Adverse events included edema (7 cases), pleural effusion (10 cases), rash (2 cases), hematotoxicity (8 cases), and muscle pain (2 cases). Gastrointestinal symptoms included chronic diarrhea (4 cases), gastric discomfort (2 cases), abdominal pain (1 case), and bloody stools (3 cases). Nine cases had occult gastrointestinal bleeding. The change in hemoglobin level from before to 1 year after treatment was -0.8, indicating a decreasing trend (13.1±2.2 before treatment, 12.3±1.1 after treatment; p=0.08). Colonoscopy findings included normal in 2 of the 13 patients, rough mucosa in the right colon in 10 patients, and total colitis in 1 patient. One case showed pseudomembranous colitis-like findings, and 2 cases showed inflammatory polypoid-like findings (1 case of solitary polyp and 1 case of polypoidosis).

Conclusion

Dasatinib has been associated with lower gastrointestinal bleeding, and its excretion in feces is thought to be one of the contributing factors. Various gastrointestinal disorders observed in this study are also suspected to be adverse reactions to the medication. Some cases had endoscopic findings suggestive of pseudomembranous colitis or inflammatory polypoid-like changes, requiring consideration of drug-induced enteritis due to dasatinib as a differential diagnosis.

Introduction

Vedolizumab (VDZ) is a monoclonal antibody therapy approved in China in 2020 for the treatment of patients with inflammatory bowel disease (IBD; Crohn's disease [CD] and ulcerative colitis [UC])² who were intolerant to conventional therapies.¹ VDZ has a unique, gut-selective, anti-lymphocyte trafficking (GSALT) mechanism of action.³ However, data on the efficacy and safety of VDZ in Chinese patients with IBD in the real-world setting are limited.⁴ This study evaluated the safety of VDZ in adult patients with IBD.

Aims & Methods

VALUE (NCT04872491) was a multicenter, single-arm, prospective, observational study to evaluate the safety of VDZ in adult Chinese patients with IBD (N=500) over a maximum observation period of 72 weeks. Incidence of adverse events (AEs), serious AEs (SAEs), treatment-related adverse drug reactions (ADRs), and AEs of special interest (AESIs) was evaluated. This was the final analysis of the VALUE study conducted in patients with IBD.

Results

A total of 500 patients (UC: n=409; CD: n=91) received VDZ 300 mg. Mean (±standard deviation) age of patients was 44.3 (±15.2) years, and 61.4% (n=307) were male. The mean duration for VDZ exposure was 414 days (UC: 416 days; CD:407 days). A total of 500 patients developed 674 AEs (Table), and the most frequent AEs were infections and infestations (I&I; UC: 115 [28.1%]; CD: 24 [26.4%]), followed by gastrointestinal disorders (GIDS; UC: 87 [21.3%]; CD: 18 [19.8%]). Incidence rates of AEs (/patient-years) were 1.2 and 1.0 in patients with UC and CD, respectively. Overall, 13 (3.2%) patients with UC and 10 (11.0%) with CD had AEs leading to study discontinuation. SAEs were observed in 78 patients with UC and 18 with CD (Table). A total of 19 AESIs were reported by patients with UC and 9 AESIs by those with CD, with the most common AESIs being I&I (UC: 13 [3.2%]; CD: 4 [4.4%]) and malignancy (UC: 3 [0.7%], CD: 2 [2.2%]). The most common I&I disorders reported by patients with UC and CD were Clostridium difficileinfection (4 [1.0%]) and pneumonia (1 [1.1%]), respectively. Overall, 17 (4.2%) patients with UC and 7 (7.7%) with CD had at least 1 AESI. A total of 91 and 15 treatment-related ADRs were observed in patients with UC and CD, respectively; I&I were the most frequently documented ADRs to VDZ treatment (Table). A total of 10 (UC: 5 [1.2%]; CD: 5 [5.5%]) patients treated under concomitant IBD advanced therapy (CIBDAT) experienced a total of 16 AEs (UC: 9; CD: 7), with the most common AEs being I&I (UC: 1 [20.0%]; CD: 2 [40.0%]) and GIDS (UC: 3 [60.0%]; CD: 1 [20.0%]) with CIBDAT. No deaths were reported during the study.

Conclusion

The VALUE study indicated that VDZ was well tolerated in Chinese patients with IBD, with no new safety concerns.

References

1. Scribano ML. World J Gastroenterol. 2018; 24: 2457-2467.
2. Yamamoto S et al., Cureus. 2024;16: e59691.
3. Soler D et al. J Pharmacol Exp Ther. 2009; 330: 864-875.
4. Baili C et al. Am J Gastroenterol. 2023; 118: S213-S214.

Disclosure

This study was funded by Takeda (China) International Trading Co. Ltd. Li Li, Haiyan Zhang, Chengxia Liu, and Xiaomei Sun have no conflicts of interest. Xiaoyu Qian and Fang Zhou are Takeda employees and hold Takeda stock options. Minhu Chen received speaker honorariums from Takeda China, AstraZeneca China, Xian Janssen, and Eisai China.
Medical writing support for the development of this abstract under the direction of the authors was provided by Vibhuti Singh, Ph.D., of Cactus Life Sciences (part of Cactus Communications), funded by Takeda (China) International Trading Co., Ltd.

Introduction

Janus kinase (JAK) inhibitors have emerged as an important therapeutic class for the management of several immune-mediated conditions, including inflammatory bowel disease (IBD), but they are associated with several side effects. A renewed attention to the safety profile of this drug class has been driven by increasing reports of JAK inhibitor-induced acneiform eruptions seen in clinical trials and real-life practice.

Aims & Methods

We aimed to investigate the epidemiology, clinical characteristics, and treatment outcomes of this condition in patients with IBD. This was an international, multicenter, retrospective cohort study that consecutively enrolled patients with IBD who were treated with JAK inhibitors and subsequently developed acne. The primary objective was to evaluate the clinical characteristics of acne presentation. Secondary objectives included determining acne prevalence, assessing its impact on quality of life, and evaluating the effectiveness of treatments.

Results

Of the 2,183 JAK inhibitor-treated patients with IBD screened, 272 developed acne and were included in the study. The crude prevalence rates of acne were 15.9% for upadacitinib, 4.3% for tofacitinib, and 1.9% for filgotinib, with dose-dependent relationships observed for upadacitinib and tofacitinib. Acne predominantly affected patients aged 30–50 years, with most cases being mild to moderate in severity. Acneiform eruptions most frequently involved the face (89%), followed by the back (33%) and chest (27%). Lesion characteristics were documented in 159 patients; papules (82%), pustules (52%), and comedones (42%) were the most frequently reported. In contrast, nodules (19%) and cysts (18%) – features associated with more severe disease – were less commonly observed. Among the 213 patients with available time-to-onset data, the median time to acne onset following JAK inhibitor initiation was 47 days (IQR: 28–98 days). Patients with a previous history of acne vulgaris were significantly more likely to develop severe drug-induced acne (p<0.0001). Although corticosteroids are known to contribute to acne, our data did not demonstrate an association between concomitant steroid use and increased acne severity. There was also no difference in time to onset or resolution of acne between the steroid-treated and non-steroid treated groups. A third of patients reported a negative impact on psychosocial well-being, and 40% required pharmacological intervention. Topical therapies were required for 106 patients (39%), with 52 (49%) showing acne improvement or resolution. Systemic oral agents were required for 38 patients (14%), including 25 patients who did not respond or had a partial response to topical therapies. Antibiotics were prescribed to 29 patients (most commonly from the tetracycline class), leading to acne improvement or resolution in 14 patients (48%). Oral isotretinoin was required for 8 patients (3%) and was effective in all but one patient. Eighteen percent of patients who developed acne (2.2% of total cohort) required a JAK inhibitor dose reduction or discontinuation, although most did not have severe disease.

Conclusion

This study is the first to characterise this adverse event in JAK inhibitor-treated patients with IBD and presents the largest cohort of JAK inhibitor-induced acne cases to date across all immune-mediated diseases. JAK inhibitor-induced acne is a common adverse effect resulting in significant psychological burden. Early identification, proactive counselling, and timely interventions, such as dose reduction or referral to dermatology, are crucial in managing this side effect.

Introduction

The use of Immune Checkpoint Inhibitors (ICI’s) have been demonstrated to significantly improve progression free-survival in a number of malignancies ⁽¹⁾. Immune related adverse effects (IRAEs) are, however, an increasingly prevalent unwanted outcome, and now a widely recognised entity, with a number of guideline based management strategies published. Gastrointestinal IRAEs (GIIRAEs), including colitis and hepatitis are among two of the most reported IRAE’s with combination ICI use accounting for 15% and 10% of all IRAE’s respectively ⁽²⁾.

Aims & Methods

We aimed to report the rates and severity of Gastrointestinal Immune Related Adverse Effects (GIIRAE’s) for patients who had received combination immunotherapy with nivolumab and ipilimumab, and analyse the investigations, treatment regime and response in a single tertiary referral centre. A retrospective cohort analysis was conducted of all patients receiving ipilimumab and nivolumab for melanoma, renal cell carcinoma and mesothelioma between the dates of 2019 to 2023. The local oncology database and electronic hospital records were reviewed. Baseline demographics, incidence, grade and treatment of GIIRAE’s were collected.

Results

A total of 99 patients on combination ICI were identified. 26 patients (26%) had a GIIRAE of whom 15% (15/99) had diarrhoea and 11% (11/99) had hepatitis. 47% (7/15) of patients with diarrhoea had radiological or endoscopic confirmation of colitis (5) or enteritis (2). Of the 5 patients with Grade 3-4 diarrhoea, 3 (60%) required escalation to infliximab, all of which only had mild colitis evident at colonoscopy. 7/11 (64%) of patients had Grade 3-4 hepatitis, with only one patient requiring escalation to steroid sparing agent, despite only 57% (4/7) being commenced on high dose intravenous steroids as recommended by current guidelines. 40% (10/26) of Grade 1-2 IRAEs were managed conservatively. Only 50% (13/26) of all identified cases had involvement of a gastroenterologist.

Conclusion

Management strategies for GIIRAEs have and continue to evolve, and our cohort highlights the heterogeneity in investigation and management practice over the course of four years. Based on our findings, symptom-based assessment of severity for diarrhoea associated IRAEs appears to be a better predictor for the need for escalation of therapy rather than severity of investigation findings given only mild colitis was found on endoscopy for all patients who required biologic therapy. For hepatitis associated IRAEs, it would appear that a less aggressive approach to steroid therapy compared to current published guidelines may be adequate. Further prospective studies with larger cohort would be of value to confirm our observations.

References

1) Sedano R, Cabrera D, Jiménez A, Ma C, Jairath V, Arrese M, Arab JP. Immunotherapy for Cancer: Common Gastrointestinal, Liver, and Pancreatic Side Effects and Their Management. Am J Gastroenterol. 2022 Dec 1;117(12):1917-1932. doi: 10.14309/ajg.0000000000001983. Epub 2022 Aug 22. PMID: 36455219.
2) Dahiya DS, Wani F, Guidi JC, Kichloo A. Gastrointestinal Adverse Effects of Immunotherapeutic Agents: A Systematic Review. Gastroenterology Res. 2020 Dec;13(6):227-232. doi: 10.14740/gr1340. Epub 2020 Dec 23. PMID: 33447301; PMCID: PMC7781271.

Introduction

Tofacitinib, filgotinib, and upadacitinib, are Janus kinase inhibitors (iJAKs) approved for inflammatory bowel disease (IBD) treatment. Although no direct comparative studies exist, potential differences in efficacy and safety are attributed to in vitro-demonstrated affinity of each molecule for different JAK isoforms. JAK1 plays a crucial role in modulating cytokine-mediated immune responses, such as IL-6 and interferon, which are involved in inflammation and skin homeostasis. Its inhibition can promote conditions that may trigger acne.
Acne may be increased in iJAK-treated patients, meaning a clinical challenge for gastroenterologists.

Aims & Methods

A retrospective study was conducted at ten referral centers in Spain, including all IBD patients who had received iJAK therapy and had at least 3 months of follow-up. Demographic data, disease-related variables, and acne characteristics when appropriate, were collected. Univariate and multivariate logistic regressions were used to identify risk factors for acne; model discrimination was assessed by AUC.

Results

A total of 549 patients included: 258 (47%) were women; 354 (64%) had ulcerative colitis, 191 (35%) had Crohn’s disease and 1% had indeterminate colitis. Mean age was 41 years (IQR 30-52). 219 patients (40%) were treated with tofacitinib, 281 (51%) with upadacitinib, and 49 (9%) with filgotinib.
Ninety patients (16%) developed acne during iJAK treatment: 69% were mild, with only 4 severe cases (4%). Acne occurred early (median onset 42 days, IQR 7-122), predominantly on the face (56%), trunk (13%) or both (31%). Acne morphology included comedones (60%), papules (59%), pustules (39%), nodular-cystic (12%), scarring (9%); 48% showed more than one morphology.
Thirty-six patients received specific acne treatment: 89% topical (antiseptics, benzoyl peroxide, retinoids), 69% systemic (antibiotics, retinoids, antiandrogens), and 44% combined treatment. 83% of those patients responded to acne specific treatment, and only 8 patients (9% of those with acne; 1.5% overall) had to discontinue iJAK treatment, with acne resolving in all cases.
Acne developed in 26%, 6% and 6% of upadacitinib, tofacitinib and filgotinib treated patients respectively (p=0.001). Multivariate analysis showed that acne development was associated with upadacitinib (OR 10.28;IC95%=4,7–22,6; p<0,001) and history of acne (OR 3.52; IC95%=1,5–8,3; p=0,004), while older age (>35 years, OR 0.31; IC95% 0,11–0,83; p=0,02) and Crohn’s disease (OR 0.47; IC95% 0,25–0,90; p=0,02) showed to be protective. This model was reliable in predicting acne development (AUC 0.79). Additionally, univariate analysis showed high dose of iJAK was also associated with acne development, which could not be confirmed in multivariate analysis.

Conclusion

Acne occurred in a relevant proportion of iJAK-treated patients, was generally mild and manageable with dermatological care, and rarely required treatment discontinuation. Risk factors for iJAK-associated acne included use of upadacitinib (probably reflecting a greater affinity for JAK1) and history of acne, while older age and Crohn’s disease were protective.
Gastroenterologists should be aware of both likelihood and management of this specific adverse event when considering iJAK therapy.

Disclosure

Y G-L, MC, GB, ER, IB, DC, M B-dA, LM, I M-J, DG, IV have provided scientific advisory / participated in educational activities / received unrestricted research grants / received payments for lecturing from Johnson & Johnson, ​Takeda, Pfizer, Amgen, AbbVie, Lilly, AlfaSigma, Ferring, Gilead.

Clinical Case Summary

Introduction: Tofacitinib is an oral small molecule JAK inhibitor approved for the treatment of moderate to severe ulcerative colitis (UC). Its efficacy and safety have been demonstrated in phase III clinical trials and supported by real-life data.
Case description: We report the case of an 18-year-old woman with a 1-year diagnosis of left-sided UC, with multiple admissions due to disease exacerbation or infections, refractory to infliximab (with azathioprine) and currently under treatment with vedolizumab and tacrolimus. She was admitted due to a severe disease exacerbation and, because of a previous history of neuropsychiatric side effects to corticotherapy, tofacitinib was initiated. In the following 6 days, there was no clinical improvement of UC, and serial blood work-up revealed moderate grade persistent peripheral eosinophilia (3000 cells/mm3) and acute kidney injury grade 1 KDIGO. Tofacitinib temporary suspension was decided, with a rapid normalization of renal function/eosinophil levels. Tofacitinib was restarted 2 days after its suspension. However, she developed moderate eosinophilia (2000 cells/mm3) again, which was considered an adverse effect (AE) to tofacitinib, leading to its suspension with eosinophilia resolution. Given the severity of the disease, after a multidisciplinary discussion, it was decided to start high-dose corticotherapy and ustekinumab with maintenance therapy every 4 weeks, and to add tacrolimus. Clinical and biochemical remission were achieved, and the patient was discharged. Three-month follow-up after tofacitinib suspension showed no recrudescence of eosinophilia.
Conclusion: Tofacitinib represents a significant advance in the management of UC patients. The drug has a good safety profile with few related AE. This case aims to warn about type IVb hypersensitivity reaction as an AE of tofacitinib not reported so far. To our knowledge this is the first case of tofacitinib-induced eosinophilia in the context of UC.