Severe Skin Reactions Research Articles

Toxic epidermal necrolysis following heart transplantation may caused by cefoperazone sodium and sulbactam sodium

BackgroundThe outcome of heart transplantation is significantly affected by perioperative infections. Individualised immunosuppression strategies are essential to reduce the risk of such infections.Case presentationWe report the successful management of a 56-year-old male patient diagnosed with dilated cardiomyopathy who underwent heart transplantation. During the perioperative period, the patient was prescribed cefoperazone sodium and sulbactam sodium, which induced a severe skin reaction: toxic epidermal necrolysis (TEN). The patient was treated with prednisone, immunoglobulins, etanercept, and other active immunomodulatory measures, together with an individualised anti-rejection regimen and physical therapy. The systemic rash resolved within a month, and the patient was successfully discharged after surgery.ConclusionEffective management of heart transplantation necessitates balancing immunosuppression and infection prevention. Individualised immunosuppressive strategies are critical for optimal clinical outcomes.

Patient Preferences for First-Line Treatment of Locally Advanced or Metastatic Urothelial Carcinoma: An Application of Multidimensional Thresholding.

Patient preferences have the potential to influence the development of new treatments for locally advanced/metastatic urothelial carcinoma (la/mUC), and therefore we explored how patients with la/mUC value different attributes of first-line treatments. An online preference survey and multidimensional thresholding (MDT) exercise were developed following a targeted literature review and qualitative interviews with physicians, patients with la/mUC, and their caregivers. Treatment attributes included two benefits (overall response rate [ORR], pain related to bladder cancer [scored 0-100; 100 being the worst pain possible]) and four treatment-related risks (peripheral neuropathy, severe side effects, mildtomoderate nausea, mildtomoderate skin reactions). A Dirichlet regression was used to estimate average preference weights. Marginal utility and the reduction in ORR that patients would accept in exchange for a 10-pointdecrease or a10% decrease in other attributes were calculated. A total of 100 patients were recruited and self-completed the survey and MDT. Mean patient age was 64.9 years (standard deviation, 7.6), 54% were female, and 38% identified as white. All included treatment attributes had a statistically significant impact on preferences. Changes in ORR had the largest impact, followed by cancer-related pain and treatment-related risks. Patients were willing to accept an 8.4% decrease in ORR to reduce their pain level by 10 points or a 7.8% decrease in ORR to reduce the risk of peripheral neuropathy by 10%. For a 10% decrease in severe side effects, mildtomoderate nausea, or skin reaction, patients would accept decreases in ORR of 5.5%, 3.7%, or 3.4%, respectively. Of the attributes tested, changes in ORR were most important to patients. Patients made tradeoffs between treatment attributes indicating that a lower ORR may be acceptable for an improvement in other attributes such as reduced cancer-related pain or the risk of treatment-related adverse events.

Treatment of Canine Leishmaniasis with Meglumine Antimoniate: A Clinical Study of Tolerability and Efficacy.

Antimoniate therapy, in association with allopurinol, is one of the first-line treatments of canine leishmaniasis (CanL). This study evaluates the potential adverse effects associated with aNm in the treatment of CanL through both a retrospective analysis and a long-term prospective study also aimed to investigate its efficacy. The retrospective study reviewed records of 87 dogs with CanL with at least one follow-up available during or at the end of therapy with aNm (Glucantime®) at a dose of 50 mg/kg administered subcutaneously twice a day in association with allopurinol. In total, 29.8% of dogs showed adverse effects during treatment as local reactions at the injection site (n = 6), severe systemic reaction to pain (originating from the inoculation site) with depression and anorexia (n = 4), systemic disease due to renal function worsening (n = 4), acute pancreatitis (n = 1), diarrhea (n = 5), vomiting (n = 3) and severe idiosyncratic skin reactions (n = 3). Of these dogs, 13 (14.9%) required treatment suspension. The prospective study included 16 dogs, selected among the LeishVet stages II and III CKD IRIS stage 1 (International Renal Interest Society staging of canine Chronic Kidney Disease) and treated with the same aNm plus allopurinol protocol as in the retrospective study and observed for 360 days; 2 dogs were excluded for severe reactions at the injection site. Mild and transient adverse events were reported in the other 4 dogs. The criteria used to evaluate the efficacy of treatment with aNm were as follows: a reduction in the clinical score and improvement and/or normalization of laboratory parameters, negativization of PCR on the bone marrow samples and disease-free interval time. The proportion of reduction in the clinical score reached 91.9% at D180. No animals showed clinical laboratory relapse during the whole study duration and interestingly, the PCR results showed complete negativity between D0 and D60 in 78.5% of animals. Veterinarians must be vigilant regarding the potentially serious adverse effects associated with aNm and promptly stop drug administration if unexpected clinical manifestations occur. On the other hand, they should not discard its use for CanL treatment since it is confirmed that aNm in association with allopurinol is highly effective in controlling CanL.

Enfortumab vedotin (EV) with pembrolizumab (P) versus chemotherapy (chemo) in previously untreated locally advanced or metastatic urothelial carcinoma (la/mUC): Analysis of cisplatin (cis)-eligible population from EV-302/KEYNOTE-A39.

4562 Background: EV-302/KEYNOTE-A39 (NCT04223856) is a phase 3, randomized, open-label, global study comparing EV+P with platinum-based chemo (PBC) for first-line (1L) treatment (tx) of patients (pts) with la/mUC regardless of cis eligibility. In EV-302, EV+P demonstrated a statistically significant and clinically meaningful benefit compared with PBC for the dual primary endpoints of progression-free survival (PFS) (hazard ratio [HR]: 0.45; P<0.00001) and overall survival (OS) (HR: 0.47; P<0.00001) in the overall pt population (Powles ESMO 2023), reducing the risk of progression and/or death by more than 50%. EV+P was FDA-approved in Dec 2023 for tx of adults with la/mUC. As cis eligibility status has long defined 1L tx, here we present results for pts who were eligible for cis at randomization. Methods: Pts with previously untreated la/mUC were randomized 1:1 to receive 3-week cycles of EV (1.25 mg/kg IV; Days 1 and 8) and P (200 mg IV; Day 1) or PBC (gemcitabine with cis or carboplatin). Select secondary endpoints included confirmed objective response rate (ORR), duration of response (DOR), and safety. Pts were deemed eligible/ineligible for cis by protocol-defined criteria and were stratified accordingly. Results: 478 pts (EV+P: 244, PBC: 234) were cis-eligible at randomization. 220 (94.0%) pts in the PBC arm received cis at Cycle 1. mPFS was 14.6 mo for EV+P; 6.5 mo for PBC (HR: 0.48, 95% CI, 0.38, 0.62). mOS was 31.5 mo for EV+P; 18.4 mo for PBC (HR: 0.53, 95% CI, 0.39, 0.72). ORR for EV+P was 70.8% with 32.5% complete response (CR) rate; mDOR (95% CI) was not reached (18.2 mo, NR). ORR for PBC was 53.0% with 15.5% CR rate; mDOR (95% CI) was 8.3 mo (5.9, 10.9). In EV+P arm, 82 pts (33.6%) remained on tx at data cutoff (DCO). 85 pts (34.8%) received subsequent therapy. 72 pts (29.5%) received any platinum-based therapy as first subsequent therapy; 43 pts (17.6%) received cis. In PBC arm, all pts were off study tx at DCO. 146 pts (62.4%) received any PD-1/L1 therapy following PBC. 83 pts received maintenance avelumab; 59 pts received PD-1/L1 therapy as 2L tx. Grade ≥3 TRAEs occurred in 53.9% of pts with EV+P and 62.7% of pts with PBC. Most common grade ≥3 TRAEs of special interest for EV were skin reactions (14.8%), hyperglycemia (7.8%), and peripheral neuropathy (5.8%). Most common grade ≥3 tx-emergent AEs of special interest for P were severe skin reactions (9.5%), pneumonitis (4.9%), and colitis (2.9%). Conclusions: EV+P improved clinical outcomes in pts who were eligible for cis with previously untreated la/mUC, reducing the risk of death by 47% compared with PBC. Results were consistent with the overall population. The AE profile of EV+P was generally manageable with no new safety signals. The results of EV-302 support EV+P as a new SOC for la/mUC, including pts who are eligible for cis. Clinical trial information: NCT04223856 .

Phase 1 study of anti–immunoglobulin-like transcript 3 (ILT3) monoclonal antibody MK-0482 + pembrolizumab + gemcitabine + nab-paclitaxel (Gem/Nab-P) in patients (pts) with metastatic pancreatic ductal adenocarcinoma (mPDAC).

4139 Background: Standard first-line treatment of mPDAC includes Gem/Nab-P doublet therapy, which typically results in an ORR of 23%-35%, a median PFS of 5-6 mo, and a median OS of 7-10 mo. ILT3 is an inhibitory receptor expressed on monocytic myeloid cells, including tolerogenic dendritic cells and myeloid-derived suppressor cells. MK-0482 is a novel humanized IgG4 monoclonal antibody targeting ILT3. ILT3 inhibition with MK-0482 has the potential to relieve immunosuppression within the tumor microenvironment. In the expansion cohort of the first-in-human phase 1 study MK-0482-001 (NCT03918278), the combination of MK-0482 + pembrolizumab + Gem/Nab-P was evaluated in pts with treatment-naive mPDAC. The safety and efficacy data from this cohort are presented. Methods: Pts aged ≥18 y with previously untreated mPDAC, measurable disease per RECIST v1.1, and an ECOG PS of 0 or 1 received MK-0482 750 mg Q3W + pembrolizumab 200 mg Q3W IV for ≤35 cycles + Gem/Nab-P (gemcitabine 1000 mg/m2; nab-paclitaxel 125 mg/m2) on days 1, 8, and 15 Q4W until PD or treatment discontinuation. The primary end point was safety. Secondary end points were ORR, DCR (CR + PR + SD), and DOR by investigator assessment per RECIST v1.1. Exploratory end points included PFS per RECIST v1.1 and OS. Results: A total of 37 pts were enrolled and received study treatment. At data cutoff (Oct 3, 2023), median follow-up was 13 mo (range 8.9-18.9). Median age was 65 y (range, 39-77). Most pts were male (54%), had an ECOG PS 1 (65%), and had ≥3 sites of metastasis (54%). Any-cause adverse events (AEs) occurred in all pts and treatment-related AEs (TRAEs) occurred in 36 pts (97%). Grade 3 or 4 TRAEs occurred in 27 pts (73%); the most frequent (≥10%) were decreased neutrophil count (27%), anemia (19%), and neutropenia (19%). No deaths due to TRAEs occurred. Immune-mediated AEs occurred in 12 pts (32%); the most frequent (≥10%) was hypothyroidism (11%). Grade 3 immune-mediated AEs occurred in 5 pts (14%; hepatitis, n = 2; severe skin reactions, n = 2; colitis, n = 1); no grade 4 or 5 events occurred. Confirmed ORR was 43% (16/37; 95% CI, 27.1-60.5), DCR was 84% (31/37; 68.0-93.8), and median DOR was 8.5 mo (range, 3.7-17.8+). Median PFS was 8.5 mo (95% CI, 5.7-12.3) and median OS was 15.6 mo (10.5-22.1); 12-mo PFS and OS rates were 35% and 60%, respectively. Biomarker data will be included in the presentation. Conclusions: MK-0482 + pembrolizumab + Gem/Nab-P showed a manageable AE profile in patients with treatment-naive mPDAC, which was generally consistent with the combined safety profiles of pembrolizumab-based immunotherapy and Gem/Nab-P, respectively. The 4-drug combination showed increased clinical efficacy compared with that historically observed for chemotherapy regimens. Further evaluation is needed to confirm the clinical activities observed. Clinical trial information: NCT03918278 .

Enfortumab vedotin (EV) with pembrolizumab (P) versus chemotherapy (chemo) in previously untreated locally advanced or metastatic urothelial carcinoma (la/mUC): Analysis of the cisplatin (cis)-ineligible population from EV-302/KEYNOTE-A39.

4563 Background: EV-302/KEYNOTE-A39 (NCT04223856) is a phase 3, randomized, open-label, global study comparing EV+P with platinum-based chemo (PBC) for first-line (1L) treatment (tx) of patients (pts) with la/mUC regardless of cis eligibility. In EV-302, EV+P demonstrated a statistically significant and clinically meaningful benefit compared with PBC for the dual primary endpoints of PFS (hazard ratio [HR]: 0.45; P<0.00001) and OS (HR: 0.47; P<0.00001) in the overall pt population (Powles ESMO 2023), reducing the risk of progression and/or death by more than 50%. EV+P was FDA-approved in Dec 2023 for tx of adults with la/mUC. As cis eligibility status has long defined 1L tx, here we present results of an analysis for pts who were ineligible for cis at randomization. Methods: Pts with previously untreated la/mUC were randomized 1:1 to receive 3-week cycles of EV (1.25 mg/kg IV; Days 1 and 8) and P (200 mg IV; Day 1) or PBC (gemcitabine with cis or carboplatin [carbo]). Select secondary endpoints included confirmed objective response rate (ORR), duration of response (DOR), and safety. Pts were deemed eligible/ineligible for cis following protocol-defined criteria and stratified accordingly. Results: 408 pts (EV+P: 198, PBC: 210) were cis-ineligible at randomization. 205 (97.6%) pts in the PBC arm received carbo at Cyle 1. mPFS was 10.6 months for EV+P; 6.1 months for PBC (HR: 0.43, 95% CI, 0.33, 0.55). mOS was not reached for EV+P and was 12.7 months for PBC (HR: 0.43, 95% CI, 0.31, 0.59). ORR for EV+P was 63.9% with 24.7% complete response (CR) rate; mDOR (95% CI) was not reached (16.3 months, NR). ORR for PBC was 34.9% with 9.1% CR rate; mDOR (95% CI) was 6.6 months (5.6, 10.2). In EV+P arm, 62 pts (31.3%) remained on tx at data cutoff (DCO). 55 pts (27.8%) received subsequent therapy. 10 pts received cis and 27 pts received carbo as first subsequent therapy. In PBC arm, all were off study tx at DCO. 114 pts (54.3%) received any PD-1/L1 therapy following PBC. 52 pts received maintenance avelumab; 58 pts received PD-1/L1 therapy as second-line tx. Grade ≥3 TRAEs occurred in 58.4% of pts with EV+P and 77.1% of pts with PBC. Most common grade ≥3 TRAEs of special interest for EV were skin reactions (16.2%), peripheral neuropathy (8.1%), and hyperglycemia (4.1%). Most common grade ≥3 tx-emergent AEs of special interest for P were severe skin reaction (14.7%), hepatitis (2.0%), and pneumonitis (2.0%). Conclusions: In this pt population with historically poor prognosis, EV+P improved clinical outcomes in pts who were ineligible for cis; results were consistent with the overall population. The risk of death was reduced by more than 50%. The AE profile of EV+P was generally manageable with no new safety signals. The results of EV-302 support EV+P as a new SOC for la/mUC, including pts who are ineligible for cis. Clinical trial information: NCT04223856 .

A phase 1/2 study of favezelimab in combination with pembrolizumab for anti–PD-1–naive relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL): An updated analysis.

7055 Background: PD-1 inhibitors such as pembrolizumab are an important treatment option for patients (pts) with R/R cHL, but treatment failure remains a significant challenge. Dual immune checkpoint blockade with a PD-1 inhibitor and a lymphocyte-activation gene 3 (LAG-3) inhibitor shows promise as a treatment option for R/R cHL. In a multicohort phase 1/2 study (NCT03598608) evaluating the anti–LAG-3 monoclonal antibody favezelimab in combination with pembrolizumab for R/R hematologic malignancies, pembrolizumab plus favezelimab demonstrated sustained antitumor activity and acceptable safety in the cohort of pts with anti–PD-1–naive R/R cHL (cohort 1). We present updated results from this cohort after additional follow-up. Methods: Eligible pts were aged ≥18 years with R/R cHL; prior treatment with or ineligibility for autologous stem cell transplantation or no response to salvage chemotherapy; no prior PD-1 inhibitor; and an ECOG PS of 0 or 1. The study comprised a safety lead-in (pembrolizumab 200 mg IV Q3W plus favezelimab 200-mg starting dose, then dose escalation to 800 mg IV Q3W using a modified toxicity probability interval method) and a dose expansion phase (pembrolizumab 200 mg Q3W plus favezelimab at the established recommended phase 2 dose of 800 mg Q3W for up to 35 cycles). Primary end point was safety. Objective response rate (ORR) per IWG 2007 criteria by investigator review was a secondary end point. Duration of response (DOR) and progression-free survival (PFS) per IWG 2007 criteria by investigator review and overall survival (OS) were exploratory. Results: Cohort 1 enrolled 30 pts. The median time from first dose to data cutoff (August 15, 2023) was 36.9 months (range, 29.4-48.6). Treatment-related adverse events (AEs) occurred in 27 pts (90%), of which the most common (≥20%) were hypothyroidism (27%), infusion-related reaction (23%), and fatigue (20%). Grade 3 or 4 treatment-related AEs occurred in 7 pts (23%). Five pts (17%) discontinued treatment due to treatment-related AEs. No deaths due to treatment-related AEs were reported. AEs of clinical interest occurred in 20 pts (67%); 3 pts (10%) had grade 3 events (colitis, pneumonitis, severe skin reaction) and 1 pt (3%) had a grade 4 event (hepatitis). The ORR was 83% (n = 25; 95% CI, 65-94); 11 pts (37%) had a complete response and 14 (47%) had a partial response. Median DOR was 17.0 months (range, 2.6-30.5), and an estimated 47% of responders remained in response at 24 months. Median PFS was 19.4 months (95% CI, 9.5-28.5), and the 24-month PFS rate was 46%. Median OS was not reached (NR; 95% CI, NR-NR), and the 24-month OS rate was 93%. Conclusions: With additional follow-up, favezelimab plus pembrolizumab continued to demonstrate sustained antitumor activity and manageable safety in pts with anti–PD-1–naive R/R cHL. Further studies to investigate this combination are warranted. Clinical trial information: NCT03598608 .

Comparison of Outcome of Concurrent Chemoradiotherapy and Sequential Chemoradiotherapy in Locally Advanced, Inoperable Squamous Cell Carcinoma of Head and Neck Region

Background: Head and neck cancer is prevalent in Bangladesh, with a majority of patients presenting with locally advanced, inoperable disease. This study aimed to compare the effectiveness and accessibility of concurrent and sequential (CCRT with RT) chemoradiotherapy in treating this condition, addressing a debate among oncologists. Materials and Methods: A quasi-experimental study at Rajshahi Medical College Hospital (June 2019 - May 2020) involved 60 inoperable head and neck cancer patients, comparing concurrent chemoradiotherapy with Cisplatin and sequential chemoradiotherapy with Paclitaxel and Cisplatin, monitoring treatment response and toxicities. Results: The mean age was 56.1 (±9.5) years in Arm-A and 56.9 (±9.4) years in Arm-B. The primary endpoint was loco-regional control and early toxicities. In the final response, 14 weeks after the completion of treatment, the overall loco-regional control rate was 86.67% and 76.67% in Arm-A and Arm-B, respectively. Severe toxicities include grade 3 reaction only and happened 18(58%) vs 13(42%) in Arm-A and Arm-B, respectively. Among severe toxicities, mucositis and skin reaction were higher in the concurrent Arm and anemia and neutropenia were higher in the sequential Arm. However, there was no actual difference in the two treatment modalities (p=>0.05). The overall treatment time was short in concurrent chemoradiotherapy (49 vs 133 days) and lower treatment cost as well, which was statistically significant (p=<0.0001). Conclusion: concurrent chemoradiotherapy proves cost-effective and accessible, demonstrating outcomes similar to sequential chemoradiotherapy. It stands as a viable treatment choice for locally advanced, inoperable head and neck squamous cell carcinoma.

Abstract PS14-05: Safety evaluation from the KEYNOTE-522 study of neoadjuvant pembrolizumab (or placebo) plus chemotherapy followed by adjuvant pembrolizumab (or placebo) in patients with early triple-negative breast cancer (TNBC)

Abstract Background: In KEYNOTE-522 (NCT03036488), neoadjuvant (neoadj) pembrolizumab (pembro) + chemotherapy (chemo) followed by adjuvant (adj) pembro led to statistically significant and clinically meaningful improvements in the primary endpoints, pCR and EFS, vs neoadj placebo (pbo) + chemo followed by adj pbo in patients (pts) with newly diagnosed, high-risk, early TNBC. In the safety population at preplanned interim analysis 4 (IA4), treatment-related AEs in the combined phases (neoadj + adj) occurred in 98.9% of pts with pembro + chemo/pembro and 99.7% of pts with pbo + chemo/pbo; immune-mediated AEs of any grade occurred in 33.5% and 11.3% of pts, respectively. We report additional safety findings, beyond the already reported safety results, on immune-mediated AEs and management in the combined phases from IA4 of KEYNOTE-522. Methods: Eligible pts were randomized 2:1 to receive neoadj pembro 200 mg or pbo Q3W + paclitaxel-carboplatin for 4 cycles and then doxorubicin or epirubicin + cyclophosphamide for 4 cycles. After definitive surgery, pts received radiation therapy as indicated + adj pembro 200 mg or pbo Q3W for up to 9 cycles. Safety was assessed in all randomized pts who received ≥1 dose, underwent surgery, or both. AEs were monitored throughout the study and for 30 d post-treatment (90 d for serious AEs). Results: At IA4 (data cut-off: March 23, 2021), median treatment duration was 13.3 (range, 0-21.9) mo with pembro + chemo/pembro (n = 783) and 13.6 (range, 0-19.8) mo with pbo + chemo/pbo (n = 389). Of 341 pts with immune-mediated AEs and infusion reactions in the pembro + chemo/pembro arm (most events occurred in neoadj phase), 224 had grade 1-2 events and 117 had grade 3–5 events. The most common immune-mediated AEs with pembro + chemo/pembro were hypothyroidism (15.1%) and severe skin reactions (5.7%); infusion reactions occurred in 18.0% of pts (table). Of 118 pts with hypothyroidism, median time to onset was 105 d (range, 7–510 d) and 106 were treated with thyroid replacement, suggesting an endocrine abnormality and need for continued thyroid replacement. Of 45 pts with severe skin reactions, median time to onset was 64 d (range, 4–479 d) and 28 were treated with corticosteroids. Of 141 pts with infusion reactions, median time to onset was 16 d (range, 1–458 d) and 85 were treated with corticosteroids. Other immune-mediated AEs of interest with pembro + chemo/pembro were adrenal insufficiency (2.6%), pneumonitis (2.2%), and hypophysitis (1.9%); most of these events were grade 2–3. All 20 pts with adrenal insufficiency were treated with hormone replacement. Of 17 pts with pneumonitis, median time to onset was 167 d (range, 22-537 d) and 12 were treated with corticosteroids; median episode duration was 92 d. Of 15 pts with hypophysitis, 14 were treated with corticosteroids. Conclusion: In pts with newly diagnosed, high-risk, early TNBC, neoadj pembro + chemo followed by adj pembro had a manageable safety profile that was generally consistent with the known safety profiles of pembro and the chemo regimens. Most immune-mediated AEs and infusion reactions were grade 1-2, manageable with treatment interruption, corticosteroids, and/or hormone replacement therapy, and did not result in treatment discontinuation. Together with the efficacy findings, our results support neoadj pembro + chemo followed by adj pembro as a standard of care regimen for these pts. Table Citation Format: Javier Cortés, Rebecca Dent, Lajos Pusztai, Heather McArthur, Sherko Kuemmel, Carsten Denkert, Yeon Hee Park, Rina Hui, Masato Takahashi, Carlos Barrios, Yalin Zhu, Xiaoli Zhang, Wilbur Pan, Vassiliki Karantza, Joyce O'Shaughnessy, Peter Schmid. Safety evaluation from the KEYNOTE-522 study of neoadjuvant pembrolizumab (or placebo) plus chemotherapy followed by adjuvant pembrolizumab (or placebo) in patients with early triple-negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS14-05.

Abstract PO2-20-07: A case report of a severe cutaneous adverse event in triple negative breast cancer treated with chemoimmunotherapy

Abstract Introduction Cutaneous adverse events related to immune checkpoint inhibitors (ICI) are common and most are mild. However, numerous case reports have documented severe ICI-related skin-toxicities such as Stevens-Johnsons Syndrome (SJS) most commonly among patients with melanoma and lung cancer as immunotherapy has now become a mainstay of treatment in these tumors. The use of ICIs in breast cancer treatment has only recently become standard of care for treatment of metastatic and high risk early-stage triple negative breast cancer with the publication of two landmark clinical trials, KEYNOTE-355 and KEYNOTE-522, respectively. While these trials report low rates of severe skin reactions, little is known about ICI-related severe skin toxicities in patients with breast cancer. Case description A 58-year-old female with clinical stage IIB (cT2N0M0) triple negative breast cancer was undergoing neoadjuvant treatment with pembrolizumab, an anti-programmed death (PD-1) monoclonal antibody, coupled with a chemotherapy back-bone of 12 weekly treatments of carboplatin and paclitaxel followed by 4 cycles of doxorubicin and cyclophosphamide. She developed an erythematous and itchy rash on the right breast and axilla approximately 61 days into her treatment course after having received her fourth dose of pembrolizumab. Over the next 10 days, she developed progression of the rash with painful red papules coalescing into reticulated plaques and dusky blistering of the skin involving the right arm, axilla, abdomen, inguinal folds, thigh, and back, totaling < 10% total body surface area. Notably, the rash did not have mucosal involvement. She was hospitalized for close monitoring and treatment. A punch biopsy of the rash revealed interface dermatitis with areas of full thickness skin necrosis consistent with erythema multiforme, SJS, toxic epidermal necrolysis (TEN), or a fixed drug eruption. Her skin continued to slough in the distribution of rash and a diagnosis of SJS was made. The patient had no response to initial treatment with high dose steroids. Cyclosporine was added, resulting in rapid improvement of her rash. The patient’s neoadjuvant treatment was stopped given the grade 3 SJS she experienced. Despite this truncated neoadjuvant treatment, she had excellent clinical response as her tumor was no longer palpable. She proceeded with a partial mastectomy and sentinel lymph node biopsy. Pathology revealed a pathological complete response. She did not receive any further systemic therapy in the adjuvant setting. Three months later, she was evaluated in clinic without evidence of SJS on physical exam. She was rapidly tapered off cyclosporine over one week without recurrence of her rash. Discussion Severe cutaneous adverse events related to ICIs remains an emerging area of study. In SJS, drug-specific CD8+ T lymphocytes utilize granulysin to mediate keratinocyte apoptosis. It is hypothesized that the blocking of the PD-1/PD-L1 interaction by ICIs results in the disruption of T-cell homeostasis leading to self-directed cytotoxic and inflammatory reactions and ultimately epidermal detachment. In contrast, Molina et al 2020 postulate that such ICI-related skin reactions may represent a separate clinical entity from SJS. In their case report of seven patients, they propose the term “progressive immunotherapy-related mucocutaneous eruption” (PIRME), which the authors suggest is characterized by delayed symptom onset, mild initial presentation, rare ocular involvement, benign clinical course, and favorable treatment response. Further characterization of ICI-related cutaneous adverse events is needed to understand the disease course, optimal treatment, and importantly, implications for re-challenging patients with immunotherapy. Clinicians taking care of breast cancer patients treated with ICIs need to be educated to recognize the associated skin toxicities as patients can rapidly worsen without appropriate treatment. Citation Format: Annie Zhang, Mara Beveridge, Bahar Moftakhar. A case report of a severe cutaneous adverse event in triple negative breast cancer treated with chemoimmunotherapy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-20-07.

Exploring the Efficacy of Hydroxybenzoic Acid Derivatives in Mitigating Jellyfish Toxin-Induced Skin Damage: Insights into Protective and Reparative Mechanisms.

The escalation of jellyfish stings has drawn attention to severe skin reactions, underscoring the necessity for novel treatments. This investigation assesses the potential of hydroxybenzoic acid derivatives, specifically protocatechuic acid (PCA) and gentisic acid (DHB), for alleviating Nemopilema nomurai Nematocyst Venom (NnNV)-induced injuries. By employing an in vivo mouse model, the study delves into the therapeutic efficacy of these compounds. Through a combination of ELISA and Western blot analyses, histological examinations, and molecular assays, the study scrutinizes the inflammatory response, assesses skin damage and repair mechanisms, and investigates the compounds' ability to counteract venom effects. Our findings indicate that PCA and DHB significantly mitigate inflammation by modulating critical cytokines and pathways, altering collagen ratios through topical application, and enhancing VEGF and bFGF levels. Furthermore, both compounds demonstrate potential in neutralizing NnNV toxicity by inhibiting metalloproteinases and phospholipase-A2, showcasing the viability of small-molecule compounds in managing toxin-induced injuries.

Evolution of radiation-induced dermatitis treatment.

Radiation-induced skin damage (RID) is the most prevalent, significant side effect of radiotherapy (RT). Nearly 95% of patients experience moderate to severe skin reactions after receiving radiation therapy. However, criteria for acute radiation dermatitis (ARD) treatment remain unavailable. Topical agents with anti-inflammatory properties may protect the skin and facilitate tissue regeneration in patients with RID. Many of these topical agents function through nuclear factor kappa B pathway regulation. They either reduce the levels of inflammatory factors or elicit anti-inflammatory properties of their own, thus preventing oxidative stress and inflammatory responses and thus enabling RID prevention and management. Herein, we explore the 25 topical agents investigated for RID prevention and management thus far and evaluate their mechanisms of action. These agents include 11 natural agents, 3 miscellaneous agents, 9 topical nonsteroidal agents, and 2 topical corticosteroids.

Pre-treatment with topical 5-fluorouracil increases the efficacy of daylight photodynamic therapy for actinic keratoses – A randomized controlled trial

BackgroundDaylight photodynamic therapy (dPDT) and topical 5-fluorouracil (5-FU) are each effective treatments for thin grade I actinic keratosis (AKs), but less so for thicker grade II-III AKs. Prolonged topical treatment regimens can be associated with severe skin reactions and low compliance.This study compares the efficacy of sequential 4 % 5-FU and dPDT with dPDT monotherapy for multiple actinic keratoses. MethodsSixty patients with a total of 1547 AKs (grade I: 1278; grade II: 246; grade III: 23) were treated in two symmetrical areas (mean size 75 cm2) of the face or scalp, which were randomized to (i) 4% 5-FU creme twice daily for 7 days before a single dPDT procedure and (ii) dPDT monotherapy. Daylight exposure was either outdoor or indoor daylight. ResultsTwelve weeks after treatment 87 % of all AKs cleared after 5-FU+dPDT compared to 74 % after dPDT alone (p<0.0001). For grade II AKs, the lesion response rate increased from 55 % with dPDT monotherapy to 79 % after 5-FU+dPDT (p<0.0056). Moderate/severe erythema was seen in 88 % 5-FU+dPDT areas compared to 41 % of dPDT areas two days after dPDT. Twelve weeks after treatment 75 % of the patients were very satisfied with both treatments. ConclusionsSequential 5-FU and dPDT was more effective than dPDT monotherapy in the treatment of AKs, especially for grade II AKs. Local skin reactions were more pronounced after combination treatment, but no patients discontinued the treatment. The combination of 5-FU and dPDT is an effective treatment of large treatment areas with high compliance and satisfaction.

Distinguishing Benign Rashes From Severe Skin Reactions From Anti-Seizure Medications

Distinguishing Benign Rashes From Severe Skin Reactions From Anti-Seizure Medications

Skin and mucosal manifestations of immune reconstitution inflammatory syndrome in people living with HIV: a review.

Opportunistic infections have significantly decreased in individuals living with human immunodeficiency virus and receiving antiretroviral therapy. However, in approximately 10%-25% of patients, severe skin reactions during immune reconstruction are constantly increasing. This may manifest as either an exacerbation of a chronic disease or the development of a new disorder, referred to as immune reconstitution inflammatory syndrome. This review focuses on the current knowledge regarding the dermatological symptoms of immune reconstitution inflammatory syndrome observed in recent years. These symptoms encompass various pathogens, neoplasms, and certain autoimmune diseases. In addition to the most common skin reactions, attention is directed towards conditions not previously described in any review, such as psoriasis.

Adverse events of biological agents in pediatric rheumatologic diseases

ABSTRACT Objectives To evaluate adverse events (AEs) in pediatric patients with rheumatologic diseases being treated with approved or off-label biologic agents (BAs). Methods This observational, retrospective, multicenter study was conducted from 2010 to 2022 in patients under 18 years of age with rheumatic diseases who were receiving interleukin-1 antibodies (Anti-IL1), interleukin-6 antibodies (Anti-IL6), and tumor necrosis factor alpha inhibitors (anti-TNF). Efficacy, AEs, and timing of AEs were collected from electronic medical records. Results Three hundred and fifteen BAs were prescribed to 237 patients. Fifty AEs occurred in 44 patients (18.6%). Anti-TNF exposure was present in 8 (72.2%) of 11 patients with latent tuberculosis (TB) and in all 7 patients with herpes infections. Four of 6 patients (66.7%) with recurrent upper respiratory tract infections and 7 of 8 patients (87.5%) with local skin reactions were on Anti-IL1. The cutoff value for latent TB development was determined as 23.5 months by ROC analysis (AUC: 0.684 ± 0.072, p = 0.038, 95% CI: 0.54–0.82). In patients who used BA for 23.5 months or more, the risk of latent TB was 5.94-fold (p = 0.024, 95% CI: 1.26–27.97). Drug rash with eosinophilia and systemic symptoms (DRESS) occurred in 2 patients on anakinra, and anaphylaxis occurred in 1 patient on anti-IL6. There were no cases of malignancy or death in any patient. Conclusion The physician should be vigilant for latent TB in patients exposed to BA for more than 2 years. While local skin reactions are more prevalent in patients receiving anti-IL1, severe skin reactions such as DRESS may also occur.

(310) Severe Delayed Skin Reaction to Antiseptic Irrigation Solution Managed with Pinch Skin Grafting After Inflatable Penile Prosthesis Surgery: A Case Report

Abstract Introduction Inflatable penile prosthesis (IPP) surgery is a common procedure for treating erectile dysfunction, and skin preparation with antiseptic solutions is a standard practice to reduce infection risk. However, some antiseptic solutions, such as chlorhexidine-based Irrisept, have been associated with severe skin reactions. Several studies have reported cases of contact dermatitis, blistering, and chemical burns following the use of chlorhexidine-based antiseptic solutions before surgery. Objective This case report aims to highlight the potential risk of severe skin reactions when using Irrisept and other chlorhexidine antiseptic solutions during penile prosthesis surgery. It also explores the novel technique of pinch skin autografting used to salvage the implant and achieve successful wound healing after delayed skin necrosis. Methods 61-year-old male with a history of prostate cancer and erectile dysfunction who underwent insertion of an IPP. Results The patient's penile shaft developed blisters 3 weeks post-implantation, which progressed to full-thickness necrosis despite conservative treatment. The distribution and location of the reaction led to the hypothesis that it was caused by the chlorhexidine-based Irrisept antiseptic. The antiseptic solution used copiously throughout the case and 10CC was injected under pressure into the drain which also may explain the reaction observed. The patient underwent wound debridement and was treated with pinch skin autografts from the bilateral thighs. The autografts resulted in 95% epithelialization with excellent cosmetic outcomes with no other complications. To the best of our knowledge, this is the first reported case of Irrisept-induced delayed skin necrosis and the use of pinch skin grafting to salvage the implant after penile prosthesis surgery. Conclusions Skin reactions to Irrisept antiseptic solution during penile prosthesis surgery are rare but can be severe. Surgeons should be cautious and consider alternative skin preparation methods in patients with a history of skin allergies or sensitivities. This case also highlights the potential of pinch skin autografting as a salvage technique for post-IPP skin reactions. A multidisciplinary approach involving reconstructive burn surgeons and specialty wound care teams may be beneficial in optimizing outcomes in such cases. Disclosure No.

Neoadjuvant Radiotherapy Is Associated with Fewer Acute Adverse Skin Reactions Without Increased Risk of Postoperative Wound Complications in High-Grade Extremity Soft Tissue Sarcoma - A Retrospective Comparative Study with A Mean Follow-Up of 7 Years

Aim: In this study, we aim to compare the adverse effects and oncological outcomes of patients with high-grade extremity soft tissue sarcoma receiving neoadjuvant or adjuvant RT. Methods: From 2008 to 2022, Sixty-four patients underwent limb-preserving surgery in our institute for localized high-grade extremity soft tissue sarcoma were included. Thirty-nine patients received adjuvant radiotherapy while twenty-five patients received neoadjuvant RT before surgery if the soft tissue sarcomas were close to the neurovascular bundles, bones or histological types of myxoid liposarcoma or rhabdomyosarcoma. Primary outcomes were acute RT-related skin adverse reactions and significant side effects comprising postoperative wound complications, pathological fractures and RT-induced sarcoma. Secondary outcomes included surgical margin quality, Local-Recurrence (LR)-free survival, metastasis-free survival and overall survivorship. Results and Discussion: Patients in the neoadjuvant RT group had significantly fewer acute RT-induced adverse skin reactions than the adjuvant RT group (p=0.044, Table 2). None in the neoadjuvant RT group suffered severe acute skin reaction (RTOG grade 3-4). Wound infection (n=2) and pathological fracture (n=1) were rare in both adjuvant and neoadjuvant RT groups (P=0.640 &amp; 1.000 respectively). Survival curves for local-recurrence-free survival, metastasis-free survival and overall survivorship of both neoadjuvant and adjuvant groups were analyzed via Kaplan-Meier Curve. All results are statistically insignificant, with p=0.835, 0.948 and 0.540, respectively. Presence of metastasis was the only statistically significant predictor of the overall survival-adjusted hazard ratio of 8.7 (95%CI 2.7-28), p&lt;0.001. Conclusion: Patients with neoadjuvant RT had lower cumulative radiation doses and fewer acute adverse skin reactions. There was no increased risk of postoperative wound complication compared to adjuvant RT. The LR-free survival, metastasis-free survival and overall survival were comparable in both groups. Our results suggested that postponing surgery to eight weeks after neoadjuvant RT and primary wound closure were associated with fewer wound complications, but further studies were warranted.

The role of polymorphism of the epidermal growth factor gene in the formation of severe manifestations of skin toxicity caused by the use of EGFR inhibitors

Epidermal growth factor receptor (EGFR) inhibitors are widely used to treat various types of cancer, such as non-small cell lung cancer, head and neck cancer, breast cancer, pancreatic cancer, colorectal cancer. During treatment, class-mediated effects such as skin toxicity, interstitial lung disease, hepatotoxicity, ocular toxicity, hypomagnesemia, stomatitis, and diarrhea may occur. The role of epidermal growth factor and its receptors in the vital activity of keratinocytes is key. Dermatological undesirable effects occur in 60–90% of patients, and often persist throughout the entire period of EGFR inhibitor therapy.&#x0D; Currently, studies of biomarkers predicting the severity of skin complications of EGFR inhibitor therapy are extremely limited. Thus, it is relevant to study genetic markers reliably associated with the development of severe skin toxicity against the background of EGFR inhibitor therapy, because the EGFR signaling pathway is important for maintaining normal physiological function of the skin. The development of severe skin reactions leads to a reduction in the dose or discontinuation of EGFR inhibitors in the treatment of cancer. Recently, progress has been made in studies of the cutaneous toxicity of EGFR inhibitors.&#x0D; Here we briefly describe the mechanism of skin toxicity caused by EGFR inhibitors, current data on the relationship of gene polymorphism and severity of manifestations of undesirable dermatological phenomena.

Favezelimab in Combination with Pembrolizumab in Patients with Anti-PD-1-Naive Relapsed or Refractory Classical Hodgkin Lymphoma: Updated Analysis of an Open-Label Phase 1/2 Study

Introduction: Programmed cell death protein 1 (PD-1) inhibitors such as pembrolizumab play an important role in the treatment of patients with relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL), but treatment failure remains a significant challenge. Lymphocyte-activation gene 3 (LAG-3) is an immune checkpoint receptor that downregulates T-cell activity and plays a role in regulating T-cell function. Dual blockade of PD-1 and LAG-3 demonstrated antitumor activity in patients with advanced melanoma in the RELATIVITY-047 trial, which led to FDA approval in this setting. Favezelimab is a humanized IgG4 monoclonal antibody directed against LAG-3 that is being investigated in combination with pembrolizumab in patients with R/R hematologic malignancies in a multicohort phase 1/2 study (NCT03598608). Prior analyses of this study demonstrated that pembrolizumab 200 mg plus favezelimab 800 mg every 3 weeks (Q3W) exhibited sustained antitumor activity and acceptable safety in the cohort of patients with anti-PD-1-naive R/R cHL (cohort 1). We present updated results from this cohort. Methods: A safety lead-in phase to determine the recommended phase 2 dose (RP2D) was followed by a dose-expansion phase. Eligible patients were ≥18 years of age; had R/R cHL after autologous stem cell transplantation (ASCT), were ineligible for ASCT, or did not respond to salvage chemotherapy; had not received prior anti-PD-1 therapy; and had an ECOG performance status of 0 or 1. In the safety lead-in, patients received pembrolizumab 200 mg IV Q3W and favezelimab at a starting dose of 200 mg that was escalated to 800 mg IV Q3W using a modified toxicity probability interval method. In the dose-expansion phase, patients received pembrolizumab 200 mg Q3W plus favezelimab at the established RP2D of 800 mg Q3W for up to 35 cycles (~2 years). CT was performed every 12 weeks and PET at weeks 12 and 24. The primary end point was safety. Objective response rate (ORR) per IWG 2007 criteria by investigator review was a secondary end point. Duration of response (DOR) and progression-free survival (PFS) per IWG 2007 criteria by investigator review and overall survival (OS) were exploratory. Results: Thirty patients with anti-PD-1-naive cHL were enrolled in cohort 1. The median age was 40.5 years (range, 19-82), 17 patients (57%) were male, 16 (53%) had an ECOG performance status of 0, and 24 (80%) had received 3 or fewer prior lines of therapy. At data cutoff (March 2, 2023), 13 patients (43%) had completed 35 cycles of study treatment, 16 (53%) had discontinued treatment (10 [33%] progressive disease, 5 [17%] adverse event [AE], 1 [3%] noncompliance with study drug), and 1 (3%) was ongoing on treatment. The median time from first dose to data cutoff was 31.5 months (range, 24.0-43.2). Treatment-related AEs occurred in 27 patients (90%), of which the most common (≥20%) were hypothyroidism (27%), infusion-related reaction (23%), and fatigue (20%). Grade 3/4 treatment related AEs occurred in 9 patients (30%). Five patients (17%) discontinued treatment because of treatment-related AEs. No deaths due to treatment-related AEs were reported. AEs of clinical interest occurred in 20 patients (67%); 3 patients (10%) had grade 3 events (colitis, pneumonitis, severe skin reaction) and 1 patient (3%) had a grade 4 event (hepatitis). Of 5 patients who received allogeneic stem cell transplantation after discontinuation or completion of study treatment, 1 had a grade 3/4 AE (increased blood bilirubin) that was unrelated to study treatment and resolved. The ORR was 80% (n = 24; 95% CI, 61-92); 10 patients (33%) had a complete response and 14 (47%) had a partial response. Twenty-nine patients (97%) had any reduction in target lesions size from baseline, and 25 (83%) had a reduction of ≥50%. Median DOR was 17.0 months (range, 2.6-30.2), and an estimated 47% of responders remained in response ≥24 months. Median PFS was 19.4 months (95% CI, 9.0-28.5), and the 24-month PFS rate was 46%. Median OS was not reached (NR; 95% CI, NR-NR), and the 24-month OS rate was 93%. Conclusion: With additional follow-up, the combination of favezelimab and pembrolizumab continued to demonstrate sustained antitumor activity and manageable safety in patients with anti-PD-1-naive R/R cHL. Analyses are underway to identify biomarkers predictive of response to the combination of favezelimab and pembrolizumab. Further studies to investigate this combination are warranted.