Corticosteroid Premedication Research Articles

Severe hypersensitivity reactions to 2 immunotherapy agents in a patient with cutaneous squamous cell carcinoma.

In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. There is currently limited data on cross-sensitivity between immunotherapy agents. In this case study, we report a case of severe anaphylaxis to both pembrolizumab and cemiplimab. Pembrolizumab (Keytruda) and cemiplimab (Libtayo) are both approved for the treatment of metastatic cutaneous squamous cell carcinoma. Infusion reactions occur rarely with immunotherapy agents. However, if infusion reactions are severe, the treatment should be discontinued, and there is no guidance as to whether another immunotherapy agent may be used. An 87-year-old-male was diagnosed with metastatic cutaneous squamous cell carcinoma expressing a PD-L1 combined positive score of 81%-90%. He was treated with pembrolizumab and, 15 minutes after completion of the first infusion, developed swelling of the eyelids, ears, and tongue in addition to a whole-body rash without pruritus. Due to the severity of the reaction, pembrolizumab was permanently discontinued and the patient was then started on cemiplimab. The patient received a high-dose corticosteroid as premedication before the first infusion of cemiplimab and tolerated the treatment without any adverse effects. However, when the corticosteroid premedication dose was decreased before the second cycle, the patient had a severe infusion reaction to cemiplimab requiring discontinuation. A patient with metastatic cutaneous squamous cell carcinoma developed a severe hypersensitivity reaction to pembrolizumab and subsequently to cemiplimab, despite premedication.

6808 Effect of Corticosteroid Premedication on Adrenal Vein Sampling in Patients with Primary Aldosteronism and Iodine Contrast Allergy

6808 Effect of Corticosteroid Premedication on Adrenal Vein Sampling in Patients with Primary Aldosteronism and Iodine Contrast Allergy

Dexamethasone is Associated with a Lower Incidence and Severity of Cytokine Release Syndrome Compared with Other Corticosteroid Regimens When Given as Premedication for Glofitamab Monotherapy in Patients with Relapsed/Refractory (R/R) Large B-Cell Lymphoma (LBCL)

Background: Glofitamab, a CD20xCD3 T-cell engaging bispecific antibody with a novel 2:1 (CD20:CD3) format, induced frequent and durable complete responses (CRs) with a manageable safety profile in pivotal expansion cohorts of an ongoing Phase I/II study (NCT03075696) in patients (pts) with R/R LBCL (Dickinson et al. NEJM 2022, Falchi et al. ASCO 2023). Cytokine release syndrome (CRS) is a potentially life-threatening toxicity caused by immune activation that can be triggered non-specifically by T-cell engaging therapies. As previously reported, corticosteroid (steroid) premedication was required to prevent or mitigate CRS in pts treated with glofitamab. Dexamethasone (Dex) was mandated in one expansion cohort to assess if this could reduce the rate and severity of CRS versus other steroids. Here, we report data from the dose-escalation and expansion cohorts in pts with R/R LBCL who received Dex only versus non-Dex premedication. Methods: Pts with R/R LBCL (diffuse LBCL not otherwise specified [DLBCL NOS], high-grade B-cell lymphoma [HGBCL], primary mediastinal LBCL [PMBCL], or LBCL arising from follicular lymphoma [trFL]) and ≥2 prior therapies received 1000mg obinutuzumab pretreatment (Gpt) 7 days prior to the first glofitamab dose. IV glofitamab was administered with step-up dosing during Cycle (C) 1 (Day 8, 2.5mg; Day 15, 10mg) followed by the target dose (30mg) on Day 1 of C2-12 (21-day cycles; 8.4 months). Steroid premedication (80mg IV methylprednisolone, or equivalent dose of prednisone [100mg] or prednisolone [100mg], or 20mg IV Dex) was given at least 60 minutes prior to Gpt and each glofitamab dose. Responses were assessed using Lugano criteria (Cheson et al. JCO 2014). CRS events were graded by ASTCT criteria (Lee et al. Biol Blood Marrow Transplant 2019). Results: As of May 1, 2023, 145 pts with R/R LBCL had received glofitamab, including 33 (22.8%) pts (DLBCL NOS, n=24 [72.7%]; HGBCL, n=2 [6.1%]; trFL, n=7 [21.2%]) who received Dex premedication before each glofitamab dose (Dex only cohort) and 112 (77.2%) pts (DLBCL NOS, n=81 [72.3%]; HGBCL, n=5 [4.5%]; PMBCL, n=6 [5.4%]; trFL, n=20 [17.9%]) who had not received Dex premedication before each glofitamab dose (non-Dex cohort). In the Dex only and non-Dex cohorts, median age was 73.0 years (range: 27-86) and 66.0 years (range: 21-90), and 26/33 (78.8%) pts and 83/112 (74.1%) pts had Ann Arbor stage III/IV disease, respectively. Median number of prior therapies was 3.0 for both cohorts. Ten (30.3%) and 37 (33.0%) pts had previously received chimeric antigen receptor T-cell therapy, and 6 (18.3%) and 22 (19.6%) pts had received autologous stem cell transplant in the Dex only and non-Dex cohorts, respectively. Median number of glofitamab cycles was 5.0 in both cohorts. CRS of any grade occurred in 48.5% of pts in the Dex only cohort and 73.2% of pts in the non-Dex cohort, and CRS leading to serious adverse events occurred in 5 (15.2%) and 27 (24.1%) pts, respectively. In both cohorts, CRS events were mostly low grade and primarily occurred during C1 (Table; Figure). Recurring Grade (Gr) ≥2 CRS was not observed in the Dex only cohort and 6 (5.4%) pts had recurring Gr ≥2 CRS in the non-Dex cohort. Median time to CRS onset and median time to resolution were similar in the two cohorts. Treatment discontinuation rate was lower in the Dex only cohort (n=21, 63.6%) versus the non-Dex cohort (n=80, 71.4%), mainly due to progressive disease (Dex only cohort, n=12 [36.4%]; non-Dex cohort, n=52 [46.4%]). In the DLBCL NOS and trFL population, the best overall response assessed by Independent Review Committee was similar between the Dex only (n=31) and non-Dex (n=101) cohorts, with CR reported in 14 (45.2%) and 44 (43.6%) pts, and 12 (38.7%) and 34 (33.7%) pts remaining in CR at data cutoff, respectively. The estimated event-free rate among complete responders at 12 months after the first CR was 83.1% (95% CI: 61.5-100.0) in the Dex only cohort and 77% (95% CI: 63.8-90.2) in the non-Dex cohort. Conclusions: The incidence, severity, and seriousness of CRS after glofitamab administration in pts with R/R LBCL were numerically lower with Dex premedication versus premedication with other steroid regimens. Response rates in the Dex only cohort were similar to those reported in the non-Dex cohort. We therefore propose Dex as the steroid of choice for premedication to prevent or mitigate CRS in pts with LBCL treated with glofitamab monotherapy, considering its half-life and potency.

Fixed Duration Mosunetuzumab Plus Polatuzumab Vedotin Has Promising Efficacy and a Manageable Safety Profile in Patients with BTKi Relapsed/Refractory Mantle Cell Lymphoma: Initial Results from a Phase Ib/II Study

Background: New treatment options are needed for patients (pts) with relapsed/refractory (R/R) mantle cell lymphoma (MCL), especially for pts with progressive disease (PD) after Bruton's tyrosine kinase inhibitor (BTKi) therapy. Outcomes for R/R MCL pts with PD after the BTKi ibrutinib are very poor, demonstrated by a median overall survival of 2.9 months (Martin et al. Blood 2016). While chimeric antigen receptor (CAR) T-cell therapies are approved for pts with R/R MCL; treatment is associated with high toxicity and difficulty with accessibility. Mosunetuzumab (Mosun) is a CD20xCD3 T-cell engaging bispecific antibody that engages and redirects T cells to eliminate malignant B cells. Polatuzumab vedotin (Pola) is a CD79b-targeted antibody-drug conjugate that inhibits cell division and induces apoptosis in B cells. This ongoing Phase Ib/II study (NCT03671018) is investigating Mosun in combination with Pola (M-Pola) in pts with R/R B cell non-Hodgkin lymphoma. Here, we report initial safety and efficacy data from an ongoing Phase II expansion cohort of pts with R/R MCL who had received prior BTKi therapy. Methods: Eligiblepts had histologically confirmed R/R MCL and had received ≥2 prior regimens (including an anti-CD20 agent, BTKi, and anthracycline- or bendamustine-based therapy). Mosun was administered subcutaneously (SC) by step-up dosing on Days (D) 1 (5mg), 8 (45mg), and 15 (45mg) of Cycle (C) 1, then 45mg on D1 of every cycle from C2D1, every 3 weeks for a total of 17 cycles. Pola (1.8mg/kg intravenous [IV] infusion) was administered on D1 of C1-6. All pts received corticosteroid premedication prior to C1 of treatment. From C2, premedication was optional for pts who did not experience cytokine release syndrome (CRS) in the previous cycle. Response was assessed by investigators using Lugano 2014 criteria (Cheson et al. J Clin Oncol 2014). Results: As of October 27, 2022, 20 pts had received M-Pola (n=10 active on treatment, n=1 completed treatment, n=9 discontinued Mosun treatment). Median age of all pts was 68.0 (range: 44-82) years, 75% were male, 95% had Ann Arbor stage III/IV disease, and 40% had a MIPI score ≥6 at study entry. Median number of prior lines of therapy (LOT) was 3 (range: 2-9). All pts had received prior BTKi therapy; 7 pts (35%) had received prior CAR T-cell therapy; and 85% (17/20) of pts were refractory to their last LOT. Median time since last LOT was 1.6 (range: 0-39) months. The proportions of pts with high-risk MCL factors at baseline were: 65% of pts with Ki-67 proliferation index ≥50%; 50% with blastoid/pleomorphic variants; and 20% with TP53 mutation. The overall median time on study was 7.2 (range: 0.4-17.5) months. The most common (≥25%) Mosun and/or Pola-related adverse events (AEs) in all pts (n=20) were CRS (50%), injection site reaction (50%), fatigue (45%), dyspnea (35%), paresthesia (30%), diarrhea (30%), myalgia (30%), infusion-related reaction (25%), and nausea (25%). Two (10%) Grade (Gr) 5 AEs occurred, both of which were due to COVID-19 pneumonia; neither were deemed treatment-related by the investigator. Ten pts (50%) experienced CRS events; 9 pts experienced Gr 1 events, and 1 pt experienced a Gr 2 event, which was managed with tocilizumab and low-flow oxygen. One pt was managed with corticosteroids and no pts required pressors or ICU admission. All CRS events resolved by the data cut-off. Treatment-related neurologic AEs, potentially consistent with ICANs, occurred in 3 pts (15%; Gr 1 confusional state and Gr 2 amnesia, 1 pt; Gr 1 agitation, 1 pt; and Gr 2 memory impairment, 1 pt). Neuropathy occurred in 3 pts (15%); all events were Gr 1. Four pts (20%) had AEs leading to treatment discontinuation: 1 pt with Gr 3 uveitis (related to M-Pola); 1 pt with Gr 3 pneumonitis (related to M-Pola); and 2 pts with Gr 5 COVID-19 pneumonia (both unrelated to M-Pola). Overall response rate (ORR) and complete response (CR) rates were 75% and 70%, respectively (Figure). Best ORR and CR rates were generally consistent in high-risk MCL subgroups (Figure). Median duration of CR was not evaluable (NE; 95% confidence interval: 3.8-NE). Conclusions: Fixed-duration Mosun SC in combination with Pola IV induced high CR rates in pts with R/R MCL who had previously received BTKi therapy, including those in high-risk subgroups and those who had received prior CAR T-cell therapy. CRs were observed early and persisted during the follow up period. M-Pola had a manageable safety profile, and all CRS events were low grade.

The preventive effects of early short-course corticosteroids on immune-related adverse events in non-small cell lung cancer patients receiving immune checkpoint inhibitors.

144 Background: Corticosteroid is effective in treating immune checkpoint inhibitor (ICI)-induced immune-related adverse events (irAEs). However, whether its earlier use prevents irAEs remains unknown. In real-world practice, non-small cell lung cancer (NSCLC) patients receiving combined immunochemotherapy are often given corticosteroids right after ICI injection to reduce subsequent chemotherapy-related adverse events. It is thus an ideal model to examine whether this earlier use of corticosteroid also reduce irAEs following immunotherapy. Methods: NSCLC patients receiving at least one cycle of ICI with or without chemotherapy were enrolled. Patients receiving ICI with corticosteroid corticosteroid premedication exposure were categorized as “corticosteroid group (CS)”, whereas patients receiving ICI without corticosteroids premedication exposure were categorized as “non-corticosteroid group (non-CS)”. Frequency of irAEs prompting systemic corticosteroid or leading to ICI discontinuation were compared between the two groups. Exploratory survival analysis was performed. Results: Among 252 eligible patients, 137 patients were categorized as CS group, and 115 patients as non-CS group. 21.9% of patients in the CS group and 30.4% of patients in the non-CS group developed irAEs prompting systemic corticosteroid use (Odds ratio [OR], 0.64; 95% confidence interval [CI], 0.35 to 1.18; p=0.15). 5.8% of patients in the CS group and 15.7% of patients in the non-CS group developed irAEs leading to ICI discontinuation (OR, 0.34; 95% CI, 0.12 to 0.85; p=0.013). In the exploratory survival analysis, early short-course corticosteroids was not associated with a higher risk for death in first-line patients (hazard ratio [HR], 1.06; 95% CI, 0.56–2) or patients receiving immunochemotherapy (HR, 0.72; 95% CI, 0.37–1.45). Conclusions: Early short-course corticosteroids following each ICI injection may reduce the rate of irAEs that leads to ICIs discontinuation. The use of prophylactic corticosteroids on irAEs in cancer patients receiving ICIs should be evaluated in future prospective studies. [Table: see text]

A Survey of Practicing Radiologists on the Use of Premedication Before Intravenous Iodinated Contrast Medium Administration

ObjectiveTo determine whether updated guidance by the ACR in 2017 advocating use of intravenous (IV) premedication in emergency department (ED) patients and inpatients with reported iodinated contrast allergy was associated with a change in clinical practice. MethodsAn anonymous survey was distributed via e-mail in October 2020 to practicing radiologist members of the ACR interrogating use of corticosteroid premedication for two clinical vignettes: an indicated routine (perform within 24 hours) inpatient contrast-enhanced CT (CE-CT) and an indicated urgent (perform within 6 hours) ED CE-CT. In both scenarios, the patient had a prior moderate hypersensitivity reaction to iodinated contrast media. Clinical management was evaluated. Data were compared to historical controls from 2009. ResultsThe response rate was 11% (724 of 6,616). For the inpatient scenario, 72% (518 of 724) would use corticosteroid premedication with CE-CT, and 28% (200 of 724) would perform noncontrast CT. For the ED scenario, 67% (487 of 724) would use corticosteroid premedication with CE-CT, and 30% (217 of 724) would perform noncontrast CT. Oral premedication (85%, 439 of 518) was preferred for routine inpatients, and rapid IV premedication (89%, 433 of 487) was preferred for urgent ED patients. Of those who provided rapid IV dosing data in the ED, two doses of corticosteroids were used by 53% (216 of 410) and one dose was used by 45% (185 of 410), with academic radiologists more likely than private or hybrid practice radiologists to administer two doses (74% [74 of 100] versus 48% [151 of 312], P < .001, odds ratio, 3.03; 95% confidence interval, 1.84-5.00). Rapid IV premedication was more commonly used in 2020 than in 2009 (60% [433 of 724] versus 29% [20 of 69], P < .001, odds ratio, 3.65; 95% confidence interval, 2.12-6.26). Antihistamine use was common in both inpatient (93%, 480 of 518) and ED settings (92%, 447 of 487). Only 32% (229 of 721) of radiologists practiced in accordance with ACR guidelines, suggesting no need for routine premedication before CE-CT in patients with prior severe hypersensitivity reaction to gadolinium-based contrast media. Nonetheless, most (93%, 670 of 724) said the ACR Manual on Contrast Media was a major determinant of their practice. ConclusionsUse of rapid IV premedication in urgent settings has increased since 2009, following updated ACR guidelines, but there is disagreement over whether one or two corticosteroid doses is required. Despite reported high reliance on ACR guidelines, deviations from those guidelines remain common. In general, when ACR guidelines were not followed, it was in a risk-averse direction.

A phase 1 dose-escalation study to investigate the safety, efficacy, pharmacokinetics, and pharmacodynamic activity of cln-619 (Anti-MICA/B antibody) alone and in combination with pembrolizumab in patients with advanced solid tumors.

2532 Background: MICA and MICB are stress-induced ligands upregulated on the majority of human tumors. Engagement of MICA/B by the activating receptor NKG2D on NK cells and several subsets of T cells results in immune-mediated target cell lysis. However, proteases in the tumor microenvironment cleave cell surface MICA/B, enabling immune evasion. CLN-619 is a humanized MICA/B-specific IgG1 monoclonal antibody designed to prevent the proteolytic release of MICA/B, restoring immune-mediated tumor cell lysis. CLN-619 is expected to have broad anti-tumor activity. Methods: This phase 1, multicenter, open-label, first-in-human dose-escalation study (NCT05117476) enrolls patients (pts) with advanced solid tumors who progressed on available therapies, were intolerant to treatment, or refused noncurative standard treatment. CLN-619 alone (dose levels (DL) of 0.1, 0.3, 1, 3, 6, 10mg/kg) were administered intravenously every three weeks. Corticosteroid pre-medication for infusion related reaction (IRR) prophylaxis were required starting at the 3 mg/kg DL. A parallel dose-escalation is exploring CLN-619 (DL 1.0 mg/kg and higher) in combination with pembrolizumab. Response (RECIST 1.1) is assessed every 9 weeks. Data from the monotherapy dose escalation are described. Results: As of Dec 2, 2022, 23 pts (median age, 63 y, range 47-83) were enrolled, 48% were male and 61% had ECOG PS 1. Major tumor types included colon (4), cervical (3), lung (3) and prostate (3). All pts received prior systemic therapy (median 3, range 1-7); 12 patients had prior checkpoint inhibitor. The median number of CLN-619 cycles received was 2 (range, 0–8). Treatment-emergent adverse events (TEAEs) in ≥20% of pts were abdominal pain (26%), nausea (22%), pyrexia (22%), and infusion related reaction (IRR) (22%). IRRs occurred at dose levels of 0.3 mg/kg and higher. All IRR occurred in Cycle 1 and resolved within 3 hours of onset. One case of Gr3 laryngeal edema occurred at the 10 mg/kg DL in the absence of required steroid premedication and led to dose discontinuation. No fatal TEAEs were reported. A nearly dose-proportional increase in CLN-619 exposure was observed between the 0.1 mg/kg and 10 mg/kg dose levels. CLN-619 half-life ranged from 87.6 to 307 hours for DL ranging from 0.1 mg/kg to 6 mg/kg. There was one confirmed complete response in a patient with recurrent salivary gland tumor who progressed following a complete response on a PD-1 blocking agent. Another patient with cervical cancer maintained SD for 9 cycles before progressing. Conclusions: CLN-619 therapy was well tolerated at doses ranging from 0.1 to 10 mg/kg and demonstrated monotherapy clinical activity, including objective response in a patient progressing after PD-1. Updated data from the dose-escalation portion of the trial will be presented. Clinical trial information: NCT05117476 .

Subcutaneous Epcoritamab + R-Dhax/C in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma Eligible for Autologous Stem Cell Transplant: Updated Phase 1/2 Results

Background: For patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who are eligible for autologous stem cell transplant (ASCT), salvage immunochemotherapy, such as rituximab, dexamethasone, cytarabine, and oxaliplatin or carboplatin (R-DHAX/C), followed by consolidation with high-dose therapy (HDT) and ASCT, is part of the standard of care. However, this treatment plan is unsuccessful in more than half of patients. Novel treatment options are needed to achieve improved responses and more favorable long-term outcomes. Epcoritamab, a subcutaneously administered bispecific antibody that targets CD3 and CD20, has demonstrated clinically meaningful antitumor activity both as a single agent (in the first-in-human phase 1/2 EPCORE NHL-1 trial; NCT03625037) and in combination with standard of care therapies (in the phase 1/2 EPCORE NHL-2 trial; NCT04663347) across B-cell non-Hodgkin lymphoma subtypes. Here we present updated results from arm 4 (epcoritamab + R-DHAX/C) of the EPCORE NHL-2 trial, which is the first clinical study of a bispecific antibody in combination with salvage immunochemotherapy in this high-risk, refractory, ASCT-eligible population. Methods: Adults with R/R CD20+ DLBCL who were eligible for HDT-ASCT were treated with standard R-DHAX/C and subcutaneous epcoritamab (21-d cycles: QW, cycles 1-3). If HDT-ASCT was deferred, patients could continue epcoritamab monotherapy (21-d cycle: QW, cycle 4; 28-d cycles: Q2W, cycles 5-9, and Q4W, cycles ≥10) until disease progression or unacceptable toxicity. Corticosteroid premedication and step-up epcoritamab dosing were required in cycle 1 to mitigate CRS. Response was determined by PET-CT using Lugano 2014 criteria. Results: As of the data cutoff on June 10, 2022, 29 patients had received epcoritamab + R-DHAX/C. The median age was 58 y (range, 28-75), 72% of patients had received 1 prior line of therapy, 28% had received 2 or 3 prior therapies, 34% had transformed disease, 66% had primary refractory disease, and 59% were refractory to their last line of therapy. Three patients had prior CAR T-cell therapy. The median duration of follow-up was 9.2 mo (range, 1.7-14.2). The most common treatment-emergent AEs (TEAEs) of any grade were thrombocytopenia (69%), anemia (45%), CRS (41%), neutropenia (41%), nausea (34%), and fatigue (28%). All CRS events were low grade (grade 1 in 31% of patients, grade 2 in 10% of patients) and resolved, with a median time to resolution of 2 d (range, 1-8). Most CRS events occurred after the first full dose. One patient experienced a grade 2 ICANS event, which resolved but led to treatment discontinuation. No clinical tumor lysis syndrome was observed, and no fatal TEAEs were reported. Of the 26 response-evaluable patients (Figure), 15 (58%) proceeded to transplant per protocol; for these 15 patients, the overall response rate (ORR) with the combination of epcoritamab + R-DHAX/C was 100% (15/15), with 80% (12/15) achieving a complete metabolic response (CMR) and 20% (3/15) achieving a partial metabolic response (PMR). Patients continuing epcoritamab monotherapy instead of HDT-ASCT had an ORR of 64% (7/11), with 45% (5/11) achieving a CMR and 18% (2/11) achieving a PMR. The primary reason for a patient not proceeding to HDT-ASCT was patient choice. Median duration of response was not reached among the 7 responders continuing epcoritamab monotherapy. In the response-evaluable population overall, the ORR was 85% (22/26); rates of CMR and PMR were 65% (17/26) and 19% (5/26), respectively. Conclusions: Subcutaneous epcoritamab in combination with R-DHAX/C demonstrated a manageable safety profile in ASCT-eligible patients with R/R DLBCL. Importantly, no new safety findings were observed. ICANS was rare, and all CRS events were low grade and resolved. High ORRs and CMR rates were observed. As of the data cutoff date, most patients had proceeded to ASCT or remained on epcoritamab in CMR. In conclusion, epcoritamab is well suited for salvage combination therapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Acute Effects of Ocrelizumab Infusion in Multiple Sclerosis Patients.

B cell-depleting therapies such as ocrelizumab (OCR) are highly effective in people with multiple sclerosis (MS). Especially at treatment start and initial infusion, infusion-related reactions (IRR) are a common adverse event. The relevance of acute changes of cell-depleting therapies on peripheral immune compartments and routine lab testing is important for clinical practice. We systematically analyzed routine blood parameters, detailed blood immunophenotyping and serum cytokine profiles in 45 MS patients starting on OCR. Blood samples were collected before and after corticosteroid premedication and directly after each OCR infusion of the first three ocrelizumab infusions. Blood B cells were rapidly depleted and accompanied only by a mild cytokine release at the first OCR infusion. Cytokine release was not significantly detectable from a third application in line with decreasing IRRs. B cell depletion was accompanied by short-lived changes in other immune cell populations in number, activation and cytokine secretion after each OCR infusion. Standard lab parameters did not show any clinically relevant changes. Our data demonstrate only mild changes during the first OCR infusion, which are not present any more during long-term treatment.

1367P JNJ-70218902 (JNJ-902), a TMEFF2 x CD3 bispecific antibody, in prostate cancer: Initial results from a phase I dose escalation study

JNJ-902 is a bispecific antibody that engages TMEFF2–expressing tumor cells and CD3 on T cells. TMEFF2 is a unique prostate cancer lineage antigen with expression independent of androgen receptor signaling and retained throughout disease progression. In preclinical studies, JNJ-902 showed exposure-dependent pro-inflammatory responses, potent T cell-mediated cytotoxicity, and robust antitumor activity. This is a 2-part open-label, phase 1 study evaluating safety, pharmacokinetics (PK), pharmacodynamics, and preliminary clinical activity of JNJ-902 monotherapy in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). In Part 1 (dose escalation), a modified continual reassessment method was used to guide decision making in dose escalation and selection of the part 2 expansion dose. Subcutaneous JNJ-902 was administered with first dose given with corticosteroid premedication. Part 2 (dose expansion) will further evaluate safety and preliminary clinical activity of JNJ-902 at the part 2 expansion dose. As of April 6, 2022, 73 pts in Part 1 received at least one dose of JNJ-902 in 9 cohorts of ascending doses. Most common treatment-related AEs were fatigue (45%), decreased appetite (44%), injection site erythema (37%), anemia (33%), back pain (25%), and arthralgia (22%). Dose-limiting toxicity was reported in 2 pts (all Grade 3; 1 pt, fall-required hospitalization; 1 pt, orthostatic hypotension and syncope). Cytokine release syndrome was reported in 4 pts and resolved within 2–3 days. No deaths related to JNJ-902 were reported. Anti-drug antibody development was uncommon. PSA decline of 50% (PSA50) was observed in 8 pts and confirmed PR in 5 pts. JNJ-902 has linear PK over range of doses studied. JNJ-902 presented a tolerable safety profile at certain doses when PSA50 and RECIST responses were observed. JNJ-902 is being developed as a therapeutic option for mCRPC pts. Part 1 (dose escalation) is ongoing and Part 2 (dose expansion) of study will initiate once part 2 expansion dose is declared. Selection of part 2 expansion dosage is currently being adjusted and dose information will be presented.

Effects of prophylactic high and low doses of corticosteroid on the efficacy of immune checkpoint blockade in murine hepatocellular carcinoma models.

e14596 Background: Immune-related adverse events (irAEs) are major hurdle to immune checkpoint blockade (ICB). Corticosteroid (CS) is effective in controlling the majority of irAEs. Although recent studies suggested CS use does not jeopardize the anti-tumor efficacy of ICB, prophylactic use of CS remains prohibited with the concerns of attenuating efficacy of ICB. This study aimed to investigate the effects of CS premedication on the efficacy of ICB in murine hepatocellular carcinoma models. Methods: Anti-mCTLA-4 (9D9C, BMS) and anti-mPD-1 antibodies (4H2, ONO) were intraperitoneally (ip) administered to tumor-bearing mice (subcutaneous Hepa 1-6 model and orthotopic BNL 1MEA.7R.1 model) with or without dexamethasone (DEXA) premedication (10 and 200 μg, equivalent to minimal anti-inflammatory dosage and pulse therapy in human, respectively). Efficacy of ICB was evaluated as tumor shrinkage. Tumor-infiltrating lymphocytes (TILs) were isolated for single cell RNA-sequencing and effector function analysis through flow cytometry. Results: In the subcutaneous model, all tumors treated with ICB alone (N=7) or ICB plus DEXA 10 μg (N=5) completely regressed, but 1 out of 7 tumors treated with ICB plus DEXA 200 μg escaped. However, the tumor growth was not significantly different between groups ( P-value &gt;0.05, multiple Mann-Whitney test). In the orthotopic model (N=5/group), the mean (± standard error) tumor weights on day 21 after tumor implantation for isotype control, ICB, ICB plus DEXA 10 μg and ICB plus DEXA 200 μg were 2.45 (± 0.54), 0.73 (± 0.18), 0.98 (± 0.65), and 0.69 (± 0.17) grams, respectively ( P-value &gt;0.05, comparing ICB plus DEXA 10 or 200 μg with ICB). At transcriptomic level, premedication with either dosage of DEXA significantly reduced the percentage of effector memory cells and increased the percentage of exhausted effector cells in the CD8 TIL population, which appeared to counterbalance the effects of ICB. However, at protein level, premedication of DEXA 10 or 200 μg did not reduce the interferon-γ or granzyme B production of CD8 TILs in both models (Table). Conclusions: CS premedication did not attenuate the efficacy of ICB. Our study provides the scientific basis to evaluate the potential of prophylactic CS in preventing ICB-induced irAEs in clinical studies.[Table: see text]

Alemtuzumab induced hemodynamic change in relapsing multiple sclerosis occurs independent of corticosteroid premedication – a retrospective multicentre study

Background Alemtuzumab (ATZ), a highly effective disease modifying treatment for relapsing multiple sclerosis (MS), is associated with the rare risk of intracerebral hemorrhage. Increase of blood pressure (BP) was hypothesized to be causative, but prior administration of high-dose methylprednisolone (HDMP) is a potential confounder.Objective To analyze BP change in MS patients treated with ATZ and prior HDMP treatment compared to patients receiving HDMP only for acute relapse.Methods In this retrospective study, 30 patients treated with ATZ/HDMP and 60 age-, sex- and disability-matched controls treated with HDMP were included. Primary endpoint was the change of systolic BP (SBP) between before ATZ cycle and the maximum value measured during the treatment cycle; secondary endpoints were change in diastolic BP (DBP) and heart rate (HR).Results Change of SBP observed in ATZ/HDMP treated patients was significantly higher than in HDMP controls (mean maximal change of 12.8 vs. 8.1 mmHg, p = 0.033). An increase of SBP exceeding 20% from baseline was observed in 5 (16.7%) patients on ATZ/HDMP compared to 3 (5.0%) on HDMP (p = 0.078). The day after the 1st ATZ infusion, mean HR was higher in the ATZ/HDMP group compared to HDMP controls (82.5 vs. 73.2 bpm, p = 0.005), although there was no significant group difference over time.Conclusions ATZ treatment induced a slight, but significant increase in SBP independent of HDMP. Although hemodynamic alterations alone seem unlikely as putative mechanism for cerebral bleedings, strict cardiovascular monitoring is recommended to reduce rare, but severe cardiovascular side effects.

Influence of Dexamethasone Premedication on Acute Lung Toxicity in Lung SBRT.

IntroductionThe cooperative group experience of thoracic sterotactic body radiation therapy (SBRT) in medically inoperable patients with early stage non-small cell lung cancer (NSCLC) historically utilized corticosteroid premedication. Patterns of care have been mixed as to whether premedication adds benefit in terms of improved lung toxicity and treatment tolerance.MethodsPatients treated for NSCLC from 2014 to 2017 with definitive thoracic SBRT (BED10≥100) at a single institution, in a prospectively collected database were evaluated. Pretreatment clinicopathologic characteristics, including Eastern Cooperative Oncology Group (ECOG) performance status, PFT parameters of FEV1, and diffusing capacity for carbon monoxide (DLCO) were collected. Treatment and dosimetric characteristics were collected, and patients were scored as to whether dexamethasone was prescribed and utilized with each fraction. Toxicity was graded on multiple domains including lung as during and 30 days after completion of treatment using Common Terminology Criteria for Adverse Events Version 4. Univariate analysis was performed with Fisher’s exact test for categorical variables and two-tailed Student’s t-test for continuous variables. Multivariate analysis was performed with Cox proportional hazards model to adjust for age, pretreatment DLCO, ECOG, tumor size, central versus peripheral location, and biological effective dose.ResultsA total of 86 patients treated with thoracic SBRT with 54–60 Gy in 3–8 fractions met inclusion criteria, with the majority (70%) receiving 5 fractions. Of these patients, 45 (52%) received 4 mg dexamethasone premedication prior to each fraction of SBRT and 41 (48%) were treated without dexamethasone premedication. Overall acute lung toxicity was low in both groups. Between the two groups of patients, 5/45 (11%) developed grade 2 or higher lung toxicity including hospital admission in the dexamethasone premedication arm vs. 2/41 (5%) without premedication (p = 0.4370, Fisher’s exact test). Freedom from acute SBRT lung toxicity was no different between dexamethasone premedication arm and no premedication (Log rank, p = 0.45). On multivariate Cox proportional hazard modeling adjusting for age, ECOG, tumor size, central vs. peripheral location, pretreatment DLCO, and BED, there was no difference in freedom from acute lung toxicity without dexamethasone premedication (HR: 0.305; 95% CI: 0.033, 2.792; p = 0.293).ConclusionsIn this retrospective analysis, pretreatment steroid prophylaxis with dexamethasone confers a similar acute toxicity profile and no added clinical benefit to treatment without pretreatment steroid prophylaxis.

161P Assessment of corticosteroid premedication for patients treated with the humanized GD2-binding monoclonal antibody naxitamab

Naxitamab (hu3F8) is a humanized monoclonal antibody intended for use in the outpatient setting and has been approved by the FDA for the treatment of high-risk (HR) relapsed/refractory (R/R) neuroblastoma in the bone and bone marrow. This accelerated approval was based on interim data from 22 patients in the pivotal phase 2 clinical study (Trial 201). During Trial 201, the protocol was amended to require premedication with corticosteroids prior to the first naxitamab infusion (C1D1) to mitigate the risk of hypersensitivity reactions.

Empiric Switching of Gadolinium-Based Contrast Agents in Patients With History of Previous Immediate Hypersensitivity Reaction to GBCA: A Prospective Single-Center, Single-Arm Efficacy Trial.

Breakthrough hypersensitivity reactions (HRs) to gadolinium-based contrast agent (GBCA) occur in 40% of patients despite corticosteroid premedication. Other strategies to reduce HRs are not well studied. The aim of this study was to prospectively evaluate HR rate to GBCA among patients with history of HR to GBCA, empirically given an alternative GBCA prior to repeat administration. From September 2019 to September 2020, patients with prior HR to GBCA received 13-hour oral corticosteroid and diphenhydramine premedication prescription with switching of GBCA to gadoterate (previously unavailable at our institution before September 2019). Power analysis (α error, 0.05; β error, 0.80) determined 21 patients were required. Patients were evaluated under a quality assurance waiver from the institutional review board. A radiologist documented the nature of initial HR and inciting GBCA, premedication received, incidence, and severity of breakthrough HR. After exclusions, we evaluated 26 patients with mild (92.3% [24/26]) or moderate (7.7% [2/26]) HR to gadobutrol (53.8% [14/26]), gadoxetate (3.8% [1/26]), and gadopentetate (3.8% [1/26]). In 38.5% (10/26), inciting GBCA was unknown but was likely gadobutrol or gadopentetate based on availability. There were 22 females. The mean patient age was 52.1 ± 15.8 years.From 27 gadoterate administrations, 59.3% (16/27) patients received corticosteroid and diphenhydramine premedication, 11.1% (3/27) received only diphenhydramine, and 29.6% (8/27) with no premedication.Hypersensitivity reaction rate after empiric switching to gadoterate was 3.7% (1 mild reaction; 95% confidence interval [CI], 0.09%-18.9%) overall with no difference in patients with (6.3% [1/16]; 95% CI, 0.15%-28.7%) or without (0%; [0/11] upper bound 95% CI, 25.0%) corticosteroid premedication. In this prospective single-arm study, empirically switching GBCA to gadoterate in patients with prior HR to GBCA substantially reduced the expected rate of subsequent HRs in patients with and without the use of corticosteroid premedication. Empirically switching GBCAs, with or without the use of corticosteroid premedication, can substantially reduce the rate of hypersensitivity breakthrough reactions.

Management of hypersensitivity reactions to enzyme replacement therapy in children with lysosomal storage diseases

BackgroundIntravenous recombinant enzyme replacement therapy (ERT) is currently available for 8 lysosomal diseases. Hypersensitivity reactions (HSRs) may be observed during this long-term treatment. ObjectiveTo evaluate the frequency and clinical treatment features of ERT HSRs and the management of desensitizations in children. MethodsMedical records were reviewed retrospectively for patients who received ERT. Those who had experienced HSRs to ERT were included in the study. The demographic characteristics of the patients, culprit enzyme, signs and symptoms, diagnostic tests, management of the reaction, and the protocol employed for the maintenance of ERT were recorded. ResultsDuring the study period, 54 patients received ERT in our institution. A total of 11 patients (20.4%) experienced HSR to ERT. All reactions were of immediate type. The most common symptoms were cutaneous manifestations. A total of 9 patients experienced urticaria, and 2 had anaphylaxis as initial reaction. Patients who had isolated cutaneous symptoms continued their treatments with antihistamines, corticosteroid premedication, slower infusion rate or both. Patients who had recurrent urticaria with these modalities or those who had anaphylaxis continued their ERT with desensitization (n = 8). A total of 3 patients required revisions in desensitization protocols because of recurrent anaphylaxis. ConclusionThe reactions that develop during this long-term treatment may be treated by premedication-prolonged infusion, but in some patients, desensitization protocols are necessary for the continuation of therapy. Revisions in desensitization protocols may be required.

Breakthrough Hypersensitivity Reactions to Gadolinium-based Contrast Agents and Strategies to Decrease Subsequent Reaction Rates: A Systematic Review and Meta-Analysis.

Background Hypersensitivity reactions to gadolinium-based contrast agents (GBCAs) that occur despite corticosteroid premedication (breakthrough reactions) are not well understood. Purpose To determine the GBCA breakthrough reaction rate overall and according to GBCA class and to determine the effect of using an alternative GBCA or allergy skin testing on the risk of a breakthrough reaction. Materials and Methods In this systematic review and meta-analysis, MEDLINE (from 1946 to 2019), Embase (from 1947 to 2019), and the Cochrane Central Register of Controlled Trials (2019 only) were searched for patients with a breakthrough reaction to a GBCA who were undergoing repeat GBCA administration. Breakthrough reaction rates were determined with random-effects modeling and meta-regression. Secondary analyses of GBCA class, switching to an alternative GBCA, and allergy skin testing were assessed. Quality Assessment of Diagnostic Accuracy Studies 2 was used to determine risk of bias and applicability. Percentages are meta-regression results and do not directly reflect raw data. Results Of the 148 identified studies, 23 were included, encompassing 120 patients and 130 GBCA administrations. The overall breakthrough reaction rate was 39% (95% confidence interval [CI]: 30%, 49%; 37 of 103 administrations). Breakthrough reaction rates for macrocyclic (36%; 95% CI: 25%, 48%; 23 of 64 administrations) and protein-binding linear (31%; 95% CI: 1%, 94%; [one of seven administrations) GBCAs did not differ (P = .90). There were insufficient analyzable data for gadodiamide, gadoversetamide, and gadopentetate. Hypersensitivity reaction rate after switching GBCAs was 50% (95% CI: 21%, 79%; three of nine administrations) with and 71% (95% CI: 21%, 95%; four of five administrations) without corticosteroid premedication, which did not differ (P = .82 and P = .17, respectively) from the observed rate when using corticosteroid premedication and the same GBCA (36%; 95% CI: 26%, 48%; 37 of 84 administrations). Hypersensitivity reaction rate after allergy skin testing (17%; 95% CI: 7%, 29%; zero of 21 studies) did not differ when compared with use of the same agent with corticosteroid premedication (P = .10). Meta-analysis limitations were the small number of patients and the high risk of bias. Conclusion Patients with a prior hypersensitivity reaction to a gadolinium-based contrast agent (GBCA) often had breakthrough reactions. The effect of switching to an alternative GBCA or using allergy skin testing to decrease reaction risk lacked enough available data for meaningful comparisons. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Prince in this issue.

Prolonged methylprednisolone premedication prior to obinutuzumab in patients with chronic lymphocytic leukemia

First obinutuzumab application is associated with infusion related reactions (IRRs) that may discourage further continuation of the drug. During our clinical practice we have observed that chronic lymphocytic leukemia (CLL) patients with autoimmune hemolytic anemia (AIHA) prolongedly receiving corticosteroids do not develop obinutuzumab IRRs. Therefore, we decided to apply prolonged corticosteroid premedication with methylprednisolone in dose 1–1.5 mg/kg for ≥7 days to all further obinutuzumab candidates. Here we present non-randomized comparison of 28 consecutive previously untreated CLL patients receiving prolonged corticosteroid premedication (15 patients) or standard premedication (13 patients) prior to the first obinutuzumab infusion. Prolonged corticosteroid premedication resulted in significant reduction of all-grade (20% vs 61.5%; p = .025) and grade III (0% vs 23.1%; p = .049) obinutuzumab IRRs. Prolonged corticosteroid premedication did not significantly affect occurrence of infective complications. Patients with CLL and AIHA receiving obinutuzumab showed continuous and stable increase in hemoglobin levels concomitantly with decrease in parameters of hemolysis.

Premedication with corticosteroids does not impact the pharmacokinetics of infliximab in inflammatory bowel disease irrespective of azathioprine cotreatment.

Loss of infliximab (IFX) effect is a clinical challenge in the management of patients with Crohn's disease (CD), but this can potentially be reduced with azathioprine (AZA) or with corticosteroids (CS). We aimed to study whether CS premedication with or without cotreatment with AZA could reduce antibody formation and affect the IFX elimination rate. A cross-sectional observational study was conducted at two centers with CD patients receiving maintenance IFX therapy for 12-18 months. In addition to IFX, patients received either CS premedication or not, with or without concominant AZA. Fifty-seven patients were included in the study. Thirty-one patients received premedication with CSs, and 11 (35.5%) of these also received AZA, whereas this was the case for 22 of 26 (84.6%) patients in the non-CS group. No difference in IFX trough level (P=0.10) or halftime elimination (P=0.31) was observed with or without CS premedication. Concomitant AZA was associated with significantly longer mean half-life of IFX (P=0.04). Total IFX antibody concentrations were 15.8 and 12.9 with and without CS, respectively, in those not receiving AZA versus 4.3 and 6.1 AU/ml with and without CS, respectively, in those receiving AZA (P=0.004). Premedication with CS did not have any effect on the frequency of antibody formation (P=0.28). In patients with CD and in maintenance IFX therapy, premedication with CS did not influence antibody formation, IFX trough levels or IFX halftime elimination, irrespective of concomitant AZA use. However, the use of AZA was associated with higher IFX trough levels and lower total IFX antibody concentrations.

Daily ascending dosing in cynomolgus monkeys to mitigate cytokine release syndrome induced by ERY22, surrogate for T-cell redirecting bispecific antibody ERY974 for cancer immunotherapy

CD3 bispecific constructs show promising therapeutic potential as anti-tumor antibodies, but it has concurrently been difficult to manage cytokine release syndrome (CRS) in clinical use. Currently, the most effective measure for reducing CRS is considered a combination of intra-patient/animal dose escalation and corticosteroid premedication. To examine how effectively an intra-animal ascending dose regimen without premedication would mitigate CRS, we compared plasma cytokine levels in two groups of cynomolgus monkeys; one group was given a single dose, and the other a three-fold daily ascending dose of a CD3 bispecific construct that targets and cross-reacts with both glypican 3 and CD3 (ERY22). Ascending doses up to 1000 μg/kg of ERY22 dramatically reduced the peak cytokine levels of IL-6, TNF-α, and IFN-γ, IL-2 as well the clinical severity of CRS compared with a single dose of 1000 μg/kg. Peak cytokine levels following the single and ascending doses were 60,095 pg/mL and 1221 pg/mL for IL-6; 353 pg/mL and 14 pg/mL for TNF-α; 123 pg/mL and 16 pg/mL for IFN-γ; and 2219 pg/mL and 42 pg/mL for IL-2. The tolerance acquired with daily ascending doses up to 1000 μg/kg remained in effect for the following weekly doses of 1000 μg/kg.