Experienced Infusion Reactions Research Articles

Impact of Premedication De-Escalation on Incidence of Infusion-Related Reactions With Daratumumab.

Daratumumab is an anti-CD38 monoclonal antibody used to treat multiple myeloma and light chain amyloidosis. Because daratumumab may cause reactions after intravenous or subcutaneous (SC) administration, the manufacturer labeling recommends administration of premedications before every dose. Given incidence of infusion reactions appears to be rare after cycle 1, in April 2022, the Mayo Clinic implemented a practice change in which premedications were omitted from all daratumumab order sets after completion of cycle 1. This study investigated the safety of this practice. A retrospective chart review at the Mayo Clinic reviewed eligible patients with multiple myeloma or amyloid light-chain (AL) amyloidosis who received their first dose of daratumumab within the 4 months preceding the date of implementation (preimplementation group) or no more than 4 months after (postimplementation group) the date of implementation on April 13, 2022. Data were collected only from the first eight once per week doses of daratumumab. The primary outcome was the incidence of infusion-related reactions. Data analyzed used descriptive statistics. Nearly all patients (95.9%) received daratumumab by SC route of administration. Of the 97 patients in the preimplementation group, >90% received premedications throughout cycles 1 and 2, and five patients (5.2%) experienced infusion reactions. Of 72 patients in the postimplementation group, <20% received premedications during cycle 2 and three patients (4.2%) experienced infusion reactions. All infusion reactions occurred within the first daratumumab cycle, indicating elimination of cycle 2 premedications did not cause any infusion reactions. No patient experienced more than one infusion reaction. Omission of premedications after cycle 1 of daratumumab did not increase the incidence of infusion. Premedications may safely be omitted after cycle 1 of daratumumab when administered by the SC route.

Abstract PR06: CD40 agonist mitazalimab in combination with mFOLFIRINOX in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC): Interim efficacy results of the OPTIMIZE-1 phase 1b/2 study

Abstract Mitazalimab is a human CD40 agonistic IgG1antibody. Targeting CD40 kickstarts the cancer immunity cycle by licensing dendritic cells leading to tumor specific T cell priming and activation. Furthermore, in PDAC CD40 agonists on myeloid cells promote degradation of the desmoplastic tumor stroma, improving influx of T cells and sensitizing the tumor to chemotherapeutic agents. OPTIMIZE-1 (NCT04888312) is a Phase 1b/2, open label, multicenter study designed to evaluate safety, tolerability, and efficacy of mitazalimab in combination with mFOLFIRINOX (Oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, irinotecan 150 mg/m2, 5-FU 2.4 g/m2) in patients with previously untreated mPDAC. In the first part of the study (phase 1b), 900 µg/kg mitazalimab was selected as the recommended phase 2 dose (RP2D). In the first 21-day treatment cycle, mitazalimab is administered IV at RP2D on day 1 and 10 and mFOLFIRINOX infusion started on day 8. In subsequent cycles, treatment follows a 14-day cycle where mitazalimab is administered 2 days after mFOLFIRINOX. The primary endpoint of this ongoing study is overall response rate (ORR) per RECIST v1.1. Secondary and exploratory endpoints include duration of response, progression free and overall survival, safety, PK and PD biomarker assessments. As of May 24, 2023, study enrolment was complete, 65 patients were treated with mFOLFIRINOX and mitazalimab 900 µg/kg (RP2D). Interim efficacy analysis comprised of 57 evaluable patients. Median follow up was 6.5 months and median exposure to treatment was 5 months. 28 patients (49%) remain on treatment, 18 (32%) continued treatment beyond 6 months, the longest being 17 months (ongoing). ORR was 43.9% (25 patients with partial response), an additional 19 patients achieved stable disease, resulting in a 77.2% disease control rate. Median time to response was 2.2 months and median duration of response was 8.7 months. The most common grade (Gr) ≥3 TEAEs were neutropenia (21.5%), anemia (12.3%), thrombocytopenia (12.3%) and hypokalemia (12.3%). Mitazalimab related Gr &amp;gt;3 AEs occurring in more than one patient were fatigue in 3 (4.6%) patients, increased ALT in 3 (4.6%) patients, diarrhea in 2 (3.1%) patients, asthenia in 2 (3.1%) patients, increased AST in 2 (3.1%) patients, and hypokalemia in 2 (3.1%) patients. 25 patients (38.5%) experienced infusion reactions (all Gr 1-2, managed with symptomatic treatment, none amounting to cytokine release syndrome) and 7 (10.8%) patients discontinued treatment due to TEAEs (pneumonia, gastric obstruction, neuropathy, bacteremia, ileal obstruction, stroke, skin reaction). In this ongoing phase 1b/2 trial, 900 µg/kg mitazalimab has shown no evidence of additive toxicity when administered in combination with mFOLFIRINOX, allowing extended treatment until progression. Interim efficacy results demonstrate encouraging antitumor activity in mPDAC with good durability of responses, meriting continued development. Citation Format: Jean-Luc Van Laethem, Karen P. Geboes, Philippe A. Cassier, Ivan Borbath, Aurélien Lambert, Emmanuel Mitry, Hans Prenen, Jean-Frédéric Blanc, Lorenzo Pilla, Mercedes Rodriguez Garrote, Roberto A. Pazo Cid, Inmaculada Gallego, Jaime Feliú, Karin Nordbladh, Peter Ellmark, Malin Carlsson, Yago Pico de Coaña, Sumeet V. Ambarkhane, Teresa Macarulla. CD40 agonist mitazalimab in combination with mFOLFIRINOX in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC): Interim efficacy results of the OPTIMIZE-1 phase 1b/2 study [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr PR06.

Efficacy and safety of mitazalimab in combination with mFOLFIRINOX in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC): An interim analysis of the optimize-1 phase 1b/2 study.

4139 Background: Mitazalimab is a human CD40 agonistic IgG1antibody. Targeting CD40 kickstarts the cancer immunity cycle by licensing dendritic cells leading to tumor specific T cell priming and activation. Furthermore, in PDAC CD40 agonists on myeloid cells promote degradation of the desmoplastic tumor stroma, improving influx of T cells and chemotherapeutic agents into the tumor. OPTIMIZE-1 (NCT04888312) is a Phase 1b/2, open label, multicenter study designed to evaluate safety, tolerability, and efficacy of mitazalimab in combination with mFOLFIRINOX (Oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, irinotecan 150 mg/m2, 5-FU 2.4 g/m2) in patients (pts) with previously untreated mPDAC. In the first part of the study (phase 1b), 900 µg/kg mitazalimab was selected as the recommended phase 2 dose (RP2D). Methods: In the first 21 day treatment cycle, mitazalimab was administered IV at RP2D on day 1 and 10 and mFOLFIRINOX infusion started on day 8. In subsequent cycles, treatment followed a 14 day cycle where mitazalimab was always administered 2 days after mFOLFIRINOX. The primary endpoint of this ongoing study is overall response rate (ORR) per RECIST v1.1. Secondary and exploratory endpoints include progression free and overall survival, safety, PK and PD biomarker assessments. Futility was prespecified as ORR≤30% in pts treated at RP2D, based on historical data with FOLFIRINOX (Conroy, 2011). Results: As of December 8, 2022, 43 pts with untreated mPDAC were treated with mFOLFIRINOX and 450 µg/kg (N = 5) or 900 µg/kg (N = 38) mitazalimab and evaluated for safety. The most common grade (Gr) ≥3 TEAEs were neutropenia (16%), fatigue (12%) and hypokalemia (12%). Mitazalimab related Gr &gt;3 AEs were fatigue in 3 (7.9%) pts, hypokalemia in 2 (5.3%) pts, diarrhea in 1 (2.6%) pt, pneumonia in 1 (2.6%) pt, increased ALT in 1 (2.6%) pt, headache in 1 (2.6%) pt, acute kidney injury in 1 (2.6%) pt. 10 pts (23%) experienced infusion reactions (all Gr 1-2) and 5 (12%) pts discontinued treatment due to TEAEs (pneumonia, gastric obstruction, neuropathy, bacteremia). At cutoff, 23 pts were evaluable for futility. Median follow up was 170 days and median exposure was 163 days. 18 pts (78%) remain on treatment, 6 (26%) beyond the 6 month treatment period. ORR was 52.2% (12 partial responses), an additional 8 pts achieved stable disease, resulting in a 91.3% disease control rate. Combination with mFOLFIRINOX had no impact on mitazalimab PK. The PD biomarker profile was consistent with the mode of action of mitazalimab, including upregulation of MCP-1 and IFN-γ. Conclusions: Mitazalimab + mFOLFIRINOX is a feasible regimen with a manageable safety profile. Mitazalimab administered at 900 µg/kg in combination with mFOLFIRINOX shows encouraging antitumor activity in mPDAC, meriting continued development. The study passes futility and continues to full accrual. Clinical trial information: NCT04888312 .

Efficacy and Safety of Tacrolimus or Infliximab Therapy in Children and Young Adults With Acute Severe Colitis.

One-third of children and young adults admitted for management of acute severe colitis (ASC) fail intravenous corticosteroids. Infliximab (IFX) or tacrolimus (TAC) is often used to prevent urgent colectomy in these patients. However, no prior studies have reviewed the outcome of pediatric patients with ASC who were treated with either IFX or TAC. We retrospectively identified 170 pediatric patients with ASC admitted to our institution who did not respond to intravenous corticosteroids and were subsequently treated with either IFX or TAC. We compared 6-month colectomy rates, time to colectomy, improvement in disease activity indices, and adverse effects. The mean age of patients in the IFX (n = 84) and TAC (n = 86) groups were 14 and 13.8 years, respectively. The median study follow-up time was 23 months. The rate of colectomy 6 months from rescue therapy was similar whether patients received IFX or TAC (22.6% vs 26.7%, respectively, P = 0.53). The mean decline in Pediatric Ulcerative Colitis Activity Index scores from admission to discharge in those treated with IFX (31.9) or TAC (29.8) was similar (P = 0.63). Three patients treated with IFX experienced infusion reactions. Six patients treated with TAC experienced changes in renal function or electrolytes, and 4 patients reported neurologic symptoms. There were no significant differences in the likelihood of colectomy 6 months after initiating IFX or TAC rescue therapy. Efficacy of both agents was comparable. The types of adverse effects differed by therapy. These data support the use of either TAC or IFX in children with ASC refractory to intravenous corticosteroids.

Abstract CT228: Phase Ib clinical study of CBP501, cisplatin and nivolumab administered every 3 weeks in patients with advanced refractory tumors. Dose escalation cohort

Abstract Background: CBP501 is a 12 amino acid calmodulin-modulating peptide that increases platinum influx into tumor cells and induces tumor immunogenic cell death. CBP501 also suppresses platinum-induced release of cytokines, such as IL-6, IL-10 and VEGF, lowers cancer stem cell populations and reduces the migration, invasion and epithelial-mesenchymal transition of tumor cells. Preclinical studies show synergistic anti-tumor activity when combined with platinum agents and immune checkpoint inhibitors (anti-PD1, PD-L1 and CTLA-4 antibodies) in the CT26 syngeneic mouse model. Here, we report dose-finding results from a Phase Ib study of CBP501 combined with cisplatin and nivolumab in a triple drug combination. Methods: An open-label phase I trial was conducted using a 3+3 design: CBP501 and cisplatin were dosed simultaneously by 1h infusion Q3W at 4 different combined dose levels (CBP501: 16 or 25 mg/m2; cisplatin: 60 or 75 mg/m2). Nivolumab (240 mg) was dosed on the same day, as a 1h infusion following CBP501/cisplatin. The DLT observation period was during the first 21-day cycle. Immuno-histochemistry for PD-L1 and CD8-positivity were performed in archival tumor samples. Results: As of 28 Dec. 2018 for AEs, 19 patients were dosed and no DLTs were reported. Treatment-related adverse events as assessed by the investigator occurred in 19 patients (100%). Fifteen patients experienced infusion reactions related to CBP501, manifesting as erythema or hives. These were managed with interruption of the infusion, administration of antihistamines, and resumption of the infusion if reactions resolved within 30 minutes (17/19 treated patients). These reactions occurred at both CBP501 dose levels evaluated. Other events occurring in &amp;gt;/= 2 patients included anemia (10), fatigue/asthenia (8), leukopenia/neutropenia/granulocytopenia (7), thrombocytopenia (5), anorexia/weight loss (4), nausea (3), vomiting (2), hypersensitivity (2) lymphopenia (2), and acute kidney injury/renal failure (2). Eleven treatment-related Grade 3 or 4 AEs occurred in six patients, anemia (4), acute renal failure (1), diarrhea (1), fatigue (1), acute encephalopathy (1), hypocalcemia (1), neutropenia/leukopenia (1), and thrombocytopenia (1). The recommended phase 2 dose (RP2D) is 60 mg/m2 cisplatin with 25 mg/m2 CBP501 and 240 mg nivolumab. Partial responses were seen for 2 heavily pretreated patients, 1 with pancreatic cancer (PD-L1 (+) tumor cells 70%, CD8 (+) cells 18%) and 1 with microsatellite stable (MSS) colorectal cancer. Disease control rate (DCR), defined as CR, PR and &amp;gt;3M SD was 35% (6 /17 evaluable patients). Notably, DCR was 50% in heavily pretreated pancreatic cancer (2/4) and cholangiocarcinoma (1/2) patients. Conclusions: The triple-drug combination is tolerable and an RP2D has been determined. Pancreatic and MSS colorectal cancers were selected for expansion cohorts. Pre- and on-treatment biopsies will be obtained to assess modulation of the immune microenvironment by combination treatment. (NCT03113188). Citation Format: Marc Matrana, Frank Tsai, Suma Satti, James Cleary, Jacob Estes, Khanh Do, Valentin Kolmakov, Takumi Kawabe, Geoffrey I. Shapiro. Phase Ib clinical study of CBP501, cisplatin and nivolumab administered every 3 weeks in patients with advanced refractory tumors. Dose escalation cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT228.

Safety of Split First Dosing Vs Standard Dosing Administration of Daratumumab Among Multiple Myeloma Patients Treated in a US Community Oncology Setting: A Real-World Observational Study

INTRODUCTIONDaratumumab (DARA) is a human IgGκ monoclonal anti-CD38 antibody for treatment of multiple myeloma (MM). In clinical trials, median durations for the 1st, 2nd and subsequent infusions were 7.0, 4.3 and 3.5 hours, respectively. To optimize the first infusion duration of DARA, the US Oncology Network (USON), a community oncology practice network, implemented a split first dose protocol. The USON split first dose protocol requires 2 IV bags, one for Day 1 and one for Day 2 of consecutive days. On each day, DARA is diluted with normal saline to a total volume of 500 mL. On each day, DARA is administered at 50 mL/hour for one hour. If no infusion events occur, the infusion rate can be increased in 50 mL/hour increments every hour to a maximum of 200 mL/hour. While the split first dose may increase convenience, limited information is available on the safety of split first dose DARA. METHODSThis was a retrospective, observational study of adult MM patients who initiated DARA in routine care within USON between 11/01/2015 - 06/30/2017 to compare infusion times and safety of DARA split first dose vs DARA standard dose schedule (i.e., 1 infusion of 16 mg/kg per FDA-approved prescribing information). In this study, patients were grouped into either the split first dose cohort or the standard dose schedule cohort according to the dosing schedule that they had experienced. Data were sourced from USON's electronic healthcare record system. Information on infusion reactions was available only through chart review, which was conducted among a random sample of patients in each study cohort. Descriptive analyses were conducted to compare demographic, clinical and treatment characteristics of MM patients who received split first dose schedule vs standard dosing schedule. Chi-square tests or Fisher's exact tests were used to assess associations between categorical variables. ANOVA/t-tests or Kruskal-Wallis tests were used to assess associations for continuous variables. A p-value of <0.05 was considered as statistically significant. RESULTSOf the 622 patients included in the landscape analysis, 365 (58.5%) had received the split first dose schedule and 258 (41.5%) had received the standard dosing schedule. Overall, the median age was 63.6 years, 54.2% male and 78.3% Caucasian. The utilization of the split first dose schedule increased significantly over time with more patients in 2017 Q2 having received split dose vs standard dose (p< 0.0001). Karnofsky performance status (KPS) scores differed significantly between patients treated with split first dose vs standard dose (p=0.02). No other baseline differences between groups were found. The median infusion duration was 4.5 hours for Day 1 of split first dose and 6.5 hours for standard dose (p<0.0001). Among patients selected for chart review (n = 302), 47.8% (88/184) of split first dose patients and 48.3% (57/118) of standard dose patients experienced at least one infusion reaction. The most common infusion reactions included lower-respiratory (26.1%), upper-respiratory (17.2%) and gastrointestinal reactions (12.5%), chills (8.9%), flushing (6.6%), with no statistically significant differences between study groups for any infusion reaction. Among patients treated with split first dose DARA, 3.8% experienced an infusion reaction during Day 2 of the split dose schedule. CONCLUSIONSAs a retrospective observational study at community-based oncology clinics, these findings provide real-world evidence on the infusion time and safety of the first infusion of DARA. This study found that the utilization of split first dose has increased over time. Interestingly, more patients in the split dose group had higher KPS scores than patients in the standard dose group, which may be due to selection of patients, at least initially, for the split first dose. This study found also that the length of the first day of the split first dose schedule is shorter than the length of the standard dosing schedule. Additionally, although determination of severity or grade was not feasible in this study, the proportion of patients in split first and standard dosing schedule groups who experienced infusion reactions was equal. This study suggests that the split first dose is comparable to the standard dose schedule and may be a practical option for patients and institutions seeking options to manage the operational considerations of DARA administrations. DisclosuresRifkin:Takeda: Consultancy; EMD Serono: Consultancy; Sandoz: Consultancy; Celgene: Consultancy; McKesson: Equity Ownership; Boehringer Ingelheim: Consultancy; Amgen: Consultancy. Singer:Janssen Scientific Affairs, LLC: Research Funding. Aguilar:McKesson Specialty Health: Employment. Baidoo:McKesson Specialty Health: Employment. Maiese:Janssen Scientific Affairs,LLC: Employment, Equity Ownership.

Tolerability of Ustekinumab in Induction and Maintenance for the Treatment of Crohnʼs Disease

BACKGROUND: Tolerance to therapy is critical for patients to receive the maximal treatment benefit. In Phase 3 clinical trials for ustekinumab (UST) for moderate to severe Crohn's disease (CD), UNITI-1 enrolled anti-TNF failures and UNITI-2 enrolled conventional therapy failures. In UNITI-1, 36.4% had previous intolerance (infusion-related reactions [IRR], delayed hypersensitivity reactions, or injection site reactions [ISR]) that led to discontinuation of the anti-TNF. UNITI-2 enrolled patients that were not intolerant to anti-TNFs, but some were intolerant to immunomodulators (39%) or corticosteroids (15%). Here we assess tolerability as measured by IRR, delayed hypersensitivity, or ISR to UST in the Phase 3 CD trials. METHODS: All enrolled patients in UNITI-1 and UNITI-2 were given an intravenous (IV) induction infusion of UST 130mg, UST ˜6 mg/kg, or placebo (PBO). The IM-UNITI maintenance study began 8 weeks after IV induction; UST IV responders were randomized to UST 90mg SC Q8W, UST 90mg SC Q12W, or PBO. Non-randomized patients, included non-responders to placebo who received 130mg IV UST, then continued to UST 90mg SC Q12W maintenance therapy; non-responders to IV UST who received UST 90 mg SC, then continued UST 90 mg SC Q8W in maintenance; and IV placebo responders who received placebo SC in maintenance. RESULTS: Overall, IRR were infrequent: 4.0% and 1.9% of all patients in UNITI 1 & 2, respectively, experienced infusion reactions to the single IV dose. There were no differences in IRR between PBO & UST, or between UST doses (UNITI 1 IRRs in 2.0%, PBO and 4.5% UST 130mg and 3.6%, UST ˜6 mg/kg; UNITI 2 IRRs in 2.9%, PBO and 2.4% UST 130mg and 1.4%, UST ˜6 mg/kg). During IM-UNITI, in non-randomized patients who were non-responders to placebo induction and received a 130mg IV injection, IRR to PBO and UST were similar and infrequent (2.5% and 1.8%, respectively). There were no anaphylactic or delayed hypersensitivity reactions to any IV dose. After SC administration, ISRs were infrequent and not different across groups. In the combined (randomized and non- randomized) population, ISRs were 1.7% with PBO, and 3.0% with UST. No serious ISRs were reported. The most common ISR was erythema, reported in 1.1% of PBO, and 1.7% of UST. There were no anaphylactic or delayed hypersensitivity reactions to any SC dose. Amongst randomized patients, ISRs were infrequent and consistent between groups. ISRs occurred in 3/418 (0.7%) of all UST 90mg Q12W injections and in 12/599 (2.0%) of all UST 90mg Q8W injections. One patient in the entire phase 3 program discontinued therapy due to ISR. CONCLUSION(S): In a broad population of patients with Crohn's disease, many of whom were intolerant to previous therapies, UST had a tolerable profile. Rates of IRR and ISR were minimal, and were not different between groups, nor populations.

Tolerability of Ustekinumab in Induction and Maintenance for the Treatment of Crohnʼs Disease

Introduction: Tolerance to therapy is critical for patients to receive the maximal treatment benefit. In Phase 3 clinical trials for ustekinumab (UST) for moderate to severe Crohn's disease (CD), UNITI-1 enrolled anti-TNF failures and UNITI-2 enrolled conventional therapy failures. In UNITI-1, 36.4% had previous intolerance (infusion-related reactions [IRR], delayed hypersensitivity reactions, or injection site reactions [ISR]) that led to discontinuation of the anti-TNF. UNITI-2 enrolled patients that were not intolerant to anti-TNFs, but some were intolerant to immunomodulators (39%) or corticosteroids (15%). Here we assess tolerability as measured by IRR, delayed hypersensitivity, or ISR to UST in the Phase 3 CD trials. Methods: All enrolled patients in UNITI-1 and UNITI-2 were given an intravenous (IV) induction infusion of UST 130mg, UST ˜6 mg/kg, or placebo (PBO). The IM-UNITI maintenance study began 8 weeks after IV induction; UST IV responders were randomized to UST 90mg SQ Q8W, UST 90mg Q12W, or PBO. Non-randomized patients could receive 130mg IV UST, then continued to SC PBO, UST 90mg Q8W, UST 90mg Q12W maintenance therapy, or discontinued. Results: Overall, IRR were infrequent: 4.0 % and 1.9 % of all patients in UNITI 1 & 2, respectively, experienced infusion reactions to the single IV dose. There were no differences in IRR between PBO & UST, or between UST doses (Table 1). During IM-UNITI, IRR to PBO and UST 130mg were similar and infrequent (Table 1). There were no anaphylactic or delayed hypersensitivity reactions to any IV dose. ISRs were infrequent and not different across groups (Table 2). In the combined (randomized and non- randomized) population, ISRs were 1.7 % with PBO, and 3.0% with UST. No serious ISRs were reported. The most common ISR was erythema, reported in 1.1 % of PBO, and 1.7% of UST. There were no anaphylactic or delayed hypersensitivity reactions to any SC dose. Amongst randomized patients, ISRs were infrequent and consistent between groups. ISRs occurred in 3/418 (0.7 %) of all UST 90mg Q12W injections and in 12/599 (2.0 %) of all UST 90mg Q8W injections. One patient in the entire phase 3 program discontinued therapy due to ISR.Table: Table. Infusion-related reactions*Table: Table. Injection site reactionsConclusion: In a broad population of patients with Crohn's disease, many of whom were intolerant to previous therapies, UST had a tolerable profile. Rates of IRR and ISR were minimal, and were not obviously different between groups, nor populations.

A study investigating the association of dermatological and infusion reactions to infliximab and infliximab trough levels.

Although infliximab is an effective therapy for inflammatory bowel disease (IBD), it is associated with dermatological events and infusion reactions. It is not known whether a relationship between these adverse events (AEs) and infliximab trough levels (ITLs) exists. To report the prevalence of infliximab-associated AEs in IBD patients receiving stable maintenance infliximab therapy, and to correlate ITLs with dermatological and infusion reactions to infliximab. Adult IBD patients receiving stable maintenance infliximab therapy were recruited from the University of Alberta Infusion Clinic (Edmonton, Alberta). ITLs were measured in blood samples collected before infusion, and the patients' records were reviewed for dermatological and infusion reactions to infliximab. One-quarter (18 of 71 [25.4%]) of patients experienced dermatological or infusion reactions to infliximab: nine (12.7%) dermatological events and nine (12.7%) infusion reactions. The median ITL was similar among patients with and without these AEs (7.2 μg⁄mL [interquartile range (IQR) 2.0 μg⁄mL to 13.3 μg⁄mL] versus 6.6 μg⁄mL [IQR 3.2 μg⁄mL to 12.7 μg⁄mL]; P=0.648). The median ITL of patients who experienced infusion reactions (2.0 μg⁄mL [IQR 0.1 μg⁄mL to 5.7 μg⁄mL]) was lower than that of patients who experienced no such AEs (6.6 μg⁄mL [IQR 3.2 μg⁄mL to 12.7 μg⁄mL]; P=0.008]) and lower than that of patients who experienced dermatological AEs (13.3 μg⁄mL [IQR 8.8 μg⁄mL to 17.4 μg⁄mL]; P<0.001). One-quarter of IBD outpatients receiving stable maintenance infliximab therapy experienced dermatological and infusion reactions. Low ITLs were correlated with infusion reactions, and normal or high ITLs with dermatological events.

Safety and efficacy of non-initial rapid infusion of rituximab plus chemotherapy in Chinese patients with CD20+ non-Hodgkin’s lymphoma

Objective: To evaluate the safety and efficacy of rapid rituximab infusion (RRI) plus chemotherapy in patients with CD20+ non-Hodgkin’s lymphoma (NHL).Research design and methods: A total of 177 patients received 4 – 6 cycles of rituximab-based chemotherapy. The first cycle was given with standard schedule. In the second and subsequent cycles, RRI was initiated. Rituximab was administered as 20% of the dose infused in the first 30 min and the remaining 80% was given over 60 min. Benadryl and dexamethasone were given before infusions. Vital signs were measured at baseline and during infusion.Results: In the first cycle, 48 patients experienced grade I – II infusion reactions and two patients showed grade III – IV infusion reactions. Six patients experienced infusion reactions during RRI. Two patients showed grade III infusion reactions to RRI and dropped out of the study. With a median follow up of 37.5 months, the 3-year overall survival and progression-free survival rates of the whole cohort were 93.1 and 81.1%, respectively.Conclusions: Our preliminary observations suggested that RRI may be safe and feasible for patients with CD20+ NHL.

A first-in-human dose-escalation study of ME-143, a second generation NADH oxidase inhibitor, in patients with advanced solid tumors

Summary Background ME-143, a second-generation tumor-specific NADH oxidase inhibitor, is broadly active against human cancers in vitro and in vivo. This first-in-human dose-escalation study evaluated the dose-limiting toxicities (DLTs), pharmacokinetics, safety, tolerability, and preliminary anti-tumor activity of ME-143 in patients with advanced solid tumors. Methods Patients with advanced solid tumors were treated in a 3 + 3 escalation design. ME-143 was administered via intravenous infusion on days 1, 8, and 15 of the first 28-day cycle, and weekly thereafter; the final cohort received twice-weekly treatment. Samples for pharmacokinetic analysis were collected during cycle 1. Treatment continued until disease progression or unacceptable toxicity. Results Eighteen patients were treated: 2.5 mg/kg (n = 3); 5 mg/kg (n = 3); 10 mg/kg (n = 3); 20 mg/kg (n = 6); 20 mg/kg twice-weekly (n = 3). There were no DLTs observed. Nearly all treatment-related toxicities were grade 1/2, specifically (all grades) nausea (22 %) and fatigue (17 %). Two patients experienced infusion reactions at the 20 mg/kg dose level, one of which was grade 4. Stable disease was documented in three patients with colorectal cancer, cholangiocarcinoma, and anal cancer. Pharmacokinetic exposures were linear and dose-dependent, with a half-life of approximately 5 h. Conclusions ME-143 was well-tolerated when administered intravenously at the maximally administered/recommended phase 2 dose of 20 mg/kg once weekly to patients with advanced solid tumors. Though limited clinical activity was observed with monotherapy, inhibitors of tumor-specific NADH oxidase such as ME-143 may derive their greatest benefit in combination with cytotoxic chemotherapy.

A pilot open‐label phase II trial of rituximab for non‐criteria manifestations of antiphospholipid syndrome

The primary objective of this study was to evaluate the safety of rituximab in antiphospholipid antibody (aPL)-positive patients with non-criteria manifestations of antiphospholipid syndrome (APS). The secondary objectives were to evaluate the effect of rituximab on the aPL profile and to evaluate the efficacy of rituximab treatment for non-criteria manifestations of APS. In this 12-month, phase II pilot study, adult aPL-positive patients with thrombocytopenia, cardiac valve disease, skin ulcer, aPL nephropathy, and/or cognitive dysfunction received 2 doses of rituximab (1,000 mg) on days 1 and 15. Antiphospholipid antibody profiles and clinical outcome measures, which were categorized as complete response, partial response, no response, or recurrence, were analyzed at preset time points. Two of 19 patients experienced infusion reactions, resulting in early termination. Twelve serious adverse events and 49 nonserious adverse events were recorded. All patients who had positive results of lupus anticoagulant, anticardiolipin, and anti-β(2)-glycoprotein I antibody tests at baseline had positive results at 24 weeks and 52 weeks. The numbers of patients with a complete response, a partial response, no response, and recurrence for the clinical outcome measures at 24 weeks were as follows: for thrombocytopenia, 1, 1, 2, and 0, respectively; for cardiac valve disease, 0, 0, 3, and not analyzed, respectively; for skin ulcer, 3, 1, 0, and 1, respectively; for aPL nephropathy, 0, 1, 0, and 0, respectively; and for cognitive dysfunction, 3, 1, 1, and not analyzed, respectively. The results of this uncontrolled and nonrandomized pilot study suggest that the safety of rituximab in aPL-positive patients is consistent with the safety profile of rituximab. Despite causing no substantial change in aPL profiles, rituximab may be effective in controlling some but not all non-criteria manifestations of APS.

Inhibitory human antichimeric antibodies to rituximab in a patient with pemphigus

Inhibitory human antichimeric antibodies to rituximab in a patient with pemphigus

A Phase 2 Study of Elotuzumab in Combination with Lenalidomide and Low-Dose Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma

A Phase 2 Study of Elotuzumab in Combination with Lenalidomide and Low-Dose Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma

New advances in the treatment of gout: review of pegloticase

Treatment-failure gout (TFG) affects approximately 50,000 patients or about 1% of the overall population of patients with gout in the United States of America. The severity of TFG is manifested by frequent acute attacks of disabling arthritis, chronic deforming joint disease, destructive masses of urate crystals (tophi), progressive physical disability, and poor health-related quality of life. Pegloticase (Krystexxa®; Savient Pharmaceuticals, Inc), a novel PEGylated urate oxidase (uricase) enzyme, has been resubmitted for US Food and Drug Administration approval. In a 6-month, placebo-controlled clinical trial, 8 mg of pegloticase for every 2 weeks induced a lytic decrease of serum urate (sUr) concentrations, leading to dissolution of tophi in 40% of patients at final visit. However, 58% were nonresponders to the defined target sUr of 0.36 mmol/L (80% were nonresponders during months 3 and 6), possibly due to anti-body formation. Also, 26%–31% experienced infusion reactions (IRs) and 77% suffered from gout flares. Although long-term data are awaited, an anti-inflammatory strategy, eg, based on glucocorticosteroids, is needed to prevent pegloticase antibody formation leading to IRs and diminished or shortened efficacy, and might also prevent gout flares. According to the current clinical data, pegloticase might have an important role as a (bridging) treatment in sUr-responsive patients for tophi clearance in severe chronic refractory gout.

Certolizumab Pegol as Salvage Therapy in Patients with CD Intolerant to or Without Adequate Response to Two Prior Anti-TNF Agents

Purpose: Certolizumab pegol (CP), an anti-TNF agent has been recently approved by the Food and Drug Administration (FDA) for treatment of Crohn's disease(CD). Other FDA approved anti-TNF agents for treatment of CD include infliximab (INF) and adalimumab (ADA). The aim of present study was to assess the efficacy of CP in pts with CD who initially responded but subsequently lost response or were intolerant to previous therapy with other ant-TNF agents specifically INF and ADA at our Institution. Methods: A retrospective review of an electronic database was performed at our Institution. We reviewed all outpt records from 04/07-06/09 in our IBD center in order to identify patients with IBD who were treated with CP. CP was administered subcutaneously in the dose of 400 mg at week 0, 2 and 4 and then after every 4 weeks. The efficacy of CP was evaluated by Harvey-Bradshaw Index (HBI) prior (HBI 1) and after (HBI 2) initiation therapy with CP. Clinical response was defined as reduction of HBI score ≥ 3 points from baseline whereas clinical remission was defined as HBI score ≤ 4 points. Results: There were 1312 consecutive IBD pts identified over this time interval. Among them, 16 pts (10 women) with CD were treated with CP who initially responded but subsequently lost response (n=6) or were intolerant (n=10) to previous therapy with other ant-TNF agents specifically INF and ADA with a mean (± SD) age 36.8 (± 12.9)yrs. The mean duration of CD was 14.7 (± 8.1)yrs. Two pts with clinically active CD (12.5%) experienced infusion reactions after initiation therapy with CP (1 pt was intolerant to INF, 1 pt was intolerant to INF and ADA) and their HBI 2 scores were not available. Therefore HBI 1 and HBI 2 scores were calculated in 14 pts. The mean HBI 1 score was 7.9 ± 5.0 whereas the mean HBI 2 score was 6.2 ± 5.6 (p=0.04). The mean duration of follow-up on therapy with CP was 5.9 (±3.8) months. Prior to initiation of therapy with CP 9 of 14 pts (64.3%) had clinically active CD (mean HBI 1 10.9 ± 3.3) whereas 5 of 14 pts were in clinical remission (mean HBI 2 2.4 ± 1.5). Among 9 pts who received therapy with CP who had active CD, upon evaluation of HBI 2 score benefit was seen in 44% overall. Clinical remission was achieved by 3 of 9 (33 %) patients; clinical response was achieved by 1 of 9 pts (11%) whereas 5 pts (55.6%) did not respond to treatment with CP. All 5 pts who began treatment with CP with CD in remission were capable of maintaining their state of remission (mean follow-up 5.2 ± 4.0 months). Conclusion: Our preliminary data suggest that the use of a third anti-TNF agent particularly CP is an effective salvage therapy in pts with CD who are intolerant to or lose their initial response to two previous anti-TNF agents (INF and ADA). Disclosure: Dr Gary Lichtenstein - Received research/grant support, support for lectures and for scientific advisory committee for Salix, Shire, Axcan, Ferring, P&G, Centocor, Abbott, UCB Inc, Bristol Meyers Squibb, Elan and Prometheus.

The impact of infliximab infusion reactions on long‐term outcomes in patients with Crohn’s disease

Little is known about long-term outcomes in patients who experience infusion reactions while receiving infliximab. To investigate long-term outcomes in patients who experience infusion reactions while receiving infliximab. Retrospective electronic chart review of long-term clinical outcomes. Clinical data on 287 patients who received infliximab infusions for Crohn's disease were reviewed, of whom 51 developed at least one infusion reaction (18%). Ileo-colonic disease (OR 2.2, 95% CI 1.1-4.4) and episodic infliximab (OR 2.4, 95% CI 1.2-4.7) were associated with a higher risk of infusion reactions in univariate analysis, but concomitant azathioprine/mercaptopurine therapy at the initiation of infliximab was associated with a reduced risk (OR 0.4, 95% CI 0.2-0.8). Only the effect of concomitant immunomodulators persisted on multivariate analysis. Patients who experienced infusion reactions were less likely to be in remission at 1 year (OR 0.6, 95% CI 0.3-1.2), 2 years (OR 0.4, 95% CI 0.2-0.8, P = 0.01), or 5 years (OR 0.4, 95% CI 0.1-1.3) and more likely to require surgery (OR 2.2, 95% CI 1.1-4.1, P = 0.01) than those who did not experience such reactions. Patients who experienced infusion reactions to infliximab had a high rate of discontinuation of therapy in this cohort. Concomitant immunomodulators and maintenance therapy reduced the risk of infusion reactions.

A phase II study of the efficacy and toxicity of alemtuzumab for the therapy of human T cell lymphotrophic virus-1 (HTLV-1)-associated adult T-cell leukemia/lymphoma (ATL)

2535 Background: HTLV-1-associated ATL is an aggressive lymphoproliferative disorder with limited effective therapy. Alemtuzumab is a humanized monoclonal antibody directed against CD52. High levels of CD52 are expressed on the surface of ATL cells. Preclinical studies in the MET-1 mouse model of ATL showed alemtuzumab to be highly active. Methods: A single institution open-label phase II study examining the response and toxicity of alemtuzumab in patients with ATL. Eligibility criteria: HTLV-1-associated ATL (chronic, acute and lymphoma type), ≥10% CD52+ malignant cells, measurable disease, age ≥18 years, AGC ≥1000/μL, platelets ≥50,000/μL, adequate physiologic status and informed consent. Results: Ten (10) patients, 6 with leukemia, 4 with lymphoma, 8 Afro-Caribbean, 1 African-American and 1 Japanese, 7 women, 3 men, median age 49 years (range, 36–62), all having received previous treatments including CHOP (7), other monoclonal antibodies (5), radioimmunotherapy (2), and radiation (1), median WBC 48,500/μL (leukemia Pts.) received alemtuzumab standard induction followed by 30 mg 3 times weekly for a minimum of 4 weeks and maximum of 12 weeks. All patients experienced infusion reactions (grade, 1–3) including hypotension, fever, rigors, chills, pruritus and urticaria; however, no patient required discontinuation of treatment. All patients developed grade 4 lymphopenia, and transient cytomegalovirus (CMV) antigenemia. Four (4) patients with leukemia responded (1 CR, 3 PR). No patient with lymphoma responded. Conclusions: Alemtuzumab has antitumor activity in HTLV-1-associated adult T cell leukemia and is well tolerated. Lymphomatous ATL appears unresponsive to alemtuzumab. The reason for this is unknown; however, antibody levels achieved in lymph nodes may be suboptimal. Accrual continues. No significant financial relationships to disclose.

Infliximab for the treatment of psoriasis: Clinical experience at the State University of New York at Buffalo

Infliximab has shown promising results for the treatment of moderate to severe psoriasis and psoriatic arthritis. We conducted a retrospective study of all 52 patients treated with intravenous infliximab for severe psoriasis at a single practice site. These patients had recalcitrant plaque psoriasis (>33% body surface area), which was unresponsive to multiple conventional systemic therapies. Intravenous infliximab was administered at a dose of 5 mg/kg at 0, 2, 6, and 14 weeks and every 8 weeks thereafter. Patients were monitored for infections, infusion reactions, side effects, and response to therapy. Fifty-two patients (men = 32, women = 20) with a mean age of 47 (range, 22-76 years old) were included in this study. They were followed for a minimum of 4 months and a maximum of 33 months (median, 22 months). Patients received a mean total number of 12 infusions (range, 3-22). Forty-six of 52 patients (88%) had a clear or almost clear improvement based on the Physician's Global Assessment done by a single physician. Twelve patients (23%) required infliximab dose escalation to maintain control of their disease. Nine patients experienced infusion reactions. Thirteen patients experienced nonopportunistic infections; however, only one infection required temporary cessation of infliximab. This was a retrospective study at a single practice site. Infliximab was extremely effective and well tolerated in this group of patients with severe, recalcitrant psoriasis. Thirty-nine of 52 patients have continued receiving treatment for a median duration of 25 months with excellent disease control. Infliximab can provide control of extensive psoriasis with continued intermittent infusions.

Humoral immune response to a ricin A chain immunotoxin in patients with metastatic melanoma.

Immunotoxins, hybrid molecules consisting of a monoclonal antibody linked to a polypeptide toxin have shown anti-tumor activity in both animal models and early clinical trials. However, their potential value in the treatment of human cancer may be limited by the development of host antibodies against the conjugate. Such antibodies could potentially alter immunotoxin pharmacokinetics and pharmacodynamics as well as precipitate serum sickness or anaphylaxis. Using a radioimmunoassay we have measured serial anti-ricin A chain (anti-RTA) and anti-murine immunoglobulin (anti-MIG) titers in 22 patients who received the anti-melanoma immunotoxin XomaZymeR-Mel. Significant titers of anti-RTA and/or anti-MIG were detected in 17 of 21 evaluable patients. Of the four patients not developing antibodies, two were likely immunosuppressed secondary to dexamethasone, and CCNU and dexamethasone respectively. Both patients who received immunotoxin at a time when they had detectable anti-immunotoxin antibodies experienced infusion reactions consistent with immune mediated allergic responses. There was a decrease in peak immunotoxin level in the one patient who had serum immunotoxin levels measured at a time when anti-RTA was present. Strategies to suppress the human immune response to immunotoxins are required before repetitive courses of immunotoxin of this design may be administered.