Incidence Of Infusion-related Reactions Research Articles

Brentuximab Vedotin Plus Bendamustine Is an Effective Salvage Regimen for Pediatric Patients with Relapsed Hodgkin Lymphoma

Background :Pediatric patients with relapsed/refractory Hodgkin Lymphoma have superior outcomes when achieving a complete remission prior to autologous stem cell transplant (ASCT). Optimal salvage regimens need to be identified as current approaches result in complete responses (CR) in approximately 25-35% of patients. The combination of brentuximab vedotin and bendamustine is highly active in adult patients with relapsed/refractory Hodgkin Lymphoma, but has not been evaluated in the pediatric population. We report our preliminary experience regarding the safety and efficacy of brentuximab vedotin and bendamustine prior to stem cell transplant (SCT) in pediatric patients treated for relapsed Hodgkin lymphoma at a single center.Methods:We performed a retrospective review of pediatric patients with relapsed Hodgkin lymphoma treated with brentuximab vedotin and bendamustine between April 2016 to July 2017. Patients received an infusion of 1.8mg/kg of brentuximab vedotin on Day 1 with bendamustine 90mg/m2 on Days 1 and 2 of 3-week cycles. Response assessment was performed and repeated following 2-3 cycles of therapy. Patients went on to SCT after achieving a CR or best response at the discretion of the treating physicians. Patients resumed post-transplant treatment with brentuximab vedotin as monotherapy for up to 16 doses.Results:Five patients (1 female, 4 males) with a median age of 16.5 years at the time of relapse (range, 12.2 -17.9 years) were treated with the combination of brentuximab/bendamustine. Four patients were in first relapse and 1 was treated in second relapse nine months following a prior ASCT. Patients received a median of 5 cycles of therapy (range 2-5 cycles), with 2 patients receiving an additional cycle of brentuximab monotherapy prior to proceeding to SCT. The main toxicity observed was infusion-related reactions, with 2 patients experiencing anaphylaxis. These individuals were able to continue planned therapy following desensitization against brentuximab. All patients were in complete remission by PET prior to SCT. Four patients underwent successful stem cell mobilization and collection. The individual treated following second relapse received an allogeneic transplant from a matched unrelated donor. All patients are alive with no evidence of disease a median of 11.3 months since beginning salvage therapy (range 1.2-15 months). Four patients are a median of 6.5 months (range 4-11 months) post-SCT and continue on brentuximab monotherapy, with 1 individual currently awaiting ASCT.Conclusions :Combination therapy with brentuximab vedotin and bendamustine was highly active in pediatric patients with relapsed Hodgkin lymphoma and would compare favorably with currently accepted salvage regimens. Incidence of infusion-related reactions can be minimized through the use of adequate premedication. These results support further evaluation of this regimen in the context of a multicenter prospective clinical trial. DisclosuresCurran:Novartis: Consultancy; Juno Therapeutics: Research Funding. Kernan:Gentium: Other: NAK received grants from Gentium during the conduct of the study, and her research was supported by The National Cancer Institute of the National Institutes of Health under award number P30 CA008748; the content is solely the responsibility of the author .

Safety of subcutaneous daratumumab in the treatment of plasma-cell disorders: A single-center experience.

e20007 Background: Daratumumab (Dara) is a CD38-directed monoclonal antibody approved for the treatment of patients with multiple myeloma (MM) and light-chain amyloidosis (AL). Infusion-related reactions (IRRs) have been reported in 28-56% of individuals receiving the conventional intravenous (IV) formulation, necessitating slow infusions and frequent use of rescue medications to mitigate complications. Recently subcutaneous (SC) Dara received approval in MM, and randomized data suggests a lower rate of IRRs compared to IV Dara. Guidelines regarding post-injection monitoring with SC Dara are not well established. This retrospective study aims to evaluate the safety of SC Dara in patients with MM and AL, and to suggest guidelines for monitoring following SC Dara administration. Methods: This single-center retrospective study included patients treated with MM or AL receiving SC Dara between June 2020 and December 2020. The primary outcome of the study was incidence of IRRs. Secondary outcomes include timing and severity of IRRs based on CTCAE version 4.0. Results: A total of 82 patients received SC Dara during the study period. Of these 82, forty-nine (60%) had previously received Dara (Dara-exposed), and 33 patients (40%) were Dara-naïve. Eight of the 82 patients (9.8%) experienced an IRR. All were grade 1 (n=5, 63%) or grade 2 (n=3, 38%) in severity. Seven patients in the Dara-naïve group experienced an IRR (21%), and one patient in the Dara-exposed group (2%) experienced injection-site erythema with the second SC dose after transitioning from IV. Three patients experienced reactions immediately after SC Dara administration, and four patients experienced delayed reactions >4 hours after SC Dara administration (median 11.9 hours; range 5-24). Among those with delayed reactions, three experienced reactions after being discharged from the treatment area but symptoms resolved without any intervention. Conclusions: In this single-center study of patients receiving SC Dara, IRRs occurred in about 10% of patients, and were more likely with a patient’s first dose of SC Dara. All reactions were mild to moderate in severity and could be managed in the outpatient setting. We suggest that Dara-naïve patients receiving their 1st SC Dara dose be monitored for one hour after SC Dara administration. Monitoring does not appear necessary for patients transitioning from IV to SC Dara or receiving subsequent doses of SC Dara. [Table: see text]

Retrospective review of accelerated daratumumab administration.

Daratumumab is an anti-CD38 monoclonal antibody approved for multiple myeloma. The initial infusion is administered over a median of 7.5 hours with subsequent infusions given over 3 to 4 hours. Studies show high incidence of infusion related reactions (IRRs) with the initial dose which decreases with subsequent infusions. Accelerated 90 minute daratumumab infusions following the second dose of standard administration are widely accepted in practice including at Beth Israel Deaconess Medical Center (BIDMC) despite limited data from small safety studies. The objective of this study is to evaluate the safety of accelerated daratumumab administration compared to standard administration. The primary outcome is the incidence of common terminology criteria for adverse events (CTCAE) version 5.0 grade 1 or higher for IRRs in accelerated and standard infusions. Secondary outcomes include non-IRR adverse events and amount of supportive care medications used pre- and post- and during accelerated and standard infusions. A total of seventy five patients received a daratumumab infusion between November 2015 and August 2019. There were a total of 420 daratumumab infusions evaluated, 317 (75.5%) were standard infusions of which 152 infusions were standard infusions that preceded an accelerated infusion. There were a total of 103 (24.5%) accelerated infusions. IRRs occurred in a total of 38 (9%) of the infusions with CTCAE grade 2 reactions occurring in total of 21 (5%) infusions and grade 1 occurring in 15 (3.6%) infusions. Overall accelerated daratumumab administration is safe and well tolerated when given following at least two standard infusions.

Safety Evaluation of Initial CT-P6 Administration for 30 min during the Switch from Reference Trastuzumab in Maintenance Infusion: A Multicenter Observational Study.

CT-P6 is a biosimilar of trastuzumab and is recommended to be administered for 30-90 min in subsequent maintenance infusions to prevent infusion-related reactions (IRRs). We administered CT-P6 for 30 min as the first injection and as an alternative to reference trastuzumab in the maintenance infusion and evaluated the safety of the administration. A total of 140 patients with breast or gastric cancer, who received a switch from tri-weekly reference trastuzumab to CT-P6 for 30 min in maintenance infusions, were retrospectively evaluated. Premedication was administered prior to an infusion of CT-P6 and a cytotoxic agent. However, premedication was not provided when CT-P6 was co-administered with pertuzumab or administered alone. The primary endpoint was the incidence of IRRs. The secondary endpoint was the incidence of diarrhea and skin toxicity. Ninety-five percent of the patients had breast cancer, and 44.3% had advance-stage cancer. The treatment included CT-P6 alone (17.9%) or with cytotoxic agents (23.6%), antihormonal drugs (25.7%), and pertuzumab (62.9%). Median administration time of trastuzumab at the switch was 13 administrations (range 2-140). Premedication was administered to 20.7% patients. One patient (0.7%) experienced grade 3 IRR. The frequency of diarrhea in the reference trastuzumab group and the CT-P6 group was 7.1 and 6.4%, respectively, and that of skin toxicity was 6.4 and 5.0%, respectively, without differences. In conclusion, we first demonstrated that an initial CT-P6 administration for 30 min during the switch from reference trastuzumab in maintenance infusion is an acceptable administration method.

Efficacy of Margetuximab vs Trastuzumab in Patients With Pretreated ERBB2-Positive Advanced Breast Cancer

ERRB2 (formerly HER2)-positive advanced breast cancer (ABC) remains typically incurable with optimal treatment undefined in later lines of therapy. The chimeric antibody margetuximab shares ERBB2 specificity with trastuzumab but incorporates an engineered Fc region to increase immune activation. To compare the clinical efficacy of margetuximab vs trastuzumab, each with chemotherapy, in patients with pretreated ERBB2-positive ABC. The SOPHIA phase 3 randomized open-label trial of margetuximab plus chemotherapy vs trastuzumab plus chemotherapy enrolled 536 patients from August 26, 2015, to October 10, 2018, at 166 sites in 17 countries. Eligible patients had disease progression on 2 or more prior anti-ERBB2 therapies and 1 to 3 lines of therapy for metastatic disease. Data were analyzed from February 2019 to October 2019. Investigators selected chemotherapy before 1:1 randomization to margetuximab, 15 mg/kg, or trastuzumab, 6 mg/kg (loading dose, 8 mg/kg), each in 3-week cycles. Stratification factors were metastatic sites (≤2, >2), lines of therapy (≤2, >2), and chemotherapy choice. Sequential primary end points were progression-free survival (PFS) by central blinded analysis and overall survival (OS). All α was allocated to PFS, followed by OS. Secondary end points were investigator-assessed PFS and objective response rate by central blinded analysis. A total of 536 patients were randomized to receive margetuximab (n = 266) or trastuzumab (n = 270). The median age was 56 (27-86) years; 266 (100%) women were in the margetuximab group, while 267 (98.9%) women were in the trastuzumab group. Groups were balanced. All but 1 patient had received prior pertuzumab, and 489 (91.2%) had received prior ado-trastuzumab emtansine. Margetuximab improved primary PFS over trastuzumab with 24% relative risk reduction (hazard ratio [HR], 0.76; 95% CI, 0.59-0.98; P = .03; median, 5.8 [95% CI, 5.5-7.0] months vs 4.9 [95% CI, 4.2-5.6] months; October 10, 2018). After the second planned interim analysis of 270 deaths, median OS was 21.6 months with margetuximab vs 19.8 months with trastuzumab (HR, 0.89; 95% CI, 0.69-1.13; P = .33; September 10, 2019), and investigator-assessed PFS showed 29% relative risk reduction favoring margetuximab (HR, 0.71; 95% CI, 0.58-0.86; P < .001; median, 5.7 vs 4.4 months; September 10, 2019). Margetuximab improved objective response rate over trastuzumab: 22% vs 16% (P = .06; October 10, 2018), and 25% vs 14% (P < .001; September 10, 2019). Incidence of infusion-related reactions, mostly in cycle 1, was higher with margetuximab (35 [13.3%] vs 9 [3.4%]); otherwise, safety was comparable. In this phase 3 randomized clinical trial, margetuximab plus chemotherapy had acceptable safety and a statistically significant improvement in PFS compared with trastuzumab plus chemotherapy in ERBB2-positive ABC after progression on 2 or more prior anti-ERBB2 therapies. Final OS analysis is expected in 2021. ClinicalTrials.gov Identifier: NCT02492711.

Evaluation of a pharmacist-driven rapid infusion rituximab conversion protocol at a multisite cancer center.

Infusion-related reactions (IRR) are a common adverse event associated with rituximab, an anti-CD20 monoclonal antibody indicated for the treatment of B-cell lymphomas. IRR risk is highest with the first infusion, which is given by a slow titration over an average of 3.5 hours. Subsequent administrations can be given over an accelerated, rapid 90-minute infusion if patients meet specific criteria. To improve rapid infusion rituximab utilization, we developed and implemented a pharmacist-driven protocol which allows pharmacists to change the administration instructions to rapid infusion. A retrospective chart review was conducted to evaluate patients age ≥18 years with B-cell lymphomas who were eligible to receive rapid infusion rituximab following protocol implementation. The primary outcome was the prevalence of the use of rapid infusion rituximab for eligible patients. Secondary outcomes included the frequency of pharmacist-initiated conversions to rapid infusion rituximab and incidence of IRR with rapid infusions. A total of 180 patients were included in this study; 89 patients in the pre-protocol group and 91 patients in the post-protocol group. Fifteen patients and 66 patients in the pre-protocol and post-protocol groups, respectively, received rapid infusion rituximab (17% vs. 73%, p < 0.00001). The pharmacist-driven protocol was used to convert 49 patients (54%) to rapid infusion. No IRR occurred in patients receiving rapid infusion rituximab. The implementation of a pharmacist-driven protocol led to a significant improvement in the use of rapid infusion rituximab and optimized chair time utilization at our institution.

Optimizing Care: Discontinuing Medications Prior to Daratumumab and Hyaluronidase-Fihj Subcutaneous Injection (OMIT)

Introduction Intravenous daratumumab (DARA IV) is generally well tolerated, but it is commonly associated with infusion-related reactions (IRRs). Per prescribing information (PI), the manufacturer recommends pre-infusion medications with diphenhydramine, acetaminophen, and a corticosteroid prior to each infusion to prevent IRRs (Darzalex™ [PI]; 2019, DarzalexFaspro™ [PI]; 2020). However, in our experience the incidence of IRRs is significantly lower after the first three infusions, if they were well tolerated. Therefore, to decrease pill burden and overmedicating the patient at Cedars-Sinai Medical Center (CSMC), the pre-infusion medications for the fourth and subsequent infusions are discontinued. The new subcutaneous (SQ) formulation daratumumab and hyaluronidase- fihj (DARA SQ) has an even lower incidence of IRRs compared to the IV formulation, 12.7% versus 34.5%, of all grades and 1.5% versus 5.4% of grade 3 respectively (Mateos MV., et al. Lancet; 2020). Given the lower risk of IRRs, CSMC recommends discontinuing pre-medications after the third DARA SQ injection, or never starting them if the patient had previously tolerated three or more DARA IV infusions and is now being switched to the SQ formulation. This strategy has been our approach and to date our patients have tolerated their infusions and/or injections. Unfortunately, there is no published literature to guide clinicians, so institutions have different approaches based upon their own anecdotal experiences or hearsay. Methods A single-center, retrospective chart review was performed on patients from a single physician who have received at least one dose of DARA SQ from June 1 through July 22, 2020 at CSMC. A total of 63 patients were screened, one patient was excluded because she required diphenhydramine with each treatment. Data collected included number of DARA SQ doses given without pre-medications, diagnosis, previous treatment with DARA IV, time since last DARA IV treatment, previous IRRs to DARA IV (graded as per CTCAE version 5.0), IRRs to DARA SQ, number of SQ doses, corticosteroids use, and if the patients had any pre-existing pulmonary conditions. The primary objective was to review the incidence of IRRs in our patients following the omission of pre-medications after the third DARA SQ injection. Results A total of 81 doses of DARA SQ were administered to 62 patients. All treatments were well tolerated, and no systemic IRRs were documented. Only one patient had a localized reaction, characterized as erythema around the injection site. Most of the patients were diagnosed with multiple myeloma (94%), one patient had smoldering myeloma, and three patients were diagnosed with amyloidosis. Most patients were previously treated with DARA IV (77%) with a median time since last IV dose of 28 days (range, 7 - 59 days). 15 of these patients had a history of mild to moderate IRRs to DARA IV: 4 were grade 1 and 11 were grade 2. The most common corticosteroid treatment was dexamethasone 20 mg weekly, ranging from 4 mg twice weekly to 40 mg weekly. 18 patients did not receive corticosteroids as part of their treatment regimen, nor as a pre-treatment medication. The majority of the patients (85%) did not have a pre-existing documented pulmonary condition. Conclusion All our patients were able to safely receive DARA SQ without pre-medications with acetaminophen and diphenhydramine beginning with the fourth dose. Furthermore, 18 patients stopped corticosteroids with subsequent injections and were able to tolerate treatment without any IRRs. Clinicians should take into consideration that corticosteroids are given not solely as pre-medication, but also as a treatment for multiple myeloma. Therefore, if the only purpose of corticosteroids is the prevention of IRRs, their administration can be avoided. A previous reaction to DARA IV did not increase the risk of IRRs to DARA SQ. Diphenhydramine can cause drowsiness which can impair a patient's ability to drive home after their treatment; corticosteroids can cause insomnia, stomach upset, and hyperglycemia. By omitting unnecessary pre-medications, these unwanted adverse drug effects can be avoided. This study demonstrates that we can safely discontinue DARA SQ pre-medications if a patient tolerates the initial three treatments of IV or SQ daratumumab. Disclosures No relevant conflicts of interest to declare.

Subcutaneous Daratumumab (DARA SC) Plus Standard-of-Care (SoC) Regimens in Multiple Myeloma (MM) across Lines of Therapy in the Phase 2 Pleiades Study: Initial Results of the Dara SC Plus Carfilzomib/Dexamethasone (D-Kd) Cohort, and Updated Results for the Dara SC Plus Bortezomib/Melphalan/Prednisone (D-VMP) and Dara SC Plus Lenalidomide/Dexamethasone (D-Rd) Cohorts

Subcutaneous Daratumumab (DARA SC) Plus Standard-of-Care (SoC) Regimens in Multiple Myeloma (MM) across Lines of Therapy in the Phase 2 Pleiades Study: Initial Results of the Dara SC Plus Carfilzomib/Dexamethasone (D-Kd) Cohort, and Updated Results for the Dara SC Plus Bortezomib/Melphalan/Prednisone (D-VMP) and Dara SC Plus Lenalidomide/Dexamethasone (D-Rd) Cohorts

Successful rechallenge with cetuximab after an infusion related reaction to panitumumab in a patient with locally advanced rectal cancer

Incidence of infusion related reaction (IR) is more common with cetuximab (Cmab) than with panitumumab (Pmab). Although little is known about rechallenge IR with monoclonal antibodies, we experienced a successful rechallenge to Cmab after IR to Pmab. A 67-year-old female patient was scheduled for chemotherapy with mFOLFOX6 plus Pmab against unresectable advanced rectal cancer in the hope of tumor shrinkage. On the first administration of Pmab, she complained of dyspnea with shortness of breath and wheezing, even after premedication with steroids and antihistamines. Her reaction was judged as Grade 2 IR to Pmab. For the next course, we tried Cmab. No IRs were observed. Since then, she has undergone seven further courses of treatment, followed by surgical resection. The patient benefited from administration of Cmab after experiencing IR to Pmab, suggesting this treatment to be an option for patients of this type who experience IR to Pmab.

Evaluation of Montelukast for the Prevention of Infusion-related Reactions With Daratumumab

BackgroundDaratumumab is an anti-CD38 monoclonal antibody indicated for the treatment of multiple myeloma. Infusion-related reactions (IRRs) are among the most common adverse events associated with daratumumab. IRRs are most common with the first infusion of daratumumab. Recommended premedications to be given prior to the daratumumab dose include acetaminophen, diphenhydramine, and a corticosteroid. There is emerging data to suggest that the addition of montelukast to this premedication regimen can lower the incidence of daratumumab-related IRRs. Patients and MethodsThis was a single-center, retrospective chart review conducted at a large, multistate health system with several different hematology/oncology practice sites. Eligible patients included those with a primary diagnosis of a plasma cell disorder who received at least 1 dose of daratumumab. The primary outcome was the incidence of IRRs with the first daratumumab infusion. ResultsA total of 141 patients receiving daratumumab-based therapy were included in this study. All patients received acetaminophen, diphenhydramine, and a corticosteroid as premedications prior to the first infusion of daratumumab. Overall, 46 (33%) patients experienced an IRR with the first infusion of daratumumab. The incidence of IRR was lower in patients that received montelukast as a premedication compared with those that did not (montelukast, n = 25 [27%]; no montelukast, n = 21 [45%]; P = .0371). Patients in each arm experienced similar rates of overall, composite pulmonary, gastrointestinal, and systemic IRR manifestations. ConclusionThe use of montelukast prior to the first daratumumab infusion led to a reduction in the incidence of IRRs in our experience.

Utilizing a novel four-drug regimen to reduce the incidence of infusion-related reactions for first-dose rituximab infusions: An institutional review of rituximab infusion-related reactions in lymphoma patients.

e19148 Background: Rituximab is a chimeric monoclonal anti-CD20 antibody utilized in the treatment of several disease states including B-cell non-Hodgkins Lymphoma. Infusion-related reactions (IRR) with rituximab occur with an incidence of up to 77% during the first infusion. The occurrence of an infusion reaction adds to the cost and time of rituximab administrations, especially with prolonged chair time and increased nursing and physician support, and decreased quality of life. The University of Arizona Cancer Center (AZCC) initiated a four-drug premedication regimen consisting of dexamethasone, famotidine, diphenhydramine, and acetaminophen. Our study examined the frequency of first-dose rituximab infusion reactions with our premedication regimen as compared to other published regimens. Methods: A retrospective chart review for all first-dose rituximab infusions was conducted for lymphoma patients treated with BR or RCHOP regimens from 11/2013 through 6/2019 at the AZCC. Data points collected included baseline patient demographics as well as rituximab infusion data. Results: In our study, the median age of the patient population was 64 years (range 22-89), 60.5% were males, and the average BSA was 2 m2 (range 1.39-3.04). The average rituximab dose was 750 mg (range 521-1140) and the average infusion time was 301 minutes (range 197-512). IRR with first time Rituximab was seen in 19 patients out of 81 total patients (23.5%). Of these IRR, 52.6% occurred in BR versus 47.4% in RCHOP. The most frequent IRR symptoms seen included flushing, itching, feeling hot, and tingling. The average infusion time for IRR patients was 334 minutes versus 284 minutes in patients not experiencing IRR. Grade 2 reactions were reported in 14 patients (73.7%) with grade 3 IRR’s reported in 5 patients (26.3%). Onset of IRR occurred on average during the first 61.6 minutes of the start of infusion (range 10-108 minutes). Conclusions: A novel four drug premedication regimen consisting of corticosteroids, antihistamines H2RA antatagonist and analgesic, resulted in a much lower rituximab infusion reaction rate (23.5%) than what has been previously reported in literature using standard premedications ( &gt; 50%). The utilization of this four drug combination therapy provides the means to reduce first dose rituximab IRR in patients while maximizing patient care and increasing the number of patients who were able to receive Rapid Rituximab during their next cycle of chemotherapy.

Ongoing Study of Obinutuzumab Short Duration Infusion in Patients with Previously Untreated Advanced Follicular Lymphoma

Introduction: In the Phase III GALLIUM study (NCT01332968), obinutuzumab (G) in combination with chemotherapy (G-chemo) demonstrated improved progression-free survival (PFS) and a comparable tolerability profile to rituximab (R)-chemo, in patients with previously untreated follicular lymphoma (FL) (Marcus et al. N Engl J Med 2017). In addition to developing more efficacious treatments for FL, there is also a need for more convenient treatments. The administration of G is associated with infusion-related reactions (IRRs). The incidence of IRRs is greatest with the first infusion and decreases significantly with subsequent infusions (Marcus et al. N Engl J Med 2017). To reduce this risk, an IRR risk-reduction strategy is used in clinical practice. However, this means that administration of G can take approximately 4 hours. Shorter infusion times would yield substantial time savings for patients and benefit outpatient infusion facilities by increasing the number of infusion chairs available during clinic hours and improving nursing efficiency. Previous studies with R have led to the development of a 90-minute short duration infusion (SDi), which is now widely used if the first dose of R is well tolerated. Two Phase II studies have previously evaluated the safety and efficacy of a 90-minute SDi of G. The GATHER study (NCT01414855), in patients with previously untreated advanced diffuse large B-cell lymphoma (Sharman et al. Leuk Lymphoma 2018) and the GATS study in Japanese patients with previously untreated non-Hodgkin lymphoma (Ohmachi et al. Jpn J Clin Oncol 2018) both demonstrated that G can be safely administered as a 90-minute SDi, after the initial cycle (C). Here, we report details of the ongoing GAZELLE study (NCT03817853; MO40597), an open-label, multicenter, Phase IV study investigating the safety of G-chemo, with G administered as a SDi (approximately 90 minutes) from C2 onwards in patients with previously untreated advanced FL, who have received G-chemo at the standard infusion rate without experiencing a grade (Gr) 3 or 4 IRR during C1. Methods: Patients with CD20-positive, previously untreated stage III or IV FL, or stage II bulky disease (Groupe d'Etude des Lymphomes Folliculaires [GELF] criteria for initiating treatment, Eastern Cooperative Oncology Group performance status [ECOG PS] 0−2, life expectancy ≥12 months) will receive G (1000mg) intravenously on Day (D) 1, D8, and D15 of C1, and on D1 of subsequent cycles (Figure), in combination with chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone [CHOP], cyclophosphamide, vincristine, and prednisone [CVP], or bendamustine at the discretion of the investigator site). The standard infusion rate of G will be administered in C1 (obinutuzumab [Gazyva] prescribing information, 2017). The primary endpoint is incidence of Gr ≥3 IRRs during C2 in patients who had previously received G at the standard infusion rate during C1, without experiencing a Gr ≥3 IRR. For the purposes of the study, an IRR was defined as an adverse event (AE) occurring during or ≤24 hours from the end of G infusion and judged by the investigator as related to the infusion. The rate of G administration at subsequent cycles will be adjusted according to the occurrence and severity of IRRs. Only patients who do not experience a Gr ≥3 IRR during C1 will receive the faster SDi infusion from C2 onwards. If any Gr ≥3 IRR occurs during or after C1 then the next dose of G will be administered at the standard infusion rate. The investigator will decide if the patient can restart with the SDi. Secondary safety endpoints include AEs, time to IRRs, type and duration of Gr ≥3 IRRs and duration of G administration by cycle. Secondary efficacy endpoints include investigator-assessed overall response rate at end of induction, PFS and overall survival at the end of the study, and complete response rate at 30 months. Total length of the study, from screening of the first patient to the end of the study, is expected to be approximately 4 years. It is estimated that 112 patients will be enrolled. Disclosures Canales: Novartis: Honoraria; SOBI: Research Funding; F. Hoffmann-La Roche Ltd: Honoraria, Speakers Bureau; iQone: Honoraria; Sandoz: Honoraria; Celgene: Honoraria; Janssen: Honoraria, Speakers Bureau; Gilead: Honoraria; Karyopharm: Honoraria; Takeda: Speakers Bureau. Buchholz:Scripps Health Care System: Employment; Scientific Advisory Committee, Roche/Genetech for the Study of the Abstract: Membership on an entity's Board of Directors or advisory committees. Mason:Abivax: Consultancy. Parreira:F.Hoffmann-La Roche Ltd: Employment, Equity Ownership, Honoraria. Tomiczek:F. Hoffmann-La Roche Ltd: Employment. Hübel:Sanofi: Consultancy, Speakers Bureau; Celgene: Consultancy, Other: Travel, Accommodations, expenses , Speakers Bureau; Hexal: Consultancy; Roche: Consultancy, Other: Travel, Accommodations, expenses , Research Funding, Speakers Bureau; Servier: Consultancy, Research Funding, Speakers Bureau.

451P - The safety of ramucirumab without H1-antihistamines as a premedication in patients with solid cancers: A retrospective study

BackgroundRamucirumab is a fully human monoclonal antibody (IgG1) developed for the treatment of solid tumors. To reduce the risk of an infusion-related reaction (IRR) with ramucirumab, H1-antihistamines are recommended as premedication. However, IRR is hardly observed in clinical practice in the ramucirumab regimen. The H1-antihistamines have several side effects, such as drowsiness and dizziness, and the use of H1-antihistamines might be restricted for the patients who need to drive a car or for elderly patients. The aim of this study was to investigate the safety of ramucirumab without H1-antihistamines as a premedication in patients with solid cancer. MethodsWe retrospectively reviewed the solid tumour patients who received ramucirumab, including regimen without H1-antihistamines at our institution between 2017 and 2019. The patients who received antiemetic steroid for cytotoxic chemotherapy was also included. The primary endpoint was the incidence of IRR during the infusion in the first cycle. The secondary endpoints were the incidence of IRR at any time and other ramucirumab related adverse events. ResultsOf the 51 patients enrolled (median age, 69.5 years; range 41 - 83), 28 (55%) were male. The origins of cancer were gastric cancer (n = 22), lung cancer (n = 26), and colon cancer (n = 3), respectively. Forty-two patients (82%) received ramucirumab in combination with antiemetic steroid for cytotoxic chemotherapy, and nine patients (18%) received ramucirumab monotherapy without steroid. No IRR was observed in this study (IRR rate, 0%; 95% CI 0 - 0.69). Among the overall 272 infusions, there were no events of IRRs or other ramucirumab related adverse events. ConclusionsThere was no IRRs without H1-antihistamines in our retrospective study. Ramucirumab without H1-antihistamines as premedication would be a favourable option for the patients who had trouble with the side effects of H1 antihistamine. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

LONG TERM SAFETY AND EFFICACY OF DARATUMUMAB RAPID INTRAVENOUS INFUSION (90 MINUTES) AFTER THE THIRD DOSE IN MULTIPLE MYELOMA PATIENTS

The anti-CD38 IgG/k antibody Daratumumab is particularly efficient alone or combined with other drugs in multiple myeloma (MM) patients. Long Infusion sched-ules of 4 to 8 hours however to avoid incidence of infusion related reactions (IRR) can reduce patients and health care professional compliance. Splitting of the first dose in two days has already reduced length of the first infusion (4 hours each). Strategies to reduce infusion time have been reported. One study (Barr H, et al., Leuke-mia 2018) showed safety in 28 patients with MM with an infusion time of 90 minutes start-ing from dose >10 in the majority.

Safety and effectiveness of enzyme replacement therapy with agalsidase alfa in patients with Fabry disease: Post-marketing surveillance in Japan

Fabry disease is a rare X-linked inherited multisystem disorder resulting from deficiency of the lysosomal enzyme alpha-galactosidase A. Currently, specific therapies, including enzyme replacement therapies, are available for Fabry disease, but clinical trials provide limited information on long-term safety and effectiveness.Agalsidase alfa was approved in Japan in 2006. The post-marketing surveillance study of all patients receiving agalsidase alfa to evaluate its long-term safety and effectiveness as a mandatory condition for its approval had been conducted for 8 years (from February 2007 to March 2015).A total of 493 patients were included in this analysis of safety and effectiveness. The overall mean follow-up period was 3.5 years (range, 0.0–7.9 years). The percentage of patients with adverse drug reactions was 24.5% (121/493) and 12.6% had infusion-related reactions (62/493). In the 256 patients without prior enzyme replacement therapy whose IgG antibody data were available, 17 were IgG antibody positive (6.6%). However, the chronological correlation between seroconversion and the incidence of infusion-related reactions was not clear.The mean brief pain inventory score of the worst pain decreased in patients with moderate and severe pain at baseline. Plasma Gb3 and urine sediment Gb3 in males with classical Fabry disease without prior enzyme replacement therapy significantly decreased. The mean yearly changes in eGFR (mL/min/1.73 m2) ranged from −2.88 to +1.00 in males with classical Fabry disease, from −2.04 to −0.95 in males with non-typical variant and from −2.64 to −1.02 in females. The lower eGFR or the more proteinuria at baseline, the faster the decrease in eGFR of the patients was observed. There was no substantial difference in cardiac parameters (left ventricular mass index, E/A wave ratio, ejection fraction, and QRS duration).In conclusion, agalsidase alfa, 0.2 mg/kg every other week, was well tolerated and controlled the progression of symptoms (especially renal and cardiac) of Fabry disease in adults. Enzyme replacement therapy should be started in Japanese patients before cardiac and/or renal symptoms of Fabry disease develop.

A Single Center Retrospective Evaluation of Daratumumab Infusion Related Reactions with Split-First Dose Day 1 and Day 2 Infusion

Introduction:Monoclonal antibody's infusion related reactions (IRRs) include anaphylaxis, anaphylactoid reactions and cytokine release syndrome. These reactions are related to the time of infusion. Incidence of IRRs in patients treated with daratumumab is reported to be about 42%. Severity of the most commonly reported IRRs, during the first dose of infusion are between grade I and II. Approved dosage of daratumumab is 16 mg/kg IV weekly given for 1 through 8 weeks, then every 2 weeks from 9th through 24th week, after which it is given every 4 weeks from 25th week onwards, its use is continued until disease progression. The goal of this study is to evaluate the IRRs at cycle 1 day 1 (C1D1) and C1D2, using split dose daratumumab (8 mg/kg) and to look for the impact of prior leukotriene receptor antagonist administration on the incidence of IRRs.Methods:To study the IRRs at day 1 using split dose daratumumab C1D1 (8 mg/kg) and C1D2 (8 mg/kg), we performed a retrospective review of medical records of relapsed/refractory (R/R) multiple myeloma patients receiving daratumumab between December 1st, 2015 to March 31st, 2018 at our center. Key variables related to each patient were recorded from Epic electronic database. Data were summarized using counts and percentages.Results:A total of 35 patients were included and the incidence of IRRs was measured. Overall, 13 (37.14%) patients developed IRRs on day 1. Out of these 13 patients, 11 (84.61%) patients had grade II IRRs, 1 (7.69%) patient had grade I IRRs and 1 (7.69%) patient had grade III IRRs.Nineteen (54.2%) patients out of a total 35 patients were pretreated with montelukast; out of these 19 patients, 5 (26.31%) patients had grade II IRRs and 1 (5.26%) patient had grade III IRRs. Thus, 31.57% patients had IRRs with montelukast pretreatment. No patient had grade I or grade IV IRRs.Sixteen (45.71%) patients out of total 35 patients were not pretreated with Montelukast; out of these 16 patients, 6 (37.5%) patients had grade II IRRs and 1 (6.25%) patient had grade I IRR. No patient had grade III or grade IV IRR. Thus, 43.75% patients had IRRs without montelukast. Overall, 12.18% reduction in IRRs was noted with pretreatment using montelukast.Conclusion:This single center study demonstrates that split dose model of daratumumab in the treatment of R/R multiple myeloma shows lower incidence of IRRs when compared to historical controls reported in the literature. Moreover, pretreatment with leukotriene receptor antagonist also appear to decreases the incidence of IRRs in our patient population. Future randomized prospective trials are needed to support these findings and improving the overall impact on tolerance for daratumumab. DisclosuresNo relevant conflicts of interest to declare.

A Descriptive Analysis of Obinutuzumab Usage in a Single Canadian Centre

Background:Chronic lymphocytic leukemia (CLL) is the most prevalent leukemia in North America with the majority of patients being over the age of 70 (Goede et al, 2014). CLL is a heterogeneous disease with some patients undergoing treatment at time of diagnosis, while others follow along a more indolent, asymptomatic course. When indicated, the choice of treatment is based on the patient's functional status, renal function and other comorbidities (Shanafelt, 2013). Previous studies have shown that unfit patients treated with Obinutuzumab plus Chlorambucil have shown prolongation of progression free survival and higher rates of complete response compared to other monoclonal based regimens (Goede et al, 2014). The aim of this study is to investigate the clinical use and uptake of Obinutuzumab in combination with Chlorambucil in a Canadian based population.Methods:All patients receiving Obinutuzumab were identified using the CLL CAISIS database. Then a retrospective chart review was conducted for patients approved for first-line antibody treatment with Obinutuzumab from January 1, 2014 to December 31, 2017. Data including patient characteristics, patterns of treatment, reported toxicities, response rates and survival data were collected and analyzed. This data was used to determine the overall safety and efficacy of this treatment regimen.Results: There were a total of 66 patients that met the inclusion criteria for this study. This cohort consisted of 54.5% males and 45.5% females, with a median age at diagnosis of 68 years (range: 46-94). Within this population 47 patients underwent florescence in situ hybridization testing, which identified 32 patients with chromosomal abnormalities. The immunoglobulin heavy chain variable region gene mutation was also tested in 41 patients, and identified 22 patients that were unmutated. At the time of treatment the median age was 73 (range: 55-98) with a median Cumulative Illness Rating Scale (CIRS) score of 8 (range: 3-15). Of the 66 patients who started treatment with Obinutuzumab, 50 patients (76%) achieved a partial response and 5 patients (8%) had no response. Of note, 21 patients (31.8%) discontinued treatment prior to completion of all six cycles due to cytopenias (4), other comorbidities (4), progression of CLL (2), decline in functional/mental status (2), patient request (2) and other (7). In regards to their treatment there was a high incidence of infusion related reactions (IRRs) on the first day of treatment, with 30 patients (45.5%) requiring intervention. There was a subset of 15 patients that had received low dose Chlorambucil prior to treatment with Obinutuzumab which resulted in a lower average lymphocyte count (38.1) and lower rate of IRRs (33%) compared to those with no prior Chlorambucil (average lymphocyte count: 66.5, rate of IRR: 42%). Due to toxicity and tolerability of Chlorambucil, dose reduction was observed in 37 patients (56%) throughout all six cycles of treatment. In the end, only 18 patients (27.3%) received all doses of Obinutuzumab and Chlorambucil while 37 patients (56%) received all doses of Obinutuzumab. Within the entire cohort, 12 patients have relapsed and 9 of these patients have required additional therapy. This relapse rate can be attributed to lack of response to Obinutuzumab (3), a 17p del (1), poor prognostic markers (5), and inadequate Obinutuzumab (1).Conclusion:In this current study, our results demonstrate that the majority of patients in this cohort were able to complete treatment with Obinutuzumab. Although our demographics were similar to previous studies, we found higher partial response rates (76%) likely due to differences in standards of practice, such as imaging studies after treatment. DisclosuresWhiteside:Roche: Membership on an entity's Board of Directors or advisory committees, Other: teaching sessions. Dawe:AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees. Johnston:Roche: Other: unrestricted grant received in the past; Abbvie: Other: unrestricted grant received in the past; Teva: Other: unrestricted grant received in the past; Gilead: Other: unrestricted grant received in the past; Janssen: Other: unrestricted grant received in the past. Banerji:Roche: Other: Unrestricted grant received in the past; Janssen: Other: Unrestricted grant received in the past; Abbvie: Other: Unrestricted grant received in the past; Gilead: Other: Unrestricted grant received in the past; Teva: Other: Unrestricted grant received in the past.

A Prospective Trial Evaluating the Safety of a Shortened Infusion of Ramucirumab in Patients with Gastrointestinal Cancer.

Lessons Learned. A shortened infusion of ramucirumab (from 60 to 20 minutes) was safe and feasible without infusion‐related reactions.Twenty‐minute infusions of ramucirumab can be an option for patients with no infusion‐related reactions during the first 60‐minute treatment.Background.Ramucirumab is usually administered over 60 minutes, during which it is unlikely to cause infusion‐related reactions (IRRs). This prospective study evaluated the safety of a shortened infusion of ramucirumab.Methods.Patients who received their first dose of ramucirumab in a 60‐minute infusion without developing IRRs were eligible and received their second ramucirumab dose for 20 minutes. The primary study endpoint was incidence of IRR during the first short‐term infusion, and the secondary endpoints were incidence of IRR at any time and adverse events other than IRR.Results.Of the 40 patients enrolled (median age, 68.5 years), 20 (55%) were male, 27 (67.5%) had stage IV gastric cancer, 25 (62.5%) received ramucirumab in combination with taxane‐based chemotherapy, and 24 (60%) received only a single administration of ramucirumab prior to their enrollment. Notably, no IRR was observed during the first short‐term infusion (IRR rate, 0%; 95% confidence interval [CI], 0%–0.72%). Among the 149 short‐term infusions performed, there were no instances of IRRs or unexpected adverse events related to the treatment (Table 1).Conclusion.For patients without development of IRRs upon the first ramucirumab administration, shortening infusion time (from 60 to 20 minutes) is safe and feasible.

Ninety-minute daratumumab infusion is safe in multiple myeloma.

Background: Daratumumab, an anti-CD38 monoclonal antibody, was first approved for the treatment of relapsed and refractory multiple myeloma (MM) in December of 2015. The approved initial infusion lasts at least 6.5 hours, second infusion for 4.5 hours and all subsequent infusions over 3.5 hours. The risk of infusion related reactions (IRRs) is very low after the second infusion, and the prolonged continued infusion time results in long days for patients. Because of our success infusing other monoclonal antibodies over shorter times, such as rituximab (Dotson et al Support Care Cancer, 2016), we hypothesized that shortening the daratumumab infusion from 3.5 hours to 90 minutes beginning with the third infusion would not increase the incidence of IRRs. Methods: This is a single-center safety study of an accelerated daratumumab infusion in patients receiving standard of care daratumumab therapy. Patients were eligible once they received at least 2 prior doses of daratumumab, administered per standard prescribing information. Previous IRR was not an exclusion criterion. The accelerated infusion was calculated to deliver 20% of the dose over the first 30 minutes, then the remaining 80% over 60 minutes, resulting in an estimated 90 minute infusion (Table 1). Patients who tolerated the infusion well were allowed to continue the accelerated rate. Premedication regimens were allowed to be altered based on previous tolerability. Simon9s two-stage optimal design was utilized to design the study based on the incidence of grade 3 or above IRR. With 80% power the design allows 7 patients to be treated in the first stage, and if no patients experienced ≥ grade 3 IRR, an additional 21 patients would be treated. Out of all 28 patients, if 2 or more experienced ≥ grade 3 IRR, the regimen would be declared as too toxic. The protocol was approved by the cancer institutional review board. Results: Baseline characteristics are listed in Table 2. Twenty eight patients were treated with daratumumab utilizing the accelerated rate, 8 of which received the accelerated infusion with their third dose of daratumumab. The premedication regimen varied patient-to-patient and did not impact tolerability of the accelerated infusion. There were 5 patients who did not receive any steroid premedication and 3 who received reduced doses ( Conclusion: An accelerated infusion rate of daratumumab delivering 20% of the dose over 30 minutes and 80% over 60 minutes is feasible and well-tolerated in patients who have received 2 prior doses of daratumumab at standard infusion rates. Starting with the third dose of daratumumab therapy, the 90-minute infusion is now standard practice at our institution. Disclosures Hofmeister: Janssen: Research Funding; Roche: Research Funding; Bristol-Myers Squibb: Research Funding; Takeda: Research Funding; Karyopharm: Research Funding; Celgene: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Thrassos: Honoraria, Membership on an entity9s Board of Directors or advisory committees.

Preliminary Results from a Phase 1/2 Study of Brentuximab Vedotin in Combination with Nivolumab in Patients with Relapsed or Refractory Hodgkin Lymphoma

BackgroundBrentuximab vedotin (BV) is an antibody-drug conjugate directed against CD30, a receptor that engages the CD30 ligand expressed on immune cells in the tumor microenvironment, promoting tumor cell growth (Montanari 2014, Hansen 2014). Through disruption of the microtubule network, BV induces apoptotic cell death, and may initiate an antitumor immune response (i.e., immunogenic cell death) through the induction of endoplasmic reticulum (ER) stress (Gardai 2015). Nivolumab is a fully human monoclonal PD-1 blocking antibody that prevents tumor immune evasion. Both agents have independent high single-agent response rates in patients (pts) with relapsed or refractory (R/R) Hodgkin lymphoma (HL), and when used in combination, may exhibit mechanistic synergy. Given the demonstrated efficacy of both BV and nivolumab, together these agents could yield improved CR rates prior to ASCT in pts with R/R HL, and potentially better long-term outcomes.MethodsA phase 1/2 study is ongoing to evaluate the safety and antitumor activity of BV administered in combination with nivolumab as first salvage therapy in pts with R/R classical HL after standard frontline chemotherapy (NCT02572167). Adult pts are treated in 21-day cycles for up to 4 cycles (12 weeks). Pts receive 1.8 mg/kg BV on Cycle 1 Day 1, and 3 mg/kg nivolumab on Cycle 1 Day 8. For cycles 2 through 4, BV and nivolumab are administered on Day 1 of each cycle at the same doses. After completion of the Cycle 4 response assessment, pts are eligible to undergo ASCT. Investigator assessment of lymphoma response and progression is per the Lugano Classification Revised Staging System for malignant lymphoma (Cheson 2014).ResultsTwenty-five pts (60% female) with a median age of 32 years (range, 18-69) have been enrolled to date. Sixty percent of pts have relapsed disease, 36% have primary refractory disease (failure to achieve CR with frontline therapy, or relapse within 3 months of completing frontline therapy), and 1 pt (4%) has unknown status. At the time of enrollment, 32% of pts presented with extranodal disease and 16% with bulky disease.At the time of the data extract, 23 pts had received treatment. An increased incidence of infusion-related reactions (IRRs) was observed at the start of combination treatment in Cycle 2 during the BV infusion leading to 1 dose delay. Premedication with corticosteroids (hydrocortisone 100 mg or equivalent) and antihistamines at Cycles 2-4 was instituted through a protocol amendment.Six pts have completed combination treatment, and all have achieved an objective response (ORR, 100%), with 3 of 6 achieving a complete metabolic response (CmR, 50%). All 6 pts have proceeded directly to ASCT. Median number of CD34+ cells collected was 12.9 x106 cells/kg (range, 5-26) in a mean number of 1.7 apheresis sessions (range, 1-2).Adverse events (AEs) for all pts are summarized prior to ASCT. Eighteen of the 23 treated pts (78%) experienced adverse events (AEs). Fifteen pts (65%) had AEs ≤ Grade 2 in severity and 3 pts (13%) experienced Grade 3 AEs. No pts experienced Grade 4 AEs pre-ASCT. Fatigue was the most common AE occurring in 35% of pts, followed by nausea (26%), rash (22%), dyspnea, myalgia, and pruritus (17% each). One pt experienced a treatment-related serious adverse event (SAE) of dehydration, hypercalcemia, and acute kidney injury. Immune-related adverse events (IrAEs) were experienced by 3 pts; 2 pts who experienced Grade 1 rash treated with topical steroids, and 1 pt who experienced Grade 1 hypothyroidism. No pts have discontinued treatment prematurely.In addition to Reed-Sternberg cells, CD30 is expressed on activated T cells. Preliminary biomarker data indicate a BV-induced decrease in the percentage of CD4+ T regulatory (Treg) cells at C1D8, with no decrease in proliferating CD8+ T cells, and no significant decrease observed in the percentage of CD4+ Th1 cells compared to baseline for 5 of 6 pts (83%). Nivolumab induced a robust expansion of T cells at C1D15.ConclusionsEarly data suggest the combination of BV and nivolumab is an active and well-tolerated salvage therapy in pts with R/R HL. While an elevated incidence of IRRs has been observed, toxicities with this regimen appear to be tolerable overall. The preliminary antitumor activity suggests this combination may be a promising option for R/R HL pts. Updated results will be shared at the time of presentation. DisclosuresHerrera:Pharmacyclics: Research Funding; Merck: Research Funding; Immune Design: Research Funding; Genentech: Research Funding; Adaptive Biotechnologies: Research Funding; Seattle Genetics: Research Funding. Bartlett:Gilead: Consultancy. Moskowitz:BMS: Honoraria, Research Funding; Seattle Genetics: Honoraria, Research Funding. Feldman:Abbvie/Pharmacyclics/Janssen: Speakers Bureau; Seattle Genetics: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. LaCasce:Seattle Genetics: Research Funding; Forty Seven Inc.: Consultancy. Ansell:Bristol Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Celldex: Research Funding; Affimed: Research Funding. Fenton:Seattle Genetics: Employment, Equity Ownership. Kato:Bristol-Myers Squibb: Employment. Fong:Seattle Genetics: Employment, Equity Ownership.