Analysis of risk factors for infusion-related reactions in patients with B-cell lymphoma during obinutuzumab treatment

Crizanlizumab, a monoclonal antibody against P-selectin, has been shown to reduce vaso-occlusive crises (VOCs) compared to placebo in patients ≥ 16 years with sickle cell disease (SCD). However, there have been rare reports of patients experiencing severe pain and subsequent complications within 24hours of crizanlizumab infusions. These events are defined as infusion-related reactions (IRRs). Informed by current literature and clinical experience, a group of content experts developed clinical guidelines for the management of IRRs in patients with SCD. We used the RAND/University of California, Los Angeles (UCLA) modified Delphi panel method, a valid, reproducible technique for achieving consensus. We present our recommendations for managing IRRs, which depend on patient characteristics including: prior history of IRRs to other monoclonal antibodies or medications, changes to crizanlizumab infusion rate and patient monitoring, pain severity relative to patient's typical SCD crises, and severe allergic symptoms. These recommendations outline how to evaluate and manage IRRs in patients receiving crizanlizumab. Future research should validate this guidance using clinical data and identify patients at risk for these IRRs.

e20513 Background: We performed a retrospective analysis to investigate the association between the lactate dehydrogenase (LDH) levels and progression-free survival (PFS) in patients with echinoderm microtubule-associated protein-like 4-anaplasticlymphoma kinase (EML4-ALK) rearrangement non-small cell lung cancer (NSCLC) receiving treatment with crizotinib. Methods: Advanced NSCLC patients with EML4-ALK rearrangement receiving treatment with crizotinib were enrolled at Peking Union Medical College and Cancer Hospital Chinese Academy of Medical Sciences between January 2007 and January 2016. Pre-treatment or post-treatment serum LDH levels were analyzed with progression-free survival (PFS) and patients’ clinical parameters. Results: Overall, 212 patients were studied. Kaplan-Meier univariate analysis showed that elevated pre-treatment LDH level (7.9 vs. 14.1 months, P = 0.004) were associated with PFS, while the mean value of post-treatment LDH level (14.3 vs. 13.3 months, P = 0.970) were not associated with PFS. Coxproportional hazards model also identified that pre-treatment LDH level (hazard ratio [HR] = 1.841, 95% confidence interval [CI] 1.062-3.190, P = 0.030) was associated with the PFS. Logistic regression analysis showed that post-treatment LDH level was associated with creatine kinase(OR = 6.712, 95% CI 3.395-13.273, P < 0.01), CKMB (OR = 6.297, 95% CI 2.953-13.427, P < 0.01), and hemoglobin(OR = 4.163, 1.741-9.956, P = 0.001). Conclusions: An elevated pre-treatment serum LDH level ( > 250U/L) is significantly associated with shorter PFS in patients with EML4-ALK rearrangement NSCLC. Post-treatment elevated serum LDH level is associated with multiple factors including muscle damage and anemia, rather than PFS.

Incidence and timing of infusion-related reactions in patients with mucopolysaccharidosis type II (Hunter syndrome) on idursulfase therapy in the real-world setting: A perspective from the Hunter Outcome Survey (HOS)

BackgroundOcrelizumab and rituximab are frequently used treatments for multiple sclerosis (MS). Data on switching from rituximab to ocrelizumab is limited.ObjectivesTo assess the frequency, severity, and factors of infusion related reactions (IRRs) in patients with MS who switch from rituximab to ocrelizumab, compared to those who stay on rituximab.MethodsProspective study on MS patients aged 18–65, on rituximab for at least 2 cycles, who either switched to ocrelizumab (switch group) or stayed on rituximab (comparator group) (n = 100 each). Participants were followed for IRRs, safety, and tolerability over 12 months.ResultsThe proportion of IRRs in patients who continue on rituximab (14%) were similar to those who switched to ocrelizumab on Day 1 (14%; p = 1.000) and Week 24 (12%; p = 0.647) but higher than at Day 15 (4%; 0.005). The risk of IRRs for the switch group was associated with the presence of B cells (CD19 and/or CD20 counts ≥1%) increasing by 5.01 (1.49, 16.82) times on Day 1 (p = 0.007). Antidrug antibodies to ocrelizumab were not associated with IRRs. No other safety concerns were identified in switching to ocrelizumab.ConclusionIRRs are similar between both groups, which suggests that it is safe to switch from rituximab to ocrelizumab.

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 ( > 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.

604 Background: Immune checkpoint inhibitors (ICIs) are widely used to treat genitourinary cancers, particularly urothelial carcinoma (UC) and renal cell carcinoma (RCC). Infusion-related reactions (IRRs) have been reported in up to 20% of all patients treated with ICIs. However, the risk of IRRs varies with the type of ICI and the accurate incidence in genitourinary cancers remains unclear. We undertook a systematic review and meta-analysis to determine the incidence of IRRs in patients with genitourinary cancers treated with ICIs. Methods: We performed a systematic search of PubMed/MEDLINE, Embase, and Web of Science to identify phase 3 randomized clinical trials (RCTs) evaluating ICIs (cytotoxic T-lymphocyte-associated protein 4 [CTLA-4], programmed cell death protein 1 [PD-1], and programmed death-ligand 1 [PD-L1] inhibitors) in patients with UC and RCC. The odds ratio [OR] of grade 1-5 and grade 3-5 IRRs was calculated and pooled by the random-effect model meta-analysis. Meta-analysis was performed based on study types as follows: 1) Studies with a design “ICI plus treatment A (including placebo/observation) vs. treatment A”, 2) Studies evaluating ICI monotherapy vs. chemotherapy in patients with UC, and 3) Studies assessing ICI plus vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKIs) vs. sunitinib in patients with RCC. When IRRs were reported in studies evaluating oral VEGF-TKIs, IRRs were referred to as hypersensitivity or anaphylactic reactions, defined in each RCT. Results: We identified 12 RCTs with 10,001 participants for the meta-analysis, out of which one evaluated a CTLA-4 inhibitor while the others evaluated PD-1 or PD-L1 inhibitors. The addition of ICIs to other systemic therapies was associated with significantly higher rates of grade 1-5 IRRs (OR=2.90, 95% confidence interval [CI]: 1.16-7.29, p = 0.02) but not of grade 3-5 IRRs (OR=2.98, 95% CI: 0.64-13.74, p = 0.16). When compared to chemotherapy, PD-1 or PD-L1 inhibitor monotherapy was not associated with an increase in either grade 1-5 (OR=0.86, 95% CI: 0.25-2.95, p = 0.81) or grade 3-5 IRRs (OR=1.13, 95% CI: 0.07-18.19, p = 0.93) in patients with UC. When compared to sunitinib in patients with RCC, the combination of ICI plus VEGF-TKIs was not associated with an increase in either grade 1-5 (OR=5.43, 95% CI: 0.62-46.07, p = 0.13) or grade 3-5 IRRs (OR=3.49, 95% CI: 0.64-19.04, p = 0.15). Sensitivity analysis performed by removing studies evaluating avelumab did not alter the overall results (data will be presented). Conclusions: Compared to the previous standard of care without ICIs, therapies with ICIs were not associated with increased IRRs in genitourinary cancers. However, the addition of ICIs to other systemic therapies was associated with an increased incidence of IRRs. The latter merits further prospective evaluation and careful consideration while designing clinical trials.

BACKGROUND: The use of two anti-HER2 monoclonal antibodies (mAbs) (pertuzumab and trastuzumab) combined with taxanes is the standard of care for first line treatment in HER2-positive metastatic breast cancer (mBC). Infusion related reactions (IRR) during first administration of anti-HER2 mAb have been reported. Reintroduction of the causal drugs is often possible, but there is no data to identify patients at highest risk of developing IRR and modalities of safe reintroduction. The aim of this study was to report patients who experienced IRR during anti-HER2 mAbs infusions at Institut Curie Hospitals (ICH) and to describe these reactions. METHODS: All IRR cases must be reported to the ICH pharmacies. We retrospectively inspected the electronic record of patients who experienced an IRR during pertuzumab (Pmab) and trastuzumab (Tmab). We collected patients’ characteristics, grade of IRR and outcomes. RESULTS: From January 2013 to December 2020, a total of 223 patients had at least one Pmab+Tmab infusion as part of their BC treatment. Among them, 28 patients (8%) with anti-HER2 mAb IRR were identified. All patients but one had an HER2-positive BC; the HER2-negative case was a HER3-mutant mBC. Twelve patients (43%) had de novo mBC. Twenty-six patients (93%) received Pmab+Tmab as first line treatment for mBC. Ten patients were previously exposed to Tmab and three to Pmab+Tmab for (neo)adjuvant treatment. At IRR onset, 21 patients (75%) had liver metastasis, with more than five liver metastases for 19 of them. Fifteen patients (55%) had liver enzymes upper normal limit. IRR occurred during first anti-HER2-mAb infusion in 22 patients (79%) despite pre-treatment with antihistaminic and/or glucosteroids for taxanes. The other IRR were reported at the 2nd, 5th, 6th, 8th and > 10th cycle of Pmab+Tmab. Sixteen IRR (57%) were attributed to Pmab infusion, 9 (32%) to Tmab infusion and 3 (11%) to Tmab and/or Pmab. Al IRR were declared to the pharmacovigilance agency. Majority of reactions were mild to moderate (54% of grade 2). Most frequent symptoms associated with IRR were: thrills (68%), hyperthermia (64%); low oxygen saturation (36%), pain (25%), hypotension (21%), cutaneous (18%) and digestive (18%) reaction. Three patients were transferred to ICU. One death was attributed to anti-HER2 mAb IRR (death was attributed to respiratory distress during the first Tmab infusion). Reintroduction off Pmab+Tmab was performed in 18 patients, after pre-treatment with antihistaminic and/or glucosteroids and with vital function monitoring in conventional hospitalization. No recurrence of IRR was observed in 15/18 patients. For the 3 patients with recurrent IRR, symptoms were mild to moderate. Objective response to anti-HER2 treatments was observed in twenty three patients (82%; 8 complete responses; 15 partial responses). Median PFS was 16 months. CONCLUSIONS: Most anti-Her2-mAb IRR occurs during first infusion, are mild to moderate and do not require a transfer in ICU. Our study suggests that patients with high liver burden might be over-represented among those experiencing an IRR. Reintroduction of Pmab+Tmab was safe in most patients, allowing the continuation of the anti-HER2 dual blockade. Citation Format: Delphine Loirat, Juliette Logeart, Pauline Vaflard, Aurélien Noret, Mathilde Saint-Ghislain, Edith Borcoman, Audrey Hurgon, Cyrille Cros, Thomas Genevee, Audrey Bellesoeur, Francesco Ricci, Florence Lerebours, Laurence Escalup, Marie-Paule Sablin, François-Clément Bidard, Paul H. Cottu, Jean-Yves Pierga. Infusion-related reactions in patients receiving pertuzumab and trastuzumab: A retrospective study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-27.

560P - Impact of Pre-Treatment Lactate Dehydrogenase (Ldh) Levels on Prognosis and Bevacizumab Efficacy in Advanced Colorectal Cancer Patients

BackgroundTo investigate the impact of pre-treatment lactate dehydrogenase (LDH) levels on the outcome of patients with metastatic colorectal cancer treated with first-line chemotherapy with or without the anti-VEGF monoclonal antibody, bevacizumab, in a phase III prospective multicentre randomized ITACa (Italian Trial in Advanced Colorectal Cancer) trial.MethodsThree hundred and seventy patients enrolled onto the ITACa first-line trial were considered for this study, 176 receiving chemotherapy (either FOLFIRI or FOLFOX) plus bevacizumab and 194 receiving chemotherapy only. Pre-treatment LDH levels were evaluated to identify a potential correlation with progression-free survival (PFS), overall survival (OS) and objective response rate.ResultsInformation on pre-treatment LDH levels was available for 344 patients. High LDH levels were predictive of a lower median PFS (8.1 months vs. 9.2 months, p< 0.0001) and median OS (16.1 months vs. 25.2 months, p< 0.0001) in the overall population. In the chemotherapy plus bevacizumab group, median PFS was 9.1 and 9.8 months in patients with high LDH and low LDH, respectively (p= 0.073), whereas in the chemotherapy-only arm it was 6.9 and 9.1 months, respectively (p < 0.0001). In patients with high LDH, the addition of bevacizumab to chemotherapy led to a reduction in the rate of progressive disease (16.4 vs. 30.5%, p= 0.081) and to a prolonged PFS (p= 0.028).ConclusionA high LDH value was confirmed as a marker of poor prognosis. Bevacizumab reduced the progressive disease rate and improved PFS in the high-LDH subgroup, making serum LDH a potentially effective an easily available and marker to select patients who benefit from bevacizumab.Trial Registration NCT01878422 ClinicalTrials.gov

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

To investigate the correlation between serum albumin-globulin ratio (AGR), lactate dehydrogenase (LDH) levels and the efficacy of induction chemotherapy in patients with newly diagnosed multiple myeloma (MM). A total of 61 MM patients admitted to Maanshan Shiqiye Hospital from July 2021 to May 2024 were retrospectively collected as the observation group, and 61 healthy individuals who underwent physical examinations during the same period were enrolled as the control group. The differences in serum AGR and LDH levels between the two groups were compared. Pearson correlation test was used to explore the correlation between serum AGR, LDH and MM. According to the efficacy of induction chemotherapy, the observation group was divided into remission group (31 cases) and non-remission group (30 cases), and the differences in baseline data between the two groups were compared. Logistic regression analysis was used to explore the relationship between serum AGR, LDH and chemotherapy efficacy. Receiver operating characteristic (ROC) curves were drawn to analyze the predictive value of serum AGR and LDH for chemotherapy efficacy, and the decision curve analysis was performed to evaluate the clinical application value of serum AGR and LDH in predicting chemotherapy efficacy. The serum AGR in the observation group was significantly lower than that in the control group (P <0.001), while the LDH was significantly higher than that in the control group (P <0.001). Pearson correlation analysis showed that serum AGR was negatively correlated with MM (r=-0.739), and LDH was positively correlated with MM (r=0.885). In the observation group, the serum AGR was significantly higher, while the serum LDH was significantly lower after chemotherapy compared to before chemotherapy (both P <0.001). In the non-remission group, the proportion of patients with ISS stage III (P=0.002) and DS stage III (P=0.001), the percentage of bone marrow plasma cells (P <0.001), and the LDH level (P <0.001) were significantly higher than those in the remission group, while the AGR (P <0.001) was significantly lower than that in the remission group. Logistic regression analysis showed that serum AGR, LDH, percentage of bone marrow plasma cells, and ISS stage were factors affecting the chemotherapy efficacy (all P <0.05). ROC curve analysis showed that serum AGR, LDH before chemotherapy, and their combination had good predictive value for the chemotherapy efficacy in MM patients, and their combination had the highest predictive value. Decision curve analysis showed that serum AGR, LDH, and their combination had clinical significance in predicting the chemotherapy efficacy in MM patients. MM patients exhibit lower serum AGR and higher LDH levels, both of which are closely related to the efficacy of induction chemotherapy. These two biomarkers can effectively predict the chemotherapy efficacy in newly diagnosed MM patients.

e20016 Background: An elevated serum LDH level is an adverse prognostic factor in NDMM. However, this category includes quantitative serum LDH levels that range from just over the upper limit of normal (ULN) to levels that may be 2 or more-fold higher than the ULN. This binary classification of serum LDH level of “normal versus elevated” fails to discriminate between the different disease biology that exists among NDMM patients with elevated serum LDH levels. Thus, we attempted to further stratify NDMM patients by the level of their serum LDH and determine its impact on OS. Methods: The cohort included patients diagnosed with NDMM from the Mayo Clinic, Rochester from 2003 - 2017 who were treated with novel agent induction therapy and had serum LDH levels measured at the time of diagnosis. The serum LDH levels were stratified into three levels: Normal (LDH &lt; 222 U/L), Elevated (LDH 223-444 U/L), and Very Elevated (LDH &gt;444 U/L or &gt;2x upper limit of normal). Survival analysis was performed using the Kaplan-Meier survival analysis and compared via the log-rank method. Results: The cohort consists of 1,196 NDMM patients with a median age of 65 (22 – 95). R-ISS classification and cytogenetic risk were available for 968 and 970 patients respectively. The median serum LDH level was (162 U/L (3- 1260)) and an elevated LDH was present in 199 patients (17%). The median OS for patients with normal (N = 997; 83%), elevated (N = 170; 13%) and very elevated (N = 29; 3%) LDH levels were 76 months, 57 months and 23 months respectively (P &lt; 0.001). The impact of these different levels of LDH on OS by R-ISS stage and cytogenetic risk is shown in the Table. Conclusions: A very small subset of NDMM patients has very elevated LDH levels that confer an exceptionally poor OS irrespective of R-ISS stage and cytogenetic risk. Future studies elucidating their disease biology responsible for such poor OS outcomes are warranted.[Table: see text]

Background: Asphyxia Neonatorum is a significant contributor to neonatal mortality and morbidity. Its burden in resource-poor countries prompts the development of investigative modalities that offers accuracy and affordability. Objective: To determine that serum CK-MB and LDH estimation could be markers of Asphyxia neonatorum, and the elevated levels directly correlate with the grade of severity of Hypoxic Ischemic Encephalopathy (HIE) as defined by Levine. Methods: In this single-center, non-interventional study, we included 100 asphyxiated neonates from level III NICU in the case group, and 100 apparently healthy neonates from the post-natal ward admitted over 18 months at RCSM Government Medical College and CPR Hospital, Kolhapur. 100 healthy neonates were the control group. Results: The median 8-hr serum CK-MB in the case group was 74 U/L and in the control group as 63.5 U/L with P&lt;0.001. Whereas the median serum LDH level in the case group was 597 U/L and the control group was 383.5 U/L with P&lt;0.001. Raised LDH (cut off 580 U/L) had 100% specificity, while CK-MB (cut off 92.6 U/L) had 100% specificity for asphyxia. Amongst the neonates with HIE (n=60), 56% had raised CK-MB (cut off 92.6) and 80% had raised LDH (cut off 580 U/L). 100% of neonates with HIE Grade III (n=9) had elevated CK-MB and LDH levels. Conclusion: The present study concluded that CK-MB and LDH as biochemical markers can be utilitarian in the diagnosis of perinatal asphyxia.

A comparison of rapid amniotic fluid markers in the prediction of microbial invasion of the uterine cavity and preterm delivery

Risk Factors Associated with the Development of Infusion-Related Reactions in Patients with Chronic Lymphocytic Leukaemia Treated with Anti-CD20 Monoclonal Antibodies: Analysis of the CLL11 Study Dataset