Risk Of Cytokine Release Syndrome Research Articles

Glofitamab Plus R-CHOP Induces High Response Rates with Minimal Cytokine Release Syndrome (CRS) in Patients (pts) with Relapsed/Refractory (R/R) Non-Hodgkin Lymphoma (NHL) and Previously Untreated (1L) Diffuse Large B-Cell Lymphoma (DLBCL): Preliminary Results from a Dose-Escalation and Safety Run-in Phase Ib Study

Glofitamab Plus R-CHOP Induces High Response Rates with Minimal Cytokine Release Syndrome (CRS) in Patients (pts) with Relapsed/Refractory (R/R) Non-Hodgkin Lymphoma (NHL) and Previously Untreated (1L) Diffuse Large B-Cell Lymphoma (DLBCL): Preliminary Results from a Dose-Escalation and Safety Run-in Phase Ib Study

Risk, Characteristics and Biomarkers of Cytokine Release Syndrome in Patients with Relapsed/Refractory AML or MDS Treated with CD3xCD123 Bispecific Antibody APVO436.

Simple SummaryCytokine release syndrome is a potentially life-threatening complication of therapy with T-cell engaging bispecific antibodies. Here we evaluated the risk, characteristics and biomarkers of treatment-emergent cytokine release syndrome in patients with relapsed/refractory acute myeloid leukemia or myelodysplastic syndrome who received weekly intravenous infusions of the CD3xCD123 bispecific antibody APVO436. Cytokine release syndrome was encountered in 10 of 46 patients (21.7%) treated with APVO436 with a cumulative Grade 3/4 cytokine release syndrome incidence of 8.7%. Cytokine profiling in patients who developed cytokine release syndrome after APVO436 infusion indicated that the predominant cytokine in this inflammatory cytokine response was IL-6. The findings from this research provide new insights regarding the biology and effective management of cytokine release syndrome in leukemia patients treated with T-cell redirecting bispecific antibodies. We evaluate the risk, characteristics and biomarkers of treatment-emergent cytokine release syndrome (CRS) in patients with relapsed/refractory acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) who received APVO436 during the dose-escalation phase of a Phase 1B study (ClinicalTrials.gov, identifier: NCT03647800). Of four patients who developed Grade ≥ 3 CRS, two received steroid prophylaxis. The dose level, gender, race, obesity, or baseline hematologic parameters in peripheral blood did not predict the risk of CRS. Patients with a higher leukemia burden as determined by a higher total WBC, higher percentage of blasts in bone marrow, or higher percentage of blasts in peripheral blood (by hematopathology or immunophenotyping) did not have a higher incidence of CRS. There was an age difference between patients who did versus patients who did not develop CRS (72.9 ± 1.6 years (Median 73.5 years) vs. 63.3 ± 2.3 years (Median: 65.0 years), which was borderline significant (p = 0.04). Premedication with steroids did not eliminate the risk of CRS. Cytokine profiling in patients who developed CRS after APVO436 infusion indicates that the predominant cytokine in this inflammatory cytokine response was IL-6. APVO436-associated CRS was generally manageable with tocilizumab with or without dexamethasone. Notably, the development of CRS after APVO436 therapy did not appear to be associated with a response. The prolonged stabilization of disease, partial remissions and complete remissions were achieved in both patients who experienced CRS, as well as patients who did not experience CRS after APVO436 infusions.

Reducing Hinge Flexibility of CAR-T Cells Prolongs Survival In Vivo With Low Cytokines Release.

Chimeric antigen receptor (CAR)-modified T cells targeting CD19 demonstrate unparalleled responses in B cell malignancies. However, high tumor burden limits clinical efficacy and increases the risk of cytokine release syndrome and neurotoxicity, which is associated with over-activation of the CAR-T cells. The hinge domain plays an important role in the function of CAR-T cells. We hypothesized that deletion of glycine, an amino acid with good flexibility, may reduce the flexibility of the hinge region, thereby mitigating CAR-T cell over-activation. This study involved generating a novel CAR by deletion of two consecutive glycine residues in the CD8 hinge domain of second-generation (2nd) CAR, thereafter named 2nd-GG CAR. The 2nd-GG CAR-T cells showed similar efficacy of CAR expression but lower hinge flexibility, and its protein affinity to CD19 protein was lower than that of 2nd CAR-T cells. Compared to the 2nd CAR-T cells, 2nd-GG CAR-T cells reduced proinflammatory cytokine secretion without diminishing the specific cytotoxicity toward tumor cells in vitro. Furthermore, 2nd-GG CAR-T cells prolonged overall survival in an immunodeficient mouse model bearing NALM-6 when tumor burden was high. This study demonstrated that a lower-flexibility of CD8α hinge improved survival under high tumor burden and reduced proinflammatory cytokines in preclinical studies. While there is potential for improved safety and efficacy, yet this needs validation with clinical trials.

Chimeric antigen receptor (CAR) T-cell therapy for people with relapsed or refractory diffuse large B-cell lymphoma.

Chimeric antigen receptor (CAR) T-cell therapy for people with relapsed or refractory diffuse large B-cell lymphoma.

The evolving status of immunotherapies in multiple myeloma: the future role of bispecific antibodies.

Treatment outcomes in multiple myeloma (MM) have improved dramatically over the past 10years. However, patients with high-risk disease such as those with Stage III disease by the Revised International Staging System, the presence of adverse cytogenetics, or who are refractory to proteosome inhibitors, immunomodulatory drugs and monoclonal antibodies may have dismal outcomes. These patients represent an urgent ongoing need in MM. One of the hallmarks of MM is immune dysfunction and a tumour-permissive immune microenvironment. Ameliorating the immune-paresis could lead to improved outcomes. The role of immunotherapies has been growing at an exponential pace with numerous agents under development in clinical trials. In the present review, we provide an overview of immunotherapies in MM, focussing on bispecific antibodies (BsAbs). We review efficacy outcomes from the published clinical trials and consider the important safety aspects of these therapies, in particular the risk of cytokine-release syndrome and immune effector cell-associated neurotoxicity syndrome, and how these compare with patients receiving chimeric antigen receptor T cells. We discuss the MM epitopes being targeted by BsAbs, either in clinical or preclinical stages, and we consider where these therapies might best fit within the future ever-changing paradigm of MM treatment.

Evidence-Based Recommendations for Nurse Monitoring and Management of Immunotherapy-Induced Cytokine Release Syndrome: A Systematic Review from the Children's Oncology Group.

Children with B-precursor acute lymphoblastic leukemia and B-cell lymphoma, particularly those with relapsed or refractory disease, are increasingly enrolled on phase II and phase III clinical trials studying immunotherapies. These therapeutic agents may be associated with a high risk of cytokine release syndrome (CRS), and nurses lack standardized guidelines for monitoring and managing patients with CRS. Six studies and one clinical practice guideline were included in this systematic review that examined the evidence of CRS following administration of chimeric antigen receptor T-cell therapy or the bi-specific T-cell engager antibody, blinatumomab. Six nursing practice recommendations (five strong, one weak) were developed based on low or very low-quality evidence: three reflect preinfusion monitoring, one focuses on monitoring during and postinfusion, and three pertain to the nurse's role in CRS management.

Pretransplant Clinical Factors Can be Used to Predict the Risk of Cytokine Release Syndrome after Haploidentical Peripheral Blood Transplantation

Study Question: What are pre-transplant factors which predict the risk of development of Cytokine Release Syndrome after Haploidentical Peripheral Blood Transplantation?Significance: Allogeneic hematopoietic cell transplantation is a cornerstone of therapy for hematologic malignancies and often a patient's only curative intent treatment. Overall outcomes for haploidentical transplantation appear to be excellent, however, this novel approach brings toxicities that are particular to its biological and clinical milieu. We recently described occurrence of severe cytokine release syndrome (CRS) after haplo-HCT. Severe CRS was associated with poor clinical outcomes, including transplant related mortality (TRM), overall survival (OS), and neutrophil engraftment (Abboud et al, BBMT, 10/2016).However, the factors predicting the occurrence severe CRS after haplo-HCT are not known. The diagnosis of CRS requires a high level of clinical suspicion, and early treatment leads to rapid resolution of symptoms. Identifying at-risk patients prior to transplantation is clinically important.Patients and Methods: All patients (150 consecutive patients) were included who underwent peripheral blood T-Cell replete haplo-HCT with PTCy from July 2009 through October 2016 at Washington University in St. Louis. Since CRS can resemble sepsis syndrome, and additionally sepsis may be a confounding factor by causing CRS independently, patients with a documented infection or clinical suspicion of sepsis were excluded from the analysis (14 patients). Steroid use may also be a confounding variable, therefore, we excluded patients who received steroids between days -5 and the development of CRS (0 patients). Clinical data was missing for only 3 out of the 150 patients, in all cases due to random errors in institutional EMR migration, therefore they were excluded from analysis and we will not undertake imputation of missing values. CRS was graded per the criteria used in our previous work, based on the standards originally proposed by Lee et al, modified to include altered mental status and new onset cardiomyopathy.Statistical Analysis: An adaptive lasso with SBC selection with split categorical predictors was used to identify 11 predictors of severe CRS (grade 2-4). Model selection was repeated 100 times using resampled (bootstrapped) subsets of the data, and the parameter estimates averaged to obtain an average representation of predictor strength.Results: The final selection of predictors included CD34+ cells received <5.0, CD34+ cell received > 5.01, T cell dose, HLA match, CMV status of recipient, presence of a prior transplant, donor was a first degree relative, sex of donor, use of myeloablative conditioning, HCT-CI score, T cell dose and age of recipient at transplant.We stratified patients into low risk (CRS grades 0-1) or high risk (CRS grades 2-4). This matches treatment guidelines which dictate that all patients with grades 3-4, and select patients with grade 2, CRS should be treated with IL-6 inhibitors or steroids.Our predictive model had excellent specificity (94%), positive predictive value (88%), and false negative rate (6%). The sensitivity (39%), negative predictive value (58%), and false positive rate (61%) were poor.Conclusions : We have created the first model for predicting the risk of CRS in haplo-SCT using pre-transplant patient and donor characteristics. Clinically, our model proves extremely reliable to rule patients in for CRS which may require treatment. If a patient is deemed high risk by our model, they have an 88% chance of subsequently developing grade 2-4 CRS. It is less useful for ruling patients out for CRS. If a patient is deemed low risk, they still have a 42% chance of developing grade 2-4 CRS. This model is immediately clinically applicable to identify patients who must be watched very closely for CRS in the post-transplant period. It is further useful in designing CRS prevention trials, as the model can be used as an enrollment criterion to select patients at high risk for CRS who would benefit from a prophylactic approach.We are currently working with one outside institution to perform external validation of our model. We are looking for other external partners to further improve the model. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Biomarkers for Predicting Toxicity and Response in Adult Acute Lymphoblastic Leukemia (ALL) Patients Treated with Blinatumomab

Introduction: Blinatumomab is a bispecific T-cell engaging monoclonal antibody, linking CD19+ B-cells with CD3+ T-cells. Blinatumomab has shown pronounced clinical benefit in relapsed/refractory (R/R) B-ALL patients. A common toxicity is cytokine release syndrome (CRS), which includes a constellation of symptoms related to systemic inflammatory response. No available conclusive data suggests that cytokine elevation predicts response to therapy, neurotoxicity, or severity of CRS. C-reactive protein (CRP) is currently used as a surrogate for IL-6 bioactivity. To this end, we sought to determine if there is an association between CRP and ferritin levels and development of CRS, neurotoxicity, and response in patients receiving blinatumomab.Methods: This IRB approved, single-center, retrospective study at Memorial Sloan Kettering Cancer Center included adult patients with R/R B-ALL treated with blinatumomab between 1/1/11 and 12/31/16. Patients without appropriate follow up were excluded. Patients were identified via electronic medical records and an internal pharmacy database. CRS was graded using the criteria outlined by Lee et al (Lee DW, et al. Blood. 2014 Jul 10;124(2):188-95). Continuous variables were summarized with medians, interquartile ranges (IQR: 25th and 75th percentiles), or ranges. Categorical variables were summarized with frequencies and percentages. Comparisons between groups were evaluated using the Wilcoxon rank sum test or Fisher's exact test for continuous and categorical variables, respectively. Maximum change in CRP or ferritin was calculated for each patient as the difference between peak value and baseline value of each respective biomarker.Results: A total of 25 patients were included. Median age was 51.7 years, with a predominant female population (56%). Eight patients (32%) had extramedullary disease at baseline; 12 patients (48%) had >50% bone marrow blasts at the time of treatment with blinatumomab. 14 patients (56%) experienced CRS during cycle 1, with ten grade 1 events and four grade 2 events. Among 11 patients who started cycle 2, two patients experienced CRS, one grade 1 and one grade 2 event. In cycle 1, median time to onset of CRS was one day (range, 0-9). Median baseline CRP was 0.94 mg/dl (range, 0.05-33.3), and days to peak CRP was two days (range, 0 - 13). Median peak CRP was significantly increased (p=0.001) in patients with CRS (20.6, IQR 17.1-31.9) compared to patients without CRS (5.2, IQR 1.7-12.0). In addition, median absolute peak ferritin level and incremental change in ferritin from baseline in cycle 1 significantly correlated to CRS (p=0.03 and 0.023, respectively). The presence of >50% blasts at pretreatment was not associated with increased incidence of CRS. Neurotoxicity was documented in six patients (24%) during cycle 1, with a median onset of nine days from the start of therapy (range, 1-23). Patients with neurotoxicity had a significantly shorter time to peak CRP, with a median of two vs. three days (p=0.031). Baseline and peak ferritin level in cycle 1 were significantly increased in patients with neurotoxicity (p=0.044 and 0.026, respectively). Eleven patients (44%) achieved a complete response and 14 patients (56%) had refractory disease. Responders were found to have significantly lower baseline CRP (p=0.008) and lower baseline ferritin values (p=0.03). No grade 4 or 5 CRS was observed and no patient discontinued therapy due to CRS.Conclusion: Our data shows there is an association between changes in biomarkers (CRP and ferritin) and development of CRS, and suggests frequent monitoring of these biomarkers may be useful in predicting patients at risk for CRS and neurotoxicity, possibly leading to earlier intervention. Considering the infrequent CRS events documented in cycle 2, our results raise the question of the required admission for patients in cycle 2. Due to a small sample size and retrospective nature of this study, these findings need to be examined prospectively to confirm the association of these biomarkers with blinatumomab-associated toxicities and inform monitoring guidelines. [Display omitted] DisclosuresHorvat:Agios: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Park:Amgen: Consultancy.

Cytokine Release Syndrome By T-cell-Redirecting Therapies: Can We Predict and Modulate Patient Risk?

T-cell-redirecting therapies are promising new therapeutic options in the field of cancer immunotherapy, but the development of these modalities is challenging. A commonly observed adverse event in patients treated with T-cell-redirecting therapies is cytokine release syndrome (CRS). Its clinical manifestation is a burden on patients, and continues to be a big hurdle in the clinical development of this class of therapeutics. We review different T-cell-redirecting therapies, discuss key factors related to cytokine release and potentially leading to CRS, and present clinical mitigation strategies applied for those modalities. We propose to dissect those risk factors into drug-target-disease-related factors and individual patient risk factors. Aiming to optimize the therapeutic intervention of these modalities, we illustrate how the knowledge on drug-target-disease-related factors, such as target expression, binding affinity, and target accessibility, can be leveraged in a model-based framework and highlight with case examples how modeling and simulation is applied to guide drug discovery and development. We draw attention to the current gaps in predicting the individual patient's risk towards a high-grade CRS, which requires further considerations of risk factors related, but not limited to, the patient's demographics, genetics, underlying pathologies, treatment history, and environmental exposures. The drug-target-disease-related factors together with the individual patient's risk factors can be regarded as the patient's propensity for developing CRS in response to therapy. As an outlook, we suggest implementing a risk scoring system combined with mechanistic modeling to enable the prediction of an individual patient's risk of CRS for a given therapeutic intervention.

Profiling of donor-specific immune effector signatures in response to rituximab in a human whole blood loop assay using blood from CLL patients

Rituximab is widely used in the treatment of haematological malignancies, including chronic lymphocytic leukaemia (CLL), the most common leukaemia in adults. However, some patients, especially those with high tumour burden, develop cytokine release syndrome (CRS). It is likely that more patients will develop therapy-linked CRS in the future due to the implementation of other immunotherapies, such as CAR T-cell, for many malignancies. Current methods for CRS risk assessment are limited, hence there is a need to develop new methods. To better recapitulate an in vivo setting, we implemented a unique human whole blood “loop” system to study patient-specific immune responses to rituximab in blood derived from CLL patients. Upon rituximab infusion, both complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) profiles were evident in CLL patient blood, coincident with CLL cell depletion. Whereas B cell depletion is induced in healthy persons in the blood loop, only patients display B cell depletion coupled with CRS. With the exception of one donor who lacked NK cells, all other five patients displayed variable B cell depletion along with CRS profile. Additionally, inhibition of CDC or ADCC via either inhibitors or antibody Fc modification resulted in skewing of the immune killing mechanism consistent with published literature. Herein we have shown that the human whole blood loop model can be applied using blood from a specific indication to build a disease-specific CRS and immune activation profiling ex vivo system. Other therapeutic antibodies used for other indications may benefit from antibody characterization in a similar setting.

Early Pharmacodynamic Changes in T-Cell Activation, Proliferation, and Cytokine Production Confirm the Mode of Action of BFCR4350A, a FcRH5/CD3 T-Cell-Engaging Bispecific Antibody, in Patients with Relapsed/Refractory Multiple Myeloma

Early Pharmacodynamic Changes in T-Cell Activation, Proliferation, and Cytokine Production Confirm the Mode of Action of BFCR4350A, a FcRH5/CD3 T-Cell-Engaging Bispecific Antibody, in Patients with Relapsed/Refractory Multiple Myeloma

Initial Clinical Activity and Safety of BFCR4350A, a FcRH5/CD3 T-Cell-Engaging Bispecific Antibody, in Relapsed/Refractory Multiple Myeloma

Initial Clinical Activity and Safety of BFCR4350A, a FcRH5/CD3 T-Cell-Engaging Bispecific Antibody, in Relapsed/Refractory Multiple Myeloma

Unbiased Metabolomic Screening Reveals Pre-Existing Plasma Signatures in Large B-Cell Lymphoma Patients Treated with Anti-CD19 Chimeric Antigen Receptor (CAR) T-Cells: Association with Cytokine Release Syndrome (CRS) and Neurotoxicity (ICANS)

Background: CAR T-cells that target CD19 have been approved by the FDA for treatment of relapsed/refractory large B cell lymphoma (r/r LBCL). Despite clinical efficacy in chemo-refractory patients, the benefit of this approach is often complicated by potentially severe toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The physiological basis of these limitations remains poorly understood, and represents an unmet clinical need. Metabolomics is a global approach that can be used to identify diverse low molecular weight biochemical entities with a wide range of functions. In this study we have employed an untargeted metabolomics approach to identify novel metabolites present in the plasma of patients treated with CAR T-cell therapy that associate with clinical outcomes and toxicities of treatment. Methods: Peripheral blood specimens were collected at the time of apheresis from 41 r/r LBCL patients treated with Axicabtagene Ciloleucel (Axi-cel; n=31) and Tisagenlecleucel (Tisa-cel; n=10). Baseline clinical characteristics and details of prior treatment were captured for all patients. Response outcomes and toxicity grading as measured by ASTCT consensus criteria for CRS and ICANS were recorded. Plasma was isolated from blood and analyzed for metabolites using a commercial Ultrahigh Performance Liquid Chromatography-Tandem Mass Spectrometry platform. Association analysis was performed using ordinal logistic regression to identify the metabolites whose plasma abundance at the time of apheresis correlated with ICANS and CRS grade (FDR ≤0.2). In addition, significant metabolites were utilized to identify perturbations of biologically relevant pathways associated with CRS/ICANS grade. Results: The median age of patients studied was 61 (range 25 - 77), with 25 (61%) males. All patients were previously treated with R-CHOP or R-EPOCH. Twenty (48.8%) patients had high or high-intermediate IPI at baseline. The patients had received a median of 3 (range, 2-6) lines of therapy prior to CAR T-cell therapy, with 21 (51.22%) having received prior autologous stem cell transplantation. At the 3-month time point, response evaluation was available for 28 Axi-cel and 10 Tisa-cel recipients. An objective response was seen in 16 (57%) and 2 (20%) patients, and death was documented in 3 (11%) and 2 (20%) patients, in the Axi-cel and Tisa-cel groups, respectively. Untargeted metabolomics revealed a total of 1,241 metabolites, detected in positive, negative and polar modes, of which 1,011 were named. These include lipids, amino acids, xenobiotics, nucleotides, partially characterized compounds, cofactors and vitamins. In examining toxicities of CAR-T cell treatment, we identified three metabolites whose abundance was negatively associated with ICANS grade (FDR ≤0.2), indicating that high abundance of these metabolites at the time of apheresis was associated with a decreased risk of (i.e. protection from) ICANS. Plasma metabolites were also found to be associated with CRS, with 23 associated with an increased risk (i.e. predisposing to) of CRS, and 204 associated with decreased risk (i.e. protection from) of CRS. Using a hypergeometric test for over-represented metabolites in the KEGG metabolic pathways (FDR ≤0.2), caffeine metabolism, glycine, serine, and threonine metabolism, arginine biosynthesis, and aminoacyl-tRNA biosynthesis were identified as the most significantly represented pathways. Conclusion: Pre-existing biochemical signatures present in the plasma at the time of apheresis are strongly associated with toxicities observed in response to commercial CD19 CAR T-cell therapies. These endogenous metabolites may serve as biomarkers for monitoring risk of toxicity associated with CD19 CAR T cell treatment and provide insight into rational clinical interventions to mitigate such risks. Disclosures Rotroff: Interpares Biomedicine LLC.: Current equity holder in publicly-traded company; CAR-T Response: Patents &amp; Royalties. Hill:Takeda: Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; AstraZenica: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding.

Glofitamab Step-up Dosing Induces High Response Rates in Patients with Hard-to-Treat Refractory or Relapsed Non-Hodgkin Lymphoma

Glofitamab Step-up Dosing Induces High Response Rates in Patients with Hard-to-Treat Refractory or Relapsed Non-Hodgkin Lymphoma

Population Pharmacokinetics and Exposure-Response Analyses for Glofitamab in Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma (R/R NHL): Confirmation of Efficacy and CRS Mitigation in Patients with Step-up Dosing

Population Pharmacokinetics and Exposure-Response Analyses for Glofitamab in Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma (R/R NHL): Confirmation of Efficacy and CRS Mitigation in Patients with Step-up Dosing

Novel Semi-Mechanistic Model Leveraging Preclinical and Clinical Data to Inform the Recommended Phase 2 Dose (RP2D) Selection for Epcoritamab (DuoBody CD3xCD20)

Introduction: Epcoritamab (DuoBody-CD3×CD20) is a subcutaneously administered bispecific antibody (bsAb) that simultaneously binds to CD3 on T cells and CD20 on malignant B cells, resulting in T-cell activation and expansion and selective T-cell-mediated killing of CD20+ cells. Target engagement (TE) and crosslinking of CD3 and CD20 (trimer formation) lead to activation and expansion of T cells, which in turn leads to tumor cell killing and is the first step driving the pharmacology of epcoritamab. Hence, the optimal clinical dose of epcoritamab can be informed by TE and trimer formation. Unlike typical monoclonal antibodies, bsAbs exhibit a hook effect in which trimer formation is impaired at high drug concentrations. Therefore, targeting complete receptor occupancy can lead to suboptimal trimer formation and clinical efficacy; instead, the aim should be to identify epcoritamab concentrations that result in maximal trimer formation. Epcoritamab is currently being investigated in an ongoing, open-label, multi-center, first-in-human trial in patients with relapsed/refractory B-cell non-Hodgkin lymphoma (NCT03625037). Endpoints include safety and identification of RP2D and pharmacokinetic/pharmacodynamic (PK/PD) analyses. Here, we present our approach for recommending the RP2D for epcoritamab based on a novel PK/PD model that predicts trimer formation. Methods: A semi-mechanistic PK/PD model was developed to quantitatively describe biodistribution of epcoritamab, trimer formation, and tumor response (Figure 1). This model makes use of preclinical data from cynomolgus monkeys, clinical PK/PD data, patient biomarker data, patient tumor characteristics, and response data. The model incorporates a minimal physiological-based PK model to predict epcoritamab concentration in tumors. The model also considers T- and B-cell dynamics, expression of CD3 and CD20 on these cells, and dynamic binding of epcoritamab to CD3 and CD20, as well as levels of trimer formation. Clinical trial simulations were performed using the PK/PD model, incorporating individual variability in key parameters, to predict the extent of trimer formation and tumor response in patients with diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). Variability in model parameters was based on either interindividual variability observed in the first-in-human trial or literature values. Results: The population PK/PD model was able to describe epcoritamab concentration-time profiles across doses (range: 0.0128-60 mg). Epcoritamab exhibited slow absorption, with Tmax of 2.8 days, a terminal half-life of 8.67 days, and target-mediated disposition (TMD). The model predicted the saturation of TMD to occur at dose levels ≥48 mg, indicating engagement and saturation of CD3 and CD20 in blood. In addition, the model was able to describe the exposure-response relationship observed in the clinic. Clinical trial simulations using the PK/PD model demonstrated that a 48-mg dose can achieve optimal trimer formation and clinical response in both FL and DLBCL. An exposure-adverse event analysis showed a flat relationship between epcoritamab exposure and risk of cytokine release syndrome (CRS) in the dose range evaluated. Based on these findings, 48 mg was identified as the potential RP2D for epcoritamab. Conclusions: For bsAbs such as epcoritamab, the optimal dose is one that leads to maximum trimer formation; hence, traditional PK modeling methodologies and exposure-response analyses are not adequate to guide RP2D selection. To overcome these limitations, we have developed a novel, semi-mechanistic PK/PD model incorporating preclinical, clinical, and patient biomarker data that identified the optimal dose for epcoritamab. This PK/PD model represents a novel approach and provides a general framework that can be applied to other CD3 bsAbs. Disclosures Li: Genmab: Current Employment. Hiemstra:Genmab: Current Employment, Current equity holder in publicly-traded company. Chiu:Genmab: Current Employment. Oliveri:Genmab: Current Employment, Current equity holder in publicly-traded company. DeMarco:Genmab: Current Employment, Current equity holder in publicly-traded company. Salcedo:Genmab: Current Employment. Lihme Egerod:Genmab: Current Employment. Gupta:Genmab: Current Employment. OffLabel Disclosure: Epcoritamab is an investigational agent undergoing evaluation in patients with relapsed/refractory B-cell non-Hodgkin lymphoma.

Odronextamab (REGN1979), a Human CD20 x CD3 Bispecific Antibody, Induces Durable, Complete Responses in Patients with Highly Refractory B-Cell Non-Hodgkin Lymphoma, Including Patients Refractory to CAR T Therapy

Odronextamab (REGN1979), a Human CD20 x CD3 Bispecific Antibody, Induces Durable, Complete Responses in Patients with Highly Refractory B-Cell Non-Hodgkin Lymphoma, Including Patients Refractory to CAR T Therapy

Subcutaneous Mosunetuzumab in Relapsed or Refractory B-Cell Lymphoma: Promising Safety and Encouraging Efficacy in Dose Escalation Cohorts

Subcutaneous Mosunetuzumab in Relapsed or Refractory B-Cell Lymphoma: Promising Safety and Encouraging Efficacy in Dose Escalation Cohorts

Clinical Impact of Cytokine Release Syndrome on Outcomes of Peripheral Blood Stem Cell Haploidentical Hematopoietic Cell Transplantation with Post-Transplant Cyclophosphamide

Peripheral blood stem cell (PBSC) as a graft source compared to bone marrow has been reported to result in lower risk of relapse after haploidentical hematopoietic cell transplantation (haplo-HCT) with use of post-transplant cyclophosphamide (PTCy) as a graft-versus-host-disease (GvHD) prophylaxis. However, cytokine release syndrome (CRS) is a common complication of this platform that can affect the outcomes of patients after PBSC haplo-HCT. CRS occurs due to rapid activation and proliferation of alloreactive donor T cells resulting in the elevated secretion of inflammatory cytokines. In this study, we sought to examine the risk factors for CRS and the effect of CRS severity on outcomes of PBSC haplo-HCT. We identified total of 271 consecutive patients with hematological malignancies who received their first PBSC haplo-HCT with PTCy-based GVHD prophylaxis at City of Hope (n=157) or Moffitt (n=114) Cancer Centers between 2014 and 2019. The median patient age at HCT was 54 years (INQ range, 37-64) for the entire cohort and 48% of the patients had HCT-CI ³3. Close to 70% of the study cohort had acute leukemia and 33% of all patients had high/very high-risk disease risk index. Myeloablative conditioning was used in 52% of the cases and 81% of all HCT recipients were CMV seropositive. The median donor age at HCT was 33 years (INQ range, 26-43). The HLA -A, -B, -C, -DRB1, -DQB1, or -DPB1 mismatch between the recipient and the donor in the GVH direction was 5/10 in 51%, 4/10 in 29% and £3/10 in 20% of cases. Offspring donors were used in 54% of the patients, sibling donors in 35%, and parent/other relative donors in 11%. Female donors to male recipients were used in only 22% of patients. The median infused CD34 dose was 5.25 x106 cells/kg (range, 2.3-22.4x106) and the CD3 dose was 2.48x108 cells/kg (range, 0.002-8.88 x108). CRS of any grade by ASTCT criteria was observed in 92% of study patients within first 7 days of HCT: 54% had grade 1, 39% grade 2, and 5.2% grade 3-4. Infused cell doses of CD34 &amp;gt;5x106 cells/kg and of CD3 &amp;gt;2.5x108 cells/kg had no significant effect on grade 3-4 CRS. On multivariable analysis, the use of reduced-intensity conditioning (RIC) was associated with increased grade 2-4 CRS (HR = 1.6, 95% CI: 1.11.-2.33, p=0.01) and grade 3-4 CRS (HR = 14.7, 95% CI: 1.97-109.5, p=0.009) compared with the myeloablative conditioning. Donor 5/10 HLA-mismatch was also associated with increased grade 2-4 CRS (HR = 1.5, 95% CI: 1.05-2.18; p=0.03) and grade 3-4 CRS (HR = 3.50, 95% CI: 1.00-12.32; p=0.05) compared with £4/10 HLA-mismatch. Non-relapse mortality (NRM) at day 100, and 1-year overall survival (OS) by CRS severity is shown in Figure. Comparing with the grade 0-1 CRS in multivariable analysis (Table), increase in CRS severity was associated with lower probability of neutrophil engraftment (HR = 0.9 for grade 2 and HR = 0.4 for grade 3-4; p=0.03). Increased CRS severity as compared to the grade 0-1 was also predictive of higher risks of NRM (HR = 1.6, 95% CI: 0.95-2.79 for grade 2 and HR = 6.6, 95% CI: 3.12-13.78 for grade 3-4; p&amp;lt;0.001), lower disease-free survival (DFS; HR = 1.3 for grade 2 and HR = 4.5 for grade 3-4; p&amp;lt;0.001) and lower OS (HR = 1.2 for grade 2 and HR = 4.1 for grade 3-4; p&amp;lt;0.001) after HCT. We observed no association between CRS severity and risk of relapse or the incidence and severity of acute GvHD after transplant. We conclude that CRS is a common complication after PB haplo-HCT/PTCy. CRS severity is associated with post-HCT outcomes with grade 3-4 CRS associated with the highest risk of NRM and overall mortality after HCT. Infused CD34 or CD3 cell doses effect on CRS is unclear. RIC and higher degree of HLA-mismatch are predictive of higher-grade CRS. Identification of modifiable risk factors can help to mitigate the risk for serious CRS and subsequent mortality after PB haplo-HCT/PTCy. Figure 1 Disclosures Nishihori: Karyopharm: Other: Research support to institution; Novartis: Other: Research support to institution. Pidala:CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Takeda: Research Funding; Janssen: Research Funding; Johnson and Johnson: Research Funding; Pharmacyclics: Research Funding; Abbvie: Research Funding; BMS: Research Funding; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees. Nakamura:Merck: Other: advisory board meeting; Alexion: Other: Support on a meeting presentation; Kyowa-Kirin: Other: Support on a meeting presentation; Celgene: Other: Support on seminar; Magenta Therapeutics: Other: Advisory board meeting; Viracor: Consultancy; Kadmon Corporation: Other: Advisory board meeting; NapaJen Pharma: Consultancy. Al Malki:Rigel Pharma: Consultancy; Jazz Pharmacuticals, Inc: Consultancy; Neximmune: Consultancy. Bejanyan:Kiadis Pharma: Membership on an entity's Board of Directors or advisory committees.

CD19 CAR-T Cells Treatment Conferred a Sustained Remission in Patients with Chemotherapy-Refractory MRD in B-ALL

Background: The persistence or recurrence of minimal residual disease (MRD) after chemotherapy predicts relapse of B-cell acute lymphoblastic leukemia (B-ALL). CD19-directed chimeric antigen receptor-modified T (CD19 CAR-T) cells have shown excitable response in B-ALL. Recently, some studies have shown that ALL patients with lower burden had higher CR rate and lower risk of CRS after CAR-T therapy (Park, et al, NEJM. 2018; 378(5):439-448. Lee, et al, Blood.128 (22):Abstract 218.). However, its role in chemotherapy-refractory MRD-positive B-ALL remains unclear. Here we aimed to assess the effectiveness and safety of CD19 CAR-T in MRD-positive B-ALL patients. Methods: Since January 2018, a total of 14 B-ALL patients with persistent (n=8) or recurrent (n=6) MRD were enrolled in the CAR-T clinical trials (ChiCTR-ONN- 16009862 and ChiCTR1800015164). The patients were from two different clinical trials about CAR-T. If patients were treated in an MRD positive state, they would be included in this analysis. All the patients received one or more infusions of autogenous CD19 CAR-T. Results: Median age was 37.5 (13-62) years and 7 patients were female. The median dose of infused CAR-T cells was 6.78´106cells/kg, and 5 patients received more than one infusion. After one cycle of CAR-T infusion, 12 patients achieved MRD-negative remission, leading a response rate of 85.7%. Of the subgroup of 5 Ph-positive patients who subsequently underwent transplantation, 2 patients died due to transplant-related toxic effects, whereas the other 3 patients all currently alive without leukemia. Of the subgroup of 9 Ph-negative patients, 8 patients did not undergo subsequent transplantation (Figure 1). Three patients finally suffered CD19-positive relapse and 1 patient suffered CD19-negative relapse. Importantly, 4 patients (50%) are in ongoing molecular remission without transplantation, with a duration of response averaging 22.9 months (range: 12.1-28.6 months). The most frequent adverse events were fever and hematopoietic toxicities. Ten patients (71.4%) had grade 1 or 2 cytokine release syndrome (CRS) and no patients died of CRS. At a median follow-up time of 599.5 days (range: 172-915 days), the probability of 2-year relapse-free survival and 2-year overall survival was 61.2%±14.0% and 78.6%±11.0%, respectively. Conclusion: In conclusion, pre-emptive CD19 CAR-T treatment is an effective and safe approach and may confer a sustained remission in B-ALL patients with chemotherapy-refractory MRD. Disclosures No relevant conflicts of interest to declare.