Severe Infusion-related Reactions Research Articles

Trials in Progress: The Randomized, Double-Blind, Placebo-Controlled Phase 1b CROSSWALK-a and Phase 2a CROSSWALK-c Trials - Crovalimab for the Treatment and Prevention of Vaso-Occlusive Episodes in Sickle Cell Disease

Background and Significance In sickle cell disease (SCD), a single point mutation in the beta-globin gene results in hemoglobin S (HbS) production, which can polymerize upon deoxygenation. Polymerization distorts the red blood cell (RBC) membrane and generates sickled RBCs, contributing to microvascular occlusions, which may present as acute, painful vaso-occlusive episodes (VOEs). For patients (pts) with SCD, 70% of emergency department visits and 90% of hospitalizations are VOE-related. 1,2 Despite existing treatments for VOE prevention, considerable morbidity and mortality remain; acute VOE treatment is limited to supportive care due to a lack of targeted therapies. Accumulating nonclinical data suggest a multimodal role for complement dysregulation in SCD pathophysiology, including in vaso-occlusion, hemolysis, inflammation, thrombogenicity, endothelial activation, and end-organ damage. 3 Crovalimab is a novel, engineered, anti-complement C5 monoclonal antibody that allows for small-volume subcutaneous (SC) injection after an initial intravenous (IV) loading dose. 4 Here, we describe two randomized, double-blind, placebo-controlled trials evaluating crovalimab in pts with SCD: CROSSWALK-a (Phase 1b; NCT04912869) and CROSSWALK-c (Phase 2a; NCT05075824). Study Design and Methods CROSSWALK-a evaluates the safety of crovalimab in managing acute uncomplicated VOEs. CROSSWALK-c evaluates the efficacy and safety of crovalimab as adjunct therapy in preventing VOEs. Pts 12-55 years old, weighing ≥40 kg with a confirmed diagnosis of sickle cell anemia (homozygous HbSS or heterozygous HbS/β 0 thalassemia) and vaccinated against N. meningitidis, H. influenzae type B and S. pneumoniae are eligible (Fig. 1 and 2). Concurrent SCD-directed therapies are allowed. CROSSWALK-a Pts must present with an acute uncomplicated VOE requiring hospitalization and parenteral opioid analgesics, and have had ≤10 VOEs in the 12 months prior to randomization. Eligible pts will be randomized 2:1 to receive a single IV weight-based tiered dose of crovalimab or placebo, and monitored during hospitalization and in an 84-day observational period followed by a safety follow-up period for a total study duration of 322 days (10.5 months). The primary objective of CROSSWALK-a is to evaluate safety up to Day 84, including: Incidence and severity of adverse eventsIncidence and severity of infusion-related reactions and hypersensitivityChange from baseline in targeted vital signs and clinical laboratory test results Efficacy, pharmacokinetic (PK), pharmacodynamic (PD), immunogenicity, and exploratory biomarker endpoints will also be evaluated. CROSSWALK-c Pts with 2-10 VOEs in the 12 months prior to randomization are eligible. Eligible pts will be randomized 1:1 to receive weight-based tiered doses of crovalimab or placebo, consisting of initial loading doses (IV: Day 1; SC: Day 2 and weekly for Weeks 2-4) and monthly maintenance SC doses Weeks 5-49 for 48 weeks of treatment. The primary objective of CROSSWALK-c is to evaluate crovalimab efficacy vs placebo up to 48 weeks, on the basis of: The annualized rate of medical facility VOEs Key secondary efficacy objectives are: Annualized rate of home VOEsAnnualized rate of acute chest syndromeAnnualized rate of days hospitalized for medical facility VOEsPt-reported fatigue in adults Safety, PK, PD, immunogenicity, and exploratory biomarker endpoints will also be evaluated. Primary results will be published upon trial readout.

5610823 TRIAL IN PROGRESS: THE RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED PHASE 1B CROSSWALK-A TRIAL EVALUATING THE SAFETY OF CROVALIMAB FOR THE MANAGEMENT OF ACUTE UNCOMPLICATED VASO-OCCLUSIVE EPISODES (VOES) IN PATIENTS (PTS) WITH SICKLE CELL DISEASE (SCD)

Background: SCD is a group of autosomal recessive red blood cell (RBC) disorders caused by a single point mutation in the β-globin gene, resulting in the production of hemoglobin S (HbS). HbS polymerizes within RBCs under certain conditions, leading to the distortion of the RBC membrane and generation of dense and sickle RBCs. These pathologic RBCs contribute to microvascular occlusions, which may present as acute, painful episodes called VOEs. Although most VOEs are managed at home, >70% of emergency department visits and >90% of hospitalizations for SCD are VOE-related.1,2 Additionally, acute chest syndrome is one of the most severe complications of VOEs and is a leading cause of mortality.3,4 As there are no targeted therapies for the management of VOEs, treatment is currently limited to pain management, blood exchange transfusion (with the risk of complications), and other supportive care, which represents a significant unmet medical need. Overall, accumulating nonclinical data suggest a multimodal role for complement dysregulation in the pathophysiology of SCD including vaso-occlusion, hemolysis, inflammation, thrombogenicity, endothelial activation, and end-organ damage.5 Complement pathway activation has been described in pts with SCD at baseline, in acute pain crises, and in pts with delayed hemolytic transfusion reaction. The complement pathway can be targeted with crovalimab, which is a novel, engineered, anti-complement C5 monoclonal antibody. In a Phase 1/2 study in patients with paroxysmal nocturnal hemoglobinuria, a complement-mediated disorder, crovalimab showed rapid and sustained complement inhibition with promising efficacy and safety.6 Aims: CROSSWALK-a (NCT04912869) is a randomized, double-blind, placebo-controlled, Phase 1b study evaluating the safety of crovalimab in managing acute uncomplicated VOEs in pts with SCD. Methods: Pts aged 12 to 55 years, weighing ≥40 kg, and with a confirmed diagnosis of SCD homozygous hemoglobin S (HbSS) or sickle cell β0 thalassemia (HbSβ0) will be enrolled (Figure). Pts must present with an acute uncomplicated VOE, requiring hospitalization and treatment with parenteral opioid analgesics. Vaccinations against Neisseria meningitidis, Hemophilus influenzae type B, and Streptococcus pneumoniae must be current. Eligible pts will be randomized 2:1 to receive either a single intravenous weight-based tiered dose of crovalimab or placebo. All pts will continue with pain management and other supportive care for their VOE, and may continue concurrent SCD-directed therapies. Pts will be followed during hospitalization until discharge and will also be followed post-discharge during an observational period. The study duration for an individual pt, including the hospitalization and observational periods, will be 12 weeks. The primary objective is to evaluate the incidence and severity of adverse events according to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0, incidence and severity of infusion-related reactions and hypersensitivity, and change from baseline in targeted vital signs and clinical laboratory test results. Efficacy, pharmacokinetic, pharmacodynamic, immunogenicity, and exploratory biomarker endpoints will also be evaluated. Protocol updates are in progress. Results: CROSSWALK-a is scheduled to be completed in September 2023. Summary: CROSSWALK-a is enrolling pts with SCD in five countries.

The use of obinutuzumab and ofatumumab in the treatment of immune thrombotic thrombocytopenic purpura.

Rituximab, an anti-CD20 monoclonal antibody, can be used to treat immune thrombotic thrombocytopenic purpura (iTTP) during acute presentation or disease relapse. Undesirable side-effects include severe hypersensitivity reactions, particularly anaphylaxis and rituximab-induced serum sickness, with a minority not maintaining a response to treatment. Alternative humanised anti-CD20 treatments, obinutuzumab and ofatumumab, have been used. A review of the UK TTP Registry showed 15 patients received these drugs over 26 treatment episodes (eight obinutuzumab and 18 ofatumumab). Indications for alternative anti-CD20 treatment were severe infusion-related reactions, acute rituximab-induced serum sickness and a short duration of disease remission. All patients achieved disease remission (ADAMTS13 [A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13] activity ≥30 iu/dl) after a median 15 days and 92% of episodes achieved complete remission (≥60 iu/dl). Seven patients required further treatment for disease relapse with a median relapse-free survival of 17.4 months. All patients continued to respond to re-treatment with the preceding drug when relapse occurred. There were four adverse events in 26 treatment episodes (15%) - two infections and two infusion reactions. These results suggest that obinutuzumab and ofatumumab may be considered as an alternative option to rituximab in the treatment of iTTP with a comparable safety profile, absence of significant hypersensitivity reactions and sustained normalisation of ADAMTS13.

‘Fast but not so Furious’: Short observation time after subcutaneous Daratumumab administration is both a safe and cost-effective strategy

BackgroundDaratumumab, an anti-CD38 monoclonal antibody, is a key component in the treatment paradigms of multiple myeloma and AL amyloidosis in both the newly diagnosed and relapsed and/or refractory setting. Intravenous (IV) daratumumab administration requires extended infusion times and is associated with higher rates of infusion related reactions (IRRs) when compared to the subcutaneous (SC) formulation. We report real world safety outcomes and infusion chair time savings associated with SC administration in daratumumab naïve patients. MethodsWe retrospectively analyzed medical records at our institution for the incidence and severity of IRRs following differing observation periods post SC daratumumab administration. Infusion chair time was calculated to quantify chair time savings with SC administration. ResultsSixty-six daratumumab naïve patients were included. Nine percent of patients developed IRRs with SC daratumumab with all reactions occurring within six hours of the first dose. All reactions were grade ≤ 2 in severity and were reversible with supportive care. Over the 18 month study period, a total of 904 SC doses were administered, amounting to a potential 1785 hours of infusion chair time savings when compared to IV administration. ConclusionSC daratumumab may be given safely with a short initial observation period and without observation for subsequent doses, resulting in reduced infusion chair time as well as administration related cost and resources.

P119: TRIAL IN PROGRESS: THE RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED PHASE 1B CROSSWALK-A TRIAL EVALUATING THE SAFETY OF CROVALIMAB FOR THE MANAGEMENT OF ACUTE UNCOMPLICATED VASO-OCCLUSIVE EPISODES (VOES) IN PATIENTS (PTS) WITH SICKLE CELL DISEASE (SCD)

Background: SCD is a group of autosomal recessive red blood cell (RBC) disorders caused by a single point mutation in the β-globin gene, resulting in the production of hemoglobin S (HbS). HbS polymerizes within RBCs under certain conditions, leading to the distortion of the RBC membrane and generation of dense and sickle RBCs. These pathologic RBCs contribute to microvascular occlusions, which may present as acute, painful episodes called VOEs. Although most VOEs are managed at home, >70% of emergency department visits and >90% of hospitalizations for SCD are VOE-related.1,2 Additionally, acute chest syndrome is one of the most severe complications of VOEs and is a leading cause of mortality.3,4 As there are no targeted therapies for the management of VOEs, treatment is currently limited to pain management, blood exchange transfusion (with the risk of complications), and other supportive care, which represents a significant unmet medical need. Overall, accumulating nonclinical data suggest a multimodal role for complement dysregulation in the pathophysiology of SCD including vaso-occlusion, hemolysis, inflammation, thrombogenicity, endothelial activation, and end-organ damage.5 Complement pathway activation has been described in pts with SCD at baseline, in acute pain crises, and in pts with delayed hemolytic transfusion reaction. The complement pathway can be targeted with crovalimab, which is a novel, engineered, anti-complement C5 monoclonal antibody. In a Phase 1/2 paroxysmal nocturnal hemoglobinuria (a complement-mediated disorder) study, crovalimab showed rapid and sustained complement inhibition with promising efficacy and safety.6 Aims: CROSSWALK-a (NCT04912869) is a randomized, double-blind, placebo-controlled, Phase 1b study evaluating the safety of crovalimab in managing acute uncomplicated VOEs in pts with SCD. Methods: Pts aged 12 to 55 years, weighing ≥40 kg, and with a confirmed diagnosis of SCD homozygous hemoglobin S (HbSS) or sickle cell β0 thalassemia (HbSβ0) will be enrolled (Figure). Pts must present with an acute uncomplicated VOE, requiring hospitalization and treatment with parenteral opioid analgesics. Vaccinations against Neisseria meningitidis, Hemophilus influenzae type B, and Streptococcus pneumoniae must be current. Eligible pts will be randomized 2:1 to receive either a single intravenous weight-based tiered dose of crovalimab or placebo. All pts will continue with pain management and other supportive care for their VOE, and may continue concurrent SCD-directed therapies. Pts will be followed during hospitalization until discharge and will also be followed post-discharge during an observational period. The maximum total study duration for an individual pt, including the hospitalization and observational periods, will be 12 weeks. The primary objective is to evaluate the incidence and severity of adverse events according to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0, incidence and severity of infusion-related reactions and hypersensitivity, and change from baseline in targeted vital signs and clinical laboratory test results. Efficacy, pharmacokinetics, pharmacodynamics, immunogenicity, and exploratory biomarker endpoints will also be evaluated. Results: CROSSWALK-a is scheduled to be completed in September 2023. Summary: CROSSWALK-a is enrolling pts with SCD in 5 countries.

Trial in Progress: The Randomized, Double-Blind, Placebo-Controlled Phase Ib CROSSWALK-a Trial Evaluating the Safety of Crovalimab for the Management of Acute Uncomplicated Vaso-Occlusive Episodes (VOEs) in Patients with Sickle Cell Disease (SCD)

BackgroundSCD is a group of autosomal recessive red blood cell (RBC) disorders caused by a single point mutation in the β-globin gene, resulting in the production of hemoglobin S. Hemoglobin S polymerizes within RBCs under certain conditions, leading to the distortion of the RBC membrane and generation of dense and sickle RBCs. These pathologic RBCs contribute to microvascular occlusions in patients with SCD, which present as acute painful episodes called VOEs. Despite the majority of VOEs being managed at home, they remain the most common reason for emergency department (ED) visits and hospitalization among patients with SCD, with > 70% of ED visits and > 90% of hospital admissions for SCD being related to VOEs (Ballas et al. Am J Hematol 2005; Lanzkron et al. Am J Hematol 2010). One of the most severe complications of VOEs is acute chest syndrome, which is a leading cause of mortality among patients with VOEs (Vichinsky et al. N Engl J Med 2000; Bartolucci et al. eBioMedicine 2016). In the absence of targeted therapies for the management of VOEs in patients with SCD, treatment is currently limited to pain management, blood exchange transfusion (with the risk of complications), and other supportive care, representing a significant unmet medical need. Activation of the complement pathway has been described in patients with SCD at baseline, in acute pain crises, and in patients with delayed hemolytic transfusion reaction. Accumulating nonclinical data have suggested a multimodal role for complement dysregulation in the pathophysiology of SCD including vaso-occlusion, hemolysis, inflammation, thrombogenicity, endothelial activation, and end-organ damage (Roumenina et al. Am J Hematol 2020). Crovalimab is a novel, engineered, anti-complement C5 monoclonal antibody. In a Phase I/II study (Röth et al. Blood 2020) in patients with paroxysmal nocturnal hemoglobinuria, a complement-mediated disorder, crovalimab demonstrated rapid and sustained complement inhibition with promising efficacy and safety.Study Design and MethodsCROSSWALK-a (NCT04912869) is a randomized, double-blind, placebo-controlled, Phase Ib study evaluating the safety of crovalimab for the management of acute uncomplicated VOEs in patients with SCD. Patients aged ≥ 12 years to ≤ 55 years, weighing ≥ 40 kg, and with a confirmed diagnosis of SCD homozygous hemoglobin S (HbSS) or sickle cell β 0 thalassemia (HbSβ 0) are eligible for the study (Figure). Patients must present with an acute uncomplicated VOE, requiring hospitalization and treatment with parenteral opioid analgesics. Vaccinations against Neisseria meningitidis, Hemophilus influenzae type B, and Streptococcus pneumoniae must be up to date. Eligible patients will be randomized 2:1 to receive either a single intravenous weight-based tiered dose of crovalimab or placebo. Patients in both study arms will continue to undergo pain management and receive other supportive care for their VOE and may also continue to receive ongoing concurrent SCD-directed therapies. Patients will be followed during the hospitalization until discharge and will continue to be followed post-discharge during an observational period. The maximum total study duration for an individual patient will be 12 weeks, which includes the hospitalization and observational periods. The primary objective is to evaluate the incidence and severity of adverse events according to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0, incidence and severity of infusion-related reactions and hypersensitivity, and change from baseline in targeted vital signs and clinical laboratory test results. Efficacy, pharmacokinetics, pharmacodynamics, immunogenicity, and exploratory biomarker endpoints will also be evaluated. [Display omitted] DisclosuresBartolucci: F. Hoffmann-La Roche Ltd: Consultancy; Bluebird: Consultancy, Research Funding; Emmaus: Consultancy; Hemanext: Consultancy; Jazz Pharma: Other: Lecture fees; AGIOS: Consultancy; GBT: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees, Steering committee, Research Funding; INNOVHEM: Other: Co-founder; Fabre Foundation: Research Funding; Addmedica: Consultancy, Other: Lecture fees, Research Funding. Ataga: Forma Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees. Callaghan: Alnylum: Current equity holder in publicly-traded company; Roche/Genentech: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Sanofi: Consultancy; Pfizer: Consultancy; Global Blood Therapeutics: Consultancy, Speakers Bureau; uniQure: Consultancy; Spark: Consultancy; Biomarin: Consultancy; Kedrion: Consultancy; Hema Biologics: Consultancy; Forma: Consultancy; Chesei: Consultancy; Agios Pharmaceuticals: Current Employment. De Franceschi: F. Hoffmann-La Roche Ltd: Consultancy. Minniti: F. Hoffmann-La Roche: Consultancy; Bluebird Bio: Other: Endpoint adjudicator; Forma: Consultancy; GBT: Consultancy; Novo Nordisk: Consultancy; CSL Behring: Other: Endpoint adjudicator; Novartis: Consultancy; Chiesi: Consultancy. Alexandrou: F. Hoffmann-La Roche Ltd: Consultancy, Current equity holder in publicly-traded company; Pfizer: Current equity holder in publicly-traded company. Imbs: F. Hoffmann-La Roche Ltd: Consultancy; Certara Inc.: Current Employment. Fox: Parexel International: Current Employment; Genentech, Inc.: Current Employment. Patel: Genentech, Inc.: Current Employment. Sostelly: F. Hoffmann-La Roche Ltd: Current Employment.

Iomab with Adoptive Cellular Therapy (Iomab-ACT): A Pilot Study of 131-I Apamistamab Followed By CD19-Targeted CAR T-Cell Therapy for Patients with Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia or Diffuse Large B-Cell Lymphoma

Background: Autologous CD19-targeted chimeric antigen receptor-modified (CAR) T-cell therapy leads to complete responses (CR) in patients (pts) with (w/) relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL, >80% CR rate) and diffuse large B-cell lymphoma (DLBCL, ~40-55% CR rate). However, following fludarabine/cyclophosphamide (Flu/Cy) conditioning and CAR T-cell therapy w/ a CD28 costimulatory domain (e.g. 19-28z CAR T-cells), rates of grade ≥3 ICANS and grade ≥3 cytokine release syndrome (CRS) in pts w/ R/R DLBCL and morphologic R/R B-ALL exceed 30%. CRS and ICANS are associated w/ considerable morbidity, including increased length of hospitalization, and may be fatal. Host monocytes appear to be the major reservoir of cytokines driving CRS and ICANS post-CAR T-cell therapy (Giavradis et al. and Norelli et al., Nature Medicine, 2018). Circulating monocytic myeloid-derived suppressor cells (MDSCs) may also blunt efficacy of 19-28z CAR T-cells in R/R DLBCL (Jain et al., Blood, 2021).The CD45-targeted antibody radioconjugate (ARC) 131-I apamistamab is being investigated at myeloablative doses as conditioning prior to hematopoietic cell transplantation in pts w/ R/R acute myeloid leukemia. However, even at low doses (4-20 mCi), transient lymphocyte and blast reduction are observed. Preclinical studies in C57BL/6 mice demonstrate low-dose anti CD45 radioimmunotherapy (100 microCi) transiently depletes >90% lymphocytes, including CD4/CD8 T-cells, B-cells, NK cells, and T-regs, as well as splenocytes and MDSCs, w/ negligible effect on bone marrow (BM) hematopoietic stem cells (Dawicki et al., Oncotarget, 2020). We hypothesized a higher, yet nonmyeloablative dose of 131-I apamistamab may achieve more sustained, but reversible depletion of lymphocytes and other CD45 + immune cells, including monocytes thought to drive CRS/ICANS. We additionally hypothesized this approach (vs Flu/Cy) prior to CAR T-cell therapy would promote CAR T-cell expansion while reducing CSF levels of monocyte-derived cytokines (e.g. IL-1, IL-6, and IL-10), thus lowering the risk of severe ICANS (Fig 1A).Study design and methods: We are conducting a single-institution pilot study of 131-I apamistamab in lieu of Flu/Cy prior to 19-28z CAR T-cells in adults w/ R/R BALL or DLBCL (NCT04512716; Iomab-ACT); accrual is ongoing. Pts are eligible for leukapheresis if they are ≥18 years-old w/ R/R DLBCL (de novo or transformed) following ≥2 chemoimmunotherapy regimens w/ ≥1 FDG-avid measurable lesion or B-ALL following ≥1 line of multi-agent chemotherapy (R/R following induction/consolidation; prior 2 nd/3 rd gen TKI required for pts w/ Ph+ ALL) w/ ≥5% BM involvement and/or FDG-avid extramedullary disease, ECOG performance status 0-2, and w/ appropriate organ function. Active or prior CNS disease is not exclusionary. Pts previously treated w/ CD19-targeted CAR T-cell therapy are eligible as long as CD19 expression is retained.See Fig 1B/C: Post-leukapheresis, 19-28z CAR T-cells are manufactured as previously described (Park et al., NEJM, 2018). Bridging therapy is permitted at investigator discretion. Thyroid blocking is started ≥48h pre-ARC. 131-I apamistamab 75 mCi is administered 5-7 days pre-CAR T-cell infusion to achieve total absorbed marrow dose ~200 cGy w/ remaining absorbed dose <25 cGy at time of T-cell infusion. 19-28z CAR T-cells are administered as a single infusion (1x10 6/kg, B-ALL pts; 2x10 6/kg, DLBCL pts).The primary objective is to determine safety/tolerability of 131-I apamistamab 75 mCi given prior to 19-28z CAR T-cells in pts w/ R/R B-ALL/DLBCL. Secondary objectives include determining incidence/severity of ICANS and CRS, anti-tumor efficacy, and 19-28z CAR T-cell expansion/persistence. Key exploratory objectives include describing the cellular microenvironment following ARC and 19-28z CAR T-cell infusion using spectral cytometry, as well as cytokine levels in peripheral blood and CRS.The trial utilizes a 3+3 design in a single cohort. If dose-limiting toxicity (severe infusion-related reactions, treatment-resistant severe CRS/ICANS, persistent regimen-related cytopenias, among others defined in protocol) is seen in 0-1 of the first 3 pts treated, then up to 6 total (up to 3 additional) pts will be treated.We have designed this study to provide preliminary data to support further investigation of CD45-targeted ARCs prior to adoptive cellular therapy. [Display omitted] DisclosuresGeyer: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Actinium Pharmaceuticals, Inc: Research Funding; Amgen: Research Funding. Geoghegan: Actinium Pharmaceuticals, Inc: Current Employment. Reddy: Actinium Pharmaceuticals: Current Employment, Current holder of stock options in a privately-held company. Berger: Actinium Pharmaceuticals, Inc: Current Employment. Ludwig: Actinium Pharmaceuticals, Inc: Current Employment. Pandit-Taskar: Bristol Myers Squibb: Research Funding; Bayer: Research Funding; Clarity Pharma: Research Funding; Illumina: Consultancy, Honoraria; ImaginAb: Consultancy, Honoraria, Research Funding; Ymabs: Research Funding; Progenics: Consultancy, Honoraria; Medimmune/Astrazeneca: Consultancy, Honoraria; Actinium Pharmaceuticals, Inc: Consultancy, Honoraria; Janssen: Research Funding; Regeneron: Research Funding. Sauter: Genmab: Consultancy; Celgene: Consultancy, Research Funding; Precision Biosciences: Consultancy; Kite/Gilead: Consultancy; Bristol-Myers Squibb: Research Funding; GSK: Consultancy; Gamida Cell: Consultancy; Novartis: Consultancy; Spectrum Pharmaceuticals: Consultancy; Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding. OffLabel Disclosure:131-I apamistamab and 19-28z CAR T-cells are investigational agents in treatment of ALL and DLBCL

Fast and safe: Optimising multiple sclerosis infusions during COVID-19 pandemic

Background: The COVID-19 pandemic challenges multiple sclerosis services to be innovative in delivering infusible therapies. To reduce time in clinical settings, and potential staff or space losses, we implemented rapid infusion protocols for selected patients.Objective: To analyse the rate of infusion related reactions and patient experience of rapid infusions of natalizumab and ocrelizumab. To document time reduction patients spent in clinical settings during the COVID-19 pandemic.Methods: Patients with prior exposure to at least three natalizumab or two 300mg ocrelizumab infusions were approved for rapid protocols. A retrospective audit and survey were completed.Results: We analysed 269 rapid natalizumab infusions and 100 rapid ocrelizumab infusions. Infusion related reactions during the natalizumab or ocrelizumab infusions occurred in two patients (1.52%) and eight patients (8%), respectively. All infusion related reactions were mild to moderate and did not require infusion discontinuation. No infusion reactions occurred during the post-infusion observation. Patient experience was positive.Conclusion: Frequency or severity of infusion related reactions in rapid infusions were no different compared to published data. In the setting of COVID-19, pandemic rapid infusion protocols could potentially save hospital resources and limit patient exposure to a high-risk clinical setting while still maintaining ongoing treatment of multiple sclerosis.

Post-Marketing Observational Study to Assess the Incidence of Infusion-Related Reactions in Adult Patients with Therapy-Related Acute Myeloid Leukemia (AML) or AML with Myelodysplasia-Related Changes Who Were Treated with CPX-351

Post-Marketing Observational Study to Assess the Incidence of Infusion-Related Reactions in Adult Patients with Therapy-Related Acute Myeloid Leukemia (AML) or AML with Myelodysplasia-Related Changes Who Were Treated with CPX-351

Long-Term Sustained Responses Following Ibrutinib Discontinuation after Frontline Therapy with Obinutuzumab Plus Ibrutinib in Patients with Chronic Lymphocytic Leukemia

Single oral targeted therapies have emerged as a standard of care in chronic lymphocytic leukemia (CLL). However, accessibility, side effects, and financial burden associated with long term administration limit their clinical use. Mainly, it is unclear in what clinical situation discontinuation of oral therapy can be recommended. The combination of type II anti-CD20 antibody obinutuzumab-Gazyva® with ibrutinib (GI) has shown a significant progression-free survival benefit in patients (pts) with CLL, including those with high-risk genomic aberrations. We conducted a phase 1b/2, single-arm, open-label trial to evaluate the safety and efficacy of GI as first-line treatment in 32 CLL pts. We report the outcome in pts that discontinued ibrutinib (either after 3 years of sustained complete response (CR) as stipulated in the clinical protocol, or due to other reasons). CLL pts enrolled in this protocol were ≥65 years old, or unfit/unwilling to receive chemotherapy. Pts received GI for six cycles, followed by daily single-agent ibrutinib. The protocol was designed to ensure that pts with a sustained CR after 36 months were allowed to discontinue ibrutinib. The median age was 66 years (IQR 59-73), and 6% of the evaluated pts had 17p deletion. All pts were able to complete the six planned cycles of obinutuzumab. The combination regimen was well-tolerated, and the most common adverse events (&amp;gt;5% CTCAE grade 3-4) were neutropenia, thrombocytopenia, and hyperglycemia. The rate and severity of infusion-related reactions (IRR) were much lower than expected (Grade≥ 3, 3%), and pts without IRR had lower serum levels of cytokines/chemokines CCL3 (P=0.0460), IFN-γ (P=0.0457), and TNF-α (P=0.0032) after infusion. The overall response rate was 100%, with nine pts (28%) achieving a CR, and four pts (12.5%) with undetectable minimal residual disease (uMRD) in the bone marrow, defined as &amp;lt;10-4 CLL cells on multicolor flow cytometry. At a median follow-up of 35.5 months (IQR 24.5-42.7) after starting treatment, 91% of the enrolled pts remain in remission with a 100% overall survival. Sixteen pts have completed a long-term follow-up of 36 months. Six pts showed CR, with three of them achieving uMRD in the bone marrow. Ten of these pts were in PR, and only one had disease progression and started treatment for symptomatic stage I disease with obinutuzumab plus venetoclax. In total, thirteen pts (41%) have stopped ibrutinib, with a median time on treatment prior to discontinuation of 35 months. Five (16%) of these pts had CRs and discontinued after 36 months. Eight additional pts (25%) had PRs and discontinued ibrutinib without being eligible: three pts discontinued prior to 36 months due to toxicities, and five pts discontinued after 36 months (3 due to side effects, and 2 due to financially driven decision). One patient eligible to discontinue ibrutinib, decided to remain on treatment despite sustained CR. After a median follow up time following ibrutinib discontinuation of 8 months (IQR 3.5-17), only two out of 13 pts have progressed (10 and 17 months after Ibrutinib discontinuation). None of the pts that stopped ibrutinib after achieving a CR have shown signs of disease progression. Of note, the pharmaceutical sponsor provided ibrutinib for the first 36 months, after which pts or their insurer became financially responsible. This particular scenario could bias the discontinuation pattern compared to a real world experience. It also provided us with a perspective about diverse factors affecting the treatment choices of pts. In summary, the obinutuzumab plus ibrutinib combination therapy was well-tolerated, with a much lower IRR rate. Efficacy compares favorably with historical controls with all pts responding to therapy, no deaths associated with treatment or disease progression, and a longer than expected time-to-progression after discontinuation of ibrutinib. The rate of ibrutinib discontinuation was higher than reported in the literature, most likely influenced by the protocol design and financial decisions driven by the switch from sponsor-provided ibrutinib to insurance or self-paid medication. Our observations regarding safety, efficacy and lack of disease progression after ibrutinib discontinuation are encouraging, and warrant confirmation in long-term prospective studies. Clinicaltrials.gov Identifier NCT02315768. Funding: Pharmacyclics LLC. Disclosures Choi: AbbVie: Consultancy, Speakers Bureau. Amaya-Chanaga:AbbVie: Ended employment in the past 24 months, Other: Research performed while employed as an investigator of this study at UCSD.. Kipps:Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Castro:Kite Pharma: Research Funding; Pharmacyclics: Research Funding; Fate Therapeutics: Research Funding.

Shorter infusion time of ocrelizumab: Results from the randomized, double-blind ENSEMBLE PLUS substudy in patients with relapsing-remitting multiple sclerosis

Background: Ocrelizumab is an approved intravenously administered anti-CD20 antibody for multiple sclerosis (MS). Shortening the 600 mg infusion to 2 hours reduces the total site stay from 5.5–6 hours (approved infusion duration including mandatory pre-medication and post-infusion observation) to 4 hours. The safety profile of shorter-duration ocrelizumab infusions was investigated using results from ENSEMBLE PLUS.Methods: ENSEMBLE PLUS is a randomized, double-blind substudy to the single-arm ENSEMBLE study (NCT03085810). In ENSEMBLE, patients with early-stage relapsing-remitting MS received ocrelizumab 600 mg infusions every 24 weeks for 192 weeks. In ENSEMBLE PLUS, ocrelizumab 600 mg administered over the approved 3.5-hour infusion time (conventional duration) is compared with a 2-hour infusion (shorter duration); the durations of the initial infusions (2×300 mg, 14 days apart) were unaffected. The primary endpoint was the proportion of patients with infusion-related reactions (IRRs) following the first Randomized Dose.Results: From November 1, 2018, to December 13, 2019, 745 patients were randomized 1:1 to the conventional or shorter infusion group. At the first Randomized Dose, 99/373 patients (26.5%) in the conventional and 107/372 patients (28.8%) in the shorter infusion group experienced IRRs. The majority of IRRs were mild or moderate; >99% of all IRRs resolved without sequelae in both groups (conventional infusion group, 99/99; shorter infusion group, 106/107). No IRRs were serious, life-threatening, or fatal. No IRR-related discontinuations occurred. During the first Randomized Dose, 22/373 (5.9%) and 39/372 (10.5%) patients in the conventional and shorter infusion groups, respectively, had IRRs leading to infusion slowing/interruption. Adverse events were consistent with the known safety profile of ocrelizumab.Conclusion: The rates and severity of IRRs were similar between conventional and shorter infusions. No new safety signals were detected. Shortening the infusion time to 2 hours reduces the total site stay time (including mandatory pre-medication/infusion/observation) from 5.5–6 hours to 4 hours, and may reduce patient and site staff burden. A short video summarizing the key results is provided in supplemental material.

Rituximab Hypersensitivity: From Clinical Presentation to Management

Rituximab is a chimeric monoclonal antibody (mAb) against CD20 molecule which is expressed on human B cells. It has been used for the treatment of various lymphoid malignancies, lymphoproliferative diseases, and rheumatologic disorders. Rituximab is generally well tolerated. However, increased use of rituximab has been associated with hypersensitivity reactions (HSRs), which can be classified as infusion-related, cytokine-release, type I (IgE/non-IgE), mixed, type III, and type IV reactions. Immediate infusion-related reactions to rituximab are quite common and decrease in frequency with subsequent infusions. However, in about 10% of patients, severe infusion-related reactions develop, which prevent its use. Some of the immediate infusion reactions are due to a cytokine-release but some reactions raise concerns for type I (IgE/non-IgE) hypersensitivity. Recent studies have shown the presence of serum anti-rituximab antibodies, either represented by the IgG or IgE isotype. In some cases, clinical manifestations of IgE-mediated reactions and cytokine-release reactions partially overlap, which is called a mixed reaction. Classified as Type III reaction, rituximab-induced serum sickness reactions have been reported in patients with autoimmune diseases and hematological malignancies. The classic serum sickness triad (fever, rash, and arthralgia) has been observed in patients mainly with an underlying rheumatologic condition. Severe delayed type IV hypersensitivity reactions including non-severe maculopapular rash to severe reactions such as Stevens–Johnson syndrome and toxic epidermal necrolysis have been rarely reported following rituximab injection. Comprehensive reviews focused on rituximab-induced HSRs are scarce. We aimed to review clinical presentations, underlying mechanisms of rituximab hypersensitivity, as well as management including rapid drug desensitization.

Ocrelizumab shorter infusion: Primary results from the ENSEMBLE PLUS substudy in patients with MS.

ObjectiveTo assess the safety of ocrelizumab (OCR) shorter duration infusion in patients with MS.MethodsENSEMBLE PLUS is a randomized, double-blind substudy to the single-arm ENSEMBLE study (NCT03085810). In ENSEMBLE, patients with early stage relapsing-remitting MS received OCR 600 mg initially as two 300 mg IV infusions 2 weeks apart and subsequently as a single 3.5-hour 600 mg infusion every 24 weeks for 192 weeks. In ENSEMBLE PLUS, OCR 600 mg administered over the approved 3.5-hour infusion time (conventional duration) is compared with a 2-hour infusion (shorter duration). The primary end point was the proportion of patients with infusion-related reactions (IRRs) after the first randomized dose (assessed during and up to 24 hours postinfusion).ResultsFrom November 1, 2018, to September 27, 2019, 580 patients were randomized 1:1 to the conventional or shorter infusion group. After the first randomized dose, 67 of 291 patients (23.1%) in the conventional and 71 of 289 patients (24.6%) in the shorter infusion group experienced IRRs. Most IRRs were mild or moderate in both groups; one patient in each group experienced a severe IRR, and in both groups, 98.6% (136 of 138) of all IRRs resolved without sequelae. No IRRs were serious, life-threatening, or fatal. No IRR-related discontinuation occurred. During the first randomized dose, 14 of 291 (4.8%) and 25 of 289 (8.7%) patients in the conventional and shorter infusion groups, respectively, had IRRs leading to infusion slowing/interruption.ConclusionThe frequency and severity of IRRs were similar between conventional and shorter OCR infusions. Shortening the infusion time to 2 hours reduces the total infusion site stay time and lessens the overall patient and site staff burden.Classification of evidenceThis interventional study provides Class I evidence that the frequency and severity of IRRs were similar at the first randomized dose using OCR (600 mg) infusions of conventional and shorter duration in patients with relapsing-remitting MS.Clinical trial identifier numberNCT03085810.

The Healthcare Professionals' Perspective on Impact and Actions Taken Following Severe Infusion Reaction Events in Oncology Centers in Europe.

PurposeThe study aim was to describe the management strategies used for severe infusion-related reactions (SIRs) and understand the impact of such events in oncology day hospitals in France, Germany, Spain, and the UK.MethodsThe study was based on qualitative telephone interviews and quantitative self-completion questionnaires and asked healthcare professionals about the impact of SIRs and consequent actions taken.ResultsThe procedures to prevent and manage SIRs were similar across countries and settings. In all countries, they were part of a larger risk-assessment and adverse events-prevention process. Preventive measures included patient history, risk assessment, pre-medication, and close monitoring of high-risk patients. The management procedures comprised stopping the infusion, triggering of the emergency chain, administering corticosteroids ± antihistamines, and hospitalization if necessary. The recalled SIRs had important consequences to affected patients, healthcare providers, and hospital organizational plans. All affected patients needed to be monitored closely for a prolonged time, thus blocking hospital beds. 44% of patients needed to be hospitalized, 17% needed resuscitation, and one patient died of cardiac arrest immediately after the start of the infusion. Importantly, 82% of patients were not re-challenged with the presumedly SIR-causing regimen or re-challenged in a later line.ConclusionSIRs are unpredictable in nature, may have an extremely rapid onset, and are potentially fatal. Such events have a profound impact on the affected and surrounding patients, the care team and the organizational plan of the day-hospitals. Specific tools to reliably identify high-risk patients and predict the occurrence of events are needed.Electronic supplementary materialThe online version of this article (10.1007/s40801-020-00185-9) contains supplementary material, which is available to authorized users.

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.

Infusion-related reactions during Natalizumab treatment: Do we still need a post-infusion observation period?

BackgroundNatalizumab (NTZ) is a humanized monoclonal antibody used in the treatment of relapsing remitting multiple sclerosis. Although NTZ is usually well-tolerated, infusion-related reactions (IRRs) may occur, and the patients have to be monitored during the infusion and for one hour afterwards. ObjectiveTo identify frequency and severity of IRRs during NTZ infusions and one-hour post-infusion observation period in a clinical practice setting. MethodsMulticenter, observational study involving three Swiss (Lugano, St. Gallen and Luzern) and two Italian (Milano and Napoli) tertiary MS centers. Predisposing factors to IRRs were investigated using multivariate Cox regression models. ResultsA total of 11′133 infusions received by 302 MS patients were analyzed (68.9% females, median age 33.6 years, median EDSS 2.5). IRRs occurred in 24 (8%) patients during NTZ infusions and in 7 (2%) during one-hour post-infusion. Only 8 patients needed pharmacological treatment, of whom 7 during NTZ infusion. Age, sex and history of allergies were not associated with risks for IRR. The frequency of post infusion IRRs after the fifth cycle was low compared to that during the first four infusions (0.83% vs 0.06%). ConclusionIn our cohort, NTZ associated IRR mainly occurred during the infusion period compared to the one-hour observational period. Also, the first IRR exclusively occurred within the first 4 NTZ administrations. However, further multi-center studies with a larger sample size are needed to capture rare and serious events that could emerge during the observational period and to make clinical recommendations.

Practical considerations and role of Daratumumab retreatment for relapsed refractory Multiple Myeloma

Daratumumab is a first-in-class anti-CD38 monoclonal antibody approved for multiple myeloma. Because of the incidence and severity of infusion-related reactions with initial doses, daratumumab is administered over 6.5 hours for the first dose. With the need for pre-medication and monitoring, patients are scheduled for a 10-hour infusion visit. In an attempt to improve patient experience as well as optimize clinic space, additional pre-medications have been added with the initial doses and rapid infusion rate has been introduced for subsequent doses.

Subcutaneous Daratumumab in Patients with Relapsed or Refractory Multiple Myeloma: Part 2 Safety and Efficacy Update of the Open-Label, Multicenter, Phase 1b Study (PAVO)

Subcutaneous Daratumumab in Patients with Relapsed or Refractory Multiple Myeloma: Part 2 Safety and Efficacy Update of the Open-Label, Multicenter, Phase 1b Study (PAVO)

Tocilizumab to Prevent Infusion-Related Events in Patients with Chronic Lymphocytic Leukemia and Co-Morbidities Treated with Obinutuzumab and Chlorambucil: Results from the Randomized Phase Ib GALACTA Trial

Tocilizumab to Prevent Infusion-Related Events in Patients with Chronic Lymphocytic Leukemia and Co-Morbidities Treated with Obinutuzumab and Chlorambucil: Results from the Randomized Phase Ib GALACTA Trial

Ibrutinib Reduces Obinutuzumab-Gazyva Infusion Related Reactions (IRR) in Patients with Chronic Lymphocytic Leukemia (CLL) and It Is Associated with Changes on Plasma Cytokine Levels

Obinutuzumab-Gazyva (G) is an anti-CD20 monoclonal antibody that has shown better outcomes in patients (pts) with chronic lymphocytic leukemia and low-grade lymphoma (Goede 2014, Marcus 2017). However, one limitation for its use when compared to Rituximab is the presence of significantly more frequent and more severe infusion related reactions (IRR). Strategies to mitigate this significant adverse event are needed particularly to allow a safer administration of this antibody to elderly pts or those with existing comorbidities. We have observed a reduction of G-induced IRR in previously untreated CLL pts that are enrolled on a phase Ib/II clinical trial (NCT02315768) that combines G with the Bruton9s tyrosine kinase inhibitor, ibrutinib (Ibr). Only 5 out of 23 pts treated have developed IRR (Grade 1-2, 17% and Grade 3, 4%). This rate of IRR is much lower as compared with rates previously reported (all grades: 65%, grade 3-4: 20% - Goede 2014), (all grades: 92%, grade 3-4: 26.3% - Freeman,2015). Moreover, there were no pts that require permanent discontinuation of G due to IRR. To understand the biology of this beneficial effect of Ibr, we performed serial cytokine measurements on plasma samples from 23 pts enrolled in this study at different time points during the first week of combined treatment (Cycle 1 prior to the first infusion of G and post G infusion on Day 1, Day 2 and Day 8) - Figure 1. We developed a multiplex assay (Luminex) to measure 7 different cytokines previously reported to be involved in IRR (IFN-g, IL-10, IL6, IL8, CCL3/MIP1-a, CCL4/MIP1-band TNF-a). Standards were set up in duplicate yielding curves from 3.2 pg/ml to 10.000 pg/ml. Assays were performed according to manufacturer9s instructions, with undiluted samples and overnight agitated incubation at 4 °C. We identified the maximum peak of cytokine levels post G infusion and compared those values with the baseline cytokine profile obtained prior to the first G infusion on Cycle 1 Day 1. The majority of pts (22 out of 23) showed cytokines maximum peaks in the middle of G-infusion during Cycle 1 Day 1 and this correlated with the onset of IRR associated symptoms in those pts that reacted to G. With the exception of IL-6, we observed statistically higher post vs. pre G infusion levels of TNF-a(p=0.0012), IFN-g(p= Our study shows that concurrent administration of Ibr (Initiated on Cycle 1 Day 1 with pre-medications) and G shows a beneficial effect decreasing the rates of IRR (Amaya-Chanaga, 2016). All pts showed a significant increase of cytokine levels post G infusion with IL-6 levels being the exception. When we compared post G infusion cytokine levels, we observed that IRR-pts had a significant increase in TNF-a, IFN-g, and CCL3 suggesting a role of these cytokines in the clinical manifestations associated with IRR. In addition, higher levels of TNF-a and IFN-g, at baseline prior to G infusion appear to be predictive of the development of IRR. Even though our sample size is small, our observations provide additional insights into the biology of G associated IRR and how to decrease effectively those adverse events using Ibr while preserving the immune function needed for the activity of this monoclonal antibody. In addition, Ibr induced modulation of signaling through the B cell receptor and patterns of cytokine release might be efficacious in preventing other monoclonal antibody IRR as well as those reactions observed in pts that receive adoptive cellular therapy (i.e. CART cell treatment). Disclosures Choi:AbbVie, Inc: Consultancy, Speakers Bureau; Gilead: Speakers Bureau; Genentech: Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Rigel: Consultancy. Amaya-Chanaga:AbbVie: Equity Ownership, Other: Research performed while employed as an investigator of this study at UCSD. Review and approval of abstract performed while employed at Pharmacyclics, LLC, an AbbVie Company.; Pharmacyclics, an AbbVie Company: Employment, Other: Research performed while employed as an investigator of this study at UCSD. Review and approval of abstract performed while employed at Pharmacyclics, LLC, an AbbVie Company.. Kipps:Celgene: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Pharmacyclics: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Verastem: Membership on an entity9s Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Genentech Inc: Consultancy, Research Funding; Janssen: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Verastem: Membership on an entity9s Board of Directors or advisory committees. Castro:F. Hoffmann-La Roche: Consultancy; Genentech, Inc: Consultancy; Pharmacyclics, LLC, an AbbVie Company:: Consultancy.