scholarly journals Cytokine release syndrome after CAR infusion in pediatric patients with refractory/relapsed B-ALL: is there a role for diclofenac?

2021 ◽  
pp. 030089162110533
Author(s):  
Sara Napolitano ◽  
Giorgio Ottaviano ◽  
Laura Bettini ◽  
Vincenzo Russotto ◽  
Sonia Bonanomi ◽  
...  
Keyword(s):  
Pediatric Patients ◽  
Lymphoblastic Leukemia ◽  
Symptom Relief ◽  
Major Complication ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Pediatric Dose ◽  
Systemic Inflammatory Reaction ◽  
Number Of Patients ◽  
B Lineage

Background: Cytokine release syndrome (CRS) is a major complication after chimeric-antigen receptor T-cell treatment, characterized by an uncontrolled systemic inflammatory reaction. We investigated the potential role of diclofenac in the management of CRS in five pediatric patients treated for relapsed/refractory B-lineage acute lymphoblastic leukemia. Methods In case of persistent fever with fever-free intervals shorter than 3 hours, diclofenac continuous infusion was initiated, at the starting dose of 0.5 mg/Kg/day, the lowest effective pediatric dose in our experience, possibly escalated up to 1 mg/Kg/day, as per institutional guidelines. Results: CRS occurred at a median of 20 hours (range 8–27) after tisagenlecleucel infusion. Diclofenac was started at a median of 20 hours (range 13–33) after fever onset. A mean of 3.07 febrile peaks without diclofenac and 0.95 with diclofenac were reported ( p = 0.02). Clinical benefit was achieved by hampering the progression of tachypnea and tachycardia. Despite fever control, CRS progressed in four of the five patients, and hypotension requiring vasopressors and fluid retention, as well as hypoxia, occurred. Vasopressors were followed by 1–2 doses of tocilizumab (one in patient 2 and two in patients 3, 4, and 5), plus steroids in patients 4 and 5. Conclusion: Based on a limited number of patients, diclofenac leads to better fever control, which translates into symptom relief and improvement of tachycardia, but could not prevent the progression of CRS.

scholarly journals Cytokine Release Syndrome after Tisagenlecleucel Infusion in Pediatric Patients with Refractory/Relapsed B-Lineage Acute Lymphoblastic Leukemia: Is there a Role for Diclofenac?

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Napolitano S ◽  
◽  
Bonanomi S ◽  
Rovelli A ◽  
Biondi A ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Pediatric Patients ◽  
Lymphoblastic Leukemia ◽  
Symptom Relief ◽  
P Value ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Pediatric Dose ◽  
Number Of Patients ◽  
B Lineage

Background: Cytokine Release Syndrome (CRS) is a major complication after Chimeric-Antigen Receptor (CAR) T cell treatment, characterized by an uncontrolled sistemic inflammatory reaction. The potential role of diclofenac in the management of CRS has been investigated in five pediatric patients treated for relapsed/refractory B-lineage acute lymphoblastic leukemia. Procedure: in case of persistent fever with fever-free intervals shorter than 3 hours, diclofenac continuous infusion was initiated, at the starting dose of 0.5 mg/Kg/day, the lowest effective pediatric dose, in our experience, possibly escalated up to 1 mg/Kg/day, as per institutional guidelines. Vital signs, O2 requirement, SpO2/FiO2 ratio and dosage of diclofenac and vasopressors until CRS resolution were recorded. Results: CRS occurred at a median of 20 hours (range 8-27) after tisagenlecleucel infusion. Diclofenac was started at a median of 20 hours (range 13-33) after fever onset. A mean of 3,07 febrile peaks without diclofenac and 0,95 with diclofenac were reported (p-value 0.02). A clinical benefit was achieved by hampering the progression of tachypnea and, mainly, tachycardia. Despite fever control, CRS progressed in four of the five patients and hypotension requiring vasopressors, fluid retention, besides hypoxia, occurred. Vasopressors were followed by 1-2 doses of tocilizumab (one in patient 2 and two in patients 3, 4, and 5), plus steroids in patients 4 and 5. Conclusion: based on a limited number of patients, diclofenac leads to a better fever control, which translates into symptom relief and improvement of tachycardia, but could not prevent the progression of CRS.

scholarly journals Diagnostic biomarkers to differentiate sepsis from cytokine release syndrome in critically ill children

2020 ◽  
Vol 4 (20) ◽  
pp. 5174-5183 ◽  
Author(s):  
Caroline Diorio ◽  
Pamela A. Shaw ◽  
Edward Pequignot ◽  
Alena Orlenko ◽  
Fang Chen ◽  
...  
Keyword(s):  
Pediatric Patients ◽  
Lymphoblastic Leukemia ◽  
Interferon Γ ◽  
Critically Ill Children ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Diagnostic Biomarkers ◽  
Increased Risk ◽  
Car T ◽  
Outcomes For Children

Abstract Chimeric antigen receptor (CAR) T-cells directed against CD19 have drastically altered outcomes for children with relapsed and refractory acute lymphoblastic leukemia (r/r ALL). Pediatric patients with r/r ALL treated with CAR-T are at increased risk of both cytokine release syndrome (CRS) and sepsis. We sought to investigate the biologic differences between CRS and sepsis and to develop predictive models which could accurately differentiate CRS from sepsis at the time of critical illness. We identified 23 different cytokines that were significantly different between patients with sepsis and CRS. Using elastic net prediction modeling and tree classification, we identified cytokines that were able to classify subjects as having CRS or sepsis accurately. A markedly elevated interferon γ (IFNγ) or a mildly elevated IFNγ in combination with a low IL1β were associated with CRS. A normal to mildly elevated IFNγ in combination with an elevated IL1β was associated with sepsis. This combination of IFNγ and IL1β was able to categorize subjects as having CRS or sepsis with 97% accuracy. As CAR-T therapies become more common, these data provide important novel information to better manage potential associated toxicities.

scholarly journals Phase I/Phase II Study of Blinatumomab in Pediatric Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia

2016 ◽  
Vol 34 (36) ◽  
pp. 4381-4389 ◽  
Author(s):  
Arend von Stackelberg ◽  
Franco Locatelli ◽  
Gerhard Zugmaier ◽  
Rupert Handgretinger ◽  
Tanya M. Trippett ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Recommended Dosage ◽  
Disease Response ◽  
Grade 3 ◽  
Minimal Residual

Purpose Blinatumomab is a bispecific T-cell engager antibody construct targeting CD19 on B-cell lymphoblasts. We evaluated the safety, pharmacokinetics, recommended dosage, and potential for efficacy of blinatumomab in children with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Methods This open-label study enrolled children < 18 years old with relapsed/refractory BCP-ALL in a phase I dosage-escalation part and a phase II part, using 6-week treatment cycles. Primary end points were maximum-tolerated dosage (phase I) and complete remission rate within the first two cycles (phase II). Results We treated 49 patients in phase I and 44 patients in phase II. Four patients had dose-limiting toxicities in cycle 1 (phase I). Three experienced grade 4 cytokine-release syndrome (one attributed to grade 5 cardiac failure); one had fatal respiratory failure. The maximum-tolerated dosage was 15 µg/m2/d. Blinatumomab pharmacokinetics was linear across dosage levels and consistent among age groups. On the basis of the phase I data, the recommended blinatumomab dosage for children with relapsed/refractory ALL was 5 µg/m2/d for the first 7 days, followed by 15 µg/m2/d thereafter. Among the 70 patients who received the recommended dosage, 27 (39%; 95% CI, 27% to 51%) achieved complete remission within the first two cycles, 14 (52%) of whom achieved complete minimal residual disease response. The most frequent grade ≥ 3 adverse events were anemia (36%), thrombocytopenia (21%), and hypokalemia (17%). Three patients (4%) and one patient (1%) had cytokine-release syndrome of grade 3 and 4, respectively. Two patients (3%) interrupted treatment after grade 2 seizures. Conclusion This trial, which to the best of our knowledge was the first such trial in pediatrics, demonstrated antileukemic activity of single-agent blinatumomab with complete minimal residual disease response in children with relapsed/refractory BCP-ALL. Blinatumomab may represent an important new treatment option in this setting, requiring further investigation in curative indications.

scholarly journals Cytokine Release Syndrome Is an Independent Risk Factor Associated With Platelet Transfusion Refractoriness After CAR-T Therapy for Relapsed/Refractory Acute Lymphoblastic Leukemia

2021 ◽  
Vol 12 ◽  
Author(s):  
Yadan Liu ◽  
Bin Liang ◽  
Yan Liu ◽  
Guoqing Wei ◽  
Wenjun Wu ◽  
...  
Keyword(s):  
Risk Factor ◽  
Acute Lymphoblastic Leukemia ◽  
Platelet Transfusion ◽  
Independent Risk Factor ◽  
Lymphoblastic Leukemia ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Car T ◽  
Grade 3 ◽  
Platelet Transfusions

Background: Chimeric antigen receptor T cell (CAR-T) therapy is successful in improving treatment outcomes for relapsed/refractory acute lymphoblastic leukemia (R/R ALL). However, toxicities associated with CAR-T therapy are being increasingly identified. Pancytopenia is one of the most common complications after CAR-T therapy, and platelet transfusions are an essential part of its supportive care.Study Design and Methods: This study aimed to assess the effectiveness of platelet transfusions for R/R ALL patients at our single center and identify associated risk factors. Overall, 44 R/R ALL patients were enrolled in this study, of whom 26 received CAR-T therapy and 18 received salvage chemotherapy.Result: Patients in the CAR-T group had a higher incidence of platelet transfusion refractoriness (PTR) (15/26, 57.7%) than those in the chemotherapy group (3/18, 16.7%) (p = 0.007). For patients receiving CAR-T therapy, multivariate analysis showed that the grade of cytokine release syndrome (CRS) was the only independent risk factor associated with PTR (p = 0.007). Moreover, higher peak serum IL-6 and IFN-γ levels suggested a higher risk of PTR (p = 0.024 and 0.009, respectively). Patients with PTR received more platelet infusion doses than those without PTR (p = 0.0426). Patients with PTR had more grade 3–4 bleeding events than those without PTR (21.4 vs. 0%, p = 0.230), and the cumulative incidence of grade 3–4 bleeding event was different (p = 0.023).Conclusion: We found for the first time that PTR is associated with the CRS grade. Improved knowledge on the mechanisms of PTR after CAR-T therapy is needed to design a rational therapeutic strategy that aims to improve the efficiency of transfusions.

From Bedside To Bench: Molecular Benchmarking Of An Fc-Optimized CD19 Antibody Used In Treatment Of Relapsed and Refractory Pediatric B-Lineage Acute Lymphoblastic Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3905-3905 ◽  
Author(s):  
Ursula J.E. Seidel ◽  
Ludger Grosse-Hovest ◽  
Patrick Schlegel ◽  
Martin Hofmann ◽  
Friedhelm R. Schuster ◽  
...  
Keyword(s):  
Pediatric Patients ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Compassionate Use ◽  
Effector Cells ◽  
Cytotoxicity Assays ◽  
Healthy Donors ◽  
B Lineage

Abstract B-lineage acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Although this disease can be curatively treated in 80% of patients by chemotherapy, prognosis for primary refractory or relapsed patients is very poor. Even after allogeneic stem cell transplantation (SCT), relapse rates are considerable and correlate significantly with persistent minimal residual disease (MRD) prior to or after SCT. Since a MRD constellation represents favorable effector-target ratios it is well suited for immunotherapy with therapeutic antibodies. We developed and produced a third-generation CD19-specific monoclonal antibody (mAb) (4G7SDIE) in clinical-grade quality at a university-owned production unit. This high affinity Fc-optimized chimerized CD19-specific mAb mediates enhanced antibody-dependent cellular cytotoxicity (ADCC) by NK cells through its improved capability to recruit FcγRIIIa bearing effector cells. In this study, 4G7SDIE was applied within the scope of a compassionate use program in pediatric patients with relapsed or refractory B-lineage ALL and characterized in vitro and in vivo. Firstly, it was confirmed that CD19 is commonly and stably expressed in pediatric B-lineage ALL by quantitative flow cytometry analysis of primary leukemic blasts (mean expression: 1.4x104 CD19 molecules/cell; range 4.5x103-2.4x104; n = 18). Hence CD19 is a well suited target for immunotherapy of pediatric B-lineage ALL. Half-saturating concentrations of 4G7SDIE on primary leukemic blasts and cell line NALM-16 were reached at EC50= 85 ng/ml (± 29). Half-maximal target cell lysis was reached at EC50 = 25 ng/ml. Furthermore, lysis of primary B-lineage ALL blasts by PBMC of 4 healthy donors could be significantly increased by 22% when adding 1 µg/ml 4G7SDIE to donor serum in 2 h-cytotoxicity assays (n = 9; p = 0.03). 4G7SDIE was applied in 11 pediatric patients with relapsed or refractory B-lineage ALL in order to reduce or eradicate MRD and thus prevent relapse in these high-risk pre- and post-transplant patients. Especially, in a post-transplant context, with a high number of allogeneic NK effector cells available, use of an ADCC-mediating mAb shows potential. In 6/9 treated patients with detectable MRD, leukemic load was reduced by ≥ 1 log or pushed below detection limit (10-4) through immunotherapy with 4G7SDIE. Moreover, 2 further patients responded to 4G7SDIE treatment. However, they received additional therapy with tyrosine-kinase inhibitors. Five of the treated patients eventually relapsed, 5 other patients went into remission after 4G7SDIE application (range 27-597 days). Concomitant in vitro 2 h-cytotoxicity assays with donor-derived PBMC of 2 treated patients showed that NK-cell mediated lysis of autologous B-lineage ALL blasts was increased by 33%, when adding 1 µg/ml 4G7SDIE or by 22% when adding autologous patient serum taken after antibody treatment (n = 8; p = 0.02). Serum half-life of 4G7SDIE in the first treatment cycles ranged between 20 h and 43 h and after infusion of 20 mg/m2, saturating serum concentrations of ≥700 ng/ml were detectable for at least 13 days. In a standardized model with MCF7-CD19-transfectants, expressing various CD19 levels on the cell surface, a correlation between increasing CD19 molecules/cell and increasing specific lysis by PBMC of healthy donors coincubated with 4G7SDIE was shown (spearman r = 0.88; p = 0.01). Strikingly, in 3 patients with residual disease detectable by flow cytometry, a down-modulation of CD19 on leukemic blasts under 4G7SDIE therapy was observed. In one patient up-regulation of CD19 after discontinuation of 4G7SDIE treatment was observed. In vitro antigenic shift assays on primary leukemic blasts showed considerable but very heterogeneous shift of CD19 surface expression. These observations hint at in vivotumor escape mechanisms and furthermore indicate selective pressure exerted by immunotherapy with 4G7SDIE, underlining its therapeutic potential, but also delineating its limitations. In conclusion, promising antileukemic effects have been observed in vitro and in vivo in this compassionate use program. However, potential CD19 down-modulation upon immunotherapy should be taken into account and may indicate the relevance of optimized treatment schedules and dosage as well as specific patient selection. We are currently setting up a clinical trial. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Case Report: Local Cytokine Release Syndrome in an Acute Lymphoblastic Leukemia Patient After Treatment With Chimeric Antigen Receptor T-Cell Therapy: A Possible Model, Literature Review and Perspective

2021 ◽  
Vol 12 ◽  
Author(s):  
Chengxin Luan ◽  
Junjie Zhou ◽  
Haixia Wang ◽  
Xiaoyu Ma ◽  
Zhangbiao Long ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Cell Therapy ◽  
B Cell ◽  
Chimeric Antigen Receptor ◽  
Lymphoblastic Leukemia ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
T Cell Therapy ◽  
Car T ◽  
Local Cytokine

Chimeric antigen receptor T (CAR-T) cell therapy has achieved remarkable clinical efficacy in treatment of many malignancies especially for B-cell hematologic malignancies. However, the application of CAR-T cells is hampered by potentially adverse events, of which cytokine release syndrome (CRS) is one of the severest and the most studied. Local cytokine-release syndrome (L-CRS) at particular parts of the body has been reported once in a while in B-cell lymphoma or other compartmental tumors. The underlying mechanism of L-CRS is not well understood and the existing reports attempting to illustrate it only involve compartmental tumors, some of which even indicated L-CRS only happens in compartmental tumors. Acute lymphoblastic leukemia (ALL) is systemic and our center treated a B-cell ALL patient who exhibited life threatening dyspnea, L-CRS was under suspicion and the patient was successfully rescued with treatment algorithm of CRS. The case is the firstly reported L-CRS related to systemic malignancies and we tentatively propose a model to illustrate the occurrence and development of L-CRS of systemic malignancies inspired by the case and literature, with emphasis on the new recognition of L-CRS.

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