Cytokine Release Syndrome in Patients Receiving Blinatumomab or Chimeric Antigen Receptor T Cells for Acute Lymphoblastic Leukemia
Craig W. Freyer, PharmD BCOP
Clinical Pharmacy Specialist Hematology/Oncology
Hospital of the University of Pennsylvania
Philadelphia, PA
Mitchell E. Hughes, PharmD BCPS
Clinical Pharmacy Specialist
Hematology/Oncology
Hospital of the University of Pennsylvania
Philadelphia, PA
The U.S. Food and Drug Administration (FDA) approval of blinatumomab (Blincyto®) in December 2014 marked the arrival of immunotherapy for relapsed/refractory B-cell acute lymphoblastic leukemia (RR B-ALL). Since then, other immunotherapy strategies have emerged, particularly the development of chimeric antigen receptor (CAR) T-cell clinical trials at some U.S. cancer centers. Blinatumomab is a bispecific T-cell engager antibody fragment that binds CD19 on B cells and CD3 on T cells, forming an immunologic synapse resulting in B-cell lysis.1 CAR T cells are virally engineered autologous T cells expressing a CD19 receptor that are capable of in vivo expansion resulting in T-cell activation and tumor lysis.2-4 Both of these CD19 targeted immunotherapies display impressive efficacy in RR B-ALL, yet present new challenges in supportive care with unique adverse events (AEs) not observed with cytotoxic chemotherapy. Both blinatumomab and CAR T cells can cause cytokine release syndrome (CRS), a potentially life-threatening inflammatory AE that pharmacists must be familiar with to optimize supportive care and maximize patient outcomes with these new immunotherapies.
CRS following blinatumomab or CAR T cells is characterized by symptoms of excessive inflammation secondary to release of numerous pro-inflammatory cytokines following T-cell activation and expansion. The implicated cytokines include IL-10, IL-6, IL-2, IFN-γ, and TNF-α, yet the magnitude of elevation shows significant interpatient variability.5 Severe febrile episodes (often > 40 °C) are common, presenting a challenge to delineate CRS versus infection. Patients may also experience myalgia, headaches, gastrointestinal distress, and fatigue. More severe sequelae include respiratory failure, neurologic toxicity (e.g., delirium, tremor, and seizures), cardiovascular compromise, tumor lysis syndrome, and disseminated intravascular coagulopathy. Using the FDA-approved dosing, blinatumomab has a reported CRS incidence of 11% for all grades and occurs only during the first cycle of treatment (usually within week 1), with symptoms correlating with T-cell expansion. CRS intensity correlates with disease burden (i.e., marrow blast count); as such, various attempts to reduce CRS have emerged throughout clinical trial experience with blinatumomab, including dexamethasone pretreatment and administration of leuko-reducing chemotherapy.6, 7 The FDA-approved labeling for blinatumomab requires two interventions to reduce CRS: a step-wise dosing approach of 9 mcg/day on days 1–7 followed by 28 mcg/day on days 8–28 of cycle 1, as well as dexamethasone pretreatment. Dexamethasone 20 mg IV is administered 1 hour prior to starting the cycle 1 day 1 infusion, as well as with the day 8 dose escalation during cycle 1, prior to day 1 starts for subsequent cycles, and anytime the infusion is interrupted for 4 hours or more. Pharmacists are instrumental in limiting the risk of CRS by ensuring appropriate dexamethasone premedication and providing nursing education to never flush the line containing blinatumomab, as this can increase risk of CRS by giving a sudden bolus of drug to the patient.1
Treatment of CRS relies on toxicity grading using the National Cancer Institute Common Terminology Criteria for Adverse Events for CRS. Grade 1 CRS consists of symptoms that are not life threatening, such as fever and constitutional symptoms, which require only symptomatic management with antipyretics and analgesics.8 A full infectious workup, including blood cultures and appropriate imaging, followed by prompt initiation of empiric antibiotics is recommended, especially in the setting of concurrent neutropenia due to limited ability to separate CRS from infection. Grade 2 CRS is characterized by symptoms requiring moderate intensity interventions, including hypotension requiring fluid resuscitation or one low-dose pressor, hypoxia requiring the addition of up to 40% oxygen, or the presence of a specific grade 2 organ toxicity. Patients with grade 3 CRS require more than one pressor or high titration of a single pressor (i.e., > 20 mcg/kg/min norepinephrine) for hypotension and must have an oxygen requirement of > 40% or a specific grade 3 organ toxicity. Blinatumomab has a short half life of approximately 2 hours, which grants tight control of drug levels throughout the treatment course. In the setting of grade 3 CRS, the infusion should be discontinued and may be restarted at 9 mcg/day once symptoms resolve.1 Dexamethasone is crucial in attenuating the excessive inflammatory cascade during blinatumomab-related CRS, yet the optimal regimen remains to be determined. One published recommendation includes a tapered regimen of dexamethasone 24 mg IV divided every 8 hours on day 1, 16 mg divided every 12 hours on day 2, followed by 8 mg daily on days 3 and 4, but the rapidity of the taper depends on the patient’s clinical status.9 Because blinatumomab relies on T-cell activation for efficacy, there is a theoretical concern that dexamethasone might impair efficacy. Low doses of dexamethasone suppress cytokine release without impairing in vitro cytotoxic effect,10 and receipt of dexamethasone did not impair outcomes in a large phase 2 study11; nevertheless the absence of randomized data warrants judicious use of dexamethasone. The IL-6 receptor antagonist tocilizumab (Actemra®) is rarely needed for blinatumomab-related CRS, in contrast to CRS following CAR T cells (as discussed below). However, a case of steroid-refractory blinatumomab-related CRS complicated by macrophage activation syndrome that was responsive to tocilizumab has been reported.12 Grade 4 CRS is characterized by life-threatening symptoms or ventilator-dependent respiratory failure, for which permanent discontinuation of blinatumomab is recommended along with the aforementioned supportive care strategies.1
CRS is a common and clinically significant AE following CAR T cells, with a variable onset following infusion and a reported all-grades incidence as high as 100% in ALL.13, 14 Despite increases in numerous cytokines, the key mediator of CRS following CAR T cells appears to be IL-6, an acute-phase reactant producing both anti- and pro-inflammatory effects, dependent on the level and signaling pathway involved. IL-6 is normally produced in response to infection, trauma, or immunological challenge, and contributes to a clinical syndrome mirroring sepsis.8 C-reactive protein (CRP) and ferritin frequently are measured following CAR T-cell infusions and are associated with CRS.15 CRP originates from the liver as an acute phase reactant and can be used as a surrogate marker for IL-6, given IL-6 monitoring can be a challenge with limited assay availability and slow turnaround time.16 Significant ferritin elevations (sometimes > 300,000 ng/m), may occur in the setting of CRS, mimicking hemophagocytic lymphohistiocytosis with associated hepatosplenomegaly and hypofibrinogenemia.
As with blinatumomab, the severity of CRS following CAR T cells is related to disease burden prior to treatment, in addition to possible associations with the dose of T cells infused and the schedule of cell infusion (100% of target dose infused on day 1 versus administered over 3 days).8,17 The presence of any grade of CRS following CAR T cells correlates with antitumor effect; however, it is unclear if patients experiencing severe CRS demonstrate greater antitumor efficacy than those with lower grade CRS.16 Grade 3 CRS following CAR T cells (or grade 2 CRS in an older patient with comorbidities) is managed with the IL-6 receptor antagonist tocilizumab at 8 mg/kg IV administered over 1 hour.16 Targeting IL-6 has become the most common management strategy for moderate to severe CRS following CAR T cells due to early clinical experience, rapid onset of efficacy, favorable tolerability, and lack of apparent detrimental effect on antitumor efficacy (although this remains experimental and expert opinion in the absence of randomized data).16 Following tocilizumab, clinical improvement can occur quickly (within a few hours), yet some patients with suboptimal response may require an additional dose of tocilizumab within several hours of the first dose.18 The IL-6 antagonist siltuximab, administered over 1 hour at 11 mg/kg, also is an option for CRS refractory to tocilizumab, but the benefit of this addition remains unclear.16,18 A hallmark of CAR T-cell CRS management has been to limit use of corticosteroids in the first-line setting given the potential to dampen CAR T-cell efficacy due to the T-cell lymphotoxic effect of steroids. On the contrary, recent data suggest up to 2 mg/ kg/day of methylprednisolone given at the peak of CRS for short intervals is unlikely to impair CAR T-cell efficacy, yet more clinical experience is needed to make a definitive statement regarding the effects of steroids on CAR T-cell efficacy.16 Dexamethasone may be preferred over methylprednisolone in the setting of neurologic toxicity given its greater blood-brain barrier penetration.16
CRS is a complicated and unique toxicity following blinatumomab and CAR T cells, which are two major therapeutic advances in the management of RR B-ALL. Grade 1–2 CRS is typically managed with supportive care, with a low threshold to administer dexamethasone in the case of progressive CRS with blinatumomab. Minimal published experience exists for tocilizumab in blinatumomab-related CRS, and thus should be reserved for steroid-refractory CRS. The cornerstone of CRS management following CAR T cells is tocilizumab. Our practice is to deliver tocilizumab within 15 minutes of order entry, with a low threshold to repeat dosing in the setting of suboptimal response. Siltuximab and ultimately high-dose corticosteroids are options for tocilizumab-refractory CRS following CAR T cells. Further research is needed to determine the effects of high-dose steroids on the clinical efficacy of CAR T cells. Pharmacists working in centers using blinatumomab and investigational CAR T cells must understand the intricacies of this unique AE and be prepared to recommend supportive care despite limited clinical experience to maximize patient outcomes with these novel therapeutic agents.
References
1. Blincyto [package insert]. Amgen Inc; Thousand Oaks, CA: 2014
2. Grupp SA, Kalos M, Barrett D, et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med. 2013;368:1509-18.
3. Brentjens RJ, Davila ML, Riviere I, et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med. 2013;5(177):1-9.
4. Lee DW, Kochenderfer JN, Stetler-Stevenson M, et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet. 2015;385(9967): 517-28.
5. Klinger M, Brandl C, Zugmaier G, et al. Immunopharmacologic response of patients with B-lineage acute lymphoblastic leukemia to continuous infusion of T cell-engaging CD19/CD3- bispecific BiTE antibody blinatumomab. Blood (ASH Annual Meeting Abstracts). 2012;119(26):6226-33.
6. Topp MS, Gokbuget N, Stein AS, et al. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. Lancet Oncol. 2015;16:57-66.
7. Topp MS, Gokbuget N, Zugmaier G, et al. Phase II Trial of the Anti-CD19 bispecific T cell-engager blinatumomab shows hematologic and molecular remissions in patients with relapsed or refractory B-precursor acute lymphoblastic leukemia. J Clin Oncol. 2014;32(36):4134-40.
8. Lee DW, Gardner R, Porter DL, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014;124(2):188- 95.
9. Rogala B, Freyer CW, Ontiveros EP, Griffiths EA, Wang ES, Wetzler M. Blinatumomab: enlisting serial killer T cells in the war against hematologic malignancies. Expert Opin Biol Ther. 2015;15(6):895-908.
10. Brandl C, Haas C, d’Argouges S, et al. The effect of dexamethasone on polyclonal T-cell activation and redirected target cell lysis as induced by a CD19/CD3-bispecific single-chain antibody construct. Cancer Immunol Immunother. 2007;56:1551-63.
11. Topp MS, Gokbuget N, Stein AS, et al. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. Lancet Oncol. 2015;16:57-66.
12. Teachey DT, Rheingold SR, Maude SL, et al. Cytokine release syndrome after blinatumomab treatment related to abnormal macrophage activation and ameliorated with cytokine-directed therapy. Blood. 2013;121(26):5154-7.
13. Maude SL, Frey N, Shaw Pa, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;271(16):1507-17.
14. Grupp S, Maude SL, Shaw P, et al. T cells engineered with a chimeric antigen receptor (CAR) targeting CD19 (CTL019) have long term persistence and induce durable remissions in children with relapsed, refractory ALL. Blood (ASH Annual Meeting Abstracts). 2014;abstract 380. Available from: www.ash.confex.com/ash/2014/webprogram/Paper69932. html
15. Teachey DT, Lacey SF, Shaw PA, et al. Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Cancer Discov. 2016;6(6):664-79.
16. Maude SL, Teachey DT, Porter DL, Grupp SA. CD19-targeted chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Blood. 2015;125(26):4017-23.
17. Frey NV, Shaw PA, Hexner EO, et al. Optimizing chimeric antigen receptor (CAR) T-cell therapy for adult patients with relapsed or refractory acute lymphoblastic leukemia (ALL). ASCO Annual Meeting Abstracts, #7002. Available from: www.meetinglibrary.asco.org/content/166823-176
18. Frey NV, Levine BL, Lacey SF, et al. Refractory cytokine release syndrome in recipients of chimeric antigen receptor (CAR) T cells. Blood (ASH Annual Meeting Abstracts). 2014;abstract 2296. Available from: www.ash.confex.com/ash/2014/webprogram/Paper76315.html