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Cytokine release syndrome and neurologic toxicities associated with chimeric antigen receptor T-cell therapy: A comprehensive review of emerging grading models
Hematol Oncol Stem Cell Ther xxx (xxxx) xxx
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REVIEW ARTICLE
Cytokine release syndrome and neurologic toxicities associated with chimeric antigen receptor T-cell therapy: A comprehensive review of emerging grading models Julio C. Chavez a, Michael D. Jain b, Mohamed A. Kharfan-Dabaja c,* a
Department of Malignant Hematology, H. Lee Moffitt Cancer Center, Tampa, FL, USA Department of Blood and Marrow Transplant and Cellular Immunotherapy, H. Lee Moffitt Cancer Center, Tampa, FL, USA c Division of Hematology–Oncology, Blood and Marrow Transplantation and Cellular Therapies Program, Mayo Clinic, Jacksonville, FL, USA b
Received 10 April 2019; received in revised form 20 May 2019; accepted 23 May 2019
KEYWORDS Chimeric antigen receptor T-cell therapy; Cytokine release syndrome; Neurotoxicity
Abstract Advances in the fields of immuno-oncology and T-cell engineering have brought autologous chimeric antigen receptor T-cell (CART) therapies from the bench to the bedside. At present, two CART products that target CD19 are commercially available: tisagenlecleucel and axicabtagene ciloleucel. They have demonstrated remarkable efficacy for their particular indications. One challenge is to compare the safety among commercially available and clinical trial CART treatments due to the use of different grading models to assess the severity of cytokine release syndrome and neurotoxicity. An unmet need exists to harmonize current grading models in order to develop uniform treatment strategies to manage these toxicities. Here, we attempt to summarize the evolution of the various grading systems for cytokine release syndrome and neurotoxicity and also highlight the major differences among them, whenever applicable. Ó 2019 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-ncnd/4.0/).
* Corresponding author at: Blood and Marrow Transplantation Program, Division of Hematology–Oncology, Mayo Clinic, 4500 San Pablo Road S, Jacksonville, FL, USA. E-mail address: [email protected] (M.A. Kharfan-Dabaja). https://doi.org/10.1016/j.hemonc.2019.05.005 1658-3876/Ó 2019 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Please cite this article as: J. C. Chavez, M. D. Jain and M. A. Kharfan-Dabaja, Cytokine release syndrome and neurologic toxicities associated with chimeric antigen receptor T-cell therapy: A comprehensive review of emerging grading models, Hematol Oncol Stem Cell Ther, https://doi.org/10.1016/j.hemonc.2019.05.005
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Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CRS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Predictors of CRS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CRS grading criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Limitations related to clinical practice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . NT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Predictors of NT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Models to grade NT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Limitations of NT grading in clinical practice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Declaration of Competing Interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Introduction Advances in the fields of immuno-oncology and T-cell engineering have brought autologous chimeric antigen receptor T-cell (CART) therapies from the bench to the bedside [1]. Presently, two CART products are already commercially available, namely, tisagenlecleucel [2,3] and axicabtagene ciloleucel [4]. Tisagenlecleucel is approved for patients up to 25 years of age with refractory or in second or later relapse B-cell precursor acute lymphoblastic leukemia (B-ALL) [2]. Moreover, tisagenlecleucel and axicabtagene ciloleucel are both approved for adult patients with relapsed or refractory (R/R) large B-cell lymphoma after two or more lines of systemic therapy including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, highgrade B-cell lymphoma, and transformed DLBCL arising from follicular lymphoma (TFL) [3,4]. Axicabtagene ciloleucel is also approved for treatment of R/R primary mediastinal large B-cell lymphoma (PMBCL) [4]. These products have demonstrated remarkable efficacy in these poor risk populations considering that the historic prognosis of patients with R/R B-ALL or DLBCL after failing two preceding lines of therapies was dismal [5]. In a single-center phase 1/2A study of 75 patients (median age, 11 years) with CD19+ relapsed or refractory B-ALL, tisagenlecleucel resulted in 12-month progression-free (PFS) and overall (OS) survival rates of 50% and 73%, respectively with a median duration of remission not being reached [2]. Pertaining to R/R DLBCL, encouraging results were reported with both axicabtagene ciloleucel and tisagenlecleucel [3,4]. Neelapu et al. [4] described an objective response rate (ORR) of 82% (complete remission [CR] = 54%) when axicabtagene ciloleucel was prescribed to 101 patients (median age, 58 years) with DLBCL (n = 77, 76%), PMBCL (n = 8, 8%), or TFL (n = 16, 16%). This is a remarkable response considering that approximately 70% of cases had failed three or more prior treatments and responses were observed despite the presence of adverse prognostic features such as bulky disease (10 cm) and activated B-cell-like subtype cell of origin, among others [4]. Similarly, in an international pivotal phase 2 study, 111 patients (median age, 58 years) were treated with tisagenlecleucel after the majority of cases (52%) had failed three or more lines of therapy, and the best reported ORR was 52% (CR = 40%) [3]. The median duration
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of response was not reached, and 79% of patients who achieved a CR were projected to remain relapse-free 12 months later [3]. Similar to axicabtagene ciloleucel, efficacy of tisagenlecleucel was demonstrated regardless of adverse risk factors, including cases with double or triple hit DLBCL [3]. While acknowledging that CART have certainly revolutionized the treatment algorithms of R/R/ B-ALL and aforementioned subtypes of B-cell lymphomas and have favorably altered the prognosis of these diseases, these therapies result in a unique array of toxicities, namely, cytokine release syndrome (CRS) and neurotoxicity (NT) also referred to as CART-related encephalopathy syndrome (CRES) or immune related effector cell-associated neurotoxicity syndrome (ICANS) [6,7]. One of the various challenges in trying to assess and compare, side by side, the safety of these commercially available CART treatments, and other CART products currently being evaluated in clinical trials is the use of various grading models to assess the severity of CRS and NT [6,8]. As a result, assigning and categorizing grading scores to toxicities may vary across published clinical trials and even across individual centers, posing a challenge to developing uniform strategies to manage these toxicities. Recently, the American Society for Blood and Marrow Transplantation (ASBMT) issued clinical practice recommendations and definitions for grading CRS and NT [7]. This represents a significant step forward toward harmonizing clinical practice. Below, we summarize the evolution of the various grading systems for CRS and NT and also highlight the major differences among them, whenever applicable.
CRS Predictors of CRS CRS is caused by the release of cytokines during in vivo CART cell expansion [9]. The toxicity of CRS results from the systemic effects of cytokines on multiple organ systems. The grading models for CRS capture the organ systems typically affected by CRS, but fever appears to be a key sign that CRS has occurred. Mechanistically, CRS originates from cytokines released by the CART cells, but may be augmented by other immune cells [4,10–12].
Please cite this article as: J. C. Chavez, M. D. Jain and M. A. Kharfan-Dabaja, Cytokine release syndrome and neurologic toxicities associated with chimeric antigen receptor T-cell therapy: A comprehensive review of emerging grading models, Hematol Oncol Stem Cell Ther, https://doi.org/10.1016/j.hemonc.2019.05.005
CRS and NT associated with CART Severe CRS causes toxicity beyond fever, hypotension responsive to fluids, and hypoxia responsive to low-level oxygen support. The likelihood of a patient experiencing severe CRS depends on patient-, tumor-, and CART-related factors. In terms of patient-related factors, the baseline inflammatory state appears to be of particular importance. Patients with a high baseline serum ferritin, C-reactive protein, or elevated baseline cytokine levels are at a higher risk of CRS [9,13]. For factors such as disease type (B-ALL vs. various histologies of B-cell lymphomas), grading systems for CRS and patient population may influence the rates of CRS reported in clinical trials, but the overall experience is that CRS is somewhat different depending on histology. Furthermore, a higher tumor burden also appears to predict a higher rate of CRS [10,14]. The rate of CRS may also be modifiable by CART design or manufacturing practices, or may be different based on the costimulatory domain used (i.e., CD28 vs. 4-1BB) [15,16]. Finally, earlier interventions with treatments such as corticosteroids and anti-interleukin 6 (IL-6) therapy (i.e., tocilizumab) appear to reduce the rates of severe CRS. For example, in patients with DLBCL, the ZUMA-1 clinical trial reported the rate of severe CRS to be 14%, whereas real-world consortia described this rate to be less than 10% likely because of earlier intervention with tocilizumab and/or corticosteroids [17,18].
CRS grading criteria Efforts have been made to harmonize and standardize grading criteria for CRS. The main grading systems that were used in the earlier CART clinical trials included the National Cancer Institute Consensus Grading [8], the University of Pennsylvania (UPenn) grading [19], the Memorial Sloan Kettering Cancer Center (MSKCC) criteria [14] and, for clinical trials, common terminology criteria for adverse events (CTCAE) [20]. In addition, the definition of CRS was refined between CTCAE v4.03 and CTCAE v5.0, where the more recent version now has CRS grading criteria similar to those reported by Lee et al. [8] Differences in grading criteria led to differences in the rate and the severity of CRS reported on a particular clinical trial. For example, in Lee et al. [8] criteria, hypotension responsive to fluids and hypoxia requiring less than 40% FiO2 is listed as Grade 2 CRS (nonsevere). However, by the UPenn system these are considered Grade 3 and are therefore consistent with severe CRS [19]. This difference is emphasized even further by an analysis of the JULIET trial of tisagenlecleucel for DLBCL, where CRS symptoms demonstrated different grading by the UPenn criteria versus Lee et al. [8,19]. In 31% of cases, the Lee grading was lower than the UPenn grading [19], in 61% it was the same grading, and in 8% of cases the Lee et al. [8] grading was higher than that of UPenn [19,21]. Additional grading criteria for CRS such as CART cell therapy associated toxicity (CARTOX) [6] were mainly adapted from Lee et al. [8]. Most recently, ASBMT, nowadays known as the American Society for Transplantation and Cellular Therapy (ASTCT), has developed consensus guidelines for grading CART toxicities including CRS [7]. This further emphasized that the key hallmarks of CRS are fever, hypotension, and/or hypoxia. Fever is required for the diagnosis of CRS, although it may
3 not persist for the entire duration of the CRS toxicity. The grading of CRS severity is then based on clinical criteria for hypotension and/or hypoxia. Although CRS may cause other organs to be affected (i.e., causing transaminitis or arrhythmias or other organ specific manifestations), it was felt that these toxicities generally occur in concert with hypotension and/or hypoxia and usually do not change the CRS treatment plan to prescribe steroids or anti-IL-6 therapy.
Limitations related to clinical practice Although the grading of CRS has been simplified by the ASBMT consensus guidelines, clinical judgment is still required. Fever, hypotension, and/or hypoxia have a differential diagnosis that includes CRS, infection (including bacterial, viral, or fungal), B symptoms in the context of tumor progression, hemophagocytic syndrome, drug effects, and others. Complicating matters further is the fact that more than one process may occur simultaneously. Park et al. [22] recently reported that severe CRS is also related to a higher rate of infections, both early and late. This may be related to corticosteroid treatment for CRS or perhaps to a yet undescribed immunosuppressive effect of CRS itself. Patient-related factors also matter. For example, bacterial sepsis early after CART therapy is not frequently reported in DLBCL, but it appears to be more commonly described in B-ALL [22]. In addition, concurrent or recent anti-cancer therapies, or immunosuppressive properties of the tumor itself may cause prolonged immunosuppression and likely increase the risk of infections. Similarly, patients with underlying cardiac or lung disease may experience more pronounced hypotension or more severe hypoxia for the same degree of cytokine release, and may need more complex management and additional supportive therapies other than simply steroids or anticytokine treatment. Overall, there is a growing trend toward earlier intervention with CRS-directed therapy, which may abrogate the severity of CRS, in our opinion. Clinical treatment decisions should take into account the pretest probability of severe CRS (based on disease type, disease burden, and underlying inflammation), the current grade of CRS, and the expected course of CRS symptoms.
NT Predictors of NT Understanding the pathogenesis of NT remains an evolving concept. NT is commonly described as a constellation of neurologic symptoms associated with immunotherapy, specifically immune cellular therapy. Recently, the ASBMT defined NT as ICANS [7]. ICANS include a variety of symptoms such as headaches, encephalopathy, aphasia, amnesia, delirium, cognitive deficits, and, more rarely, confusion [7,8]. There seems to be a biphasic clinical presentation of NT with initial neurologic symptoms accompanying classical CRS, and a second phase of NT that occurs at a later time generally without obvious clinical CRS [23]. Clinical and molecular predictors of NT have been extensively studied. Although some are similar across various clinical trials, others vary owing to differences in the study
Please cite this article as: J. C. Chavez, M. D. Jain and M. A. Kharfan-Dabaja, Cytokine release syndrome and neurologic toxicities associated with chimeric antigen receptor T-cell therapy: A comprehensive review of emerging grading models, Hematol Oncol Stem Cell Ther, https://doi.org/10.1016/j.hemonc.2019.05.005
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population, age, and CART construct (costimulation with 41BB vs. CD28). In a cohort of various B-cell malignancies (BALL, CLL, and non-Hodgkin lymphomas), the Fred Hutchinson Cancer Research Center (FHCRC) reported that severity of NT was associated with underlying diagnosis (B-ALL), disease burden in the bone marrow, pre-existing neurologic comorbidities, lymphodepleting chemotherapy with fludarabine, infused CART cell dose, and even severity of CRS [24]. Specifically, in B-ALL, the MSKCC reported that disease burden (>5% blasts in the bone marrow), CART cell peak, and CRS severity were directly correlated with the severity of NT [25]. In aggressive B-cell lymphomas, the ZUMA-1 trial reported that a high tumor burden and a higher peak of CART cells after infusion were significantly associated with severe NT [4]. In pediatric B-ALL, the Children’s Hospital of Philadelphia found that pre-existing neurologic conditions and CRS (maximum grade) correlated with severe NT [26]. Biologic and molecular variables have been studied as potential factors associated with NT. Endothelial activation of the CNS vasculature has been suggested by the FHCRC experience which showed that hypoalbuminemia, weight gain, disseminated intravascular dissemination (DIC) signs and elevated cerebrospinal fluid (CSF) protein (particularly albumin), and increased concentrations and ratio of angiopoietin 2 (ANG2) correlated with Grade > 3 NT, reflecting disruption of the blood–brain barrier [24]. In the same study, there were increased serum levels of myeloid and T cell cytokines such as IL-6, IL-10, interferon (IFN) gamma, IL-2, and the monocyte chemoattractant protein-1 (MCP-1) seen in the first 36 hours preceding development of Grade 3 NT. The ZUMA-1 trial reported that Grade 3 NT were associated with elevated concentrations of granulocyte–monocyte colony stimulating factor (GM-CSF), IL-2, granzyme B, MCP-1, and ferritin [4]. Animal models have helped improve our knowledge and understanding of the pathophysiology of CRS and NT, its pro-inflammatory cytokines profile, and potential therapeutic interventions. In murine models, treatment with tocilizumab prevented severe CRS but could not lower the frequency of NT. However, IL-1R blockade was able to prevent both conditions when administered within the first 24 hours of CART cells infusion [27–29]. Most recently, catecholamines derived from myeloid cells were found to amplify CRS after CAR T-cell infusion in mice, hence representing a possible therapeutic target [30].
Models to grade NT Although some trials used center-specific grading criteria for CRS such as the UPenn and MSKCC grading systems, grading of NT has been undertaken by mainly using the CTCAE v.4.03 (later using CTCAE v.5) across cell therapy studies. Earlier studies included neurologic symptoms into the CRS toxicity and grading. NT is thought to have a biphasic presentation with neurologic symptoms during the CRS period; and a second phase of NT that starts once CRS symptoms improve and typically occurs beyond 5–7 days after CART cell infusion [6]. Thus, an accurate NT grading system that discriminates NT from neurologic symptoms associated with
CRS is needed in order to help provide more precise treatment guidance. The CTCAE v 4.03 has been used as the main NT grading criteria across the majority (particularly multicenter studies) of CART cell therapy trials in B-cell lymphomas and BALL [2–4,14,31]. Briefly, mild NT or Grade 1–2 neurologic toxicity was considered in patients presenting with mild to moderate symptoms leading to impairment of activities of daily living (ADLs). Severe NT (defined as Grade > 3) is associated with motor weakness, altered mentation, seizures, increased intracranial pressure (ICP)/papilledema, and is often accompanied by significant cognitive impairment that leads to severely compromised self-care ADLs. As ability to perform basic and instrumental ADLs is an important component of NT grading, there was a need for accurate evaluation tools such as the Mini-Mental State Examination (MMSE) assessment. Although the MMSE accurately screen patients with progressive and chronic cognitive decline, such as dementia, it is cumbersome as a daily bedside test and may not assess with accuracy the acute mental changes that typically occur in the setting of NT from CART cell therapy. A group of investigators developed the CARTOX-10 assessment, which is a simplified NT assessment that included a 10-point scale. In this grading system, NT was defined as CRES and grading included, in addition to the CARTOX-10 assessment, evaluation of the ICP (presence of papilledema and/or increased CSF opening pressure) and presence of seizures and/or motor weakness [6]. The CARTOX-10 scale is a 10-point assessment of cognitive skills that includes orientation (space, time, and person), naming, concentration, speech, and writing ability. Thus, severe CRES (or Grade > 2) could be seen in patients with a CARTOX-10 score of 0–2 and/or presence of partial/generalized seizures and/or clinical evidence of increased ICP. Some institutions have adopted this system because of its simplicity in comparison to CTCAE v4.03, but its applicability could be cumbersome, especially when evaluating CSF opening pressure (a lumbar puncture will be required to evaluate the ICP) and/or papilledema are required to complete the grading. Finally, to the best of our knowledge, it has not yet been validated in prospective multicenter clinical trials. With the ultimate goal of harmonizing the definition and grading of NT, the ASBMT recently published new grading criteria for NT that will be applied to all immune effector cell-based therapies, apart from CART. The definition of CRES was based on the presence of encephalopathy related to CART cell therapy [7]. In the new ASBMT-proposed definition, ICANS consists of neurologic symptoms such as altered level of consciousness, aphasia, depressed cognitive skills, motor weakness, seizures, and cerebral edema [7]. Other signs and symptoms such as headaches, tremors, myoclonus, and hallucinations were excluded from ICANS as they are less specific, even though they are recognized as being present in the context of immune effector cell therapies side effects. The ICANS grading also utilizes a 10-point cognitive skill assessment called immune cell effector encephalopathy (ICE) score, which is similar to CARTOX but adds the assess-
Please cite this article as: J. C. Chavez, M. D. Jain and M. A. Kharfan-Dabaja, Cytokine release syndrome and neurologic toxicities associated with chimeric antigen receptor T-cell therapy: A comprehensive review of emerging grading models, Hematol Oncol Stem Cell Ther, https://doi.org/10.1016/j.hemonc.2019.05.005
CRS and NT associated with CART ment of the ability to follow commands. It also adds to the grading assessment of the level of consciousness, motor weakness, increased ICP, and seizures. In contrast to the CTCAE grading system, any seizure (including nonconvulsive EEG findings) is considered at least Grade 3 ICANS. The definition of increased ICP has also been modified, and measuring of the CSF opening pressure and/or papilledema assessments (using the modified Frisen scale) are no longer required (but still recommended). Elevated ICP can be also assessed via neuroimaging (i.e., focal edema on imaging) or physical examination (such as new cranial nerve palsy or decorticate/decrebrate posture) different from the CARTOX-10/CRES definition.
Limitations of NT grading in clinical practice Similar to CRS, NT definition, classification, and grading have evolved in order to simplify the assessment of patients and to provide guidance for appropriate interventions to treat or minimize neurologic toxicity. The standard treatment of neurologic complications related to immune cell effector therapies continues to be supportive in nature with/without corticosteroids. As the understanding of the pathophysiology of NT continues to improve, it is expected that more treatment options will emerge for this particular complication. Thus, developing a grading system that is more user-friendly and reproducible will be of paramount importance. Data reporting of toxicities is strongly encouraged as regulators may require these data in order to assess the safety of post-marketing use of immune effector cell therapies. With prior grading systems, the needed data will likely prove to be cumbersome to institutions focusing on cell therapies. Adapting simplified grading systems may facilitate more accurate reporting of toxicity data, especially pertaining to severity.
Discussion The availability of CART therapies has revolutionized the treatment of R/R DLBCL and B-ALL. At present, use of the two commercially approved CARTs is relegated to the later stages of the disease based on current indications. Ongoing clinical trials are presently evaluating the role of CART in earlier stages of various subtypes of B-cell lymphomas and other hematologic neoplasms. Moreover, ongoing randomized controlled trials are even challenging well-established treatments paradigms such as high-dose therapy and autologous hematopoietic cell transplantation in DLBCL after the first relapse. The existence of various grading models for CRS and NT, originally developed at single institutions, has complicated assigning and categorizing grading scores to toxicities. This is a major barrier to developing uniform strategies to manage these toxicities. The recently published ASBMT consensus certainly represents a step in the right direction to harmonize practice by providing a uniform grading system for CRS and NT. As future CART products continue to emerge with their own unique toxicity profiles, it is possible that the ASBMT consensus model for CRS and NT grading will need to adapt accordingly.
5 The ASBMT grading system for CRS and NT needs to be incorporated in future clinical trials using cell-based therapies in order to assess its utility. It is unknown whether this will be applicable to other immune effector cell therapies such as T-cell infiltrating lymphocytes of TCRs.
Declaration of Competing Interest JCC: consultancy for Kite/Gilead, Novartis, Genentech, Bayer, and Karyopharm. Speaker Bureau for Genentech. MDJ: consultancy: Kite/Gilead. MAK-D: no relevant financial COI in relation to this manuscript. Other non-relevant COI (Consultancy: Pharmacyclics, Daiichi Sankyo; Speaker bureau: Seattle Genetics, Alexion Pharmaceuticals, Incyte Corp.).
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REVIEW ARTICLE
Cytokine release syndrome and neurologic toxicities associated with chimeric antigen receptor T-cell therapy: A comprehensive review of emerging grading models Julio C. Chavez a, Michael D. Jain b, Mohamed A. Kharfan-Dabaja c,* a
Department of Malignant Hematology, H. Lee Moffitt Cancer Center, Tampa, FL, USA Department of Blood and Marrow Transplant and Cellular Immunotherapy, H. Lee Moffitt Cancer Center, Tampa, FL, USA c Division of Hematology–Oncology, Blood and Marrow Transplantation and Cellular Therapies Program, Mayo Clinic, Jacksonville, FL, USA b
Received 10 April 2019; received in revised form 20 May 2019; accepted 23 May 2019
KEYWORDS Chimeric antigen receptor T-cell therapy; Cytokine release syndrome; Neurotoxicity
Abstract Advances in the fields of immuno-oncology and T-cell engineering have brought autologous chimeric antigen receptor T-cell (CART) therapies from the bench to the bedside. At present, two CART products that target CD19 are commercially available: tisagenlecleucel and axicabtagene ciloleucel. They have demonstrated remarkable efficacy for their particular indications. One challenge is to compare the safety among commercially available and clinical trial CART treatments due to the use of different grading models to assess the severity of cytokine release syndrome and neurotoxicity. An unmet need exists to harmonize current grading models in order to develop uniform treatment strategies to manage these toxicities. Here, we attempt to summarize the evolution of the various grading systems for cytokine release syndrome and neurotoxicity and also highlight the major differences among them, whenever applicable. Ó 2019 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-ncnd/4.0/).
* Corresponding author at: Blood and Marrow Transplantation Program, Division of Hematology–Oncology, Mayo Clinic, 4500 San Pablo Road S, Jacksonville, FL, USA. E-mail address: [email protected] (M.A. Kharfan-Dabaja). https://doi.org/10.1016/j.hemonc.2019.05.005 1658-3876/Ó 2019 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Please cite this article as: J. C. Chavez, M. D. Jain and M. A. Kharfan-Dabaja, Cytokine release syndrome and neurologic toxicities associated with chimeric antigen receptor T-cell therapy: A comprehensive review of emerging grading models, Hematol Oncol Stem Cell Ther, https://doi.org/10.1016/j.hemonc.2019.05.005
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Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CRS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Predictors of CRS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CRS grading criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Limitations related to clinical practice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . NT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Predictors of NT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Models to grade NT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Limitations of NT grading in clinical practice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Declaration of Competing Interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Introduction Advances in the fields of immuno-oncology and T-cell engineering have brought autologous chimeric antigen receptor T-cell (CART) therapies from the bench to the bedside [1]. Presently, two CART products are already commercially available, namely, tisagenlecleucel [2,3] and axicabtagene ciloleucel [4]. Tisagenlecleucel is approved for patients up to 25 years of age with refractory or in second or later relapse B-cell precursor acute lymphoblastic leukemia (B-ALL) [2]. Moreover, tisagenlecleucel and axicabtagene ciloleucel are both approved for adult patients with relapsed or refractory (R/R) large B-cell lymphoma after two or more lines of systemic therapy including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, highgrade B-cell lymphoma, and transformed DLBCL arising from follicular lymphoma (TFL) [3,4]. Axicabtagene ciloleucel is also approved for treatment of R/R primary mediastinal large B-cell lymphoma (PMBCL) [4]. These products have demonstrated remarkable efficacy in these poor risk populations considering that the historic prognosis of patients with R/R B-ALL or DLBCL after failing two preceding lines of therapies was dismal [5]. In a single-center phase 1/2A study of 75 patients (median age, 11 years) with CD19+ relapsed or refractory B-ALL, tisagenlecleucel resulted in 12-month progression-free (PFS) and overall (OS) survival rates of 50% and 73%, respectively with a median duration of remission not being reached [2]. Pertaining to R/R DLBCL, encouraging results were reported with both axicabtagene ciloleucel and tisagenlecleucel [3,4]. Neelapu et al. [4] described an objective response rate (ORR) of 82% (complete remission [CR] = 54%) when axicabtagene ciloleucel was prescribed to 101 patients (median age, 58 years) with DLBCL (n = 77, 76%), PMBCL (n = 8, 8%), or TFL (n = 16, 16%). This is a remarkable response considering that approximately 70% of cases had failed three or more prior treatments and responses were observed despite the presence of adverse prognostic features such as bulky disease (10 cm) and activated B-cell-like subtype cell of origin, among others [4]. Similarly, in an international pivotal phase 2 study, 111 patients (median age, 58 years) were treated with tisagenlecleucel after the majority of cases (52%) had failed three or more lines of therapy, and the best reported ORR was 52% (CR = 40%) [3]. The median duration
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of response was not reached, and 79% of patients who achieved a CR were projected to remain relapse-free 12 months later [3]. Similar to axicabtagene ciloleucel, efficacy of tisagenlecleucel was demonstrated regardless of adverse risk factors, including cases with double or triple hit DLBCL [3]. While acknowledging that CART have certainly revolutionized the treatment algorithms of R/R/ B-ALL and aforementioned subtypes of B-cell lymphomas and have favorably altered the prognosis of these diseases, these therapies result in a unique array of toxicities, namely, cytokine release syndrome (CRS) and neurotoxicity (NT) also referred to as CART-related encephalopathy syndrome (CRES) or immune related effector cell-associated neurotoxicity syndrome (ICANS) [6,7]. One of the various challenges in trying to assess and compare, side by side, the safety of these commercially available CART treatments, and other CART products currently being evaluated in clinical trials is the use of various grading models to assess the severity of CRS and NT [6,8]. As a result, assigning and categorizing grading scores to toxicities may vary across published clinical trials and even across individual centers, posing a challenge to developing uniform strategies to manage these toxicities. Recently, the American Society for Blood and Marrow Transplantation (ASBMT) issued clinical practice recommendations and definitions for grading CRS and NT [7]. This represents a significant step forward toward harmonizing clinical practice. Below, we summarize the evolution of the various grading systems for CRS and NT and also highlight the major differences among them, whenever applicable.
CRS Predictors of CRS CRS is caused by the release of cytokines during in vivo CART cell expansion [9]. The toxicity of CRS results from the systemic effects of cytokines on multiple organ systems. The grading models for CRS capture the organ systems typically affected by CRS, but fever appears to be a key sign that CRS has occurred. Mechanistically, CRS originates from cytokines released by the CART cells, but may be augmented by other immune cells [4,10–12].
Please cite this article as: J. C. Chavez, M. D. Jain and M. A. Kharfan-Dabaja, Cytokine release syndrome and neurologic toxicities associated with chimeric antigen receptor T-cell therapy: A comprehensive review of emerging grading models, Hematol Oncol Stem Cell Ther, https://doi.org/10.1016/j.hemonc.2019.05.005
CRS and NT associated with CART Severe CRS causes toxicity beyond fever, hypotension responsive to fluids, and hypoxia responsive to low-level oxygen support. The likelihood of a patient experiencing severe CRS depends on patient-, tumor-, and CART-related factors. In terms of patient-related factors, the baseline inflammatory state appears to be of particular importance. Patients with a high baseline serum ferritin, C-reactive protein, or elevated baseline cytokine levels are at a higher risk of CRS [9,13]. For factors such as disease type (B-ALL vs. various histologies of B-cell lymphomas), grading systems for CRS and patient population may influence the rates of CRS reported in clinical trials, but the overall experience is that CRS is somewhat different depending on histology. Furthermore, a higher tumor burden also appears to predict a higher rate of CRS [10,14]. The rate of CRS may also be modifiable by CART design or manufacturing practices, or may be different based on the costimulatory domain used (i.e., CD28 vs. 4-1BB) [15,16]. Finally, earlier interventions with treatments such as corticosteroids and anti-interleukin 6 (IL-6) therapy (i.e., tocilizumab) appear to reduce the rates of severe CRS. For example, in patients with DLBCL, the ZUMA-1 clinical trial reported the rate of severe CRS to be 14%, whereas real-world consortia described this rate to be less than 10% likely because of earlier intervention with tocilizumab and/or corticosteroids [17,18].
CRS grading criteria Efforts have been made to harmonize and standardize grading criteria for CRS. The main grading systems that were used in the earlier CART clinical trials included the National Cancer Institute Consensus Grading [8], the University of Pennsylvania (UPenn) grading [19], the Memorial Sloan Kettering Cancer Center (MSKCC) criteria [14] and, for clinical trials, common terminology criteria for adverse events (CTCAE) [20]. In addition, the definition of CRS was refined between CTCAE v4.03 and CTCAE v5.0, where the more recent version now has CRS grading criteria similar to those reported by Lee et al. [8] Differences in grading criteria led to differences in the rate and the severity of CRS reported on a particular clinical trial. For example, in Lee et al. [8] criteria, hypotension responsive to fluids and hypoxia requiring less than 40% FiO2 is listed as Grade 2 CRS (nonsevere). However, by the UPenn system these are considered Grade 3 and are therefore consistent with severe CRS [19]. This difference is emphasized even further by an analysis of the JULIET trial of tisagenlecleucel for DLBCL, where CRS symptoms demonstrated different grading by the UPenn criteria versus Lee et al. [8,19]. In 31% of cases, the Lee grading was lower than the UPenn grading [19], in 61% it was the same grading, and in 8% of cases the Lee et al. [8] grading was higher than that of UPenn [19,21]. Additional grading criteria for CRS such as CART cell therapy associated toxicity (CARTOX) [6] were mainly adapted from Lee et al. [8]. Most recently, ASBMT, nowadays known as the American Society for Transplantation and Cellular Therapy (ASTCT), has developed consensus guidelines for grading CART toxicities including CRS [7]. This further emphasized that the key hallmarks of CRS are fever, hypotension, and/or hypoxia. Fever is required for the diagnosis of CRS, although it may
3 not persist for the entire duration of the CRS toxicity. The grading of CRS severity is then based on clinical criteria for hypotension and/or hypoxia. Although CRS may cause other organs to be affected (i.e., causing transaminitis or arrhythmias or other organ specific manifestations), it was felt that these toxicities generally occur in concert with hypotension and/or hypoxia and usually do not change the CRS treatment plan to prescribe steroids or anti-IL-6 therapy.
Limitations related to clinical practice Although the grading of CRS has been simplified by the ASBMT consensus guidelines, clinical judgment is still required. Fever, hypotension, and/or hypoxia have a differential diagnosis that includes CRS, infection (including bacterial, viral, or fungal), B symptoms in the context of tumor progression, hemophagocytic syndrome, drug effects, and others. Complicating matters further is the fact that more than one process may occur simultaneously. Park et al. [22] recently reported that severe CRS is also related to a higher rate of infections, both early and late. This may be related to corticosteroid treatment for CRS or perhaps to a yet undescribed immunosuppressive effect of CRS itself. Patient-related factors also matter. For example, bacterial sepsis early after CART therapy is not frequently reported in DLBCL, but it appears to be more commonly described in B-ALL [22]. In addition, concurrent or recent anti-cancer therapies, or immunosuppressive properties of the tumor itself may cause prolonged immunosuppression and likely increase the risk of infections. Similarly, patients with underlying cardiac or lung disease may experience more pronounced hypotension or more severe hypoxia for the same degree of cytokine release, and may need more complex management and additional supportive therapies other than simply steroids or anticytokine treatment. Overall, there is a growing trend toward earlier intervention with CRS-directed therapy, which may abrogate the severity of CRS, in our opinion. Clinical treatment decisions should take into account the pretest probability of severe CRS (based on disease type, disease burden, and underlying inflammation), the current grade of CRS, and the expected course of CRS symptoms.
NT Predictors of NT Understanding the pathogenesis of NT remains an evolving concept. NT is commonly described as a constellation of neurologic symptoms associated with immunotherapy, specifically immune cellular therapy. Recently, the ASBMT defined NT as ICANS [7]. ICANS include a variety of symptoms such as headaches, encephalopathy, aphasia, amnesia, delirium, cognitive deficits, and, more rarely, confusion [7,8]. There seems to be a biphasic clinical presentation of NT with initial neurologic symptoms accompanying classical CRS, and a second phase of NT that occurs at a later time generally without obvious clinical CRS [23]. Clinical and molecular predictors of NT have been extensively studied. Although some are similar across various clinical trials, others vary owing to differences in the study
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population, age, and CART construct (costimulation with 41BB vs. CD28). In a cohort of various B-cell malignancies (BALL, CLL, and non-Hodgkin lymphomas), the Fred Hutchinson Cancer Research Center (FHCRC) reported that severity of NT was associated with underlying diagnosis (B-ALL), disease burden in the bone marrow, pre-existing neurologic comorbidities, lymphodepleting chemotherapy with fludarabine, infused CART cell dose, and even severity of CRS [24]. Specifically, in B-ALL, the MSKCC reported that disease burden (>5% blasts in the bone marrow), CART cell peak, and CRS severity were directly correlated with the severity of NT [25]. In aggressive B-cell lymphomas, the ZUMA-1 trial reported that a high tumor burden and a higher peak of CART cells after infusion were significantly associated with severe NT [4]. In pediatric B-ALL, the Children’s Hospital of Philadelphia found that pre-existing neurologic conditions and CRS (maximum grade) correlated with severe NT [26]. Biologic and molecular variables have been studied as potential factors associated with NT. Endothelial activation of the CNS vasculature has been suggested by the FHCRC experience which showed that hypoalbuminemia, weight gain, disseminated intravascular dissemination (DIC) signs and elevated cerebrospinal fluid (CSF) protein (particularly albumin), and increased concentrations and ratio of angiopoietin 2 (ANG2) correlated with Grade > 3 NT, reflecting disruption of the blood–brain barrier [24]. In the same study, there were increased serum levels of myeloid and T cell cytokines such as IL-6, IL-10, interferon (IFN) gamma, IL-2, and the monocyte chemoattractant protein-1 (MCP-1) seen in the first 36 hours preceding development of Grade 3 NT. The ZUMA-1 trial reported that Grade 3 NT were associated with elevated concentrations of granulocyte–monocyte colony stimulating factor (GM-CSF), IL-2, granzyme B, MCP-1, and ferritin [4]. Animal models have helped improve our knowledge and understanding of the pathophysiology of CRS and NT, its pro-inflammatory cytokines profile, and potential therapeutic interventions. In murine models, treatment with tocilizumab prevented severe CRS but could not lower the frequency of NT. However, IL-1R blockade was able to prevent both conditions when administered within the first 24 hours of CART cells infusion [27–29]. Most recently, catecholamines derived from myeloid cells were found to amplify CRS after CAR T-cell infusion in mice, hence representing a possible therapeutic target [30].
Models to grade NT Although some trials used center-specific grading criteria for CRS such as the UPenn and MSKCC grading systems, grading of NT has been undertaken by mainly using the CTCAE v.4.03 (later using CTCAE v.5) across cell therapy studies. Earlier studies included neurologic symptoms into the CRS toxicity and grading. NT is thought to have a biphasic presentation with neurologic symptoms during the CRS period; and a second phase of NT that starts once CRS symptoms improve and typically occurs beyond 5–7 days after CART cell infusion [6]. Thus, an accurate NT grading system that discriminates NT from neurologic symptoms associated with
CRS is needed in order to help provide more precise treatment guidance. The CTCAE v 4.03 has been used as the main NT grading criteria across the majority (particularly multicenter studies) of CART cell therapy trials in B-cell lymphomas and BALL [2–4,14,31]. Briefly, mild NT or Grade 1–2 neurologic toxicity was considered in patients presenting with mild to moderate symptoms leading to impairment of activities of daily living (ADLs). Severe NT (defined as Grade > 3) is associated with motor weakness, altered mentation, seizures, increased intracranial pressure (ICP)/papilledema, and is often accompanied by significant cognitive impairment that leads to severely compromised self-care ADLs. As ability to perform basic and instrumental ADLs is an important component of NT grading, there was a need for accurate evaluation tools such as the Mini-Mental State Examination (MMSE) assessment. Although the MMSE accurately screen patients with progressive and chronic cognitive decline, such as dementia, it is cumbersome as a daily bedside test and may not assess with accuracy the acute mental changes that typically occur in the setting of NT from CART cell therapy. A group of investigators developed the CARTOX-10 assessment, which is a simplified NT assessment that included a 10-point scale. In this grading system, NT was defined as CRES and grading included, in addition to the CARTOX-10 assessment, evaluation of the ICP (presence of papilledema and/or increased CSF opening pressure) and presence of seizures and/or motor weakness [6]. The CARTOX-10 scale is a 10-point assessment of cognitive skills that includes orientation (space, time, and person), naming, concentration, speech, and writing ability. Thus, severe CRES (or Grade > 2) could be seen in patients with a CARTOX-10 score of 0–2 and/or presence of partial/generalized seizures and/or clinical evidence of increased ICP. Some institutions have adopted this system because of its simplicity in comparison to CTCAE v4.03, but its applicability could be cumbersome, especially when evaluating CSF opening pressure (a lumbar puncture will be required to evaluate the ICP) and/or papilledema are required to complete the grading. Finally, to the best of our knowledge, it has not yet been validated in prospective multicenter clinical trials. With the ultimate goal of harmonizing the definition and grading of NT, the ASBMT recently published new grading criteria for NT that will be applied to all immune effector cell-based therapies, apart from CART. The definition of CRES was based on the presence of encephalopathy related to CART cell therapy [7]. In the new ASBMT-proposed definition, ICANS consists of neurologic symptoms such as altered level of consciousness, aphasia, depressed cognitive skills, motor weakness, seizures, and cerebral edema [7]. Other signs and symptoms such as headaches, tremors, myoclonus, and hallucinations were excluded from ICANS as they are less specific, even though they are recognized as being present in the context of immune effector cell therapies side effects. The ICANS grading also utilizes a 10-point cognitive skill assessment called immune cell effector encephalopathy (ICE) score, which is similar to CARTOX but adds the assess-
Please cite this article as: J. C. Chavez, M. D. Jain and M. A. Kharfan-Dabaja, Cytokine release syndrome and neurologic toxicities associated with chimeric antigen receptor T-cell therapy: A comprehensive review of emerging grading models, Hematol Oncol Stem Cell Ther, https://doi.org/10.1016/j.hemonc.2019.05.005
CRS and NT associated with CART ment of the ability to follow commands. It also adds to the grading assessment of the level of consciousness, motor weakness, increased ICP, and seizures. In contrast to the CTCAE grading system, any seizure (including nonconvulsive EEG findings) is considered at least Grade 3 ICANS. The definition of increased ICP has also been modified, and measuring of the CSF opening pressure and/or papilledema assessments (using the modified Frisen scale) are no longer required (but still recommended). Elevated ICP can be also assessed via neuroimaging (i.e., focal edema on imaging) or physical examination (such as new cranial nerve palsy or decorticate/decrebrate posture) different from the CARTOX-10/CRES definition.
Limitations of NT grading in clinical practice Similar to CRS, NT definition, classification, and grading have evolved in order to simplify the assessment of patients and to provide guidance for appropriate interventions to treat or minimize neurologic toxicity. The standard treatment of neurologic complications related to immune cell effector therapies continues to be supportive in nature with/without corticosteroids. As the understanding of the pathophysiology of NT continues to improve, it is expected that more treatment options will emerge for this particular complication. Thus, developing a grading system that is more user-friendly and reproducible will be of paramount importance. Data reporting of toxicities is strongly encouraged as regulators may require these data in order to assess the safety of post-marketing use of immune effector cell therapies. With prior grading systems, the needed data will likely prove to be cumbersome to institutions focusing on cell therapies. Adapting simplified grading systems may facilitate more accurate reporting of toxicity data, especially pertaining to severity.
Discussion The availability of CART therapies has revolutionized the treatment of R/R DLBCL and B-ALL. At present, use of the two commercially approved CARTs is relegated to the later stages of the disease based on current indications. Ongoing clinical trials are presently evaluating the role of CART in earlier stages of various subtypes of B-cell lymphomas and other hematologic neoplasms. Moreover, ongoing randomized controlled trials are even challenging well-established treatments paradigms such as high-dose therapy and autologous hematopoietic cell transplantation in DLBCL after the first relapse. The existence of various grading models for CRS and NT, originally developed at single institutions, has complicated assigning and categorizing grading scores to toxicities. This is a major barrier to developing uniform strategies to manage these toxicities. The recently published ASBMT consensus certainly represents a step in the right direction to harmonize practice by providing a uniform grading system for CRS and NT. As future CART products continue to emerge with their own unique toxicity profiles, it is possible that the ASBMT consensus model for CRS and NT grading will need to adapt accordingly.
5 The ASBMT grading system for CRS and NT needs to be incorporated in future clinical trials using cell-based therapies in order to assess its utility. It is unknown whether this will be applicable to other immune effector cell therapies such as T-cell infiltrating lymphocytes of TCRs.
Declaration of Competing Interest JCC: consultancy for Kite/Gilead, Novartis, Genentech, Bayer, and Karyopharm. Speaker Bureau for Genentech. MDJ: consultancy: Kite/Gilead. MAK-D: no relevant financial COI in relation to this manuscript. Other non-relevant COI (Consultancy: Pharmacyclics, Daiichi Sankyo; Speaker bureau: Seattle Genetics, Alexion Pharmaceuticals, Incyte Corp.).
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Please cite this article as: J. C. Chavez, M. D. Jain and M. A. Kharfan-Dabaja, Cytokine release syndrome and neurologic toxicities associated with chimeric antigen receptor T-cell therapy: A comprehensive review of emerging grading models, Hematol Oncol Stem Cell Ther, https://doi.org/10.1016/j.hemonc.2019.05.005