Chinese expert consensus on the management of chimeric antigen receptor T cell therapy-associated coagulopathy

Chimeric antigen receptor T-cell (CAR-T) therapy has greatly improved the disease remission rate and long-term survival rate of patients with relapsed/refractory hematological malignancies.^[1–3] Currently, several commercial CAR-T products are available in the market and numerous CAR-T clinical trials have been conducted. Attention should be paid to the safety of CAR-T therapy. The main adverse effects of CAR-T therapy are cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS).^[4] Moreover, CAR-T therapy-associated coagulopathy (CARAC) is also prominent [Supplementary Table 1]. Among the patients with hematological malignancies, including B-cell acute lymphoblastic leukemia (B-ALL), non-Hodgkin lymphoma, and multiple myeloma (MM), more than half of them experienced thrombocytopenia or showed at least one abnormal coagulation parameter after CAR-T therapy. Approximately 19.6% of coagulopathy patients experienced clinically significant bleeding and 14% to 50% of coagulopathy patients further developed disseminated intravascular coagulation (DIC); 6.7% to 42.9% of DIC patients died. The current international grading criteria and treatment guidelines for CAR-T therapy-related adverse events only focus on CRS and ICANS, while CARAC has not been systematically summarized. To standardize the management of CARAC and to promote the safe application of CAR-T therapy, experts from Thrombosis and Hemostasis Group and Biotherapeutics Committee formulated this consensus based on worldwide clinical experience and research progress (detailed information was in the Supplementary File).

Definition of CARAC

In the studies using CAR-T therapy for hematological malignancies, researchers have found that the rate of coagulopathy is higher among severe CRS patients and its severity is positively correlated with CRS grade. Besides, coagulopathy often occurs from day 6 to day 10 after CAR-T cell infusion, closely following the elevated levels of interleukin (IL)-6 and other cytokines, and gradually relieves with the control of CRS. Consequently, CARAC is a clinical syndrome, which occurs in a short term (mostly within 28 days) after CAR-T cell infusion. It is related to the release of cytokines and is characterized by bleeding and/or thrombosis, which is accompanied by decreased platelets (PLT) levels and coagulopathy.

Recommended Grades

According to the US National Clinical Diagnosis and Treatment Guidelines Database Grading System, the evidence is graded [Supplementary Table 2].

Diagnosis

Basic conditions

CARAC is triggered by CRS after CAR-T cell infusion; therefore, CARAC is diagnosed by the presence of CRS (grade IIa). High tumor burden before infusion, the rapid expansion of CAR-T cells in vivo, and high-grade CRS are the high-risk factors for CARAC (grade IIa). Patients with CRS are characterized by elevated serum levels of IL-1β, IL-6, IL-8, IL-10, IL-15, IFN-γ, tumor necrosis factor (TNF)-α, etc. Among them, elevated IL-6 is the most common and significant (grade IIa). Consequently, the diagnosis of CARAC should be based on the elevated levels of IL-6 and other cytokines. The ratio of post-infusion to baseline IL-6 level is suggested to judge whether IL-6 elevates.

Clinical manifestation

According to its developmental process, CARAC can be categorized into the hypercoagulation stage, bleeding stage, and organ failure stage. Bleeding is the main clinical manifestation of CARAC and is usually spontaneous, involving multiple sites. WHO bleeding scale is recommended to evaluate the degree of bleeding (grade IIa). Some patients may experience shock or microcirculation failure, which is life-threatening due to the dysfunction of multiple organs. The abnormal clinical manifestations always occur when abnormal laboratory indicators are present; therefore, clinicians should pay more attention to patients whose laboratory indicators turn abnormal.

Laboratory indicators

The diagnosis of CARAC should be based on the progressive decrease in PLT count, prolongation in activated partial thromboplastin time (APTT) and prothrombin time (PT), decrease in fibrinogen (FIB), and increase in fibrin degradation products (FDP) and D-dimer. The risk of DIC increases if the PLT count is <50 × 10⁹/L or decreases ≥ 50% within 24 h, D-dimer is ≥ 5 mg/L, prolongation of PT is ≥ 3 s, prolongation of APTT is ≥ 10 s, or FIB is  < 1.0 g/L (grade IIa). Thromboelastogram records the comprehensive functional status of all the parameters in the coagulation process and can be used as a supplement to the traditional coagulation indicators (grade IIb). Thrombin-antithrombin complex, alpha 2-plasmin inhibitor-plasmin complex, tissue plasminogen activator-inhibitor complex, and soluble thrombomodulin have good diagnosis performance for DIC in different underlying diseases, and can also be helpful for CARAC diagnosis (grade IIa). PLT endothelial cell adhesion molecule-1, tissue factor, von Willebrand factor, angiopoietin-2, and other biomarkers, which reflect vascular endothelial function, can also be used to assist CARAC diagnosis (grade IIb).

Application of DIC scoring system

CARAC can progress to DIC. Therefore, it is important to diagnose and treat DIC at an early stage. Once the coagulation indicators turn abnormal, the Chinese DIC Scoring System (CDSS) or International Society on Thrombosis and Haemostasis (ISTH) DIC Scoring System are recommended to evaluate DIC (grade IIa).

Differential Diagnosis

Sepsis-induced DIC

Sepsis is defined as life-threatening organ dysfunction caused by the dysregulated host response to infection. Sepsis-induced DIC is characterized by systemic activation of coagulation and inhibition of fibrinolysis. It mainly causes a hypercoagulable state, which results in microvascular thrombosis, thereby affecting organ microcirculation and inducing organ dysfunction [Supplementary Table 3].

Hemophagocytic lymphohistiocytosis (HLH)

HLH occurs among a few severe CRS patients after CAR-T therapy and is mainly characterized by decreased PLT count and FIB level. Currently, the criteria of CAR-T-related HLH have not been unified yet, but all criteria emphasized ferritin level, organ dysfunction, and hemophagocytosis. These may overlap with CARAC, but the cytokine profile is not the same; furthermore, HLH has a lesser effect on the coagulation system than CARAC [Supplementary Table 4].

Chemotherapy-induced thrombocytopenia

Chemotherapy (including lymphodepletion)-induced thrombocytopenia (CIT) is defined as the peripheral blood PLT count of <100 × 10⁹/L after chemotherapy. Its main cause is myelosuppression. Differentially, CIT recovers within 2 to 3 weeks after chemotherapy.

CAR-T therapy-related delayed-onset thrombocytopenia

CAR-T therapy-related delayed-onset thrombocytopenia is the late hematological toxicity, which appears after 28 days of CAR-T therapy, and is far beyond the pretreatment chemotherapy period. Its incidence is as high as 76% and is significantly associated with previous transplantation and severe CRS.

Treatment

The principle of CARAC treatment is early diagnosis, accurate evaluation, removal of the cause, and management based on CRS levels. CARAC can be comprehensively managed according to the flowchart provided in Supplementary Figure 1. Specific measures are as follows.

CRS management

Cytokine antagonist: The most common and significantly elevated cytokine in CRS is IL-6. The IL-6 receptor antagonist tocilizumab has been approved by Food and Drug Administration and has been widely used for the treatment of CRS after CAR-T therapy. The IL-6 monoclonal antibody siltuximab has also shown a beneficial effect on CRS (grade IIb). Additionally, other cytokines antagonists have also been applied for the CRS treatment, including IL-1 receptor antagonist anakinra (grade IIb) and TNF-α antagonist etanercept (grade III). Currently, tocilizumab, siltuximab, and anakinra are recommended to treat CRS by the National Comprehensive Cancer Network (NCCN) guidelines. We suggest that patients with grade ≥2 CRS accompanied by CARAC use cytokine antagonists.

Glucocorticoid: The application of glucocorticoids can improve both coagulation indicators and bleeding symptoms (grade IIa). However, early clinical studies found that, although glucocorticoid could control CRS, it affected the function of CAR-T cells or inhibited the proliferation of CAR-T cells in vivo, thereby showing potential adverse effects on the anti-tumor efficacy of CAR-T therapy. The application of glucocorticoid in coagulation dysfunction is needed to be adjusted according to specific clinical conditions. Consequently, we recommend that patients with grade ≥2 CRS accompanied by CARAC use glucocorticoids.

Replacement therapy

Bleeding is the main feature of CARAC. Replacement therapy can decrease the risk of bleeding and control active bleeding. Patients with grade ≥2 CRS accompanied by CARAC should receive replacement therapy. The dose of replacement therapy should be adjusted timely according to PLT count, FIB, PT, and APTT levels.

PLT suspension: PLT suspension should be transfused when the PLT count is <20 × 10⁹/L or the PLT count is <50 × 10⁹/L with active bleeding (grade III).

Fresh frozen plasma and prothrombin complex concentrates: When the prolongation of PT is ≥ 3 s and/or that of APTT ≥ 10 s, fresh frozen plasma should be transfused at a dose of 10 to 15 mL/kg or prothrombin complex concentrates should be transfused as appropriate (grade III).

Fibrinogen and cryoprecipitate: Among patients with grade ≥3 CRS accompanied by CARAC, the risk of bleeding is very high. We suggest monitoring the FIB level daily and supplementing FIB concentrates or cryoprecipitate appropriately. The goal is to maintain the FIB level ≥1.5 g/L until CRS grade is ≤3 (grade IIa). When the FIB level is <1.5 g/L, the suggested supplementary dose of FIB concentrates is ([1.5−measured level]/0.017) mg/kg. The cryoprecipitate contains factor VIII and FIB. If the FIB level is unknown but suspected to be very low, the supplementary dose of cryoprecipitate should be 0.1 to 0.2 units/kg of the body weight. Patients with prolonged APTT can also use cryoprecipitate.

Anticoagulant therapy

Anticoagulant therapy can be applied based on controlling CRS. For patients with grade 2 CRS accompanied by CARAC, anticoagulant therapy should only be used at the time of replacement treatment (grade III). For patients with grade ≥3 CRS accompanied by CARAC, anticoagulant therapy is not generally used. We recommend using low-molecular heparin at a dose of 4000 to 6000 U/day. The dose should be reduced to half when PLT is <50 × 10⁹/L and should be stopped when PLT is <20 × 10⁹/L (grade IV).

Anti-fibrinolytic therapy

For patients with grade ≥3 CRS accompanied by CARAC, if the secondary fibrinolysis is the main reason for bleeding, anti-fibrinolytic therapy can be used (grade IV).

Conflicts of interest

None.