Editor’s Note: As scheduled, the 2024 China Society of Clinical Oncology (CSCO) guidelines conference has arrived, with many CSCO oncology treatment guidelines being updated or published for the first time. In the field of hematologic oncology, the much-anticipated CAR-T cell therapy guidelines have been significantly updated. The “CSCO CAR-T Cell Therapy for Malignant Hematological Diseases and Management of Related Infections Guidelines 2023” (referred to as the 2023 Guidelines) has been renamed to “CSCO CAR-T Cell Therapy for Malignant Hematological Diseases Guidelines 2024” (referred to as the 2024 Guidelines). At the conference, Professor Wenjun Zhang from Tongji Hospital affiliated with Tongji University and the Tongji University Institute of Hematology shared the key updates of the 2024 Guidelines. The highlights are organized below for our readers.
The 2024 Guidelines include four sections: First, targeting CD19 CAR-T cell therapy for B-cell non-Hodgkin lymphoma (B-NHL); second, targeting BCMA CAR-T cell therapy for multiple myeloma (MM); third, targeting CD19 CAR-T cell therapy for adult relapsed/refractory acute B lymphoblastic leukemia (R/R B-ALL); fourth, management of adverse reactions from CAR-T therapy. Compared to the 2023 Guidelines, the most significant addition is the new fourth section on the management of adverse reactions from CAR-T therapy. There are also important updates in the other three sections.
Management of Adverse Reactions from CAR-T Therapy
01. Cytokine Release Syndrome (CRS)
According to the grading system of the American Society for Transplantation and Cellular Therapy (ASTCT), the 2024 Guidelines classify the severity of CRS from low to high based on clinical manifestations of fever, hypotension, and hypoxemia.
The treatment approach varies based on the severity level. For instance, a single maximum dose of tocilizumab is 800 mg, which can be administered repeatedly; if CRS does not improve or even worsens 24 hours after treatment, escalation to the next level of management is recommended; early intervention with tocilizumab and steroids does not affect the proliferation and efficacy of CD19 CAR-T cells in B-ALL and B-NHL.
It should be noted that the new guidelines have not yet recommended the use of siltuximab, ruxolitinib, or dasatinib for the treatment of CRS, nor plasma exchange for severe CRS.
02. Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS)
In 2017, Neelapu’s team first introduced the concept of “CAR-T cell-related encephalopathy syndrome (CRES),” which was further refined by the American Society for Transplantation and Cellular Therapy (ASTCT) in 2019 to “Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS).” The definition of ICANS more accurately reflects the pathophysiological characteristics of neurological disorders and has gained wider acceptance and application in clinical diagnosis and treatment. This guideline adopts the ICANS terminology for neurologic adverse reactions related to CAR-T cell therapy. The ICANS grading system is established based on the CAR-T cell therapy-related toxicity (CARTOX) 10-point scale (CARTOX-10) and the Immune Effector Cell Encephalopathy (ICE) score.
Treatment approaches vary according to the grade. The binding of tocilizumab to the IL-6 receptor causes an increase in serum free IL-6 levels, which in turn increases the concentration of IL-6 in the cerebrospinal fluid, potentially exacerbating neurotoxicity. Therefore, the use of corticosteroids is more crucial than tocilizumab in managing ICANS.
Additionally, toxicity management for specific groups includes: (1) ALL: CRS and ICANS are management priorities. Immune toxicity is stronger with a high tumor burden, requiring more aggressive management. For ALL patients with a high tumor burden (bone marrow blasts ≥40%), if the fever persists, direct treatment with tocilizumab is advisable; patients with a low tumor burden are treated according to standard protocols. (2) NHL: Multidisciplinary team (MDT) management throughout the process, local CRS, systemic CRS, and ICANS risk identification and intervention are guided by the “CAR-T Cell Therapy NHL Adverse Effects Clinical Management Expert Consensus.” (3) MM: Unique delayed neurotoxicity related to targets. Delayed neurotoxicities include cranial nerve paralysis (most commonly the seventh cranial nerve), neuropathy, and Parkinsonian syndromes. The mechanisms behind delayed neurotoxicity are unclear, but low-level BCMA expression in the central nervous system and the migration of CAR-T cells mediating off-target effects may play a role.
03. Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-like Syndrome (IEC-HS)
IEC-HS is a pathological and biochemical hyperinflammatory syndrome independent of CRS and ICANS. Its characteristics include: (1) manifestations of macrophage activation syndrome (MAS)/hemophagocytic lymphohistiocytosis (HLH); (2) attributed to immune effector cell therapy, considered a delayed manifestation post-CRS management; (3) exacerbated or new-onset cytopenia, hyperferritinemia, coagulopathy with hypo-fibrinogenemia, and/or transaminase abnormalities. IEC-HS can be diagnosed based on common clinical or laboratory indicators (such as elevated ferritin, initial improvement or worsening inflammation after CRS treatment, elevated liver transaminases, etc.) and other clinical or laboratory signs (such as elevated lactate dehydrogenase, other coagulopathies, high direct bilirubin, etc.), and interventions are tailored to the severity of symptoms.
Due to the lack of prospective studies and data on IEC-HS treatment methods, treatment recommendations are based on expert opinions, evidence from CRS/IEC-HS cohorts, and/or previous analyses of treatments for primary (pHLH) and secondary (sHLH) hemophagocytic lymphohistiocytosis. Various treatment options are available for third-line and subsequent treatments, and it is advisable to choose the appropriate treatment method based on the specific condition of the patient.
Additionally, supportive treatments for IEC-HS can include monitoring, cytopenia, coagulation dysfunction, and infection management, such as daily monitoring of blood counts, coagulation functions, and fibrinogen levels; maintaining hemoglobin >7 g/dL; using cryoprecipitate or fibrinogen replacement for active treatment, maintaining fibrinogen levels >100 mg/dL (without bleeding) and >150 mg/dL (with bleeding); and empirical anti-infection management.
04. CAR-T Related Coagulopathy (CARAC)
CARAC refers to a clinical syndrome characterized by bleeding and/or thrombosis, associated with cytokine release, and accompanied by thrombocytopenia and coagulation abnormalities shortly after CAR-T cell infusion. Clinical manifestations often include thrombosis and disseminated intravascular coagulation (DIC) complications such as pulmonary embolism, deep vein thrombosis, skin petechiae/ecchymosis, jaundice, hypotension, and difficulty breathing. Laboratory results show a decrease in platelets and abnormal coagulation indicators. Management of CARAC is based on the CRS grade, with recommended treatments including prophylactic and supportive care, infection prevention/treatment, anti-inflammatory and liver protection treatments, and drugs that promote platelet production.
05. Immune Effector Cell-Associated Hematotoxicity (ICAHT)
In 2023, the journal Blood published “Immune Effector Cell-Associated Hematotoxicity (ICAHT): EHA/EBMT Consensus Grading and Best Practice Recommendations.” According to these recommendations, ICAHT is divided into early and late stages, and the severity of ICAHT is graded into four levels based on the absolute neutrophil count (ANC).
Short-term management of ICAHT includes transfusion of concentrated red cells or platelets, prophylactic or therapeutic use of granulocyte colony-stimulating factor (G-CSF), and specific bacterial/fungal prevention for certain patients, along with viral/pneumocystis prophylaxis for all patients.
06. B-Cell Aplasia/Hypogammaglobulinemia
B-cell aplasia is defined as a disease caused by the depletion or absence of B-cells. The mechanism of CAR-T induced B-cell aplasia is the on-target off-tumor effect of CD19-targeted CAR-T therapy, which can reduce B-cell counts and levels of immunoglobulin M (IgM). Studies have shown that hypogammaglobulinemia can occur at various times after CAR-T infusion, with an incidence of about 67% after 90 days, and in some patients, it can persist for years. The main clinical manifestation is frequent infections.
The treatment strategy for B-cell aplasia/hypogammaglobulinemia involves intravenous immunoglobulin replacement therapy (5 g × 3 days, IV). The frequency of infusion is once a month after CAR-T infusion until B-cells return to normal range or for six months post-infusion; for high-risk groups, continue once a month until high-risk factors are resolved and immunoglobulin levels normalize. For high-risk groups with severe, persistent, or recurrent infections and IgG ≤ 400 mg/dl, it is important to regularly monitor serum IgG, IgM, IgA, and peripheral blood CD19+ or CD20+ B-cell counts.
07. Infections
The incidence of various types of infections post-CAR-T cell therapy is about 55%, with severe infections (≥ grade 3) accounting for about 33%. Most infections occur within 1 to 2 years after CAR-T cell therapy, with an infection rate of up to 40% within one month post-therapy. Factors increasing the risk of infection include: number of previous treatments, infections within the last 100 days, use of corticosteroids or tocilizumab, febrile neutropenia, CD22-targeted CAR-T cell therapy, hypogammaglobulinemia, and other potential risk factors for early severe infections (including ICANS, tocilizumab, and corticosteroid use).
Pre-treatment infection screening should include routine, laboratory, pathogen, and imaging studies. There is currently no evidence-based medicine evidence to support routine bacterial prophylaxis during immunotherapy; viral infections that need prevention include HSV/VZV, CMV, EBV, HCV; all patients should use fluconazole, and high-risk patients need filamentous fungus (mold) infection prophylaxis; pneumocystis prophylaxis is recommended for all patients. Diagnosis of infections should be through medical history, laboratory tests, pathogen tests, and imaging studies. The principle of infection treatment is to manage according to severity.
Special recommendations for infection management during treatment include: (1) CRS and infection differentiation: Refer to the “CAR-T Cell Therapy NHL Adverse Effects Clinical Management Pathway Guidelines.” While there are clinical similarities between the two, no specific biomarkers currently exist to clearly differentiate them, and cases of CRS combined with infection occur. Therefore, anticipating and intervening in the development of both conditions is crucial. CRS grading and infection severity do not show significant differences at the cytokine level. When CRS is combined with severe infection, a secondary rise in IL-6 levels may occur, and there are expectations to develop a prediction model using IL-8, IL-1β, and IFN-γ to improve the specificity of distinguishing CRS from infection, but sufficient clinical data is still lacking. If the two cannot be clearly distinguished, the guiding principle is preventative anti-infection combined with CRS grade treatment. (2) Special infection monitoring: Includes tuberculosis, histoplasmosis, listeriosis, and nocardiosis; medical history is important, especially when routine anti-infection treatments are ineffective, consideration of these special pathogens is necessary; (3) Diagnosis of new coronavirus infection in patients: Generally, CAR-T cell therapy should be postponed, specific guidance can refer to the “NCCN Guidelines for Cancer-Associated Infections”; if urgent treatment is required due to uncontrollable tumor progression, treatment should be carried out based on the clinical judgment of the physician.
08. Secondary Tumors
To date, the incidence of cancer after CAR-T product administration remains low. However, there is still a potential for carcinogenesis due to genomic integration or other mechanisms by the current generation of viral vectors. Due to limited sample sizes, follow-up duration, and rigor of follow-up studies, it is still not possible to estimate the likelihood of secondary tumors after CAR-T therapy, nor to definitively link CAR-T therapy with secondary tumor occurrence. More rigorous large-sample case-control studies are needed. Management principles for secondary tumors include: (1) early detection, diagnosis, and treatment; (2) for hematologic cancers, combining new drugs for relief followed by allogeneic hematopoietic stem cell transplantation; (3) regular post-CAR-T therapy follow-ups, such as PET/CT, bone marrow biopsies, routine blood tests, lactate dehydrogenase, and tumor markers; (4) a minimum follow-up of 15 years post-CAR-T therapy, lifelong if possible, with any secondary tumors promptly reported to health and drug regulatory authorities for related pathological and genetic testing.
09. Allergic Reactions
The diagnostic criteria for allergic reactions during CAR-T therapy are primarily rashes, usually occurring within two weeks after cell infusion, characterized by blanching upon pressure, and typically resolving on their own within 3 to 5 days. The cause of these reactions, besides allergies, could be capillary endothelial fragility induced by cytokine release, which may or may not be accompanied by thrombocytopenia. Management principles for high-risk groups include excluding patients with hypersensitivity reactions at enrollment; strict control of processes and reagents during the CAR-T cell manufacturing process; and prophylactic use of anti-allergy medications (such as diphenhydramine or promethazine).
10. Abnormal Proliferation of CAR-T Cells
Within 28 days of CAR-T cell infusion, peripheral blood CAR-T cell proliferation is monitored, with blood samples collected every 2-3 days in the first two weeks, then weekly thereafter. Specific time points are days 1, 3, 5, 7, 10, 14, 21, and 28 post-infusion. Diagnostic criteria for abnormal proliferation include a peripheral white blood cell count ≥10×10^9/L; lymphocytes comprising ≥70% of white blood cells; and an absolute count of CAR+T cells >600 cells/µL. Key considerations include: (1) Is the proliferation of CAR-T cells consistent with changes in tumor size? (2) Are CAR-T cells proliferating in locations other than peripheral blood, such as in the skin, lungs, liver, etc.? (3) Is uncontrolled proliferation of activated T cells caused by viral infection? Management principles involve corticosteroids and other immunosuppressants (such as anti-thymocyte globulin or anti-CD52 antibodies). In severe cases, a combination of two or more immunosuppressants may be used.
Targeting CD19 CAR-T Cell Therapy for B-NHL
Compared to the 2023 guidelines, the 2024 guidelines include a new indication for targeting CD19 CAR-T cell therapy as a third-level recommendation for mantle cell lymphoma that has undergone second-line or higher treatment, including Bruton’s tyrosine kinase (BTK) inhibitors.
“Targeting BCMA CAR-T Cell Therapy for MM”
Compared to the 2023 guidelines, the 2024 guidelines elevate the recommendation for targeting BCMA CAR-T cell therapy for MM that has progressed after at least three lines of therapy from a second-level to a first-level recommendation.
In the pre-treatment assessment section, the 2024 guidelines add the following: (1) The guideline suggests an ECOG score of ≥3, but an ECOG score is not an absolute contraindication to CAR-T therapy, especially for patients with no better treatment options, as clinicians can weigh the benefits and patient desires; (2) Patients with renal impairment can receive CAR-T cell therapy, with caution advised when creatinine clearance is <30 ml/min; (3) The incidence of cardiac events during CAR-T cell therapy is approximately 26%, with a recommended left ventricular ejection fraction (LVEF) >40%, although patients with cardiac amyloidosis may display a preserved ejection fraction type of heart failure, requiring more attention during treatment; (4) Clinical trials have shown that anti-GPRC5D CAR-T can serve as a salvage therapy for relapse or progression after anti-BCMA CAR-T treatment, with conditional units as an optional target for testing, not mandatory.
In the evaluation standards section, the 2024 guidelines add that: (1) CAR-T cell therapy efficacy evaluations should adopt the International Myeloma Working Group (IMWG) standards; (2) Most patients who respond to CAR-T treatment for MM achieve bone marrow minimal residual disease (MRD) negativity(by flow cytometry) within a month, but immunofixation electrophoresis conversion or normal light chain ratios may take longer, with some patients reaching optimal efficacy only after several months; (3) It is recommended to assess efficacy on days 14 and 28 after CAR-T cell infusion and monthly thereafter until optimal efficacy is achieved; for patients with extramedullary disease, an evaluation one month after CAR-T therapy is suggested using MRI, CT, or X-ray, with PET-CT considered three months later.
Additionally, the 2024 guidelines also add content on long-term follow-up: (1) Long-term follow-up mainly includes: monitoring for continuous remission of the primary disease, long-term adverse effects, and infection prevention and treatment; (2) Follow-up schedule: Assessments at 14 and 28 days post-CAR-T cell therapy, monthly assessments within six months, every two months from 6 to 12 months, a comprehensive assessment every three months in the second year, and every six months or based on clinical conditions thereafter. Assessment indicators primarily include MM efficacy evaluation indicators and post-CAR-T cell therapy toxicity detection indicators; (3) Maintenance therapy: Maintenance therapy may extend the progression-free survival (PFS) and overall survival (OS) of CAR-T therapy patients, but to date, there are no high-level evidence-based clinical data reports on maintenance schedules or durations, only case reports suggest immunomodulators may be effective, but further clinical studies are needed to confirm; (4) Management of relapsed patients: Currently, salvage treatment options for relapse after anti-BCMA CAR-T cell therapy lack high-level evidence-based clinical data, treatment can refer to the latest domestic and international guidelines or expert consensus, including clinical trials (new drugs or CAR-T, such as GPRC5D CAR-T), previously sensitive drugs, and new or unused combined treatment regimens. Additionally, drugs previously ineffective after CAR-T treatment may become sensitive again. A retrospective study showed that non-BCMA target bispecific antibodies and CAR-T treatments have a higher treatment response.
Targeting CD19 CAR-T Cell Therapy for Adult R/R B-ALL
Compared to the 2023 guidelines, the 2024 guidelines elevate the recommendation for targeting CD19 CAR-T cell therapy in R/R B-ALL for patients aged 18 to 65 from a second-level to a first-level recommendation.
In pre-treatment imaging assessments, the addition of “PET-CT for extramedullary lesions” is new; the timing of infusion has been changed to “generally between days 2 to 7 after lymphodepletion”; in post-treatment monitoring, “lymphocyte subsets” are newly recommended at a second-level, and “immunoglobulins” are added as a first-level recommendation in CAR-T kinetics. New first-level recommendations in efficacy evaluation include “other fusion genes or mutation genes (limited to those positive)” and “imaging evaluation of CNS and other extramedullary disease sites.”
Other Issues to Note:
01
Apheresis: The total blood volume processed during apheresis should be determined based on the absolute lymphocyte count (ALC) of the donor. If ALC ≥ 0.5×10^9/L, the target blood volume is 7–12 L; if ALC <0.5×10^9/L, the target blood volume is 12 L. Mononuclear cells (MNCs) are crucial raw materials for CAR-T production, and their quantity critically impacts the production process and product quality, with a requirement to collect at least 1×10^9 MNCs.
02
Bridging therapy post-apheresis: B-ALL is a highly aggressive disease that can progress rapidly. For some patients with fast-progressing B-ALL, bridging therapy before infusion post-apheresis is necessary to reduce disease burden and CAR-T immunotoxicity. If the clinical physician assesses the patient as having a stable low tumor burden during the CAR-T preparation cycle, bridging therapy may not be needed. The bridging plan should be decided after evaluating the patient’s response to previous treatments, overall tumor burden, and tumor-involved sites, with the principle of minimizing adverse reactions, such as the MP (6-mercaptopurine + prednisone) regimen. Bridging chemotherapy should consider the timing of CAR-T infusion, ensuring subsequent CAR-T infusion, generally recommending no use of pegaspargase within 4 weeks before CAR-T infusion; no anthracyclines, vincristine, 6-thioguanine, methotrexate, cytarabine, asparaginase within 1 week before infusion; and no corticosteroids, hydroxyurea, tyrosine kinase inhibitors within 3 days before infusion. Other drug washout periods recommended include no radiation therapy within 1 week before CAR-T infusion (lung radiation should be spaced 2 weeks, CNS site radiation 8 weeks); no intrathecal chemotherapy within 1 week before infusion.
03
CNS involvement: The product information for brexucabtagene autoleucel and tisagenlecleucel explicitly states they are not suitable for cases with CNS involvement. The Naxolone clinical trial also excluded patients with active CNS leukemia and in the “Naxolone Injection Clinical Application Guidelines (2023 Edition)” clinical use recommendations exclude those with severe CNS diseases. However, clinical studies have suggested that CAR-T cells can cross the blood-brain barrier and have shown some efficacy in patients with CNS involvement. Therefore, in clinical practice, careful evaluation is needed to assess whether CAR-T cell therapy is beneficial for patients with central infiltration. For patients below CNS-2 level (cerebrospinal fluid white cell count <5 cells/µl, with visible primitive lymphocytes), if the clinical physician considers that the patient could benefit from CAR-T cell therapy, it can be performed (level III recommendation), and it is crucial to pay close attention to the occurrence of ICANS and take preventative measures.
04 Management after relapse: Participate in clinical trials.
Expert Introduction
Professor Wenjun Zhang
Vice Director of the Cancer Center at Tongji Hospital, affiliated with Tongji University
Vice Director of the Hematology Research Institute, Tongji University
Doctor of Medicine, Associate Chief Physician, Associate Professor, Associate Researcher, Doctoral Supervisor
Primarily engaged in basic and clinical research on hematologic cancer immunotherapy and leukemia stem cell targeted intervention. As the principal investigator, he has led three National Natural Science Foundation projects, projects from the Shanghai Science and Technology Commission, and Shanghai Shenkang research projects; as a core member, he has participated in two National Key R&D Programs of the Ministry of Science and Technology and two key projects of the National Natural Science Foundation. He has published over ten SCI papers as the first and corresponding author, authored and co-authored three books, filed seven national patents, and his research achievements have won the Shanghai Science and Technology Progress Second Prize in
2014, was selected in 2015 as a leading discipline leader in Shanghai’s “One Belt One” training program, and in the Shanghai Medical Park New Star training plan; in 2018, he received funding from the “Shanghai Talent Development Fund”; in 2019, he was honored with the “Shanghai Outstanding Young Physician” title; in 2021, he received the highest honor for young talents in the Shanghai health system, the “Silver Snake Award.”
