October 3, 2022

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JAMA·Oncology: NfL can predict neurotoxic complications of CAR-T therapy!

JAMA·Oncology: NfL can predict neurotoxic complications of CAR-T therapy!



 

JAMA·Oncology: NfL can predict neurotoxic complications of CAR-T therapy!

As a “star” therapy in the field of tumor immunotherapy, chimeric antigen receptor T cells (CAR-T) have been approved for use in refractory acute B lymphocytic leukemia, relapsed and refractory large B cell lymphoma and other blood Treatment of systemic tumors [1-2].

 

However, while CAR-T therapy improves the prognosis of tumor patients, it may also cause adverse reactions of varying degrees. Immune effector cell-associated neurotoxicity syndrome (ICANS) can occur in 40%-60% of patients , and in severe cases, coma, epilepsy, cerebral edema and even death can occur [3-4].

How to identify high-risk groups of ICANS early has become an important issue for clinicians.

 

Studies have shown that serum neurofilament light chain protein (NfL) levels are associated with the severity of ICANS after CAR-T therapy [5].

However, whether the increase in NfL is an acute reaction after CAR-T treatment or a chronic change that exists before treatment is still uncertain.

The association between NfL and known ICANS risk factors also needs to be further elucidated.

 

Recently, a team led by Omar H. Butt of Washington University Sitman Cancer Center in St. Louis published an important research result in the journal JAMA Oncology [6].

 

Baseline plasma NfL levels were higher in patients with ICANS compared with patients without ICANS (87.6 pg/mL vs 29.4 pg/mL, P < 0.001).

 

Baseline NfL levels were associated with ICANS severity , but not with risk factors such as demographic characteristics, tumor history, history of neurological non-neoplastic disease, and exposure to neurotoxic therapy.

Predicting the occurrence of ICANS in patients based on baseline NfL levels has an accuracy of 96%.

 

This study shows that NfL levels before CAR-T cell infusion can be used to predict the occurrence of ICANS after treatment.

This finding can also help clinicians identify high-risk groups of ICANS as early as possible, and then provide an important reference for the optimization and rational application of CAR-T therapy.

 

JAMA·Oncology: NfL can predict neurotoxic complications of CAR-T therapy!

 

To explore the changes in NfL levels in patients during CAR-T treatment and the association between NfL and ICANS and related risk factors, the researchers retrospectively analyzed patients from Washington University in St. Louis and Case Western Reserve University Hospital who received CD19 CAR-T The medical records of T-treated patients and the severity of ICANS and cytokine release syndrome were classified according to American Society for Transplantation and Cell Therapy criteria [7].

 

The investigators detected plasma NfL levels at baseline (before lymphocyte clearance), at the time of lymphocyte clearance, and on days 1, 3, 7, 14, and 30 of CAR-T infusion. Laboratory test results such as platelet count and C-reactive protein on days 1, 3, 5, and 7.

 

Subsequently, the researchers compared the NfL levels of ICANS patients with different severities, explored the relationship between various clinical indicators and NfL levels, and used the receiver operating characteristic (ROC) curve to evaluate the accuracy of each risk factor in predicting ICANN .

 

The study included 30 patients with a median age of 64 years. Baseline NfL was elevated in patients with ICANS of any degree, grades 1-2, and ≥3 compared with patients without ICANS (29.4 pg/mL), 87.6 pg/mL and 115.3 pg/mL, respectively and 71.7 pg/mL.

 

JAMA·Oncology: NfL can predict neurotoxic complications of CAR-T therapy!

Plasma NfL levels in patients with different grades of ICANS

 

The researchers also found that patients with ICANS had higher NfL levels at any time point than those without ICANS during CAR-T treatment, and this trend continued until day 30 after cell infusion.

 

JAMA·Oncology: NfL can predict neurotoxic complications of CAR-T therapy!

Plasma NfL levels at different time points in patients receiving CAR-T therapy

 

In addition, patients’ baseline NfL level was associated with the severity of ICANS (r = 0.74; P < 0.001), but with risk factors such as demographic characteristics, tumor history, neurological non-neoplastic disease, and exposure to neurotoxic therapy. It doesn’t matter.

 

JAMA·Oncology: NfL can predict neurotoxic complications of CAR-T therapy!

Correlation analysis between baseline NfL and various clinical indicators

 

Predicting the occurrence of ICANS in patients based on the baseline NfL level has an accuracy of 96% (area under the ROC curve 0.96), and the sensitivity and specificity are 91% and 95%, respectively, which are better than other clinical indicators.

 

Comparison of the accuracy of each clinical index in predicting ICANS (orange is the baseline NfL)

 

The samples of this study came from registered clinical studies, the medical records and related data are complete, and the research conclusions are true and credible.

According to the results of this study, NfL levels before CAR-T cell infusion can be used to predict the occurrence of ICANS after treatment.

Determination and analysis of NfL levels before treatment can help clinicians identify high-risk groups in ICANS in a timely manner, take relevant intervention measures, and then improve patient prognosis.

 

For patients with ICANS, NfL was already elevated before CAR-T cell infusion, suggesting that these patients had a certain degree of nervous system damage before treatment.

This view also provides a new entry point for the study of the pathophysiology and pathogenesis of ICANS. In addition, the continuous increase of NfL within 30 days of CAR-T cell infusion also indicates that after the acute phase symptoms of ICANS disappear, hidden nerve damage may still persist, and its clinical significance is also worthy of further analysis and interpretation by researchers.

 

This study also has its limitations. For example , most of the patients included in the study were treated with Axicabtagene Ciloleucel.

Whether the conclusion is also applicable to patients treated with other CAR-T products remains to be explained by further research ; The efficacy of NfL levels between different grades of ICANS is insufficient; CSF specimens and imaging data are lacking in the determination of peripheral blood NfL levels.

 

In the future prospective, large-sample CAR-T therapy research design stage, the preoperative NfL level can be used to screen the enrolled population or set subgroups, and then further explore the clinical reference role of this indicator.

The exploration of the physiological and pathological mechanisms of NfL will also help to further understand the pathogenesis of ICANS, so that patients can benefit from CAR-T therapy while avoiding this dangerous adverse reaction as much as possible.

 

 

 

 

 

 

 

 


references

1. Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. N Engl J Med. Dec 28 2017;377(26):2531-2544. doi:10.1056 /NEJMoa1707447

2. Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. N Engl J Med. Feb 1 2018;378(5):439-448. doi:10.1056/NEJMoa1709866

3. Park JH, Riviere I, Gonen M, et al. Long-Term Follow-up of CD19 CAR Therapy in Acute Lymphoblastic Leukemia. N Engl J Med. Feb 1 2018;378(5):449-459. doi:10.1056 /NEJMoa1709919

4. Gust J, Taraseviciute A, Turtle CJ. Neurotoxicity Associated with CD19-Targeted CAR-T Cell Therapies. CNS Drugs. Dec 2018;32(12):1091-1101. doi:10.1007/s40263-018-0582-9

5. Schoeberl F, Tiedt S, Schmitt A, et al. Neurofilament light chain serum levels correlate with the severity of neurotoxicity after CAR T-cell treatment. Blood Adv. May 24 2022;6(10):3022-3026. doi: 10.1182/bloodadvances.2021006144

6. Butt OH, Zhou AY, Caimi PF, et al. Assessment of Pretreatment and Posttreatment Evolution of Neurofilament Light Chain Levels in Patients Who Develop Immune Effector Cell-Associated Neurotoxicity Syndrome [published online ahead of print, 2022 Sep 1]. JAMA Oncol . 2022;10.1001/jamaoncol.2022.3738. doi:10.1001/jamaoncol.2022.3738

7. Lee DW, Santomasso BD, Locke FL, et al. ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. Biol Blood Marrow Transplant. Apr 2019;25(4):625-638. doi:10.1016 /j.bbmt.2018.12.758

JAMA·Oncology: NfL can predict neurotoxic complications of CAR-T therapy!

(source:internet, reference only)


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