Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Correspondence
  • Published:

Profile of capillary-leak syndrome in patients received chimeric antigen receptor T cell therapy

Bone Marrow Transplantation volume 57, pages 661–663 (2022)Cite this article

Subjects

Autologous T cells modified to express a recombinant chimeric antigen receptor (CAR-T) for tumor-related antigens has demonstrated exciting efficacy in treating hematological malignancies as well as other diseases [1,2,3]. Until now the US Food and Drug Administration has approved five products commercially and there are growing numbers of clinical trials being conducted around the world. Besides the promising outcomes of the novel treatment, the toxicities followed by CAR-T therapy are the main barrier to its application. The most frequent and described toxicities are cytokine release syndrome (CRS), which is a hyperimmune inflammatory response caused by the rapid increase in excessive cytokines as results of activation and proliferation of CAR-T cells. The clinical manifestations of CRS present as fever, fatigue, edema, acute kidney injury, cardiac toxicity, capillary-leak syndrome (CLS) and other symptoms of systemic inflammatory response syndrome [4,5,6]. As a syndrome of the severe CRS, CLS is characterized by profound vascular leakage, resulting in the transfer of protein-rich fluid from the intravascular to the interstitium. On the one hand, it leads to insufficient vascular content and reduced effective circulating blood volume, which can manifest clinically as hypotension, low central venous pressure, blood concentration, hypoproteinemia, shock and acute kidney injury; on the other hand, fluid entering the interstitium can cause pleural infusion, pericardial effusion and ascites, causing non-cardiogenic pulmonary edema, intestinal edema, muscle edema, oliguria and weight gain. Therefore, patients can present with severe generalized edema and insufficient effective circulating blood volume at the same time. However, the spectrum of CLS associated with CAR-T cell therapy has not been systematically evaluated, which can be a life-threatening complication. Therefore, as the use of CAR-T therapy continues to expand, it is of great significance to characterize the profile of CLS to help providing better management. A total of 40 ALL patients were included in this study with 11(11/40, 27.5%) patients diagnosed as CLS and 29 non-CLS. The baseline characteristics and outcomes of them are described in supplemental materials and Supplementary Table S1.

An analysis of the prevalence of symptoms associated with the diagnosis of CLS has been conducted. Edema, defined as unexplained weight gain >3% in 24 h, occurred at 5.1 days post-CAR-T infusion in 9(81.8%) patients with a mean duration of 8.1 days. Nine (81.8%) CLS patients developed hypotension, where the mean lowest systolic blood pressure was 80 mm/Hg and the mean lowest diastolic blood pressure was 48 mm/Hg. And the average duration of hypotension was 3.5 days. Moreover, the lowest SpO2 level was lower in CLS patients than in non-CLS patients (87.3% vs. 95.6%, p = 0.0028). For treatment, 7(63.6%) CLS patients used vasopressor and 10(90.9%) patients used diuretics. Half of the non-CLS patients received gamma globulin infusion while more than 90% of the CLS patients received it.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1

References

  1. Schuster SJ, Bishop MR, Tam CS, Waller EK, Borchmann P, McGuirk JP, et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2018;380:45–56.

    Article  Google Scholar 

  2. Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378:439–48.

    Article  CAS  Google Scholar 

  3. Park JH, Rivière I, Gonen M, Wang X, Sénéchal B, Curran KJ, et al. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N Engl J Med. 2018;378:449–59.

    Article  CAS  Google Scholar 

  4. Gutgarts V, Jain T, Zheng J, Maloy MA, Ruiz JD, Pennisi M, et al. Acute kidney injury after CAR-T cell therapy: low incidence and rapid recovery. Biol Blood Marrow Transplant. 2020.

  5. Burstein DS, Maude S, Grupp S, Griffis H, Rossano J, Lin K. Cardiac profile of chimeric antigen receptor T cell therapy in children: a single-institution experience. Biol Blood Marrow Transpl. 2018;24:1590–5.

    Article  Google Scholar 

  6. Lee DW, Santomasso BD, Locke FL, Ghobadi A, Turtle CJ, Brudno JN, et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transpl. 2019;25:625–38.

    Article  CAS  Google Scholar 

  7. Case R, Ramaniuk A, Martin P, Simpson PJ, Harden C, Ataya A. Systemic capillary leak syndrome secondary to coronavirus disease 2019. Chest. 2020;158:e267–e8.

    Article  CAS  Google Scholar 

  8. de Chambrun MP, Cohen-Aubart F, Donker DW, Cariou P-L, Luyt C-E, Combes A, et al. SARS-CoV-2-induces acute and refractory relapse of systemic capillary leak syndrome (Clarkson’s disease). Am J Med. 2020.

  9. de Chambrun MP, Constantin J-M, Mathian A, Quemeneur C, Lepere V, Combes A, et al. Clarkson’s disease episode or secondary systemic capillary leak-syndrome: that is the question! Chest. 2021;159:441.

    Article  Google Scholar 

  10. Wu MA, Fossali T, Pandolfi L, Carsana L, Ottolina D, Frangipane V, et al. COVID-19: The key role of pulmonary capillary leakage. An observational cohort study. medRxiv. 2020. https://www.medrxiv.org/content/10.1101/2020.05.17.20104877v1.

  11. Casadei Gardini A, Aquilina M, Oboldi D, Lucchesi A, Carloni S, Tenti E, et al. Separate episodes of capillary leak syndrome and pulmonary hypertension after adjuvant gemcitabine and three years later after nab-paclitaxel for metastatic disease. BMC Cancer. 2013;13:542.

    Article  Google Scholar 

  12. Strati P, Ahmed S, Furqan F, Fayad LE, Lee HJ, Iyer SP, et al. Prognostic impact of corticosteroids on efficacy of chimeric antigen receptor T-cell therapy in large B-cell lymphoma. Blood. 2021;137:3272–6.

    Article  CAS  Google Scholar 

  13. Liu S, Deng B, Pan J, Yin Z, Lin Y, Ling Z, et al. Corticosteroids do not influence the efficacy and kinetics of CAR-T cells for B-cell acute lymphoblastic leukemia. Blood. 2019;134:228.

    Article  Google Scholar 

  14. Xie Z, Chan EC, Long LM, Nelson C, Druey KM. High-dose intravenous immunoglobulin therapy for systemic capillary leak syndrome (Clarkson disease). Am J Med. 2015;128:91–5.

    Article  CAS  Google Scholar 

  15. Prete M, Urso L, Fatone MC, Pinto V, Perosa F. Antiphospholipids syndrome complicated by a systemic capillary leak-like syndrome treated with steroids and intravenous immunoglobulins: a case report. Medicine. 2016;95:e2648.

    Article  CAS  Google Scholar 

  16. Natterer J, Perez MH, Di Bernardo S. Capillary leak leading to shock in Kawasaki disease without myocardial dysfunction. Cardiol Young. 2012;22:349–52.

    Article  Google Scholar 

Download references

Funding

This work was supported by the grants from 973 Program (2015CB964900), the Natural Science Foundation of China (82000179), Key Project of Science and Technology Department of Zhejiang Province (2018C03016-2, 2015C03G2150011), Zhejiang public welfare foundation (GF18H180002).

Author information

Authors and Affiliations

  1. Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Jingjing Feng, Mi Shao, Yongxian Hu & He Huang

  2. Liangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, China

    Jingjing Feng, Mi Shao, Yongxian Hu & He Huang

  3. Institute of Hematology, Zhejiang University, Hangzhou, China

    Jingjing Feng, Mi Shao, Yongxian Hu & He Huang

  4. Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China

    Jingjing Feng, Mi Shao, Yongxian Hu & He Huang

Authors
  1. Jingjing Feng
    View author publications

    Search author on:PubMed Google Scholar

  2. Mi Shao
    View author publications

    Search author on:PubMed Google Scholar

  3. Yongxian Hu
    View author publications

    Search author on:PubMed Google Scholar

  4. He Huang
    View author publications

    Search author on:PubMed Google Scholar

Contributions

JF collected the data and designed and write the article. MS collected the data. YH and HH designed the research and reviewed the article.

Corresponding authors

Correspondence to Yongxian Hu or He Huang.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Notation of prior abstract publication/presentation Selected data were presented in abstract form at the 2018 American Society of Hematology meeting

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Feng, J., Shao, M., Hu, Y. et al. Profile of capillary-leak syndrome in patients received chimeric antigen receptor T cell therapy. Bone Marrow Transplant 57, 661–663 (2022). https://doi.org/10.1038/s41409-022-01562-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41409-022-01562-4

This article is cited by

Search

Advanced search

Quick links