Pharmaceutical Medicine

, Volume 33, Issue 2, pp 83–88 | Cite as

Monitoring CAR-T-Cell Therapies Using the Nordic Healthcare Databases

  • Torbjörn CallréusEmail author
  • Tarec Christoffer El-Galaly
  • Mats Jerkeman
  • Peter de Nully Brown
  • Morten Andersen
Current Opinion


Following intense research efforts, modulation of the immune system has finally proved to be a viable approach for treating malignant disease. Recently, chimeric antigen receptor redirected T cells have achieved promising outcomes in patients with B-cell malignancies and they are currently also being investigated in other haematological malignancies, solid tumours and viral infections. Compared with traditional biopharmaceuticals, the properties of genetically modified chimeric antigen receptor redirected T-cell therapies differ in many aspects, thereby posing challenges in terms of post-authorisation data collection and data analysis. We believe that the network of population-based Nordic healthcare databases has some characteristics that can help provide important data on these new types of advanced products. In particular, the possibility of very long follow-up periods with a limited loss to follow-up is an important strength. Given the limited source population and slow access to data, a Nordic chimeric antigen receptor redirected T-cell monitoring project should be seen as complementary to other surveillance initiatives.


Compliance with Ethical Standards


Morten Andersen and Torbjörn Callréus belong to the Pharmacovigilance Research Group at the Department of Drug Design and Pharmacology, University of Copenhagen, receiving funding by the Novo Nordisk Foundation (NNF15SA0018404). No funding was specifically received for the preparation of this article.

Conflict of Interest

Mats Jerkeman has received research grants from Gilead, Abbvie, Janssen and Celgene, and personal fees from Gilead, Janssen, Acerta, Roche and Celgene. Tarec Christoffer El-Galaly has received travel grants from Takeda (ICML 2017) and Roche (ASH 2016) and has been employed by F. Hoffmann-La Roche, Ltd. since January 2019. Morten Andersen has participated in research projects funded by AstraZeneca, H. Lundbeck & Mertz, Novartis, Pfizer and Janssen, with grants paid to the institutions where he has been employed, and has personally received fees from Medicademy, the Danish Pharmaceutical Industry Association, for leading and teaching pharmacoepidemiology courses. Torbjörn Callréus and Peter de Nully Brown have no conflicts of interest that are directly relevant to the content of this article.


  1. 1.
    McCune JS. Rapid advances in immunotherapy to treat cancer. Clin Pharmacol Ther. 2018;103(4):540–4.CrossRefGoogle Scholar
  2. 2.
    Almasbak H, Aarvak T, Vemuri MC. CAR T cell therapy: a game changer in cancer treatment. J Immunol Res. 2016;2016:5474602.CrossRefGoogle Scholar
  3. 3.
    Chang ZL, Chen YY. CARs: synthetic immunoreceptors for cancer therapy and beyond. Trends Mol Med. 2017;23(5):430–50.CrossRefGoogle Scholar
  4. 4.
    June CH, Sadelain M. Chimeric antigen receptor therapy. N Engl J Med. 2018;379(1):64–73.CrossRefGoogle Scholar
  5. 5.
    Wei G, Ding L, Wang J, Hu Y, Huang H. Advances of CD19-directed chimeric antigen receptor-modified T cells in refractory/relapsed acute lymphoblastic leukemia. Exp Hematol Oncol. 2017;6:10.CrossRefGoogle Scholar
  6. 6.
    Yu S, Li A, Liu Q, Li T, Yuan X, Han X, et al. Chimeric antigen receptor T cells: a novel therapy for solid tumors. J Hematol Oncol. 2017;10(1):78.CrossRefGoogle Scholar
  7. 7.
    Zhang C, Liu J, Zhong JF, Zhang X. Engineering CAR-T cells. Biomark Res. 2017;5:22.CrossRefGoogle Scholar
  8. 8.
    Commission implementing decision granting marketing authorisation under Regulation (EC) No. 726/2004 of the European Parliament and of the Council for “Yescarta—axicabtagene ciloleucel”, an orphan medicinal product for human use. Accessed 1 Nov 2018.
  9. 9.
    Commission implementing decision granting marketing authorisation under Regulation (EC) No. 726/2004 of the European Parliament and of the Council for “Kymriah—tisagenlecleucel”, an orphan medicinal product for human use. Accessed 1 Nov 2018.
  10. 10.
    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(5):439–48.CrossRefGoogle Scholar
  11. 11.
    Jakobsen LH, Bogsted M, Brown PN, Arboe B, Jorgensen J, Larsen TS, et al. Minimal loss of lifetime for patients with diffuse large B-cell lymphoma in remission and event free 24 months after treatment: a Danish population-based study. J Clin Oncol. 2017;35(7):778–84.CrossRefGoogle Scholar
  12. 12.
    Shi Q, Schmitz N, Ou FS, Dixon JG, Cunningham D, Pfreundschuh M, et al. Progression-free survival as a surrogate end point for overall survival in first-line diffuse large B-cell lymphoma: an individual patient-level analysis of multiple randomized trials (SEAL). J Clin Oncol. 2018;36(25):2593–602.CrossRefGoogle Scholar
  13. 13.
    Gisselbrecht C, Glass B, Mounier N, Singh GD, Linch DC, Trneny M, et al. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol. 2010;28(27):4184–90.CrossRefGoogle Scholar
  14. 14.
    Crump M, Kuruvilla J, Couban S, MacDonald DA, Kukreti V, Kouroukis CT, et al. Randomized comparison of gemcitabine, dexamethasone, and cisplatin versus dexamethasone, cytarabine, and cisplatin chemotherapy before autologous stem-cell transplantation for relapsed and refractory aggressive lymphomas: NCIC-CTG LY.12. J Clin Oncol. 2014;32(31):3490–6.CrossRefGoogle Scholar
  15. 15.
    Crump M, Neelapu SS, Farooq U, Van Den Neste E, Kuruvilla J, Westin J, et al. Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study. Blood. 2017;130(16):1800–8.CrossRefGoogle Scholar
  16. 16.
    Schuster SJ, Svoboda J, Chong EA, Nasta SD, Mato AR, Anak O, et al. Chimeric antigen receptor T cells in refractory B-cell lymphomas. N Engl J Med. 2017;377(26):2545–54.CrossRefGoogle Scholar
  17. 17.
    Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377(26):2531–44.CrossRefGoogle Scholar
  18. 18.
    Neelapu SS, Tummala S, Kebriaei P, Wierda W, Gutierrez C, Locke FL, et al. Chimeric antigen receptor T-cell therapy: assessment and management of toxicities. Nat Rev Clin Oncol. 2018;15(1):47–62.CrossRefGoogle Scholar
  19. 19.
    Berlin JA, Glasser SC, Ellenberg SS. Adverse event detection in drug development: recommendations and obligations beyond phase 3. Am J Public Health. 2008;98(8):1366–71.CrossRefGoogle Scholar
  20. 20.
    Summary of risk management plan for YESCARTA (axicabtagene ciloleucel). Accessed 1 Nov 2018.
  21. 21.
    Summary of the risk management plan for Kymriah (tisagenlecleucel). Accessed 1 Nov 2018.
  22. 22.
    Leick MB, Maus MV. Toxicities associated with immunotherapies for hematologic malignancies. Best Pract Res Clin Haematol. 2018;31(2):158–65.CrossRefGoogle Scholar
  23. 23.
    Eichler HG, Abadie E, Breckenridge A, Flamion B, Gustafsson LL, Leufkens H, et al. Bridging the efficacy-effectiveness gap: a regulator’s perspective on addressing variability of drug response. Nat Rev Drug Discov. 2011;10(7):495–506.CrossRefGoogle Scholar
  24. 24.
    Martin D, Gagne JJ, Gruber S, Izem R, Nelson JC, Nguyen MD, et al. Sequential surveillance for drug safety in a regulatory environment. Pharmacoepidemiol Drug Saf. 2018;27(7):707–12.CrossRefGoogle Scholar
  25. 25.
    Li L, Kulldorff M. A conditional maximized sequential probability ratio test for pharmacovigilance. Stat Med. 2010;29(2):284–95.Google Scholar
  26. 26.
    Eichler HG, Bloechl-Daum B, Bauer P, Bretz F, Brown J, Hampson LV, et al. “Threshold-crossing”: a useful way to establish the counterfactual in clinical trials? Clin Pharmacol Ther. 2016;100(6):699–712.CrossRefGoogle Scholar
  27. 27.
    Jarow JP. Use of external controls in regulatory decision-making. Clin Pharmacol Ther. 2017;101(5):595–6.CrossRefGoogle Scholar
  28. 28.
    Lim J, Walley R, Yuan J, Liu J, Dabral A, Best N, et al. Minimizing patient burden through the use of historical subject-level data in innovative confirmatory clinical trials: review of methods and opportunities. Ther Innov Regul Sci. 2018;52(5):546–59.Google Scholar
  29. 29.
    Furu K, Wettermark B, Andersen M, Martikainen JE, Almarsdottir AB, Sorensen HT. The Nordic countries as a cohort for pharmacoepidemiological research. Basic Clin Pharmacol Toxicol. 2010;106(2):86–94.CrossRefGoogle Scholar
  30. 30.
    Tynkkynen LK, Alexandersen N, Kaarboe O, Anell A, Lehto J, Vrangbk K. Development of voluntary private health insurance in Nordic countries: an exploratory study on country-specific contextual factors. Health Policy. 2018;122(5):485–92.CrossRefGoogle Scholar
  31. 31.
    Olen O, Askling J, Sachs MC, Frumento P, Neovius M, Smedby KE, et al. Childhood onset inflammatory bowel disease and risk of cancer: a Swedish nationwide cohort study 1964–2014. BMJ. 2017;358:j3951.CrossRefGoogle Scholar
  32. 32.
    Avorn J, Kesselheim A, Sarpatwari A. The FDA Amendments Act of 2007: assessing its effects a decade later. N Engl J Med. 2018;379(12):1097–9.CrossRefGoogle Scholar
  33. 33.
    Furu K, Kieler H, Haglund B, Engeland A, Selmer R, Stephansson O, et al. Selective serotonin reuptake inhibitors and venlafaxine in early pregnancy and risk of birth defects: population based cohort study and sibling design. BMJ. 2015;350:h1798.CrossRefGoogle Scholar
  34. 34.
    Stephansson O, Kieler H, Haglund B, Artama M, Engeland A, Furu K, et al. Selective serotonin reuptake inhibitors during pregnancy and risk of stillbirth and infant mortality. JAMA. 2013;309(1):48–54.CrossRefGoogle Scholar
  35. 35.
    Kieler H, Artama M, Engeland A, Ericsson O, Furu K, Gissler M, et al. Selective serotonin reuptake inhibitors during pregnancy and risk of persistent pulmonary hypertension in the newborn: population based cohort study from the five Nordic countries. BMJ. 2012;344:d8012.CrossRefGoogle Scholar
  36. 36.
    But A, De Bruin ML, Bazelier MT, Hjellvik V, Andersen M, Auvinen A, et al. Cancer risk among insulin users: comparing analogues with human insulin in the CARING five-country cohort study. Diabetologia. 2017;60(9):1691–703.CrossRefGoogle Scholar
  37. 37.
    Ludvigsson JF, Andersson E, Ekbom A, Feychting M, Kim JL, Reuterwall C, et al. External review and validation of the Swedish national inpatient register. BMC Public Health. 2011;11:450.CrossRefGoogle Scholar
  38. 38.
    Carstensen B, Borch-Johnsen K. Register-based studies of diabetes. Scand J Public Health. 2011;39(7 Suppl.):175–9.CrossRefGoogle Scholar
  39. 39.
    Chatzidionysiou K, Hetland ML, Frisell T, Di GD, Hellgren K, Glintborg B, et al. Opportunities and challenges for real-world studies on chronic inflammatory joint diseases through data enrichment and collaboration between national registers: the Nordic example. RMD Open. 2018;4(1):e000655.CrossRefGoogle Scholar
  40. 40.
    Wasterlid T, Brown PN, Hagberg O, Hagberg H, Pedersen LM, D’Amore F, et al. Impact of chemotherapy regimen and rituximab in adult Burkitt lymphoma: a retrospective population-based study from the Nordic Lymphoma Group. Ann Oncol. 2013;24(7):1879–86.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Drug Design and PharmacologyUniversity of CopenhagenCopenhagenDenmark
  2. 2.Department of HematologyAalborg University HospitalAalborgDenmark
  3. 3.Department of OncologyLund UniversityLundSweden
  4. 4.Department of HematologyCopenhagen University HospitalCopenhagenDenmark

Personalised recommendations