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. 2021 Sep 13;9(9):CD013365.
doi: 10.1002/14651858.CD013365.pub2.

Chimeric antigen receptor (CAR) T-cell therapy for people with relapsed or refractory diffuse large B-cell lymphoma

Moritz Ernst  1 , Annika Oeser  1 , Burcu Besiroglu  1 , Julia Caro-Valenzuela  1 , Mohamed Abd El Aziz  2 , Ina Monsef  1 , Peter Borchmann  3 , Lise J Estcourt  4 , Nicole Skoetz  5 , Marius Goldkuhle  1
Affiliations

Chimeric antigen receptor (CAR) T-cell therapy for people with relapsed or refractory diffuse large B-cell lymphoma

Moritz Ernst et al. Cochrane Database Syst Rev. .

Abstract

Background: Diffuse large B-cell lymphoma (DLBCL) is an aggressive cancer of the lymphatic system. About 30% to 40% of people with DLBCL experience relapse and 10% are refractory to first-line treatment usually consisting of R-CHOP chemotherapy. Of those eligible for second-line treatment, commonly consisting of salvage chemotherapy followed by autologous stem-cell transplantation (ASCT), around 50% experience relapse. With a median overall survival of less than six to 12 months, the prognosis of individuals who relapse or are refractory (r/r) to advanced lines of treatment or of those who are ineligible for ASCT, is very poor. With the introduction of chimeric antigen receptor (CAR) T-cell therapy, a novel treatment option for these people is available.

Objectives: To assess the benefits and harms of chimeric antigen receptor (CAR) T-cell therapy for people with relapsed or refractory (r/r) DLBCL.

Search methods: An experienced information specialist performed a systematic database search for relevant articles on CENTRAL, MEDLINE and Embase until September 11th, 2020. We also searched trial registries and reference lists of identified studies up to this date. All search results were screened by two authors independently and a third author was involved in case of discrepancies.

Selection criteria: We included prospectively planned trials evaluating CAR T-cell therapy for people with r/r DLBCL. We had planned to include randomised controlled trials (RCTs) and we flexibly adapted eligibility criteria to the most reliable study designs available. We excluded studies involving fewer than 10 participants with r/r DLBCL and studies with a proportion of participants with r/r DLBCL below 70%, unless data were reported separately for this subgroup.

Data collection and analysis: Two review authors extracted data and performed risk of bias ratings independently. A third author was involved in case of disagreements. As our search did not yield any completed RCTs, prospective controlled non-randomised studies of interventions (NRSIs) or prospective observational studies with a control group, we did not meta-analyse data and reported all results narratively. We adopted the GRADE approach to assess the certainty of the evidence for prioritised outcomes.

Main results: We identified 13 eligible uncontrolled studies evaluating a single or multiple arms of CAR T-cell therapies. We also identified 38 ongoing studies, including three RCTs. Ten studies are awaiting classification due to completion with no retrievable results data or insufficient data to justify inclusion. The mean number of participants enrolled, treated with CAR T-cell therapy and evaluated in the included studies were 79 (range 12 to 344; data unavailable for two studies), 61 (range 12 to 294; data unavailable for one study) and 52 (range 11 to 256), respectively. Most studies included people with r/r DLBCL among people with other haematological B-cell malignancies. Participants had received at least a median of three prior treatment lines (data unavailable for four studies), 5% to 50% had undergone ASCT (data unavailable for five studies) and, except for two studies, 3% to 18% had undergone allogenic stem-cell transplantation (data unavailable for eight studies). The overall risk of bias was high for all studies, in particular, due to incomplete follow-up and the absence of blinding. None of the included studies had a control group so that no adequate comparative effect measures could be calculated. The duration of follow-up varied substantially between studies, in particular, for harms. Our certainty in the evidence is very low for all outcomes. Overall survival was reported by eight studies (567 participants). Four studies reported survival rates at 12 months which ranged between 48% and 59%, and one study reported an overall survival rate of 50.5% at 24 months. The evidence is very uncertain about the effect of CAR T-cell therapy on overall survival. Two studies including 294 participants at baseline and 59 participants at the longest follow-up (12 months or 18 months) described improvements of quality of life measured with the EuroQol 5-Dimension 5-Level visual analogue scale (EQ-5D-5L VAS) or Function Assessment of Cancer Therapy-Lymphoma (FACT-Lym). The evidence is very uncertain about the effect of CAR T-cell therapy on quality of life. None of the studies reported treatment-related mortality. Five studies (550 participants) reported the occurrence of adverse events among participants, ranging between 99% and 100% for any grade adverse events and 68% to 98% for adverse events grade ≥ 3. In three studies (253 participants), 56% to 68% of participants experienced serious adverse events, while in one study (28 participants), no serious adverse events occurred. CAR T-cell therapy may increase the risk of adverse events and serious adverse events but the evidence is very uncertain about the exact risk. The occurrence of cytokine release syndrome (CRS) was reported in 11 studies (675 participants) under use of various grading criteria. Five studies reported between 42% and 100% of participants experiencing CRS according to criteria described in Lee 2014. CAR T-cell therapy may increase the risk of CRS but the evidence is very uncertain about the exact risk. Nine studies (575 participants) reported results on progression-free survival, disease-free survival or relapse-free survival. Twelve-month progression-free survival rates were reported by four studies and ranged between 44% and 75%. In one study, relapse-free survival remained at a rate of 64% at both 12 and 18 months. The evidence is very uncertain about the effect of CAR T-cell therapy on progression-free survival. Thirteen studies (620 participants) provided data on complete response rates. At six months, three studies reported complete response rates between 40% and 45%. The evidence is very uncertain about the effect of CAR T-cell therapy on complete response rates.

Authors' conclusions: The available evidence on the benefits and harms of CAR T-cell therapy for people with r/r DLBCL is limited, mainly because of the absence of comparative clinical trials. The results we present should be regarded in light of this limitation and conclusions should be drawn very carefully. Due to the uncertainty in the current evidence, a large number of ongoing investigations and a risk of substantial and potentially life-threatening complications requiring supplementary treatment, it is critical to continue evaluating the evidence on this new therapy.

Trial registration: ClinicalTrials.gov NCT02772198 NCT01865617 NCT02445248 NCT00924326 NCT03310619 NCT03207178 NCT02030834 NCT03097770 NCT02631044 NCT03344367 NCT03355859 NCT02348216 NCT02926833 NCT01138579 NCT02132624 NCT01475058 NCT02776813 NCT03189836 NCT03579927 NCT01735604 NCT01815749 NCT01318317 NCT02652910 NCT02933775 NCT02976857 NCT03598179 NCT03287817 NCT03570892 NCT03610724 NCT02431988 NCT04049513 NCT03373071 NCT02374333 NCT02659943 NCT02706405 NCT02728882 NCT02737085 NCT02892695 NCT03233854 NCT03277729 NCT03528421 NCT03579888 NCT03704298 NCT03720457 NCT04231747 NCT04381741 NCT04450069 NCT04456023 NCT04464200 NCT04486872 NCT04526834 NCT04545762 NCT03630159 NCT02028455 NCT01840566 NCT03019055 NCT03744676 NCT03483103 NCT03484702 NCT03575351 NCT04002401 NCT03391466.

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Conflict of interest statement

  1. Moritz Ernst: none known

  2. Annika Oeser: none known

  3. Burcu Besiroglu: none known

  4. Julia Caro‐Valenzuela: none known

  5. Mohamed Abd El Aziz: none known

  6. Ina Monsef: none known

  7. Peter Borchmann: consultancy and payment for lectures including service on speakers bureaus: DLBCL; Novartis, Celgene, Gilead, Miltenyi

  8. Lise J Estcourt: none known

  9. Nicole Skoetz: none known

  10. Marius Goldkuhle: none known

Figures

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Please note that, for the outcome‐level assessments, a blank space indicates that the outcome was not reported by the study.
See this image and copyright information in PMC

Update of

  • doi: 10.1002/14651858.CD013365

References

References to studies included in this review

Beider 2019 {published data only (unpublished sought but not used)}
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Hirayama 2019 {published data only (unpublished sought but not used)}
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PLATFORM {published data only (unpublished sought but not used)}
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Schuster 2017 {published data only (unpublished sought but not used)}
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Tong 2020 {published data only}
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TRANSCEND‐NHL‐001 {published data only (unpublished sought but not used)}
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Ying 2019 {published data only (unpublished sought but not used)}
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ZUMA‐1 {published data only (unpublished sought but not used)}
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References to studies excluded from this review

Batlevi 2019 {published data only}
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Buhmann 2013 {published data only}
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Cao 2019 {published data only}ChiCTR‐ONN‐16009862ChiCTR1800019288
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ChiCTR‐OPN‐16009069 {unpublished data only}ChiCTR‐OPN‐16009069
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Chong 2020 {published data only}
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Enblad 2018 {published data only}
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Jain 2019 {published data only}
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NCT01475058 {unpublished data only}
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NCT02776813 {unpublished data only}
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NCT03189836 {published data only}
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NCT03196830 {published data only}
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NCT03436771 {published data only}
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NCT03579927 {unpublished data only}
    1. NCT03579927. CAR CD19-CD28-zeta-2A-iCasp9-IL15-transduced cord blood NK cells, high-dose chemotherapy, and stem cell transplant in treating participants with B-cell lymphoma. clinicaltrials.gov/show/NCT03579927 (first received 2018).
Sauter 2014a {published data only}
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Sesques 2020 {published data only}
    1. Sesques P, Ferrant E, Safar V, Wallet F, Tordo J, Dhomps A, et al. Commercial anti-CD19 CAR T cell therapy for patients with relapsed/refractory aggressive B cell lymphoma in a European center. American Journal of Hematology 2020;95(11):1324-33. - PubMed
Srour 2020 {published data only}
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Wang 2014 {published data only}
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Wang 2016 (NHL2) {published data only}
    1. Wang X, Popplewell LL, Wagner JR, Naranjo A, Blanchard MS, Mott MR, et al. Phase 1 studies of central memory-derived CD19 CAR T-cell therapy following autologous HSCT in patients with B-cell NHL. Blood 2016;127(24):2980-90. - PMC - PubMed
Wang 2016a (NHL1) {published data only}
    1. Popplewell L, Wang X, Naranjo A, Blanchard S, Wagner J, Wong CL, et al. Phase I studies of cellular immunotherapy using central memory derived-CD19-specific T cells following autologous stem cell transplantation for patients with high-risk intermediate grade B-lineage non-Hodgkin lymphoma. Blood 2015;126 (23):930.
    1. Wang X, Popplewell LL, Wagner JR, Naranjo A, Blanchard MS, Mott MR, et al. Phase 1 studies of central memory-derived CD19 CAR T-cell therapy following autologous HSCT in patients with B-cell NHL. Blood 2016;127(24):2980-90. - PMC - PubMed
Wang 2020 {published data only}ChiCTR‐OPN‐16008526
    1. ChiCTR-OPN-16008526. An open-label, single-center and single-arm clinical study of sequential infusion of anti-CD22 and anti-CD19 CAR-T cells for patients with relapsed or refractory B-cell malignancies. who.int/trialsearch/Trial2.aspx?TrialID=ChiCTR-OPN-16008526 (first received 2016).
    1. Huang L, Wang N, Cao Y, Li C, Xiao Y, Xiao M, et al. CAR22/19 cocktail therapy for patients with refractory/relapsed B-cell malignancies. Blood 2018;132(Suppl 1):1408.
    1. Wang N, Hu X, Cao W, Li C, Xiao Y, Cao Y, et al. Efficacy and safety of CAR19/22 T-cell cocktail therapy in patients with refractory/relapsed B-cell malignancies. Blood 2020;135(1):17-27. - PubMed

References to studies awaiting assessment

ChiCTR‐ONC‐16008911 {unpublished data only}ChiCTR‐ONC‐16008911
    1. ChiCTR-ONC-16008911. CD19-targeted CAR-T cell therapy for MRD of B-cell lymphoma. chictr.org.cn/showproj.aspx?proj=15018 (first received 2016).
ChiCTR‐OPN‐16009847 {unpublished data only}ChiCTR‐OPN‐16009847
    1. ChiCTR-OPN-16009847. An open label, single center, single arm clinical study for sequential infusion of anti-CD19 CAR-T and anti-CD22 CAR-T therapy following autologous hematopoietic stem cell transplantation (auto-HSCT) for relapsed, refractory and high-risk B cell lymphoma. chictr.org.cn/com/25/historyversionpuben.aspx?regno=ChiCTR-OPN-16009847 (first received 2016).
ChiCTR‐OPN‐17013507 {unpublished data only}ChiCTR‐OPN‐17013507
    1. ChiCTR-OPN-17013507. A single-center, single-arm, open-label, dose escalation study to evaluate the safety & preliminary anti-tumor activity of CD19 single-chain antibody chimeric antigen receptor T cells (CAR-T-19) for the treatment of patients with relapsed/refractory B-cell leukemia/lymphoma. chictr.org.cn/showproj.aspx?proj=22440 (first received 2017).
NCT02652910 {unpublished data only}
    1. NCT02652910. Memory-enriched CAR-T cells immunotherapy for B cell lymphoma (MeCAR). clinicaltrials.gov/ct2/show/NCT02652910 (first received 2016).
NCT02933775 {unpublished data only}
    1. NCT02933775. CD19-redirected autologous cells (CAR-CD19 t cells). clinicaltrials.gov/ct2/show/NCT02933775 (first received 2016).
NCT02976857 {unpublished data only}
    1. NCT02976857. A phase 1 study evaluating safety and efficacy of C-CAR011 treatment in DLBCL subjects. clinicaltrials.gov/ct2/show/NCT02976857 (first received 2018).
NCT03097770 {unpublished data only}
    1. NCT03097770. Treatment of relapsed and/or chemotherapy refractory B-cell malignancy by tandem CAR T cells targeting CD19 and CD20. clinicaltrials.gov/ct2/show/NCT03097770 (first received 2017).
NCT03598179 {unpublished data only}
    1. NCT03598179. XLCART001 treatment in relapsed/refractory/high-risk B-cell malignancy subjects. clinicaltrials.gov/ct2/show/NCT03598179 (first received 2018).

References to ongoing studies

ALEXANDER {unpublished data only}
    1. Eudract_2016-004682-11. A single arm, open-label, multi-centre, phase I/II study evaluating the safety and clinical activity of AUTO3, a CAR T cell treatment targeting CD19 and CD22 and consolidation with anti PD-1 antibodies. clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-00... (first received 2016).
    1. NCT03287817. CD19/22 CAR t cells (AUTO3) for the treatment of diffuse large B cell lymphoma. clinicaltrials.gov/show/NCT03287817 (first received 2016).
BELINDA {unpublished data only}
    1. NCT03570892. Tisagenlecleucel in adult patients with aggressive B-cell non-Hodgkin lymphoma. clinicaltrials.gov/show/NCT03570892 (first received 2018).
BIANCA {unpublished data only}
    1. NCT03610724. Phase II open label trial to determine safety & efficacy of tisagenlecleucel in pediatric non-Hodgkin lymphoma patients. clinicaltrials.gov/show/NCT03610724 (first received 2019).
ChiCTR1800017686 2018 {unpublished data only}ChiCTR1800017686
    1. ChiCTR1800017686. Anti-CD19 CAR-T cell therapy for relapsed and refractory CD19-positive lymphoma. chictr.org.cn/showproj.aspx?proj=29929 (first received 2018).
COBALT {unpublished data only}
    1. NCT02431988. Evaluation of CAR19 T-cells as an optimal bridge to allogeneic transplantation. clinicaltrials.gov/show/NCT02431988 (first received 2016).
ENABLE {unpublished data only}
    1. George P, Dasyam N, Giunti G, Mester B, Bauer E, Andrews B, et al. Third-generation anti-CD19 chimeric antigen receptor T-cells incorporating a tlr2 domain for relapsed or refractory B-cell lymphoma: a phase I clinical trial protocol (ENABLE). BMJ Open 2020;10 (2):e034629. - PMC - PubMed
Eudract_2017_002088‐16‐IT {unpublished data only}
    1. Eudract_2017_002088-16-IT. CD19-CART01 in pediatric patients affected by relapsed/refractory CD19+ acute lymphoblastic leukemia and non Hodgkin lymphoma. who.int/trialsearch/Trial2.aspx?TrialID=EUCTR2017-002088-16-IT (first received 2018).
JPRN‐JapicCTI‐183914 {unpublished data only}183914
    1. JPRN-JapicCTI-183914. A phase 2 multicenter, open-label, single-arm study of KTE-C19 in Japanese patients with refractory or relapsed large B cell lymphoma. clinicaltrials.jp/user/showCteDetailE.jsp?japicId=JapicCTI-183914 (first received 2018).
NCT02374333 {unpublished data only}
    1. NCT02374333. Pilot study of redirected autologous T cells engineered to contain humanized anti-CD19 in patients with relapsed or refractory CD19+ leukemia and lymphoma previously treated with cell therapy. clinicaltrials.gov/show/NCT02374333 (first received 2014).
NCT02659943 {unpublished data only}
    1. NCT02659943. T cells expressing a fully-human antiCD19 chimeric antigen receptor for treating B-cell malignancies. clinicaltrials.gov/show/NCT02659943 (first received 2016).
NCT02706405 {unpublished data only}
    1. NCT02706405. JCAR014 and durvalumab in treating patients with relapsed or refractory B-cell non-Hodgkin lymphoma. clinicaltrials.gov/show/NCT02706405 (first received 2016).
NCT02728882 {unpublished data only}
    1. NCT02728882. Study evaluating the efficacy and safety with CAR-T for recurrent or refractory diffuse large B cell lymphoma. clinicaltrials.gov/show/NCT02728882 (first received 2015).
NCT02737085 {unpublished data only}
    1. NCT02737085. The sequential therapy of CD19-targeted and CD20-targeted CAR-T cell therapy for diffuse large B cell lymphoma (DLBCL). clinicaltrials.gov/show/NCT02737085 (first received 2016).
NCT02892695 {unpublished data only}
    1. NCT02892695. PCAR-119 bridge immunotherapy prior to stem cell transplant in treating patients with CD19 positive leukemia and lymphoma. clinicaltrials.gov/show/NCT02892695 (first received 2016).
NCT03233854 {unpublished data only}
    1. NCT03233854. CD19/CD22 chimeric antigen receptor T cells and chemotherapy in treating patients with recurrent or refractory CD19 positive diffuse large B-cell lymphoma or B acute lymphoblastic leukemia. clinicaltrials.gov/show/NCT03233854 (first received 2017).
NCT03277729 {unpublished data only}
    1. NCT03277729. A phase I/II study to evaluate the safety of cellular immunotherapy using autologous T cells engineered to express a CD20-specific chimeric antigen receptor for patients with relapsed or refractory B cell non-Hodgkin lymphomas. clinicaltrials.gov/show/NCT03277729 (first received 2017).
NCT03528421 {unpublished data only}
    1. NCT03528421. Assessment of safety and efficacy of IM19 for relapsed or refractory NHL patients. clinicaltrials.gov/show/NCT03528421 (first received 2017).
NCT03579888 {unpublished data only}
    1. NCT03579888. CD19-specific T cells post alloSCT. clinicaltrials.gov/show/NCT03579888 (first received 2020).
NCT03704298 {unpublished data only}
    1. NCT03704298. Safety and efficacy of axicabtagene ciloleucel in combination with utomilumab in adults with refractory large B-cell lymphoma. clinicaltrials.gov/show/NCT03704298 (first received 2018).
NCT03720457 {unpublished data only}
    1. NCT03720457. Human CD19 targeted t cells injection (CD19 CAR-T) therapy for relapsed and refractory CD19-positive lymphoma. clinicaltrials.gov/show/NCT03720457 (first received 2018).
NCT04231747 {unpublished data only}
    1. NCT03720457. A study of CC-97540, CD19-targeted NEX-T chimeric antigen receptor (CAR) T cells, in subjects with relapsed or refractory B-cell non-Hodgkin lymphoma. clinicaltrials.gov/show/NCT04231747 (first received 2020).
NCT04381741 {unpublished data only}
    1. NCT04381741. CD19 CAR-T expressing IL7 and CCL19 combined with PD1 mAb for relapsed or refractory diffuse large B cell lymphoma. clinicaltrials.gov/show/NCT04381741 (first received 2020).
NCT04450069 {unpublished data only}
    1. NCT04450069. CLBR001 and SWI019 in patients with relapsed refractory B-cell malignancies. clinicaltrials.gov/show/NCT04450069 (first received 2020).
NCT04456023 {unpublished data only}
    1. NCT04456023. Study of tisagenlecleucel in Chinese adult patients with relapsed or refractory diffuse large B-cell non-Hodgkin lymphoma (DLBCL). clinicaltrials.gov/show/NCT04456023 (first received 2020).
NCT04464200 {unpublished data only}
    1. NCT04464200. 19(T2)28z1xx chimeric antigen receptor (CAR) T cells in people with B-cell cancers. clinicaltrials.gov/show/NCT04464200 (first received 2020).
NCT04486872 {unpublished data only}
    1. NCT04486872. An exploratory clinical trial of autologous humanized anti-cluster of differentiation antigen 19/20(CD19/CD20) dual specific CAR-T cells Injection. clinicaltrials.gov/show/NCT04486872 (first received 2020).
NCT04526834 {unpublished data only}
    1. NCT04526834. Phase 1 study of autologous CD30.CAR-T in relapsed or refractory CD30 positive non-Hodgkin lymphoma. clinicaltrials.gov/show/NCT04526834 (first received 2020).
NCT04545762 {unpublished data only}
    1. NCT04545762. Anti-CD19 chimeric antigen receptor T cells for treatment of relapsed or refractory non-Hodgkin lymphoma. clinicaltrials.gov/show/NCT04545762 (first received 2020).
PORTIA {unpublished data only}
    1. NCT03630159. Study of tisagenlecleucel in combination with pembrolizumab in R/R diffuse large B-cell lymphoma patients. clinicaltrials.gov/show/NCT03630159 (first received 2018).
Rivers 2018 {unpublished data only}
    1. Rivers J, Annesley C, Summers C, Finney O, Pulsipher MA, Wayne AS, et al. Early response data for pediatric patients with non-Hodgkin lymphoma treated with CD19 chimeric antigen receptor (CAR) T-cells. Blood 2018;132(Suppl 1):2957.
Sauter 2015 {unpublished data only}
    1. Sauter CS, Riviere I, Bernal Y, Wang X, Purdon T, Yoo S, et al. Phase I trial of 19-28z chimeric antigen receptor modified T cells (19-28z CART) posthigh dose therapy and autologous stem cell transplant (HDT-ASCT) for relapsed and refractory (rel/ref) aggressive B-cell non-Hodgkin lymphoma (B-NHL). Journal of Clinical Oncology 2015;33(15 Suppl 1):8515.
    1. Sauter CS, Senechal B, Riviere I, Ni A, Bernal Y, Wang X, et al. CD19 CAR T cells following autologous transplantation in poor-risk relapsed and refractory B-cell non-Hodgkin lymphoma. Blood 2019;134(7):626-35. - PMC - PubMed
Shah 2019 {unpublished data only}
    1. Shah NN, Zhu F, Keever-Taylor C, Schneider D, Kruger W, Worden A, et al. Clinical results of a first-in-human phase 1 study of point-of-care manufactured bispecific anti-CD19, anti-CD20 chimeric antigen receptor modified t (CAR-20.19-T) cells for relapsed, refractory, non-Hodgkin lymphoma (NHL). Biology of Blood and Marrow Transplantation 2019;25 (3 Suppl):S63-4.
TRANSCEND ‐ OUTREACH {unpublished data only}
    1. NCT03744676. A safety trial of lisocabtagene maraleucel (JCAR017) for relapsed and refractory (R/R) B-cell non-Hodgkin lymphoma (NHL) in the outpatient setting. clinicaltrials.gov/show/NCT03744676 (first received 2018).
TRANSCEND ‐ PILOT (TRANSCEND‐NHL‐006) {unpublished data only}
    1. NCT03483103. Lisocabtagene maraleucel (JCAR017) as second-line therapy (TRANSCEND-NHL-006). clinicaltrials.gov/show/NCT03483103 (first received 2018).
TRANSCEND ‐ WORLD {unpublished data only}
    1. Eudract_2017-000106-38. TRANSCEND WORLD a phase 2, single-arm, multi-cohort, multi-center trial to determine the efficacy and safety of JCAR017 in adult subjects with aggressive B-cell non-Hodgkin lymphoma (TRANSCEND WORLD). clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2017-00... (first received 2017).
TRANSFORM {unpublished data only}
    1. Eudract_2018-000929-32. TRANSFORM a global randomized multicenter phase 3 trial to compare the efficacy and safety of JCAR017 to standard of care in adult subjects with high-risk, transplant-eligible relapsed or refractory aggressive B-cell non-Hodgkin lymphomas (TRANSFORM). clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2018-00... (first received 2018).
    1. NCT03575351. A study to compare the efficacy and safety of JCAR017 to standard of care in adult subjects with high-risk, transplant-eligible relapsed or refractory aggressive B-cell non-Hodgkin lymphomas. clinicaltrials.gov/show/NCT03575351 (first received 2018).
ZUMA‐14 {unpublished data only}
    1. NCT03153462. Axicabtagene ciloleucel expanded access study (ZUMA-9). clinicaltrials.gov/show/NCT03153462 (first received 2017).
    1. NCT04002401. Safety and efficacy of axicabtagene ciloleucel in combination with either rituximab or lenalidomide in participants with refractory large B-cell lymphoma (ZUMA-14). clinicaltrials.gov/show/NCT04002401 (first received 2019).
ZUMA‐7 {unpublished data only}
    1. Eudract_2017-002261-22. A phase 3, randomized, open-label study evaluating the efficacy of axicabtagene ciloleucel versus standard of care therapy in subjects with relapsed/refractory diffuse large B cell lymphoma (ZUMA-7). clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2017-00... (first received 2017).
    1. Eudract_2017-002261-22-NL. A study evaluating the effectiveness of axicabtagene ciloleucel versus standard of care therapy in subjects with diffuse large B cell lymphoma returning after, or resistant to, initial treatment. clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2017-00... (first received 2018).
    1. NCT03391466. Efficacy of axicabtagene ciloleucel compared to standard of care therapy in subjects with relapsed/refractory diffuse large B cell lymphoma. clinicaltrials.gov/show/NCT03391466 (first received 2017).

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