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

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.

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

Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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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.