Letter to the Editor Regarding “Comparing Efficacy, Safety, and Preinfusion Period of Axicabtagene Ciloleucel versus Tisagenlecleucel in Relapsed/Refractory Large B Cell Lymphoma”

Abstract

We read with great interest the recent indirect treatment comparison (ITC) between axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) for relapsed/refractory diffuse large B cell lymphoma (r/r DLBCL) by Oluwole et al. [1Oluwole OO Jansen JP Lin VW et al.Comparing efficacy, safety, and preinfusion period of axicabtagene ciloleucel versus tisagenlecleucel in relapsed/refractory large B cell lymphoma.Biol Blood Marrow Transplant. 2020; 26: 1581-1588Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar]. We agree with the authors that in the absence of direct head-to-head trials, ITCs can be valuable to inform treatment decision making but can be confounded by cross-trial differences. Their study concluded that axi-cel may have better efficacy than tisa-cel based on a matching-adjusted indirect comparison (MAIC) analysis using data from the 2 pivotal trials of these therapies, ZUMA-1 [2Locke FL Ghobadi A Jacobson CA et al.Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial.Lancet Oncol. 2019; 20: 31-42Abstract Full Text Full Text PDF PubMed Scopus (1061) Google Scholar] and JULIET [3Schuster SJ Bishop MR Tam CS et al.Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma.N Engl J Med. 2019; 380: 45-56Crossref PubMed Scopus (1759) Google Scholar], respectively. We considered the same research question and data sources in our own recent investigation [4Zhang J Li J Ma Q Yang H Signorovitch J Wu E. A review of two regulatory approved anti-CD19 CAR T-cell therapies in diffuse large B-cell lymphoma: Why are indirect treatment comparisons not feasible?.Adv Ther. 2020; 37: 3040-3058Crossref PubMed Scopus (32) Google Scholar] but determined that such an ITC was infeasible owing to irreconcilable differences between the ZUMA-1 and JULIET trials. Although the MAIC method implemented by the authors adjusted for some cross-trial difference in patient characteristics, a number of fundamental cross-trial differences were not accounted for and render the ITC results difficult to interpret. Many of the cross-trial differences stem from the fact that ex vivo cell therapy clinical trials require a complex process from enrollment to infusion of chimeric antigen receptor T cell (CAR-T) therapy, which leads to differences in trial designs and selection processes for patient enrollment. These differences, as summarized below, create a high risk of bias for cross-trial comparisons of outcomes based on MAIC analysis, well beyond the usual risks that are inherent in any comparison of nonrandomized groups. First, the 2 trials differed in the allowance of bridging chemotherapy after enrollment. The JULIET trial allowed bridging treatment before lymphodepleting chemotherapy (LDC) to maintain patients with a poor prognosis while they awaited infusion; the majority (90%) of the JULIET patients received bridging chemotherapy [3Schuster SJ Bishop MR Tam CS et al.Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma.N Engl J Med. 2019; 380: 45-56Crossref PubMed Scopus (1759) Google Scholar]. In contrast, the ZUMA-1 protocol did not allow bridging chemotherapy. In the real-word setting, most patients who are treated with either tisa-cel or axi-cel have received bridging chemotherapy. The use of bridging chemotherapy has been associated with a poor prognosis [5Jain MD Jacobs MT Nastoupil LJ et al.Characteristics and outcomes of patients receiving bridging therapy while awaiting manufacture of standard of care axicabtagene ciloleucel CD19 chimeric antigen receptor (CAR) T-cell therapy for relapsed/refractory large B-cell lymphoma: results from the US Lymphoma CAR-T Consortium.Blood. 2019; 134: 245Google Scholar, 6Andreadis C Tam CS Borchmann P et al.Correlation of bridging and lympho-depleting chemotherapy with clinical outcomes in patients with relapsed/refractory diffuse large B-cell lymphoma treated with tisagenlecleucel.Blood. 2019; 134: 2883Crossref Google Scholar, 7Sesques P, Ferrant E, Safar V, et al. Use of commercial anti-CD19 CAR T cell therapy for patients with relapsed/refractory aggressive B cell lymphoma in a European center [e-pub ahead of print]. Am J Hematol. https://doi.org/10.1002/ajh.25951. Accessed August 24, 2020.Google Scholar, 8Pinnix CC Gunther JR Dabaja BS et al.Bridging therapy prior to axicabtagene ciloleucel for relapsed/refractory large B-cell lymphoma.Blood Adv. 2020; 4: 2871-2883Crossref PubMed Scopus (81) Google Scholar]. For example, a real-world study of patients treated with axi-cel reported that patients who received bridging chemotherapy before infusion had significantly poorer overall survival and progression-free survival compared with those who did not (overall survival: hazard ratio, 3.34, P< .01; progression-free survival: hazard ratio, 1.43, P= .04) [5Jain MD Jacobs MT Nastoupil LJ et al.Characteristics and outcomes of patients receiving bridging therapy while awaiting manufacture of standard of care axicabtagene ciloleucel CD19 chimeric antigen receptor (CAR) T-cell therapy for relapsed/refractory large B-cell lymphoma: results from the US Lymphoma CAR-T Consortium.Blood. 2019; 134: 245Google Scholar]. This difference in protocol also may have resulted in the inclusion of patients with differing prognoses in the 2 trials, with ZUMA-1 including more patients with less of an expected need for bridging therapy. The ITC conducted by Oluwole et al did not adjust for this fundamental difference in trial designs. We believe that this limitation alone introduces substantial confounding into their ITC. There are additional, compounding limitations as well. Differences in the scheduling process for leukapheresis and enrollment between the ZUMA-1 and JULIET trials were not accounted for by Oluwole et al. In JULIET, leukapheresis and enrollment were performed regardless of manufacturing slot availability. In ZUMA-1, leukapheresis and enrollment were not permitted until a manufacturing slot became available, and patients who could not wait for a slot were not enrolled. This difference in patient enrollment processes, together with the differential use of bridging therapy, indicates that the ZUMA-1 and JULIET patient cohorts are not representative of the same clinical population at enrollment or infusion, making comparison of outcomes across these trials prone to substantial bias. Oluwole et al also presented a comparative analysis that included retrospectively imputed mortality during the preinfusion period. This analysis introduces additional bias because it does not include mortality among patients who met the eligibility criteria for ZUMA-1 but were not enrolled due to lack of a manufacturing slot; such patients would have been enrolled in JULIET. A number of additional cross-trial differences led to further risks of bias that the authors did not address but are important to consider. First, differences in LDC regimens were not accounted for. All patients in ZUMA-1 received fludarabine-cyclophosphamide (Flu/Cy) chemotherapy, whereas in JULIET, 74% of patients received Flu/Cy at a lower dose than that used in ZUMA-1, and 19% received bendamustine [2Locke FL Ghobadi A Jacobson CA et al.Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial.Lancet Oncol. 2019; 20: 31-42Abstract Full Text Full Text PDF PubMed Scopus (1061) Google Scholar,3Schuster SJ Bishop MR Tam CS et al.Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma.N Engl J Med. 2019; 380: 45-56Crossref PubMed Scopus (1759) Google Scholar]. In addition, 7% of the patients in JULIET did not receive any LDC if their white blood cell count was ≤1000 cells/µL within 1 week before tisa-cel infusion [6Andreadis C Tam CS Borchmann P et al.Correlation of bridging and lympho-depleting chemotherapy with clinical outcomes in patients with relapsed/refractory diffuse large B-cell lymphoma treated with tisagenlecleucel.Blood. 2019; 134: 2883Crossref Google Scholar]. These differences are likely to be confounding, because the choice of LDC regimens may be associated with patient outcomes [6Andreadis C Tam CS Borchmann P et al.Correlation of bridging and lympho-depleting chemotherapy with clinical outcomes in patients with relapsed/refractory diffuse large B-cell lymphoma treated with tisagenlecleucel.Blood. 2019; 134: 2883Crossref Google Scholar]. Specifically, a post hoc analysis of JULIET reported that patients who received Flu/Cy LDC achieved numerically better outcomes compared with those who received bendamustine or no LDC (overall response rate, 57.6% for Flu/Cy versus 40.9% for bendamustine versus 25% for no LDC) [6Andreadis C Tam CS Borchmann P et al.Correlation of bridging and lympho-depleting chemotherapy with clinical outcomes in patients with relapsed/refractory diffuse large B-cell lymphoma treated with tisagenlecleucel.Blood. 2019; 134: 2883Crossref Google Scholar]. Second, differences in the use of subsequent treatments after the initial study drug infusion were not considered in the ITC. For example, some eligible patients in ZUMA-1 received a second infusion of axi-cel, whereas no patients in JULIET were retreated after the initial infusion of tisa-cel. In addition, a higher proportion of patients underwent stem cell transplantation after infusion in ZUMA-1 (11%) compared with JULIET (6%) [2Locke FL Ghobadi A Jacobson CA et al.Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial.Lancet Oncol. 2019; 20: 31-42Abstract Full Text Full Text PDF PubMed Scopus (1061) Google Scholar,3Schuster SJ Bishop MR Tam CS et al.Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma.N Engl J Med. 2019; 380: 45-56Crossref PubMed Scopus (1759) Google Scholar]. ITCs can provide valuable evidence for decision makers in the absence of head-to-head randomized trials. However, to do so, they require reasonable similarity in study designs and enrollment criteria, as highlighted by long-standing and recent guidance [9Pocock SJ. The combination of randomized and historical controls in clinical trials.J Chronic Dis. 1976; 29: 175-188Abstract Full Text PDF PubMed Scopus (280) Google Scholar, 10European Agency for the Evaluation of Medicinal Products. ICH E10 Choice of control group in clinical trials.(CPMP/ICH/364/96). Available at: https://www.ema.europa.eu/en/ich-e10-choice-control-group-clinical-trials. Accessed July 31, 2020.Google Scholar, 11National Institute for Health Care and Excellence (NICE). NICE DSU technical support document 18: Methods for population-adjusted indirect comparisons in submissions to NICE. Available at: http://nicedsu.org.uk/wp-content/uploads/2017/05/Population-adjustment-TSD-FINAL.pdf. Accessed April 28, 2020.Google Scholar]. Conclusions drawn from ITCs between trials with substantial design differences, such as ZUMA-1 and JULIET, should be interpreted with extreme caution or be avoided to prevent misinforming treatment choices or patient access. Additional data from ongoing or future real-word studies are needed to provide insight into the comparative effectiveness and safety of axi-cel and tisa-cel for r/r DLBCL. J.Z. and Q.M. are employees of and hold stock/options in Novartis Pharmaceuticals. H.Y., J.S., and E.W. are employees of Analysis Group, which received consulting fees from Novartis. J.L. was an employee of Analysis Group, Inc. at the time of the correspondence. Editorial assistance was provided by Shelley Batts, an employee of Analysis Group. Funding for this assistance was provided by Novartis. Comparing Efficacy, Safety, and Preinfusion Period of Axicabtagene Ciloleucel versus Tisagenlecleucel in Relapsed/Refractory Large B Cell LymphomaBiology of Blood and Marrow TransplantationVol. 26Issue 9PreviewRelapsed large B cell lymphoma (LBCL) has a poor prognosis. Patients with relapsed or refractory disease are treated similarly with salvage chemotherapy and autologous stem cell transplantation (ASCT) for those with chemotherapy-sensitive disease. The likelihood of an objective response and ability to proceed to ASCT is only 40% to 52%, with median progression-free survival of 6 to 12 months and overall survival (OS) of 1 t o2 years [1-3]; however, these numbers are even lower in patients who are refractory to multiple lines of therapy. Full-Text PDF Open ArchiveResponse to Letter to Editor Regarding "Comparing Efficacy, Safety, and Preinfusion Period of Axicabtagene Ciloleucel versus Tisagenlecleucel in Relapsed/Refractory Large B Cell Lymphoma"Biology of Blood and Marrow TransplantationVol. 26Issue 12PreviewWe thank you for the opportunity to respond to the letter to the editor from Zhang et al. Large B cell lymphoma in the relapse setting has a poor prognosis because of resistance to chemotherapy. CAR T cell therapy with axicabtagene ciloleucel (axi-cel) and tisangenlecleucel (tisa-cel) have yielded high objective response rates. We presented a matching adjusted indirect comparison (MAIC) that showed higher objective response rate, complete response rate, and overall survival with axi-cel but a higher rate of grade 1-2 CRS compared with tisa-cel in patients who received infusion of the agents. Full-Text PDF Open Archive

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