Lines of therapy before autologous stem cell transplant and CAR‐T affect outcomes in aggressive Non‐Hodgkin's lymphoma

Three anti-CD19 chimeric antigen receptor (CAR) T-cell therapy products, have been approved by the US Food and Drug Administration (FDA) since 2017 for patients with large B-cell lymphoma (LBCL) relapsing or refractory (R/R) to two more lines of therapy.1-3 High-dose chemotherapy and autologous stem cell transplant (ASCT) remains the standard of care for patients with R/R LBCL who demostrate chemosensitivity (complete response (CR) or partial response (PR)) to second-line chemotherapy (chemo). Ongoing clinical trials are currently comparing ASCT to CAR-T in the second-line setting. Patients treated on the registration trials and in the real-world setting were heavily pre-treated (≥ 3 prior lines of therapy: ZUMA-1 – 69%, JULIET- 51%, US CAR-T consortium- 74%).1, 2, 4 Due to the aggressive nature of this heavily pre-treated R/R population, the timing of CAR-T referral is important. The median time from apheresis to CAR-T cell infusion in one real-world experience was 28–44 days depending on the product.5 Other factors contributing to overall wait time include the availability of specialists and treatment centers, travel, especially for those in remote areas, or international patients with lack of access to CAR-T, and insurance approval. While waiting, patients may require additional treatment to maintain control over the disease. Increasing wait times of receiving CAR-T therapy doubled the predicted 1-year mortality rate in a study using a health system-level discrete simulation model.6 The objective of our study was to identify how the number of prior lines of therapy impacted ASCT and CAR-T patients' outcomes. A retrospective review of patients who received ASCT and/or axicabtagene ciloleucel (axi-cel) for R/R aggressive LBCL from June 2016 – April 2020 at Mayo Clinic, Rochester, was performed. The study was conducted in accordance with the Declaration of Helsinki and was approved by Mayo Clinic IRB. Patients were managed, including the decision for bridging therapy and the timing of imaging pre-ASCT and post-ASCT or CAR-T based on the institutional guidelines and treating physician's discretion. Additional details on the methodology regarding assessment of baseline characteristics, definitions of lines of therapy, and response assessment are provided in supplement. Different comparisons made between groups were based on the lines of therapy before ASCT or CAR-T encountered in the real-world setting (Figure S1, consort diagram). Patients underwent ASCT either after two (ASCT [2]) or three (ASCT [3]) lines of chemo. As for CAR-T groups, the earliest possible indication patients could undergo CAR-T (CAR-T[early]) was either after two lines of chemotherapy (CAR-T [2]) and/or after ASCT [2]. Those not meeting the CAR-T[early] criteria were grouped as CAR-T[late]. Additionally, patients could undergo CAR-T immediately post ASCT relapse (CAR-T[ASCT]) without any interval treatment. This group comprised patients from both ASCT [2] and ASCT [3] groups. Those not meeting the CAR-T[ASCT] criteria were grouped as CAR-T[other], as these required additional therapy between ASCT and CAR-T. All the analyses were performed in R3.6.3, p values were two-sided, and the significance level was set at <0.05. A total of 105 patients underwent ASCT, and 62 underwent CAR-T therapy in the study period. Of the ASCT patients, 87 received ASCT after two lines of chemotherapy (ASCT [2]) and 18 received ASCT after three lines of chemotherapy (ASCT [3]). The baseline characteristics of the entire ASCT and CAR-T cohorts, are shown in Table S1. The comparison of ASCT [2], and ASCT [3] groups is shown in Table S2. Twenty-six patients (25%) of the ASCT group (n = 19, ASCT [2] and n = 7, ASCT [3]) received CAR-T as subsequent therapy. All the characteristics were comparable between the two groups except the ASCT [3] group had a higher percentage of patients with progressive disease after first-line (44% vs 21%, p < 0.001) and second line therapies. With a median follow up of 19.7 months, the 1-year event-free survival (EFS) rate was significantly higher for the ASCT [2] group 67%, (95%CI 58%–78%) vs ASCT [3] 44%, (95%CI 27%–75%; p = 0.015), Figure 1(A). However, there was no significant difference noted in the 1-year overall survival (OS) rates (Figure 1(B)). Among the CAR-T recipients (n = 62), 28 (45%) patients had undergone previous ASCT. Only 25/62 (40%) patients received CAR-T at the earliest possible indication (CAR-T[early]), of which 15 patients belonged to the CAR-T [2] group and 10 patients to the ASCT [2] group (Table 1). The baseline characteristics of the CAR-T[early] vs CAR-T[late] groups were comparable. At a median follow-up of 12.1 months in the CAR-T cohort, there was a trend towards improved 1-year EFS (48%, (95%CI 32–72) vs CAR-T [late] 30%, (95%CI 18%–49%) p = 0.055) and OS (75%, (95%CI 60–95) vs CAR-T [late] 56%, (95%CI 42%–76%) p = 0.053) in the CAR-T[early] group (Figure 1(C) and (D)). Next we compared CAR-T[ASCT] (n = 14, 10 - ASCT [2], and four - ASCT [3]) and CAR-T[other] (n = 48) groups. A significantly higher patient proportion in the CAR-T[other] group (75% vs 43%, p = 0.03) required bridging therapy before CAR-T infusion (Table 1). The CAR-T[ASCT] group had a significantly higher 1-year OS rate of 77% (95%CI 60–100) compared to 60% (95%CI 47–76) in the CAR-T[other] group (p = 0.039), Figures 1(E) and (F). Lastly, ASCT [3] group (n = 18) and CAR-T [2] group (n = 15) were analyzed and both groups were comparable (Table S3), except CAR-T [2] group had significantly more patients with progressive disease to second line chemo (87% vs 44%, p = 0.01), and a shorter median time from diagnosis to infusion. At a median follow-up of 9.9 months, there was no significant difference noted in 1-year EFS or OS rates between the two groups (Figure 1(G) and (H)). This report provides clinical outcomes in a single large academic center for both ASCT and CAR-T based on prior lines of therapy encountered clinically in the real world. Multiple studies have attempted to identify the patient, disease, and product-related factors that could predict durable responses to CAR-T, to allow for better patient selection. We attempted to determine when CAR-T would optimally be incorporated based on prior lines of therapy encountered in the clinical setting, other than indicated per the FDA label. We found that 1-year EFS rate was longer for ASCT [2] vs. ASCT [3] patients (67% vs 44%). The CORAL trial also demonstrated a progressively shorter EFS and OS with subsequent lines of therapy. We, however, did not identify a difference in the 1-year OS rate between ASCT [2] and ASCT [3] groups, likely owing to small numbers and the use of subsequent therapies in the ASCT [3] group (7/18). In addition, the ASCT [3] group also comprised of patients with a more primary refractory disease, a group known to have poor outcomes. The CAR-T (early) group showed a trend towards a better 1-year EFS and OS and CAR-T[ASCT] group had significantly improved OS likely suggesting better disease biology as chemosensitivity is required to proceed with ASCT. This was also evident based on an increased need for bridging therapy in the CAR-T(other) group. Sermer et al. have previously compared CAR-T outcomes to alternate therapies beyond two prior treatment lines and showed worsening CAR-T outcomes with successive lines of therapy.7 The alternate therapies group in the study however, comprised of patients treated over a long period (2001–2017), and included treatments other than ASCT. A recent analysis by Locke et al. identified higher tumor burden, lower CAR-T cell expansion, a proinflammatory tumor microenvironment, and increasing doubling time of CAR-T cells as factors associated with a lack of durable response. These factors were notably pronounced with an increasing number of lines of therapy and supported the observation that CAR-T efficacy decreases with increasing lines of therapy.8 Worse outcomes with successive lines of treatment are likely from a combination of increased disease refractoriness, high-risk disease features, and worse CAR-T cell product fitness. The degree that each of these and other factors contribute to worsening outcomes is yet to be determined. Our cohort had only 40% of patients (25/62) referred at the earliest possible indication for CAR-T per the FDA label. Early referral, therefore, is key to improving CAR-T outcomes to avoid logistic delays and need for bridging therapy. For patients achieving less than a CR after first salvage, whether to attempt another salvage or proceed with CAR-T remains unanswered. Large registry studies are currently ongoing in this direction. Our analysis comparing ASCT(3) to CAR-T(2) did not identify a difference in the 1-year EFS or OS rates. This is possibly due to a higher proportion of chemo-refractory disease to second-line treatment in the CAR-T(2) group, shorter time from diagnosis to infusion and overall small patient numbers in the cohort. This study is limited by its retrospective nature, small patient numbers and short median follow-up time which likely have some bearing on the lack of survival differences in the comparisons made. However, comparing ASCT and CAR-T cohorts over the same time period avoids the effect of differences in supportive care and a single-center analysis provides a more homogenous cohort with respect to practice patterns. Larger cohorts with longer follow-up are needed to understand the implication of sequencing of these treatment modalities. Referral for earlier use of CAR-T remains low and needs to be emphasized to avoid delays and improve access to a potentially curative therapy. Thomas M. Habermann: Consulting or Advisory Role: Celgene, Kite/Gilead. Stephen M. Ansell: Honoraria: WebMD, Research to Practice; Research Funding: Bristol-Myers Squibb, Seattle Genetics, Affimed Therapeutics, Regeneron, Trillium Therapeutics, AI Therapeutics, ADC Therapeutics. N.N. Bennani: Purdue Pharma: Other: Advisory Board; Verastem: Other: Advisory Board; Affimed: Research Funding; Kite/Gilead: Research Funding; Daiichi Sankyo, Inc.: Other: Advisory board. Yi Lin: Juno: Consultancy; Legend BioTech: Consultancy; Merck: Research Funding; Takeda: Research Funding; Gamida Cells: Consultancy; Sorrento: Consultancy, Membership on an entity's Board of Directors or advisory committees; Vineti: Consultancy; Bluebird Bio: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Janssen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding. The remaining authors declare no conflict of interest. Conception and design: Arushi Khurana, Yi Lin, Ivana Micallef Provision of study materials or patients: Yi Lin, Jonas Paludo, N. Nora Bennani, JC Villasboas, Stephen M. Ansell, Patrick B. Johnston, Ivana Micallef, Thomas M. Habermann, David J. Inwards Collection and assembly of data: Arushi Khurana, Matthew Hathcock, Abdullah S. Al Saleh, Sangeetha Gandhi, Tuan Truong Data analysis and interpretation: Arushi Khurana, Matthew Hathcock, Ivana Micallef, Yi Lin, Thomas M. Habermann, Abdullah S. Al Saleh Manuscript writing: All authors. Final approval of manuscript: All authors. Accountable for all aspects of the work: All authors. Appendix S1 Supporting Information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.