TO THE EDITOR:
T-cell–redirecting strategies, including chimeric antigen receptor (CAR) T cells and bispecific antibodies (BsAbs), have improved the prognosis of patients with relapsed/refractory (R/R) follicular lymphoma (FL).1, 2, 3, 4, 5, 6 BsAbs were approved based on single-arm trials including patients who experienced progressive disease after ≥2 lines of treatment. Complete response rate (CRR) was 60% to 74%,2,3,6 with a 4-year progression-free survival (PFS) of 39% in the longest follow-up.7 Information regarding real-world outcomes and predictive factors is scarce.8
In the CAR T-cell therapy setting, recent bendamustine exposure before leukapheresis is associated with a deleterious impact on T-cell fitness and reduced efficacy after infusion.1,9,10 Given the similarities in the mechanism of action, we aimed to assess the role of this alkylating agent before BsAbs in patients with R/R FL.
We conducted a multicenter, international study including patients with R/R FL treated at 15 sites with CD20/CD3-targeted BsAbs, both commercially available and clinical trials, from November 2017 until March 2024. The study was approved by the Ethics Committee of the Vall d’Hebron Hospital Board (EOM[AG]005/2024[6231]) and was conducted in accordance with the Declaration of Helsinki.
We compared safety and efficacy outcomes of BsAb therapy between patients with recent bendamustine exposure (≤24 months from last bendamustine dose until BsAb start) and bendamustine-naïve patients (supplemental Table 1). Missing-at-random values were imputed using the chained equations method.11 Inverse probability of treatment weighting (IPTW) was applied using 13 covariates (supplemental Table 2). Analyses were repeated with a 12-month cutoff, and a sensitivity analysis was conducted restricting inclusion to patients who received BsAbs in monotherapy.
The study included 194 patients with R/R FL who received BsAbs as second- or later-line treatment. Patients with remote (>24 months) bendamustine exposure (n = 52 [27%]) or lacking washout data (n = 3 [2%]) were excluded. Our final data set included 139 patients: 26 recently exposed and 113 bendamustine-naïve patients (supplemental Figure 1). Baseline characteristics were similar across groups (Table 1).
Table 1.
Baseline characteristics of the study patient population
| Variable | All (N = 139) |
Benda ≤24 (n = 26) |
No benda (n = 113) |
P value |
|---|---|---|---|---|
| Patient characteristics | ||||
| Age, median (IQR), y | 63 (54-73) | 68 (56-75) | 63 (54-72) | .44 |
| Male sex, n (%) | 78 (56) | 12 (46) | 66 (58) | .28 |
| ECOG ≥1, n (%) | 47 (35) | 11 (42) | 36 (33) | .37 |
| FLIPI int-high, n (%) | 99 (83) | 14 (61) | 85 (88) | .01 |
| Stage IV, n (%) | 71 (51) | 12 (46) | 59 (52) | .67 |
| >1 extranodal site, n (%) | 23 (20) | 6 (27) | 17 (19) | .20 |
| >2 prior lines, n (%) | 45 (32) | 8 (31) | 37 (33) | 1.00 |
| POD24, n (%) | 69 (53) | 14 (58) | 55 (52) | .66 |
| Prior HCT, n (%) | 35 (25) | 3 (12) | 32 (28) | .08 |
| Prior CAR T cells, n (%) | 4 (3) | 2 (8) | 2 (2) | .20 |
| LDH >ULN, n (%) | 43 (33) | 7 (30) | 36 (33) | 1.00 |
| CRP >ULN, n (%) | 34 (59) | 8 (67) | 26 (57) | .70 |
| Ferritin >ULN, n (%) | 30 (26) | 23 (25) | 7 (29) | .80 |
| ALC, median (IQR), per mm3 | 1100 (800-1520) | 910 (600-1300) | 1135 (815-1600) | .15 |
| CD3+ cells, median (IQR), per mm3 | 700 (534-1000) | 695 (450-902) | 724 (547-1026) | .30 |
| CD4+ cells3, median (IQR), per mm3 | 360 (250-458) | 265 (182-442) | 387 (308-470) | .24 |
| CD8+ cells, median (IQR), per mm3 | 333 (195-470) | 333 (222-460) | 334 (170-486) | .80 |
| Treatment characteristics | ||||
| Treatment in a trial, n (%) | 111 (85) | 21 (84) | 90 (85) | 1.00 |
| Combo, n (%) | 46 (33) | 8 (31) | 38 (34) | 1.00 |
| Type of bispecific, n (%) | .50 | |||
| Epcoritamab | 55 (40) | 11 (42) | 44 (39) | |
| Mosunetuzumab | 55 (40) | 8 (31) | 47 (42) | |
| Glofitamab | 12 (9) | 2 (8) | 10 (9) | |
| Odronextamab | 2 (1) | 1 (4) | 1 (1) | |
| Not specified | 15 (10) | 4 (15) | 11 (9) | |
The following data (n) were missing in the variables: POD24 (n = 10), treatment in a trial (n = 8), ALC (n = 6), CD3 (n = 84), CD4 (n = 81), CD8 (n = 81), ECOG (n = 3), FLIPI (n = 20), number of extranodal sites (n = 27), CRP (n = 44), ferritin (n = 23), and LDH (n = 8). Boldface values are statistically significant (P < 0.05).
ALC, absolute lymphocyte count; benda, bendamustine; CRP, C-reactive protein; ECOG, Eastern Cooperative Oncology Group; FLIPI, Follicular Lymphoma International Prognostic Index; HCT, hematopoietic cell transplant; IQR, interquartile range; LDH, lactate dehydrogenase; POD24, progression of disease with 24 months of first-line treatment; ULN, upper limit of normal.
Concerning safety, recently exposed and bendamustine-naïve patients presented similar rates of cytokine release syndrome (35% vs 49%; P = .2; mostly grade 1-2), immune effector cell–associated neurotoxicity syndrome (0 vs 5%; P = .6; all grade 1), and infections (61% vs 70%; P = .5; supplemental Table 3).
Focusing on efficacy, of 133 evaluable patients (96%), the overall response rate (ORR) was 87%, and the CRR was 70%; both end points were similar between recently exposed vs naïve patients (84% vs 87% [P = .68] and 68% vs 70% [P = .86]). Median duration of response (DoR) was not reached (NR) in either cohort, with an estimated 1-year DoR of 70% vs 76% (hazard ratio [HR], 1.19; 95% confidence interval [CI], 0.48-2.91; P = .70; supplemental Table 4).
With a median follow-up of 21.8 months (95% CI, 17.8-25.5), the median PFS was 19 months (95% CI, 14 to NR) vs NR (95% CI, 28 to NR) in the recently exposed vs bendamustine-naïve patients, with a 1-year PFS of 68% vs 69% (HR, 1.36; 95% CI, 0.71-2.59; P = .40; Figure 1). A higher CD8+ T-cell count was associated with prolonged PFS, confirmed in multivariable analysis (MVA); we did not observe this relation with CD4+ lymphocytes (supplemental Figure 2; supplemental Table 5). Additional variables with an impact on PFS in the MVA were progression of disease within 24 months of first-line treatment and an increased C-reactive protein (supplemental Figure 3). Median overall survival (OS) was NR in either cohort, with a 1-year OS of 84% vs 91% (HR, 2.21; 95% CI, 0.83-5.89; P = .11; Figure 1). Similar efficacy was observed after balancing for baseline characteristics (supplemental Tables 2 and 4; Figure 1).
Figure 1.
Survival after CD20/CD3-targeted BsAb therapy in patients with R/R FL according to bendamustine exposure. (A) PFS between recently exposed (≤24 months) and naïve patients. (B) Adjusted PFS between recently exposed (≤24 months) and naïve patients. (C) OS between recently exposed (≤24 months) and naïve patients. (D) Adjusted OS between recently exposed (≤24 months) and naïve patients.
Given the heterogeneous washout interval (median, 14 months; interquartile range, 4-20), we analyzed the impact of bendamustine timing; we did not identify an increase in the risk of progressive disease and/or death as washout became shorter (supplemental Figure 4). Furthermore, in the additional analysis with a 12-month cutoff (n = 12), efficacy was comparable between recently exposed and naïve patients (supplemental Tables 4,6-7; supplemental Figure 5). Because most patients (73%) had received 6 cycles, we were not able to assess the impact of bendamustine dose; however, the latter did not influence outcomes in our previous CAR T-cell study.9
Finally, we focused on patients receiving BsAb monotherapy (n = 93 [67%]). Again, similar ORR, CRR, DoR, and PFS were observed (data not shown). OS was shorter for the recently exposed subset in the unbalanced analysis (HR, 2.92; 95% CI, 1.04-8.20; P = .04); however, after IPTW adjustment, survival remained comparable (HR, 1.97; 95% CI, 0.65-5.94; P = .20; supplemental Table 8).
In this study, a recent bendamustine exposure did not confer a negative impact on BsAb efficacy. Both cohorts were balanced for most baseline characteristics, and the IPTW-adjusted analysis further mitigated potential differences. Importantly, these results differ from CAR T-cell data; in that setting, a recent bendamustine exposure is associated with decreased CAR T-cell expansion and lower efficacy in large B-cell lymphoma (LBCL), mantle cell lymphoma, and FL.1,9,10,12,13 However, BsAbs may rely differently on specific T-cell subsets. In line with this hypothesis, the EPCORE NHL-1 study offering epcoritamab to patients with LBCL in third or later line showed similar efficacy between bendamustine-exposed and -naïve patients, despite CD4+ lymphopenia and increased PD-1/HLA-DR expression in this cell subset; interestingly, CD8+ T cells remained unchanged.14 Furthermore, the ongoing trial of epcoritamab combined with bendamustine and rituximab (BR) in frontline FL presented a 96% CRR with a 30-month PFS of 83% (N = 25),15 comparing favorably with historical BR results.16,17 Again, selective CD4+ T-cell depletion was reported, whereas CD8+ T cells increased and remained elevated throughout treatment. In our study, bendamustine exposure did not affect CD8+ lymphocyte values, and this was the T-cell subset associated with PFS. This is a significant finding because published data indicate that response to BsAbs seems to be primarily driven by CD8+ effector cells.18, 19, 20
Concerning real-world BsAb data, Shumilov et al reported a shorter PFS for patients with LBCL who had a recent (<6 months) bendamustine exposure before glofitamab (n = 24) than patients with a longer washout or no exposure (n = 46)21; however, it did not retain significance in the MVA.21 On the contrary, Brooks et al reported a large data set of patients (n = 245) with aggressive B-cell lymphoma receiving glofitamab or epcoritamab, of whom 47 were bendamustine exposed and response evaluable: ORR was 57%, and CR was 28%, in line with their general results (ORR, 52%; CR, 25%)22; washout data were not available. Finally, high response rates were reported in bendamustine-exposed patients with mantle cell lymphoma after glofitamab.23 Future results in FL will further address this issue, given its distinct disease biology.24
The main limitations of this study are derived from its retrospective nature and the small number of patients in the recently exposed cohort, which can be explained by the indolent nature of FL and prolonged time to next treatment; given the limited sample size, the study could be underpowered to detect smaller but clinically relevant outcome differences. Even though there was not a perfect balance across baseline characteristics, robust propensity score adjustment methodology mitigated their potential impact. Because previous studies focused on a shorter washout, we analyzed the same end points for patients exposed within 12 months, confirming similar results; noteworthy, this cutoff yielded inferior CAR T-cell outcomes in our previous study.9 Finally, even though the number of patients with an even shorter washout was insufficient for another evaluation, the continuous analysis (supplemental Figure 4) did not suggest a deleterious impact with a very recent exposure.
In conclusion, we did not observe a negative impact of recent bendamustine exposure on BsAb outcomes. A potential explanation could be selective CD4+ T-cell depletion after exposure to this alkylating agent, sparing CD8+ lymphocytes, which seem to drive BsAb efficacy. With the increasing armamentarium for FL, and considering ongoing second-line BsAb trials, sequencing data are key to aid decision-making in clinical practice. Larger prospective cohorts are warranted to confirm these results.
Conflict-of-interest disclosure: G.I. reports consulting fees from Autolus, Bristol Myers Squibb (BMS), Kite/Gilead, Miltenyi, and Regeneron; honoraria from AbbVie, AstraZeneca, BMS, Kite/Gilead, Miltenyi, Sobi, Roche, and Lilly; and travel support from AbbVie, AstraZeneca, Kite/Gilead, Miltenyi, and Roche. D.A.R.-G. reports consulting fees from AbbVie and Regeneron; and advisory board fees from Genentech, Ipsen, and Tempus. A.M.G.-S. reports honoraria and/or consulting fees from AbbVie, AstraZeneca, BeiGene, BMS, Genmab, Gilead/Kite, GSK, Ideogen, Incyte, Janssen, Kyowa Kirin, Lilly, Miltenyi, Regeneron, Roche, Sobi, and Takeda; and research support from Gilead/Kite. A. Serna reports honoraria from Roche, Johnson & Johnson, AstraZeneca, Lilly, Behring, Incyte, and AbbVie. A. Sureda reports honoraria from Takeda, BMS/Celgene, MSD, Janssen, Amgen, Novartis, Gilead/Kite, Sanofi, Roche, Alexion, Genmab, and AbbVie; consultancy fees from Takeda, BMS/Celgene, Novartis, Janssen, Gilead, Sanofi, Genmab, and AbbVie; and speaker's bureau fees and research support from Takeda. C.Y.C. reports consulting fees/advisory fees/honoraria from Roche, Janssen, Gilead, AstraZeneca, Lilly, BeiGene, Menarini, Dizal, AbbVie, Genmab, Sobi, CRISPR Therapeutics, BMS, and Regeneron; speaker’s bureau fees from Janssen, AstraZeneca, BeiGene, Genmab, AbbVie, Roche, and MSD; research funding from BMS, Roche, AbbVie, MSD, and Lilly; and travel expenses from Lilly and BeiGene. M.H. reports consultancy fees and honoraria from AbbVie, AstraZeneca, Genmab, Johnson & Johnson, Merck, Roche, and Takeda; and research support (to institution) from AbbVie, Arvinas, AstraZeneca, BMS, Celgene, Genentech, Genmab, Incyte, Johnson & Johnson, Merck, Novartis, Pfizer, Roche, and Takeda. P.B. reports honoraria from Allogene, Amgen, BMS, Kite/Gilead, Janssen, Jazz Pharmaceuticals, Miltenyi, Novartis, and Nektar. P.A. reports consultancy fees and honoraria from Roche, AbbVie, Gilead, BMS, AstraZeneca, Johnson & Johnson, Incyte, Regeneron, and Genmab. P.A.T. reports consultation fees from AbbVie, Genmab, AstraZeneca, and Roche; speaker fees from AbbVie, AstraZeneca, and Roche; and research funding (to institution) from AbbVie, Genmab, and AstraZeneca. The remaining authors declare no competing financial interests.
Acknowledgments
Acknowledgments: The authors thank the patients and their families for their participation in this study.
Contribution: G.I., P.B., and P.A. contributed to conception and design; G.I., E.R.K., D.A.R.-G., A.M.G.-S., P.A.T., D.T., I.C., D.Q., P.G., E.V., G.V., A.J.-U., M.B.-O., A. Serna, S.H., B.D.L.C., J.L., S.C., L.M., A.C., R.C., M.C., J.-M.S., F.B., A. Sureda, S.S., M.H., P.B., and P.A. were responsible for provision of study material or patients; G.I., P.B., P.A., and V.N.G. collected, assembled, analyzed, and interpreted data; and all authors contributed to manuscript writing, provided final approval of manuscript, and are accountable for all aspects of the work.
Footnotes
P.B. and P.A. are joint senior authors.
Data are available from the corresponding author, Gloria Iacoboni (giacoboni@vhio.net), on request.
The full-text version of this article contains a data supplement.
Supplementary Material
References
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