Comparison of auto-HCT and CAR T-cell therapy in patients with relapsed DLBCL in partial remission

About 60% of patients with diffuse large B-cell lymphoma (DLBCL) respond well to frontline treatment with rituximab in combination with an anthracycline-based regimen. Patients who relapse following frontline treatment, however, have poor outcomes, and there remains an unmet need for an optimal treatment strategy in this population. The current practice for fit patients with relapsed or refractory DLBCL—including those who relapse or progress within a year of their original diagnosis—is treatment with an alternative salvage regimen. Patients achieving either complete remission or partial remission (PR) after salvage are then treated with high-dose chemotherapy and autologous hematopoietic cell transplantation (auto-HCT) consolidation. However, with the advent of chimeric antigen receptor (CAR) T-cell therapy, there is now another treatment option for patients with PR following salvage chemotherapy.      

The Center for International Blood and Marrow Transplant Research (CIBMTR) recently reported high clinical efficacy of auto-HCT in DLBCL patients achieving PR, but the efficacy of auto-HCT in this population has not been compared with CAR T-cell therapy in prospective trials.¹ Here we present the key findings from a recently published study by Shadman, et al.² published in Blood comparing the outcomes in patients with DLBCL achieving PR as the best response to therapy who receive either auto-HCT or CAR T-cell therapy.

Study design

This was a retrospective cohort study of data from the CIBMTR that included adult patients aged ≥18 years with DLBCL, high-grade B-cell lymphoma (BCL) with MYC and BCL2 and/or BCL6 rearrangements, or primary mediastinal B-cell lymphoma (PMBCL) and achieving a PR per 2014 Lugano criteria—confirmed by computed tomography or positron emission tomography (PET)—who underwent either auto-HCT between 2013 and 2019 or CAR T-cell therapy with axicabtagene ciloleucel between 2018 and 2019.

The primary endpoint was progression free survival (PFS), defined as time from either auto-HCT or CAR T-cell therapy to relapse or death from any cause.

Secondary endpoints were:

• Overall survival (OS), defined as time from treatment to death of any cause.
• Cumulative incidence of non-relapse morality (NRM), defined as death without preceding disease progression.
• Cumulative incidence of relapse/progression defined as time from treatment to relapse or disease progression and hematopoietic recovery.

Subgroup analyses were performed for:

• patients with an available PET scan before auto-HCT or CAR T-cell therapy.
• patients who received ≤2 or >2 prior lines of treatment.

Results

Baseline characteristics

A total of 411 patients who received either auto-HCT (n = 266) or CAR T-cell therapy (n = 145) while in PR were included; 62% of those were male, and patients in the auto-HCT group received fewer median lines of prior therapies compared to those in the CAR T-cell therapy group (2 vs 3; p < 0.001) (Table 1).

Table 1. Baseline characteristics*

Best responses to auto-HCT and CAR T-cell therapy

In the univariate analysis:

• Patients in the auto-HCT group showed a higher 2-year PFS (p = 0.1) and OS (p = 0.004) compared with those in the CAR T-cell therapy group (Table 2).
• Cumulative incidence of relapse/progression at 1 year (p = 0.03) and 2 years (p = 0.05) was lower in the auto-HCT group compared to the CAR T-cell therapy group (Table 2).  
• The 100-day cumulative incidence of NRM was 4% vs 2% in the auto-HCT and CAR T-cell therapy groups, respectively (p = 0.3) (Table 2).

In the subgroup analyses:

The 2-year PFS was similar in patients with an available PET scan before auto-HCT or CAR T-cell therapy (p = 0.1) (Table 2). However, consolidation with auto-HCT was associated with a lower 2-year cumulative incidence of relapse/progression (p = 0.03) and improved 2-year OS (p = 0.006). Patients in the auto-HCT group with ≤2 prior lines of therapy had a higher 100-day NRM (p = 0.01) and a superior OS at 2 years (p = 0.04) compared to patients in the CAR T-cell therapy group (Table 2).

In patients with early treatment failure (primary refractory disease or relapse within 12 months of diagnosis), there was no significant difference in 2-year PFS between the auto-HCT and CAR T-cell therapy groups (p = 0.05) (Table 2). However, there was lower relapse/progression rate (p = 0.006) and superior OS at 2-years (p = 0.003) in the auto-HCT group compared to the CAR T-cell therapy group, respectively.

Table 2. Univariate and subgroup analyses for outcomes in patients treated with auto-HCT or CAR T while in a PR

Auto-HCT, autologous hematopoietic cell transplantation; CAR-T, chimeric antigen receptor T-cell therapy; CI, confidence interval; NRM, non-relapse mortality; OS, overall survival; PFS, progression free survival; PR, partial remission. *Adapted from Shadman, et al.2 †Values in bold are statistically significant.
Outcomes	Total, n	Prob (95% CI), %	Total, n	(95% CI), %	p value†
Univariate analysis
NRM (cumulative incidence)	256		138		0.2
100-day		4 (2–7)		2 (0–5)	0.3
1-year		7 (4–11)		3 (1–6)	0.05
2-year		9 (5–13)		6 (1–16)	0.6
Cumulative incidence of progression/relapse	256		138		0.01
1-year		34 (28–40)		45 (37–54)	0.03
2-year		40 (33–46)		52 (41–63)	0.05
PFS	256		138		0.1
1-year		59 (53–65)		52 (43–61)	0.2
2-year		52 (46–58)		42 (30–53)	0.1
OS	266		145		0.01
1-year		76 (70–81)		67 (59–75)	0.1
2-year		69 (63–74)		47 (33–60)	0.004
Subgroup analysis
NRM (cumulative incidence)	215		119		0.2
100-day		3 (1–5)		2 (0–5)	0.5
1-year		6 (3–9)		3 (1–6)	0.1
2-year		7 (4–11)		3 (1–6)	0.04
Cumulative incidence of progression/relapse	215		119		0.007
1-year		33 (27–39)		46 (36–55)	0.03
2-year		39 (32–46)		54 (42–66)	0.03
PFS	215		119		0.04
1-year		61 (55–68)		52 (42–61)	0.1
2-year		54 (47–61)		43 (32–55)	0.1
OS	222		126		0.005
1-year		79 (73–84)		69 (60–77)	0.06
2-year		71 (65–77)		49 (34–63)	0.006

In the multivariate analysis:

CAR T-cell therapy was associated with a significantly higher risk of relapse/progression (hazard ratio [HR], 1.49; 95% confidence interval [CI], 1.08–2.05; p = 0.01) and mortality (HR, 1.63; 95% CI, 1.14–2.33; p = 0.008) compared with auto-HCT. An additional analysis was performed after propensity score matching of the who cohorts, and although the HRs of primary and secondary endpoints were directionally consistent with the overall multivariate analysis, the associations were no longer statistically significant.

Safety

• A total of 143 patients—91 from auto-HCT and 52 from the CAR T-cell therapy group—died during follow-up.
• The most common cause of death in both groups was the primary disease, which accounted for 74% and 75% of deaths in the auto-HCT and CAR T-cell therapy groups, respectively.
  • Other causes of death included infection (6%) and organ failure (4%) in the auto-HCT group and infection (4%), cytokine release syndrome (4%), organ failure (4%), and malignancies (4%) in the CAR T-cell therapy group.

Conclusion

This retrospective study showed that patients with DLBCL achieving PR with salvage chemotherapy and subsequently treated with auto-HCT showed similar PFS to CAR T-cell therapy but had a lower incidence of relapse and improved OS. The findings from this analysis support the role of auto-HCT in transplant eligible patients with relapsed DLBCL that achieved PR, but further studies are warranted to understand its role in patients with fewer lines of salvage therapy. The findings from this study should be interpreted in the context of certain limitations such as the retrospective nature of the study, unbalanced cohorts, the subjectivity of PR definition (especially in the non-clinical setting), and lack of independent centralized reading of the scans by the transplant centers. Although results from three (TRANSFORM [NCT03575351], ZUMA-7 [NCT03391466], and BELINDA [NCT03570892]) ongoing randomized phase III trials comparing the efficacy and safety of each of the three approved CAR T-cell products (lisocabtagene maraleucel, axicabtagene ciloleucel, and tisagenlecleucel) are awaited to inform the second-line of therapy in relapsed/refractory patients, the findings from the current study are important in helping to inform clinical decisions for patients with relapsed DLBCL.