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Sequencing immune-based therapies in B-cell malignancies
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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.
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:
Subgroup analyses were performed for:
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*
Characteristics, % (unless otherwise stated) |
Auto-HCT |
CAR-T |
p value† |
---|---|---|---|
Median age (range), years |
58 (18–80) |
60 (24–91) |
0.07 |
≥60 years |
44 |
50 |
0.25 |
Race |
|
|
<0.001 |
Caucasian |
62 |
83 |
|
African American |
22 |
7 |
|
Other |
4 |
1 |
|
Median follow-up (range), months |
38 (3–79) |
12 (3–26) |
|
At diagnosis |
|
|
|
Disease stage III–IV |
61 |
55 |
0.99 |
High-grade B-cell lymphoma, with MYC |
16 |
17 |
0.84 |
Elevated LDH |
28 |
26 |
0.53 |
Extra-nodal involvement |
51 |
50 |
0.51 |
Time from diagnosis to auto-HCT or CAR-T |
|
|
0.30 |
≤12 months |
39 |
44 |
|
>12 months |
61 |
56 |
|
Prior treatments |
|
|
|
Refractory to first line therapy |
60 |
55 |
0.61 |
Median (range), n |
2 (1–6) |
3 (2–11) |
<0.001 |
>2 lines |
33 |
67 |
<0.001 |
Pre auto-HCT or CAR-T |
|
|
|
KPS ≥90 |
51 |
39 |
0.09 |
Largest node |
|
|
0.05 |
<3 cm |
15 |
15 |
|
3–5 cm |
24 |
18 |
|
>5 cm |
29 |
41 |
|
Imaging |
|
|
0.36 |
PET or PET/CT |
83 |
87 |
|
CT |
17 |
13 |
|
Conditioning regimen |
|
|
|
BEAM |
76 |
NA |
|
Bu/Cy |
6 |
NA |
|
CBV |
16 |
NA |
|
Other |
16 |
NA |
|
Lymphodepletion regimen |
|
|
|
Flu/Cy |
NA |
100 |
|
Year of auto-HCT or CAR-T |
|
|
|
2018 and after |
20 |
100 |
<0.001 |
Auto-HCT, autologous hematopoietic cell transplantation; BEAM, carmustine, etoposide, cytarabine and melphalan; Bu/Cy, busulfan/cyclophosphamide; CAR-T, chimeric antigen receptor T-cell therapy; CBV, cyclophosphamide, carmustine, etoposide; CT, computed tomography; DLBCL, diffuse large B-cell lymphoma; Flu/Cy, fludarabine, cyclophosphamide; KPS, Karnofsky Performance Score; LDH, lactate dehydrogenase; NA, not applicable; PET, positron emission tomography; PR, partial remission. |
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
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 |
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. |
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.
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.
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