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Relapse following standard therapeutic approaches is common in patients with advanced-stage, indolent non-Hodgkin lymphomas (iNHL). Two autologous anti-CD19 chimeric antigen receptor (CAR) T-cell products, axicabtagene ciloleucel (axi-cel), and tisagenlecleucel (tisa-cel), both approved for the treatment of relapsed/refractory (R/R) large B-cell lymphoma (LBCL), are currently under investigation in the phase II ZUMA-5 (NCT03105336) and ELARA (NCT03568461) trials for patients with iNHL, including follicular lymphoma (FL), and marginal zone lymphoma (MZL).
During the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition, updates on both ZUMA-5 and ELARA trials were presented by Caron Jacobson,1 and by the Lymphoma Hub Executive Steering Committee member Nathan Fowler,2 respectively. Here, we combine key points from these sessions.
ZUMA-5 is a multicenter, single arm, phase II study of axi-cel for the treatment of R/R FL and MZL after ≥ 2 prior lines of therapy. An interim analysis of 96 patients in the ZUMA-5 trial was previously covered on the Lymphoma Hub. In the current analysis, 151 patients with R/R iNHL were enrolled, and 124 patients with FL, and 22 patients with MZL were treated (total = 146).
Selected patient characteristics at baseline for the expanded cohort were as follows:
Other patient characteristics were similar to those reported in the previous analysis.
The efficacy analysis included 104 evaluable patients (FL, n = 84; MZL, n = 20) with a median follow-up of 17.5 months (range, 1.4–31.6 months).
The overall response rate (ORR) for all patients was 92% (95% CI, 85–97), and complete response (CR) rate was 76% (95% CI, 67–84).
Figure 1. Best overall response rates1
CR, complete response; FL, follicular lymphoma; MZL, marginal zone lymphoma; ND, undefined/not done; ORR, objective response rate; PR, partial response; SD, stable disease.
Table 1. Key secondary efficacy results1
CI, confidence interval; DOR, duration of response; FL, follicular lymphoma; MZL, marginal zone lymphoma; NE, not estimable; OS, overall survival; PFS, progression-free survival. |
|||
Outcome |
FL |
MZL |
All patients |
---|---|---|---|
Median follow-up, months (range) |
18.5 (12.2–31.6) |
12.1 (1.4–26.8) |
17.5 (1.4–31.6) |
Median DOR, months (95% CI) |
NE (20.8–NE) |
10.6 (8.1–NE) |
NE (20.8–NE) |
12-month DOR rate, % (95% CI) |
77.0 (65.5–85.1) |
NE (NE–NE) |
71.7 (60.7–80.1) |
Median PFS, months (95% CI) |
NE (23.5–NE) |
11.8 (9.1–NE) |
NE (23.5–NE) |
12-month PFS, % (95% CI) |
77.5 (66.6–85.2) |
45.1 (15.2–71.4) |
73.7 (63.3–81.6) |
Median OS, months (95% CI) |
NE (NE–NE) |
NE (NE–NE) |
NE (NE–NE) |
12-month OS, % (95% CI) |
92.8 (84.7–96.7) |
92.9 (59.1–99.0) |
92.9 (85.6–96.5) |
The safety analysis included all treated patients (n = 146), with a median follow-up of 15.1 months (range, 0.5–31.6 months). Table 2 summarizes safety outcomes of interest.
Table 2. Safety outcomes1
AE, adverse events, CRS, cytokine release syndrome; FL, follicular lymphoma; MZL, marginal zone lymphoma. |
|||
Outcome |
FL |
MZL |
All patients |
---|---|---|---|
Any AE, % |
99 |
100 |
99 |
Grade ≥ 3 CRS*, % Median time to onset, days (range) |
6 4 (1–15) |
9 4 (1–9) |
7 4 (1–15) |
Grade ≥ 3 neurologic events†, % Median time to onset, days (range) |
15 7 (1–177) |
41 7 (3–19) |
19 7 (1–177) |
The results of pharmacokinetic and pharmacodynamic analyses were similar to those reported in the previous analysis.
Axi-cel is a promising approach for the treatment of patients with R/R iNHL, demonstrating high rates of durable responses that were consistent among patients with high-risk features. The safety profile was manageable and appeared to be favorable for FL compared with data previously reported for LBCL. Based upon the manageable safety profile, the possibility of outpatient treatment is to be investigated.
ELARA is a single-arm, multicenter, phase II study evaluating the efficacy and safety of tisa-cel in patients with R/R FL. The trial recently met its primary endpoint (CR rate); secondary endpoints include overall response rate (ORR), DOR, PFS, OS, and safety.
Eligibility criteria:
The study design is depicted in Figure 2. First efficacy assessment was performed at Month 3. Efficacy and safety follow-up will be done every 3 months for the first 12 months, and then every 6 months until study completion.
Figure 2. Study design2
O-Benda, obinutuzumab and bendamustine; R2, lenalidomide and rituximab; R-CHOP; rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone; R-GemOx, rituximab, gemcitabine, oxaliplatin; tisa-cel, tisagenlecleucel.
*Administered in 43.3% of patients. The most common regimens included R-GemOx, R-CHOP, and O-Benda. A few patients received idelalisib and R2.
†Fludarabine (daily IV dose of 25 mg/m2 for 3 days) plus cyclophosphamide (daily IV dose of 250 mg/m2 for 3 days), OR bendamustine (daily IV dose of 90 mg/m2 for 3 days).
‡Dose range: 0.6–6 × 108 CAR+ viable T cells in a single IV infusion.
A total of 97 patients have been enrolled, with a median age of 57.0 years (range, 29–73 years). The study population was heavily pretreated, with a median of four prior therapies (range, 2–13). Baseline characteristics are presented in Table 3.
Table 3. Baseline characteristics2
Auto-HSCT, autologous hematopoietic stem cell transplantation; ECOG PS, European Cooperative Oncology Group performance status; FLIPI, follicular lymphoma international prognostic factor index; mAb, monoclonal antibody; PI3K, phosphoinositide 3-kinase inhibitor; POD24, progression of disease within 24 months. |
|
Characteristic, % |
N = 97 |
---|---|
ECOG PS before infusion 0 1 |
56.7 39.2 |
Stage III–IV disease |
83.5 |
FLIPI ≥ 3 |
59.8 |
Prior therapies ≥ 3 Auto-HSCT Anti-CD20 mAb and alkylating agents PI3K inhibitors Lenalidomide and rituximab |
76.3 36.1 100 20.6 17.3 |
POD24 from first anti-CD20 mAb-based therapy |
59.8 |
Refractory to last line of therapy |
77.3 |
Refractory to ≥ 2 regimens |
75.5 |
Median follow-up was 9.9 months (range, 6.0–15.6), and median DOR was not reached. Fifty-two patients were evaluable. Efficacy outcomes are presented in Table 4.
Table 4. Outcomes2
CR, complete response; ORR, overall response rate; PFS, progression-free survival; PR, partial response |
|
Outcomes, % |
N = 52 |
---|---|
CR |
65.4 |
PR |
17.3 |
ORR (CR + PR) |
82.7 |
6-month PFS (95% CI) |
73.2 (58.2–83.5) |
Median follow-up for safety was 6.5 months (range, 0.2–15.6). Most patients (94.8%) experienced an AE of any grade, and 73.2% of these were suspected to be related to tisa-cel. The frequency of Grade 3–4 AEs was 70.1%, of which 38.1% were suspected to be related to tisa-cel. Table 5 provides the Grade ≥ 3 AEs of special interest. There were three deaths, and all were due to disease progression.
Table 5. Grade ≥ 3 AEs of special interest2
AEs, adverse events. |
|
Grade ≥ 3 AEs*, % |
N = 97 |
---|---|
Neutropenia |
24.7 |
Anemia |
12.4 |
Thrombocytopenia |
8.2 |
Infections |
4.1 |
Serious neurological adverse reactions |
1.0 |
Median onset of neurological events was 8.5 days (range, 4–190), and only one Grade ≥ 4 immune effector cell-associated neurotoxicity syndrome (ICANS) was reported. Median onset of CRS was 4.0 days (1–14), and there were no Grade ≥ 3 CRS events. All neurological events and CRS were managed with suitable approaches including tocilizumab and corticosteroids.
This analysis demonstrated that tisa-cel may be an effective option for heavily pretreated patients with R/R FL. CR and ORR rates were 65% and 83%, respectively. Median DOR, PFS, and OS were not reached for all patients. Safety analysis did not produce any new safety concerns. There were no deaths considered related to the study treatment.
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