Lisocabtagene maraleucel (liso-cel), is an investigational, CD19-directed, defined composition, 4-1BB chimeric antigen receptor (CAR) T-cell product administered at equal doses of CD8+ and CD4+ CAR T cells, and it is currently under evaluation in several subtypes of relapsed or refractory (R/R) lymphoma.
TRANSCEND-CLL-004 (NCT03331198) is a phase I/II trial investigating the safety and efficacy of liso-cel as monotherapy or in combination with ibrutinib in patients with R/R chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Initial phase I results of the combination cohort were presented by William Wierda during the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition.1
TRANSCEND-NHL-001 (NCT02631044) is a phase I seamless design study evaluating the safety and efficacy of liso-cel in B-cell non-Hodgkin lymphoma. During ASH 2020, Maria Lia Palomba presented the initial results from the R/R mantle cell lymphoma (MCL) cohort receiving liso-cel.2 Liso-cel has been recently approved by the U.S. Food and Drug Administration (FDA) for the treatment of adults with R/R diffuse large B-cell lymphoma (DLBCL), Grade 3B follicular lymphoma (FL), or primary mediastinal large B-cell lymphoma (PMBCL), based on favorable results from TRANSCEND-NHL-001. European Medicines Agency approval is currently being sought.
Here, we are pleased to summarize these two talks.
Update from the TRANSCEND-CLL-004 trial1
In this study, patients with R/R CLL/SLL received lymphodepleting chemotherapy followed by liso-cel infusion. Results from the phase I combination cohort (outlined in red in Figure 1) were presented. The results of the phase I monotherapy arm (n = 23) were previously summarized here.
Figure 1. TRANSCEND-CLL-004 study design1
CAR, chimeric antigen receptor; Cy, cyclophosphamide; DL, dose level; Flu, fludarabine; liso-cel, lisocabtagene maraleucel.
The phase I combination cohort included patients:
- With R/R CLL/SLL who progressed on ibrutinib at the time of enrolment; or
- With high-risk features and received ibrutinib for ≥ 6 months but achieved less than a complete response (CR); or
- With ibrutinib-resistant mutations including BTK or PLCɣ2 mutations; or
- Who had prior ibrutinib exposure without contraindications to reinitiating ibrutinib
Patients continued or restarted ibrutinib up to a target dose of 420 mg at enrolment, for up to 90 days following liso-cel infusion, or longer in case of clinical benefit. Bridging therapy was allowed.
Primary objectives were safety and determination of recommended dose for the dose expansion part of the study. Dose-limiting toxicities (DLTs) were evaluated in the first 28 days after liso-cel infusion.
Results
Table 1 provides baseline characteristics among dose levels. Most patients (95%) had high-risk disease, were heavily pretreated, and were all R/R to ibrutinib.
Table 1. Patient characteristics1
BTKi, Bruton tyrosine kinase inhibitor; DL, dose level; R/R, relapsed or refractory; Ven, venetoclax. |
|||
Characteristic |
Combination cohort (DL1/DL2 + ibrutinib; |
DL1 + ibrutinib |
DL2 + ibrutinib |
---|---|---|---|
Median age, years (range) |
61 (50–77) |
58 (50–70) |
61 (51–77) |
Median time since diagnosis, months (range) |
121 (21–252) |
84 (31–176) |
127 (21–252) |
Bulky disease ≥ 5 cm, n (%) |
6 (32) |
0 (0) |
6 (40) |
Received bridging therapy, n (%) |
8 (42) |
2 (50) |
6 (40) |
Stage, n (%) |
|
|
|
High-risk feature (any), n (%) |
18 (95) |
4 (100) |
14 (93) |
Median lines of prior therapy, n (range) |
4.0 (1–10) |
4.5 (1–5) |
3.0 (2–10) |
Safety
Liso-cel plus ibrutinib combination was well tolerated with no DLTs observed.
- Any grade cytokine release syndrome (CRS) occurred in 14 patients (74%) with a median time to onset of 6.5 days (range, 1–13) and a median duration of 6 days (range, 3–13)
- Any grade neurological events (NEs) occurred in 6 patients (32%) with a median time to onset of 8 days (range, 5–12) and a median duration of 6.5 days (range, 1–8)
- Tocilizumab and/or corticosteroids were used to manage these events
- No Grade 4 CRS or NEs were reported
Table 2 summarizes Grade ≥ 3 adverse events (AEs) at both dose levels. No Grade 5 AEs were reported. Dose reductions or treatment discontinuation due to ibrutinib-related treatment-emergent AEs (TEAEs) were uncommon.
Table 2. Safety outcomes1
AE, adverse events; CRS, cytokine release syndrome; DL, dose level; NE, neurological event; TEAE, treatment-emergent AE. |
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AE, n (%) |
Combination cohort (DL1/DL2 + ibrutinib; |
DL1 + ibrutinib |
DL2 + ibrutinib |
---|---|---|---|
Grade 3/4 TEAEs |
18 (95) |
4 (100) |
14 (93) |
Grade 3 CRS |
1 (5) |
1 (25) |
0 (0) |
Grade 3 NEs |
3 (16) |
0 (0) |
3 (20) |
Grade 3/4 ibrutinib-related TEAEs* |
7 (37) |
2 (50) |
5 (33) |
Ibrutinib dose reduction due to TEAE |
2 (11) |
0 (0) |
2 (13) |
Ibrutinib discontinuation due to TEAE |
4 (21) |
1 (25) |
3 (20) |
Response
Best overall response and rates of undetectable minimal residual disease (uMRD; sensitivity of ≤ 10–4) are shown in Figure 2.
Figure 2. Best overall response and uMRD at 10-month follow-up1
A Best overall response; B uMRD at any time point.
CI, confidence interval; CR, complete response; CRi, CR with incomplete hematologic recovery; DL, dose level; PR, partial response; uMRD, undetectable minimal residual disease (≤ 10-4).
Most patients remained in remission at 10-month follow-up. Patients who responded achieved an early response by Day 30 after liso-cel infusion.
The two liso-cel dose levels did not affect CAR+ T-cell expansion differently, while median peak CAR+ T-cell expansion occurred by Day 11 in the combination cohort.
Conclusion
In summary, these initial findings suggest a favorable tolerability with low rates of Grade 3 CRS or NEs. This heavily pretreated patient cohort with R/R CLL/SLL achieved rapid and high response rates and uMRD when liso-cel was combined with ibrutinib. The safety profile was similar among dose levels, and DL2 (100 × 106 CAR+ T cells) was identified as the recommended dose for the expansion cohort. Further evaluation of the combination of liso-cel and ibrutinib is currently ongoing.