Page 35 - 2022_01-Haematologica-web

Recent developments for patients with R/R FL
Table 2. Selected chimeric antigen receptor T-cell and bispecific antibody trials and outcomes.
CAR T-cell product
Axicabtagene ciloleucel82 Tisagenlecleucel85
Bispecific antibody
Mosunetuzumab92 Glofitamab93 Epcoritamab94 Odronextamab95
Anti-CD47 antibody
Magrolimab97
Phase Prior lines of treatment
II ≥2 II ≥2
Phase Prior lines of treatment
I ≥2 I ≥1 I ≥1 I ≥1
Phase Prior lines of treatment
Ib/II ≥1
N. of patients ORR with FL (%)
84 94 94 86
N. of patients ORR with FL (%)
62 68 44 71 12 90 28 93
N. of patients ORR with FL (%)
28 66*
CRR PFS
(%) (time point, %)
79 18 mo, 69% 66 6 mo, 76%
CRR PFS, (%) median (mo)
50 11.8 48 11.8 50 N/A 75 12.8
CRR PFS, (%) median (mo)
24* N/A
DoR (time point, %)
18 mo, 69% N/A
DoR, median (mo)
20.4 10.8 N/A 7.7
DoR, median (mo)
N/A
CRS, % (grade III-IV)
78 (6) 48.5 (0)
CRS, % (grade III-IV)
23 (1.6) 50.3 (3.5)* 59 (0)* 62.2 (7.1)*
Anemia, % (grade III-IV)
27 (15)
ICANS, % (grade III-V)
56 (15) 9.3 (1.0)
ICANS, % (grade III-V)
45 (0) 3.5 (1.2)* 8 (4)* (3.9)*
*All patients with non-Hodgkin lymphoma, those with follicular lymphoma not reported individually. Data were collected from published papers and abstracts; comparisons cross trials are not possible because of the different eligibility criteria and other differences. FL: follicular lymphoma; ORR: overall response rate; CRR: complete response rate; PFS: progression-free survival; DoR: duration of response; CRS: cytokine release syndrome; ICANS: immune effector cell associated neurotoxicity; N/A: not available or not report- ed; mo: months.
syndrome occurring in 49% (all grade 2 or below) and neurotoxicity in 9% (all grade 2 or below, apart from a single grade 4 event which was self-limited). Another study is evaluating the activity of lisocabtagene maraleu- cel in the same setting (NCT04245839).
An array of clinical trials is in development with the aim of improving CAR T-cell therapy in B-cell lym- phoma.86 Possible avenues include the use of combination products such as BTK inhibitors and checkpoint inhibitors, bispecific CAR targeting multiple lymphoma epitopes, and armored CAR products intended to over- come the immunosuppressive tumor microenvironment.
The current CD19-directed CAR T-cell results are encouraging, although longer-term data will be necessary to define the ultimate value of these treatments. There would be obvious appeal if this single-administration therapy produced prolonged disease-free remissions in a significant proportion of patients. Additionally, mitiga- tion of cytokine release syndrome and neurotoxicity, either via supportive measures or less toxic CAR T-cell products, would broaden the applicability of these thera- pies, particularly if they can be administered in the outpa- tient setting. Assuming long-term efficacy is established, and with improvements in the avoidance and manage- ment of toxicities, CAR T cells will represent an appeal- ing option in the therapeutic algorithm.
Antibody-drug conjugates
Antibody-drug conjugates enable targeted delivery of potent cytotoxic drugs to tumor cells, minimizing sys- temic toxicity. Such agents, targeting common B-cell anti- gens, have been developed across the spectrum of B-cell lymphomas, with polatuzumab vedotin and loncastux- imab tesirine recently approved for patients with diffuse large B-cell lymphoma.87,88 Polatuzumab vedotin targets the CD79b antigen and has shown promising response rates alone or in combination with rituximab for patients with FL (overall response rate 70%, complete response rate 45%).89 However, high rates of cumulative peripheral neuropathy were noted when prolonged cycles were administered, a significant concern in the context of the chronicity of FL. Furthermore, when combined with B-R in a randomized phase II study, polatuzumab did not improve the complete response rate or PFS for patients
with FL, in contrast to the observations made in patients with diffuse large B-cell lymphoma.87 Several combina- tions of polatuzumab with other agents active in FL are currently being investigated.90 The CD19-directed anti- body loncastuximab tesirine also showed activity in 14 patients with FL with an overall response rate of 79% and a complete response rate of 64%.91 Combination studies with rituximab (NCT04998669) and a comparison of this agent versus idelalisib (NCT04699461) are planned.
Bispecific antibodies
A novel approach to lymphoma immunotherapy has been the use of bispecific T-cell engager therapies, which incorporate a CD3-binding component that engages T cells and a second tumor antigen-binding domain, most commonly CD20 in B-cell lymphoma. These agents func- tion to induce activation and cytotoxic activity of T cells against CD20-expressing lymphoma cells. Like autolo- gous CAR T-cell therapy, bispecific T-cell engagers recruit the patient’s native T cells to target lymphoma, with the advantage of being an “off-the-shelf” option that bypass- es the time and logistical challenges entailed in genetic modification of T cells. Early-phase clinical trials have demonstrated very encouraging results, with high response rates of 68-90% in patients with relapsed/refrac- tory FL, including complete responses in the majority of patients (Table 2).92-95 Limited follow-up is currently avail- able to evaluate response duration, although preliminary data demonstrated durable responses lasting at least 18 months in patients having achieved a complete response after completion of therapy. Toxicities of concern include cytokine release syndrome and neurotoxicity, similar to the toxicities of CAR T-cell therapy, although these events were only observed during the initial one or two infusions, and both rates and severity were lower than those with CAR T-cell therapies. Further mitigation of toxicity may be possible via step-up dosing and/or subcu- taneous administration. If durable responses are demon- strated and toxicity proves manageable, this class of agents appears to hold very significant promise in FL. Combination studies with other immune interventions or cytotoxic agents are under development (NCT04712097, NCT04663347, NCT04246086) and are evaluating the use of bispecific therapy in earlier phases of FL treatment.
haematologica | 2022; 107(1)
27