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Recent developments for patients with R/R FL
toxicity, and the opportunity for re-treatment, we favor the 2 x 2 Gy approach for local treatment of symptomatic relapsed/refractory FL.
For systemic treatment, radioimmunotherapy was developed in the last two decades with 131I coupled to tositumomab and 90Y-ibritumomab tiuxetan, which pro- duced high rates of response.42 Various logistical and eco- nomic considerations account for the lack of widespread use of these agents, and only ibritumomab remains avail- able in North America and Europe. Furthermore, since both agents target the CD20 antigen, their efficacy in patients recently exposed to rituximab is possibly hin- dered by competition with rituximab for target antigens. To circumvent this, radioimmunoconjugates targeting dif- ferent cell surface antigens have been developed. Encouraging preliminary results were noted with 177Lu- lilotomab satetraxetan, a CD37-directed antibody, in patients with refractory FL, and a registration phase II study is currently underway (NCT01796171).43
Targeted therapies: exploiting tumor cell vulnerabilities
Benefits and limits of phosphoinositide 3-kinase inhibitors
FL and other lymphomas exhibit constitutive overactiva- tion of the phosphoinositide 3-kinase (PI3K)-AKT-mecha-
nistic target of rapamycin (mTOR) pathway, which has important roles in proliferation, growth, and survival of both normal and cancer cells.44 Signaling through the B-cell receptor and other cell-surface receptors, which might be critical for lymphoma survival, also depends on this path- way. As a result, PI3K is now a target of significant interest in treating FL, with a number of targeted inhibitors demon- strating activity in multiply refractory disease, and four agents approved in the USA (Table 1).45-49 Approved PI3K inhibitors have all been evaluated in single-arm phase II studies, limiting comparison between PI3K inhibitors or with other treatment modalities (Table 1). Response rates were between 42% and 66% and the median PFS was between 10 and 13 months for the four agents, which were all evaluated in FL that had relapsed after or had been refractory to at least two prior lines of treatment. Differences in the efficacy and toxicity of these inhibitors are largely related to the specific subunits targeted by the therapy.44 Class 1 PI3K is composed of a heterodimer con- taining a p110 subunit (a, b, g or d) and a regulatory subunit. The g and d subunits are more specifically expressed in leukocytes, whereas the a and b subunits are widely expressed in normal tissue, although all have been implicat- ed in lymphomagenesis.
Idelalisib, the first approved PI3K inhibitor, is d-specific, and was shown to generate high response rates in FL refractory to at least two prior lines of treatment includ- ing anti-CD20 and alkylator therapy.45,46 Complete
Table 1. Selected trials and outcomes with targeted therapies in relapsed or refractory follicular lymphoma.
PI3K inhibitors (approved)
Idelalisib46
Duvelisib47
Umbralisib48
Copanlisib49
Copanlisib + rituximab53 Rituximab control arm
PI3K inhibitors (ongoing studies)
Parsaclisib (daily dosing)51 Parsaclisib (weekly dosing)51
Zandelisib + rituximab52 Zandelisib
BTK inhibitors
Ibrutinib54
Acalabrutinib56
Acalabrutinib + rituximab56 Zanubrutinib + obinutuzumab57
mTOR inhibitors
Everolimus58 Temsirolimus59
BCL2 inhibitors
Venetoclax60
Venetoclax - BR61 BR control arm
Venetoclax - rituximab61
Phase Prior lines of therapy
II ≥2
II ≥2
II ≥2
II ≥2
III ≥I III ≥1
II ≥2 II ≥2
Ib ≥1 Ib ≥1
II ≥2 Ib ≥1 Ib ≥1 Ib ≥1
II ≥1 II ≥1
I ≥1 II ≥1
II ≥1
II ≥1
N. of patients ORR with FL
72 66
83 42
117 45
104 59
184 85 91 54
74 72 22 64
9 78 39 79
110 21 12 33 13 39 36 72
23 61 39 54
29 38
51 84 51 84
52 35
CRR
PFS, median (months)
DoR, median (months)
11
10
11
14
20.4* 17.3*
NR N/A
N/A N/A
19.4 NR NR NR
N/A 13.3
27
N/A N/A
N/A
OS
2y: 70%
2y: 60%
N/A
2y: 69%
3y: 83% 3y: 81%
N/A N/A
N/A N/A
1y 78% N/A N/A N/A
median: 29.4 mo 3y: 73%
N/A
N/A N/A
N/A
14
1 10 5 11
20
37 21
13.5 13.6
N/A N/A
11 8 8 39
N/A 26
17
75 69
17
13
22 19
15.8 N/A
N/A N/A
4.6 N/A N/A 25
7.2* 12.7
11
N/A N/A
6.6
11
*Overall population including patients with chronic lymphocytic leukemia/small cell lymphoma, marginal zone lymphoma and follicular lymphoma. Data were collected from published papers and abstracts; cross-trial comparisons are not possible because of 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; OS: overall survival; PI3K = phosphoinositide 3-kinase; BTK: Bruton tyrosine kinase; mTOR: mechanistic target of rapamycin; BR: bendamustine and rituximab; NR: not reached; N/A: not available or not reported; y: years; mo: months.
haematologica | 2022; 107(1)
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