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Page 8 of 19 Casadei et al. J Cancer Metastasis Treat 2022;8:21 https://dx.doi.org/10.20517/2394-4722.2022.05

Tafasitamab is another mAb, recently developed for targeting the B-lymphocyte antigen CD19. This surface
antigen is broadly expressed during B-cell development, highly preserved across most B-cell malignancies,
and still detectable in relapsed diseases. Tafasitamab monotherapy showed encouraging results in a phase
IIa study published in 2018, where 29% of the participating R/R FL patients obtained an objective response
(CRR 9%); median PFS in this cohort was 8.8 months at a median follow-up of 21 months . Considering
[65]
these results, several clinical trials are now ongoing to evaluate the efficacy of tafasitamab in combination
with other target drugs such as lenalidomide (NCT04680052) and the phosphatidylinositol 3-kinase (PI3Kδ)
inhibitor parsaclisib (NCT04809467).

Radioimmunotherapy
Given the high radiosensitivity of FL cells, combined with the constant and intense expression of CD20 on
90
their surface, anti-CD20 RIT drugs have been developed for treatment of relapsed patients. Y ibritumomab
tiuxetan, in particular, was associated with high ORR of approximately 80% after a single administration
and 12-month PFS. Patients obtaining a CR tend to have longer PFS, lasting up to four years in around 30%
of cases . The drug received Food and Drug Administration (FDA) and Italian medicine agency (Agenzia
[66]
Italiana del Farmaco, AIFA) approval for consolidation of CR in FL patients after first-line therapy and for
the treatment of FL that is R/R after rituximab. Nevertheless, the use of RIT is limited by adequate bone
marrow cellularity and reduced bone marrow infiltration by lymphoma.

Lenalidomide
The immunomodulatory agent (imid) lenalidomide acts through a variety of mechanisms; in vitro studies
[67]
demonstrated its ability to synergize with rituximab through enhancement of ADCC . This led to the
hypothesis of the possibility to overcome rituximab-refractoriness by combining the anti-CD20 monoclonal
antibody with lenalidomide. The phase II study published by Chong et al. in 2015 demonstrated the efficacy
of lenalidomide both as monotherapy and in combination with rituximab (R ), with an ORR of 63% and
2
[68]
PFS of 24 months for responders . Shortly after, Leonard and colleagues published the results of a
randomized multicenter trial (Alliance) demonstrating the superiority of R compared with lenalidomide
2
single agent (ORR 76% vs. 53%, CRR 20% vs. 39%); median time to progression (TTP) was significantly
2
[69]
longer for the R arm than lenalidomide alone (2 vs. 1.1 years) . In 2019, the results of the Augment trial
showed that R was also associated with a statistically significant improvement in ORR and PFS (39.4% vs.
2
14.1%) compared with rituximab monotherapy , leading to FDA, European Medicine Agency (EMA), and
[70]
AIFA approval of this combination in the setting of relapsed or refractory FL after at least one previous
therapy. The MAGNIFY trial (NCT01996865) is currently exploring the effect on PFS of maintenance with
R vs. rituximab alone after 12 cycles of lenalidomide plus rituximab in patients with indolent NHL, with
2
particular attention on POD24-positive patients.
Moreover, as stated above, a phase III clinical trial (NCT04680052) is testing the efficacy and safety of R
2
compared to R plus tafasitamab, a humanized anti-CD19 monoclonal antibody that has already shown
2
promising results as a single agent in R/R FL .
[65]
Tazemetostat
Tazemetostat is a first-in-class inhibitor of the enhancer of zeste homolog 2 (EZH2) histone
methyltransferase, an enzyme that has a fundamental role in the formation of GCs . The molecule harbors
[71]
a mutation in approximately 25% of FL . The drug blocks both the mutant (mut) and wild-type (wt) forms
[19]
of EZH2, but the results of the phase II study in which it was evaluated showed better outcomes in
EZH2mut patients: ORR was 69% in this population versus 35% in EZH2wt patients, with 13% vs. 4% CRR,
[71]
respectively. Median PFS was 13.8 months in EZH2mut patients and 11.1 months in the EZHwt group .