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Casadei et al. J Cancer Metastasis Treat 2022;8:21 https://dx.doi.org/10.20517/2394-4722.2022.05 Page 11 of 19

FL microenvironment, which plays a key role in the pathogenesis of the disease. In particular, these agents
increase the dependence of tumor cells on the activity of BCL-2 over different anti-apoptotic proteins: this
[91]
leads to an improved efficacy of venetoclax in FL preclinical models . This finding may provide a rationale
for investigating the combination of PI3Ki and venetoclax in clinical trials. The recently published Contralto
study explored the safety and efficacy of venetoclax in association with the BR regimen (Arm B),
[92]
comparing this combination with BR (Arm C) and with the chemo-free arm R-venetoclax (Arm A). While
the combination arm showed the highest rates of toxicity, with increased need of dose reductions and
treatment interruptions, response rates were similar to Arm C: ORR was 84% and CRR was 75% at primary
response assessment (PRA); after one year of follow-up, ORR was 49% and CRR was 43%. The chemo-free
R-venetoclax arm, on the other hand, showed only modest anti-lymphoma activity, with ORR of 35% and
CRR of 17% at PRA. Notably, most patients in this cohort had received several prior therapy lines and
presented high-risk features such as refractoriness to last treatment and advanced stage disease. Responding
patients, however, seem to achieve durable remissions: at one-year follow-up, an ORR of 27% was
registered, with 19% CRR . Based on these results, other trials are currently studying the best way to
[92]
optimize the combination of venetoclax with chemo-immunotherapy; one study in particular is exploring
obinutuzumab-bendamustine in association with a non-continuous dosing schedule of venetoclax
(NCT03113422).

Antibody-drug conjugated
The last two decades saw the development of another new category of drugs, namely antibody-drug
conjugates (ADC), which allow the administration of antiblastic agents while minimizing their AEs thanks
to their targeted mechanism of action. The compounds consist of a monoclonal antibody moiety,
responsible for the selective binding to the lymphoma cell, linked to a cytotoxic molecule, which is
conveyed directly into the malignant cell.

Studies of ACDs in FL include the anti-CD22 pinatuzumab vedotin and the anti-CD79b polatuzumab
vedotin, both harboring as a cytotoxic agent a molecule of monomethyl auristatin E (MMAE) [93,94] . The
ROMULUS study proved that both agents, associated with rituximab, can induce objective responses in
pre-treated FL lymphoma patients (ORR 62% for R-pina vs. 70% for R-pola), with significantly higher CRR
[95]
for R-pola (45% vs. 5% with R-pina). Median PFS was 15 months for patients receiving R-pola . Several
trials have been designed that combine polatuzumab with obinutuzumab and various different agents, such
as lenalidomide, venetoclax, and mosunetuzumab, in order to test the potential synergy of these targeted
molecules in treating FL.

Loncastuximab tesirine is an anti-CD19 ADC whose cytotoxic molecule is represented by a
pyrrolobenzodiazepine dimer. The drug has recently received accelerated FDA approval for the treatment of
R/R DLBCL following the results of the LOTIS 2 phase II trial . The phase I study in which the drug was
[96]
evaluated included 14 FL patients, who obtained an ORR of 79% with 64% CRR; mDOR was not reached in
[97]
this cohort . Ninety-eight percent of patients had at least one treatment-emergent adverse event, which
was generally manageable and reversible with dose delays and/or reductions. Hematologic toxicities were
common, whereas fatigue was the most common non-hematologic AE (42.6%); other significant toxicities
were represented by nausea (32.2%), peripheral edema and effusions (47%), skin- and nail-related
alterations (54%, mainly represented by skin rash in sun-exposed areas), and increase of liver enzymes
(31%) . The ongoing LOTIS 6 randomized phase II study (NCT04699461), comparing the efficacy of
[97]
loncastuximab tesirine with idelalisib in R/R FL, may lead to approval of the ADC in this setting. It remains
to be seen, however, whether the recent developments in PI3Ki applications in FL will impair the success of
the trial.