Page 48 - Read Online

Page 10 of 19 Casadei et al. J Cancer Metastasis Treat 2022;8:21 https://dx.doi.org/10.20517/2394-4722.2022.05

umbralisib withdrawal for chronic lymphocytic leukemia (CLL), SLL, and for the two other approved
indications of FL and marginal zone lymphomas (MZL). The decision was based on the recently updated
results of the UNITY-CLL phase III trial, which showed an increasing imbalance in OS in favor of the
control arm (obinutuzumab+ chlorambucil) in CLL and SLL. Currently, additional molecules are
undergoing clinical evaluation and showing promising results: parsaclisib and zandelisib are highly selective
[80]
and potent inhibitors of the PI3Kδ isoform . The high selectivity for the enzymatic target helps reducing
the immune-mediated AEs and the risk for infections, although an attentive monitoring is always required.

Recently, a matching-adjusted indirect comparison was conducted between tazemetostat and idelalisib,
duvelisib, copanlisib, and umbralisib. A systematic literature review allowed for the identification of six
published trials that were sufficiently comparable in terms of study design and eligibility criteria. Despite the
many limitations of such an analysis, after adjusting for baseline population differences, tazemetostat
emerged as the safest and most tolerable option with comparable efficacy outcomes .
[81]

BTK-inhibitors
The idea of treating FL by blocking the B-cell receptor (BCR) signaling pathway has also been pursued by
employing the inhibitors of the Bruton tyrosine kinase (BTK). Ibrutinib, however, has shown unsatisfactory
activity in phase II clinical trials, with the DAWN study achieving only 21% ORR and median PFS of five
months . Responses seem to be higher in CARD11WT patients and in those harboring mutations of
[82]
FOXO1 and KMT2D . Overall, ibrutinib does not represent an effective strategy for R/R FL. Nevertheless,
[83]
new generations of highly selective and potent BTK-inhibitors (BTKi) are undergoing evaluation in this
setting. Zanubrutinib, for instance, is an irreversible and orally bioavailable BTKi, which proved safe and
effective in combination with obinutuzumab in a phase I study . The trial enrolled a cohort of 36 patients
[84]
with FL, among whom the ORR was 72% [with 14 cytokine release syndrome (CRS)]; upper respiratory
tract infections (39%), contusion (28%), fatigue (25%), and cough (22%) were the most common AEs among
FL patients . A phase II study is currently ongoing comparing zanubrutinib plus obinutuzumab and
[84]
obinutuzumab monotherapy in R/R FL patients (NCT03332017). Furthermore, a third generation of BTKi
has recently been developed with the aim of overcoming the resistance that lymphoproliferative diseases can
put up against traditional (irreversible) BTKi. Pirtobrutinib is the first-in-class, orally available non-covalent
BTKi, and it is capable of blocking the enzyme even in the presence of epitope alterations such as the C481
[85]
mutation . The BRUIN phase I/II study enrolled 323 patients, including 12 FL patients; among the eight
FL patients who were evaluable for efficacy, ORR was 50% . Pirtobrutinib also displays a 98% selectivity for
[85]
BTK versus 370 other kinases, reducing the risk for off-target toxicities. The results of the BRUIN study
show that the drug is very well tolerated, and no dose-limiting toxicities were registered; the most common
AEs were fatigue, diarrhea, and contusion, while the most common Grade ≥ 3 AE was neutropenia .
[85]
Overall, both covalent and non-covalent BTKi show great results in the treatment of chronic lymphocytic
leukemia (CLL), Waldenstrom macroglobulinemia (WM), and mantle cell lymphoma (MCL), whereas their
[86]
role in FL remains to be clarified and their use is currently not recommended outside of clinical trials .
Venetoclax
Venetoclax is a BH3-mimetic small molecule that impairs the anti-apoptotic activity of BCL-2, thus
restoring apoptosis in lymphoma cells. The drug has largely entered the therapeutic armamentarium of CLL
and MCL, where it shows significant antitumor activity with a favorable safety profile both alone and in
combination with other agents [87-89] . Despite being characterized by the overexpression of the antiapoptotic
protein BCL-2, FL did not show the expected sensitivity to venetoclax in clinical trials. Among 29 patients
with FL enrolled in the phase I trial by Davids et al. the ORR was 38% with a CRR of 14%; median PFS was
11 months . Recent studies have begun to clarify the mechanisms by which PI3Kδ-inhibitors interfere with
[90]