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D. Qualls and G. Salles
responses, while rare, appear to be durable, and idelalisib has been shown to have a similar efficacy in patients who experienced early progression after first-line therapy.45,50 Copanlisib, a pan-PI3K inhibitor with specificity for the a and d isoforms, had similar activity in patients who had received at least two lines of therapy but requires weekly intravenous infusions for 3 or 4 weeks.49 Duvelisib is a d- and g-specific PI3K inhibitor and umbralisib is a d- and casein kinase-1-specific inhibitor. With the limitation of cross-trial comparisons and a possible learning curve dur- ing the development of the different PI3K inhibitors, umbralisib appears to have a better tolerability than that of idelalisib or duvelisib.48
There are major limitations regarding PI3K inhibitor monotherapy, including the limited duration of response with a median PFS of approximately 1 year and toxicities with chronic therapy. Class toxicities, including diar- rhea/colitis, transaminase elevations, rash, neutropenia, and rarely pneumonitis, along with infectious complica- tions, limit the utility of these agents. Due to the a iso- form specificity of copanlisib, toxicities including hyper- tension and hyperglycemia are unique to copanlisib, and while transient, represent a potential limitation to its use in certain populations.
Other PI3K inhibitors are in development and toxicity profiles may improve with changes in PI3K specificity and dosing regimens.51 Currently approved oral PI3K inhibitors are administered on a daily or twice-daily basis throughout treatment. Zandelisib and parsaclisib, d-spe- cific PI3K inhibitors, are being evaluated using unique dosing schedules intended to mitigate toxicity. Zandelisib was administered on days 1-7 of each 28-day cycle start- ing in cycle 2 in a phase Ib study.52 A phase II study of parsaclisib is evaluating both daily dosing and weekly dosing after an initial 8-week daily dosing period.51
The use of combination therapies may offer the greatest opportunity to leverage the efficacy of PI3K inhibitors while addressing the limited duration of responses. A ran- domized phase III trial, CHRONOS-3, evaluated rituximab with or without copanlisib in relapsed indolent non- Hodgkin lymphoma (60% FL), and demonstrated a PFS benefit from copanlisib with rituximab versus placebo plus rituximab.53 The relatively modest prolongation in response duration (20.4 vs. 17.3 months) for patients with FL should be weighed with the constraints of frequent infusions. Further areas of exploration include the combi- nation of other targeted therapies such as BCL2 and mTOR inhibitors. However, caution is still required, as several studies evaluating combinations, including idelalisib plus entospletinib, idelalisib with lenalidomide and rituximab, and dactolisib with abiraterone or everolimus have result- ed in unacceptable toxicity profiles. There is also potential for synergy with immunotherapies via T regulatory cell inhibition, but caution should be employed, as PI3K inhibitor-associated hepatotoxicity and colitis are thought to be immune-mediated and may worsen with immune- activating therapies such as checkpoint inhibitors.
A challenging path for Bruton tyrosine kinase inhibitors
FL cells express functional B-cell receptors, and depend on downstream signaling pathways for survival. This provided a rationale to investigate the activity of Bruton tyrosine kinase (BTK) inhibitors in patients. However, in a pivotal single-agent phase II study evaluating 110
patients with double-refractory disease, the overall response rate observed with ibrutinib was only 21%, with a complete response rate of 11%.54 While the dura- tion of response was 19 months, the median PFS was only 5 months (Table 1). These disappointing results might be explained by the biological heterogeneity of FL, the presence of mutations in BTK, or bystander effects of the drug on the microenvironment.55 A large randomized study (NCT01974440) combining ibrutinib with standard immunochemotherapy regimens has completed accrual, and results are anticipated shortly. Other combinations with ibrutinib are being evaluated and other BTK inhibitors (acalabrutinib, zanubrutinib) are also being tested, including a randomized study of obinutuzumab with or without zanubrutinib (NCT03332017).56,57 It is hoped that these studies will clarify the potential role of BTK inhibitors in patients with FL.
Inhibitors of the mTOR pathway: a missed opportunity?
It is also noteworthy that the mTOR pathway is dys- regulated in a substantial proportion of cases of FL, partic- ularly those with mutations activating RRAGC, ATP6V1B2 and ATP6AP1 and inactivating the upstream regulator SESTRIN1. The oral mTORC1 inhibitor everolimus was found to be active with an overall response rate of 61% (and a median response duration of 11.5 months) (Table 1).58 Temsirolimus, which requires intravenous administration, achieved overall and com- plete response rates of 54% and 26%, respectively, and the median PFS was 13 months.59 Of note, these clinical results were observed prior to our knowledge of the molecular alterations involving this pathway, and it would be interesting to evaluate whether their presence is associated with higher efficacy of mTOR inhibitors.
The unexpected results of BCL2 inhibitors
With persistent BCL2 expression linked to the hallmark t(14:18) translocation, one would expect that BCL2 inhibitors would demonstrate activity in FL. In the initial phase I study, response to single-agent venetoclax was observed in 38% of 29 patients (with 17% reaching a complete response), and the median PFS and duration of response were 11 and 27 months, respectively (Table 1).60 Based on these preliminary results, venetoclax was com- bined with rituximab (single-arm study) or with B-R (ran- domized phase II study) to gauge its clinical value. Results demonstrated a lack of significant benefit from the addi- tion of venetoclax to B-R (while toxicity was significantly increased) and only modest benefit when venetoclax was added to rituximab.61 Several hypotheses for this limited activity have been raised, including: (i) the possibility that BCL2-deregulated expression is critical in early steps of the development of FL, but that tumor cells subsequently acquire other genetic alterations and no longer depend on BCL2 for their survival; (ii) the role of alternative actors of the apoptotic machinery (BCLX-L) in protecting these cells from dying; and (iii) mutations in the BCL2 gene that can impair venetoclax binding.62
Epigenetic therapies
Mutations in genes involved in chromatin organization appear as early founding events in germinal center B-cell lymphomagenesis. FL relies on epigenetic dysregulation to allow maintenance of a germinal center phenotype, thereby facilitating cell survival and proliferation.
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haematologica | 2022; 107(1)