Duvelisib: a new phosphoinositide-3-kinase inhibitor in chronic lymphocytic leukemia
Anna M Frustaci1, Alessandra Tedeschi1, Marina Deodato1, Giulia Zamprogna1, Roberto Cairoli1 & Marco Montillo*,1
1 Department of Hematology, Niguarda Cancer Center, ASST Grande Ospedale Metropolitano Niguarda, Piazza Ospedale Maggiore 3, Milano, Italy
*Author for correspondence: Tel.: +39 026 444 4074; Fax:+39 02 64443263; [email protected]
P110-γ and -δ act in lymphocytes chemotaxis, presenting distinct, nonredundant roles in B- and T-cell migration and adhesion to stromal cells. Moreover, phosphoinositide-3-kinase-γ inhibition contributes to regulate macrophage polarization inhibiting cancer growth. Duvelisib (IPI-145) is an oral first-in-class, dual phosphoinositide-3-kinase inhibitor targeting p110-δ/γ exerting its activity in preclinical studies across dif-ferent prognostic groups. In a large Phase III study, duvelisib showed superior progression-free survival and overall response rate compared with ofatumumab, thus leading to its approval for relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. Immune-related effects are the main rea-son for treatment suspension, thus affecting survival benefit. Nevertheless, the correct management of adverse events, eventually including dose modification, allows patients to remain on treatment. In conclu-sion, duvelisib represents a promising treatment in chronic lymphocytic leukemia and a salvage therapy after ibrutinib.
First draft submitted: 25 November 2018; Accepted for publication: 17 April 2019; Published online:
29 May 2019
Keywords: chronic lymphocytic leukemia • CLL • dual inhibition • duvelisib • novel agents • PI3K • SLL
Chronic lymphocytic leukemia (CLL) treatment and prognosis has been revolutionized during the past 5 years by the introduction of novel agents interfering on B-cell receptor (BCR) activation and subsequent downstream signaling that is crucial for maintenance and proliferation of leukemic cells.
The discovery of different kinases, including SYK, BTK and PI3K, mediating BCR signal has led to clinical development of BCR inhibitors in CLL and other hematologic malignancies [1].
Idelalisib is a potent, oral, selective small-molecule inhibitor of PI3Kδ [2]. Based on the favorable data coming from a large multicenter Phase III trial [3], idelalisib in combination with rituximab, was the first PI3Kδ inhibitor approved in 2014 for relapsed/refractory (R/R) CLL and treatment-naive patients with TP53 disruption (i.e., TP53 mutations and/or 17p13 deletion by FISH). Duvelisib is a first-in-class, oral, dual PI3K-δ/PI3K-γ inhibitor, recently approved for the treatment of relapsed or refractory CLL/small lymphocytic lymphoma (SLL) and relapsed or refractory follicular lymphoma [4,5]. Targeting of both PI3K-δ and -γ isoforms induces apoptosis in CLL samples in vitro, abrogates bone marrow stromal cell-mediated survival and inhibits BCR-mediated signaling and chemotaxis in response to C-X-C motif chemokine 12 (CXCL12) [6].
This review is focused on duvelisib mechanism of action, clinical experience and future application.
BCR signaling in CLL
The BCR signaling pathway is essential for B-lymphocyte differentiation, proliferation, survival and apoptosis. Both, a ‘tonic’ antigen independent and an antigen-dependent activation can trigger the generation of BCR signal. BCR surface immunoglobulins mediate antigen binding that triggers the phosphorylation of the immunoreceptor tyrosine-based activation mofits, which then act as docking sites to activate SYK. SYK activation leads to BCR signal transduction, through the B-cell linker proteins and the downstream signaling BTK and phospholipase C-γ2. Moreover, the LYN tyrosine kinase-dependent phosphorylation of the cytoplasmatic CD19 domain recruits PI3Ks
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BCR CD19
LYN PIP2 PIP3 Cytoplasm
SYK PI3K Akt
CD79 A/B
mTOR
BTK
PLC 2 NK- B
Cell survival Nucleus
Figure 1. B-cell receptor signal cascade. The B-cell receptor is composed by a membrane-bound antibody embedded
in the phospholipid bilayer that recognizes antigens, and a signal-transduction moiety disulfide-linked heterodimer
(CD79). Binding of antigen to the membrane-associated immunoglobulin triggers activation of the kinases SYK, LYN
and BTK, with subsequent propagation through PI3K/AKT, PLC-γ2 and NF-κB pathways, resulting in B-cell activation
and proliferation.
BCR: B-cell receptor.
to the membrane. PI3K and BTK activation induces several downstream kinases such as protein kinase B (Akt), mammalian target of rapamycin and mitogen-activated protein kinase leading to B-cells apoptosis, transcription, proliferation and migration [7–9]. The hyperactivation of antigen-dependent BCR signaling and nuclear factor (NF)-κB pathways sustains CLL pathological processes (Figure 1).
Notably, CLL-BCRs present differential degrees of somatic mutations, which correlate with patients clinical outcome. Surface IgM and IgD immunoglobulins are expressed by most of leukemic cells. Notably, those cells expressing elevated levels of CD38, ZAP70 and presenting unmutated immunoglobulin heavy chain variable region (IGHV) status are more sensible to IgM stimulation. On the contrary, CLL cells with mutated IGHV generally show constitutive phosphorylation of signaling proteins and reduced responses to BCR stimulation (‘anergy’). Moreover, while IGHV-mutated CLL-BCRs recognize a limited set of antigens, unmutated CLL-BCRs recognize a wide range of antigens, autoantigens and other environment antigens (Figure 2) [10].
Phosphoinositide-3 kinase
The PI3K family is categorized into three classes based on substrate preference and sequence homology. Class I PI3K, the most commonly involved in human neoplasia, is further divided into two subgroups, class IA and class IB [11,12]. Class IA includes three catalytic subunits (p110-α, β and δ), while the last catalytic subunit p110-γ belongs to Class IB (Figure 3). PI3K-γ has two unique adaptor subunits p84 and p101, distinct from the p85 adaptor used by PI3K-δ [13].
The link between p85 or p101/84 with the catalytic domains results in the conversion of phosphatidylinositol (4,5)-biphosphate (PIP)2 to phosphatidylinositol (3,4,5)-trisphosphate (PIP3). This process is reversibly regulated by a phosphatase (PTEN). PI3K activation by receptor ligation induces relocalization and activation of AKT, promoting different downstream mechanisms that include inhibition of proapoptotic Bcl-2 family members, regu-lation of the NF-kB transcription factor, inhibition of p53-mediated apoptosis and stimulation of the mammalian target of rapamycin (Figure 4) [14].
PI3K-α and -β isoforms are responsible for cellular proliferation and insulin signaling, respectively. Importantly, the PI3K p110-α and -β isoforms are expressed ubiquitously, whereas the PI3K p110-δ and -γ isoforms are
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Mutated CLL Unmutated CLL
Antigen CD19 c38 Antigen
LYN P P SYK PI3K P LYN P P PI3K P
P P SYK
CD79 A/B CD79 A/B BTK
BTK ZAP70
P
P P
Signaling Signaling
Figure 2. Mutated and unmutated signaling pathway. Mutated CLL cells express constitutive signaling proteins
phosphorylation and reduced signaling response activation after B-cell receptor triggering by antigens. Unmutated
CLL show BCRs specific for autoantigens and are generally highly sensible to antigen stimulation similarly to those
expressing high levels of CD38 and ZAP70.
CLL: Chronic lymphocytic leukemia.
Regulatory subunit
(p85 or p84/p101)
Catalitic subunit (p110)
PI3K class IA PI3K class IB
PI3Kα PI3Kβ PI3Kδ PI3Kγ
Figure 3. Phosphoinositide-3-kinase family.
preferentially expressed in leukocytes where they present distinct and non-overlapping roles as regard immune cell function [15].
PI3K-δ inhibition decreases immunosuppressive regulatory T cells (Tregs) in the tumor microenvironment [16,17], whereas PI3K-γ inhibition decreases immunosuppressive myeloid cells [18,19].
The value of PI3K-γ/δ inhibition in CLL
PI3K-δ contributes approximately 50% of the total PI3K activity in lymphocytes and its role is crucial for B cells. Mice with inactivating PI3K-δ mutations have reduced numbers of B1 and marginal zone B cells, low levels of immunoglobulins, poor responses to immunization and defective BCR and CD40 signaling and can develop inflammatory bowel disease [20].
In contrast, the contributions of PI3K-γ have been mainly defined in T cells and myeloid cells [21–23].
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Grow factor
Receptor TK
PIP2
PTEN
PI3K PIP3
P P
AKT
PDK1 mTORC2
Figure 4.
mTORC1
Phosphoinositide-3-kinase
pathway.
The process of immune surveillance depends on chemokine-directed migration of lymphocytes into and within lymphoid organs. In CLL, microenvironment protects malignant cells allowing their migration to favorable niches in response to chemotactic factors, such as the chemokine SDF1-α/CXCL12 [24]. Through cell–cell contact and soluble factors in fact, the interaction with resident stromal cells provides survival and proliferative advantage to leukemic cells [25,26].
Studies in mice lacking either p110-δ or p110-γ reported that p110-γ-deficient T cells but not B cells showed reduced chemotactic responses to the lymphoid chemokines, CCL19, CCL21 and CXCL12. On the contrary, B cells deficient in p110-δ showed diminished chemotactic responses, especially to CXCL13, diminished homing to Peyer’s patches and splenic white pulp cords [6,27,28]. P110-γ acts in T-cell chemotaxis activating chemokine receptors via p101-dependent binding to Gβ/γ subunits [29,30]. PI3K-γ signals are enhanced in leukemic cells in response to CD40L/IL-4 stimulation and both p110-γ and p101 are more highly expressed in lymph node than peripheral blood [31]. Together, these data demonstrate the existence of distinct and nonoverlapping roles of p110-δ and p110-γ in lymphocyte function and immune cell trafficking.
In a study comparing ex vivo PI3K-γ, δ and dual γ/δ inhibition, PI3K-γ-selective knockdown impaired cell mi-gration to a similar extent as PI3K-δ-selective inhibition, while dual blockade showed a significantly greater negative effect on migration than PI3K-γ inhibition alone [31]. It is known that PI3K-mediated signaling is constitutively activated in CLL and patients with IGHV-unmutated status show significantly greater PI3K expression compared with those with IGHV-mutated CLL [32]. Notably, the reduced migration of CLL cell in PI3K-γ inhibition was demonstrated to be independent from IGHV mutational status and ZAP70 expression. Moreover, PI3K-γ inhi-bition reduced Akt phosphorylation and its downstream targets in CLL cells; noteworthy, a significantly greater inhibition was observed with PI3K-γ/δ inhibitor [31].
As previously mentioned, migration of normal human B lymphocytes seems to be only minimally affected by PI3K-γ. In mice, migration to chemokines in transwell assays is not affected in PI3K-γ-deficient B cells and homing to tissues is not altered when transferred to normal hosts [21,31].
PI3K-γ signal plays a role also in cell-mediated immunity. Macrophages control the switch between immune stimulation and suppression during inflammation and cancer. Kaneda et al. showed that selective inactivation of macrophage PI3K-γ stimulates and prolongs NF-κB activation and inhibits C/EBP-β activation, thus promoting an immunostimulatory transcriptional program that restores CD8+ T-cell activation and cytotoxicity. Notably, while PI3K-γ inhibition does not directly activate T cells, PI3K-δ inhibition suppresses T-cell activation in vitro and promotes tumor growth in vivo [33]. The regulation of macrophage polarization state could represent therapeutic targets for the control of immunosuppression in CLL.
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CD4+ T cell
Tumor associated
IL-4 myeloid cell
Malignant Cytokine
PI3K ,
B cell
PI3K ,
IL-4
CD40L receptor Cytokine
receptor
CXCR4 Signaling via
CD40R PI3K indip pathways
PI3K , Migration
PI3K , CXCL12
activation
inhibition CXCL4
and
PI3K , polarization
signals
CXCL12 CXCL5 inhibition
CXCL13
Stromal/nurse-like cell BCR
PI3K ,
inhibition
Figure 5. Phosphoinositide-3-kinase-δ and -γ inhibition. Malignant B cells receive growth and survival signals from BCR activation and
mesenchymal cells via PI3K-δ,γ pathways. This process is supported by T cells and myeloid cells within the tumor microenvironment with
signaling occurring via PI3K-dependent and -independent mechanisms. PI3K-δ inhibition reduces survival and proliferation of malignant B
cells. PI3K-γ inhibition blocks migration and/or polarization of T cells and myeloid cells and results in the loss of key support cells in the
microenvironment.
BCR: B-cell receptor.
Furthermore, data from preclinical studies demonstrated that PI3K-γ and PI3K-δ have unique, nonredundant functions in CLL cell migration and adhesion to stromal cells. Overall, these findings indicate that dual PI3K targeting may have a unique impact on CLL biology with potential therapeutic benefit (Figure 5).
Duvelisib: introduction of the drug
Duvelisib (IPI-145) is an oral first-in-class, dual PI3K inhibitor structurally similar to idelalisib, but targeting both p110-δ and p110-γ. Its mechanism of action consists of binding, in a competitive and reversible manner, p110 subunit to the ATP-binding pocket [34]. In preclinical studies, duvelisib demonstrated an effect on adaptive and innate immunity by inhibiting B- and T-cell proliferation and basophil activation and blocking neutrophil migra-tion, thus leading to a potential therapeutic effect in inflammatory and autoimmune disease [35,36]. Furthermore, the dual inhibition showed to reduce tumor and spleen myeloid-derived suppressor cells.
Ex vivo IPI-145 added to CLL cells, abrogated BCR and bone marrow stromal cell-mediated survival and inhibited proliferation and activation of AKT in leukemic cells. Furthermore, CLL cells cocultured with IPI-145 did not exhibit significant secretion levels of CCL3 and CCL4 in response to BCR activation and showed the inhibition of chemotaxis toward CXCL12. The effect of the drug was maintained in all prognostic subgroup samples including those with 11q or 17p deletion (11q-, 17p-), IGHV-unmutated status and previous CLL treatment [6].
In an ibrutinib-resistance model, duvelisib was able to antagonize BCR cross-linking-activated prosurvival signals in primary CLL cells and cause direct killing in primary CLL cells in a dose- and time-dependent manner, without generating direct cytotoxicity to normal B cells. Importantly, samples that were resistant to ibrutinib were still susceptible to killing from IPI-145 even though BTK exerts its effect both upstream and downstream of PI3K, suggesting PI3K may compensate after BTK/phospholipase C-g2 mutations/disruption [37]. PI3K-γ has a key role in the migration and activation of T cells and myeloid cells that provide survival and proliferative advantage to malignant CLL cells within the tumor microenvironment. Accordingly, duvelisib demonstrated its ability to hamper the survival benefits conferred to CLL cells by microenvironment overcoming signals from the PI3K/AKT/S6 pathway and promoting apoptosis in CLL even in presence of stromal microenvironment [6,38].
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Clinical studies
In a Phase I, open-label, dose-escalation and cohort expansion study, duvelisib was administered with a dosage ranging from 5 to 100 mg twice daily (BID), in 210 patients with advanced B-cells hematologic malignancies including CLL. Maximum tolerated was determined to be 75 mg BID [39].
O’Brien et al. recently reported safety and efficacy results of two CLL populations analyzed in the expansion cohort: 55 patients with R/R CLL/SLL, coming from the dose-escalation cohort who received duvelisib 25 or 75 mg BID and 18 treatment-naive patients treated with 25 mg BID. The previously treated group had a median age of 66 years and a median of four prior lines of therapy, including seven patients (13%) previously treated with ibrutinib or idelalisib. More than half presented TP53 aberrations (TP53 mutations and/or 17p deletion) and 86% unmutated IGHV status. Median duration of treatment was 24 weeks with no differences between the two dose cohorts.
Thirty-one (56.4%) patients showed a response, complete in one case. No differences were noted in the response rate with 25 or 75 mg. Median time to response was 1.87 months. Similar to other BCR inhibitors, duvelisib induced a nondose-dependent lymphocytosis regressing to baseline values around the fifth month. Responses did not differ among patients with high-risk prognostic features. Two of the seven patients previously treated with a BCR inhibitor obtained a partial remission (PR). Median duration of response (DOR) in responders was 21 months (23 months in patients with TP53 aberrations) and median progression-free survival (PFS) 15.7 months. Median overall survival was not reached.
Treatment-naive population had a median age of 74 years and, similarly to previously treated patients, IGHV-unmutated status and 17p deletion/TP53 mutation in 82 and 55% of cases, respectively. Overall response rate (ORR) was 83.3% and did not differ in 17p-/TP53-mutated or IGHV-unmutated patients. Median time to response was 3.7 months. Median DOR, PFS and OS were not reached [40].
As previously reported in the dose-escalation study phase [39], both in pretreated and treatment-naive patients, duvelisib showed an early, sustained, no-dose dependent inhibition of p-AKT and Ki-67 with a maximal inhibition at 25 mg.
Results from the Phase I study led to design the ‘DUO trial’, a Phase III, multicenter, randomized, open-label study of duvelisib 25 mg BID versus ofatumumab in patients with R/R CLL/SLL. Notably, prior therapy with BCR inhibitors represented exclusion criteria for study enrollment. Overall, 319 patients were included: 160 in the duvelisib and 159 in the ofatumumab arm with the same median age of 69 years. Nearly 70% and almost one-third of patients in both treatment groups showed unmutated IGHV mutational status and 17p- and/or TP53 mutations, respectively. Roughly, half of the patients in both groups presented with a bulky disease. Median number of prior therapies was 2, both for duvelisib and ofatumumab. After a median follow-up of 22.4 months, the study reached its primary end point, duvelisib being superior to ofatumumab in terms of PFS (median: 13.3 vs 9.9 months). This PFS benefit also applied to high-risk cytogenetic profiles and resulted significantly longer (17.6 months) as for Investigator response assessments. ORR was 73.8% with duvelisib versus 45.3% with ofatumumab; all but two cases obtained a partial response with the dual inhibitor. Lymph node reduction was particularly evident with duvelisib (85 vs 15.7% with ofatumumab). Median OS was not reached in either of the two arms [41].
In a univariate analysis high tumor burden, 17p deletion and 11q deletion did not seem to impact on duvelisib outcome, while at the multivariate examination patients with a negative trisomy 12 status showed better survival [42].
Noteworthy, in a subsequent study, patients progressing after ofatumumab were allowed to start treatment with duvelisib and this could explain the extended survival experienced also in those treated with ofatumumab [41].
The outcome of 90 patients following the crossover was reported as an abstract at the ASH 2018 meeting. At the time of the data cut, 73/90 patients (81%) discontinued duvelisib mainly (39/73) due to adverse events (AEs), while disease progression was recorded in 19 cases. Nearly half of the 90 patients had C Binet status, 23% carried TP53 aberrations and the majority received ≥3 lines of therapy before duvelisib. Despite ofatumumab having been fully administered in over 60% of cases, median PFS with duvelisib resulted significantly longer, 15 versus 9 months, with no differences in 17p-deleted cases. Response rate reached 77% and ORR superiority was even more evident compared with ofatumumab in patients with TP53 disruption (80 vs 15%) [43].
Overall, 45 patients received duvelisib for more than 2 years. Baseline disease characteristics were similar to those of patients interrupting treatment before 2 years. Median exposure to the dual inhibitor was 31 months and median PFS 37 months with an investigator-assessed ORR of nearly 90%, including 16% complete remission [44].
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Considering the low rate of complete remissions obtained with duvelisib as single agent, some trials are ongoing with the aim of testing efficacy and tolerability of duvelisib in combination with other compounds. In 32 previously untreated CLL, duvelisib was administered together with fludarabine, cyclophosphamide and rituximab at the dose of 25 mg BID except for six patients receiving 25 mg once/daily. Median age was 55 years. 8/32 patients (25%) had 11q deletion; 5/32 (15%) presented either 17p deletion or TP53 mutation; more than half had an unmutated IGHV status. Almost all patients obtained a response, partial in the great majority. Notably, 81% of cases, corresponding to 26 patients, resulted negative for bone marrow minimal residual disease. 2/32 patients progressed at a median follow-up of 21 months, one of them had 17p deletion and complex karyotype. One patient developed a Richter transformation after disease progression. Two cases of secondary malignancies were reported [45].
Safety
In the Phase 1 study, duvelisib showed an acceptable risk profile with the majority of patients presenting mild AEs. Different drug dosages did not impact on the incidence or severity of side effects in fact, in the two largest dose cohorts (25 and 75 mg BID), a similar rate of grade 3–4 AEs and AEs leading to discontinuation occurred. Grade 3–4 neutropenia was reported in 33 and 43% of cases (treatment-naive and R/R patients, respectively) but rarely led to duvelisib discontinuation. Consistent with previous observations with idelalisib, transaminase elevations and diarrhea resulted the most frequent nonhematologic AEs and the most common nonhematological grade ≥3 side effect. Transaminitis appeared early after drug initiation and was easily manageable with temporary interruption in four/six patients and further dose reduction in two of them. On the other hand, severe diarrhea/colitis appeared 6–9 months after starting duvelisib in 15% of patients, differently from the more common grade 1–2 intestinal toxicity appearing earlier. Noteworthy, compared with indolent lymphomas, in treatment-naive CLL population, diarrhea represented a common (78%) and, in some cases, severe event. Anyway, neither transaminitis nor diarrhea were reported, as grade 4. Similar to idelalisib, the risk of diarrhea/colitis or hepatologic toxicity was significantly higher in untreated patients compared with previously treated. Pneumonitis was reported in five (9.1%) patients with no relationship to the dose administered. Infections were common in this study (exceeding 70% incidence for all grades) as expected for a pretreated population. Respectively, three and two cases of Pneumocystis carinii and cytomegalovirus reactivation occurred. Infections were fatal in five cases of R/R CLL. AEs represented the main reason for treatment discontinuation in 20/55 patients and in two cases considered related to duvelisib, led to death [40].
In the Phase III trial, specifically addressed to previously treated CLL, median time of patient exposure to duvelisib exceeded 1 year. Neutropenia (33%) and diarrhea (51%) were confirmed as the most frequent hematologic and nonhematologic AE, respectively. Colitis was reported in further 13% of cases. Median time to first event of diarrhea or colitis was approximately 4 and 7 months, respectively, and both the events occurred more frequently with the PI3K inhibitor than with ofatumumab. Notably, almost 90% of patients in the duvelisib arm experienced a ≥3 grade AE with duvelisib (48% in the ofatumumab arm).
Severe-immune toxicity appeared under duvelisib treatment and was managed with temporary drug interruption and steroids. More people developed an infection with duvelisib compared with ofatumumab (69 vs 43%). Pneumocystis jirovecii pneumonia occurred in three patients treated with duvelisib, none of them taking the prophylaxis as required by protocol. Overall, 19 fatal AEs occurred on the duvelisib arm, four of which were assessed by investigators as related to study drug [41].
At a long-term observation, the great majority of patients still on duvelisib after 2 years experienced a grade ≥3 AE. Although most common severe AEs decreased over time, incidence of diarrhea and colitis did not reduce with an extended follow-up. Notably, duvelisib dose reduction due to intestinal toxicity management allowed patients to remain on treatment [44].
Regarding combination treatment, duvelisib in association with fludarabine, cyclophosphamide and rituximab led to high frequency of neutropenia and thrombocytopenia, including grade 3–4 (34 and 47%, respectively). Most common nonhematologic AEs were nausea, fatigue, fever, diarrhea, transaminitis, anorexia and vomiting; most of those were grade 1–2. Nevertheless, about a third of patients required duvelisib dose reduction and 31% discontinued chemotherapy early due to toxicity [45].
Discussion
It is well known that phosphatidylinositol-3-kinase pathway plays a main role in the regulation of cell proliferation and survival. The inhibition of PI3K isoform δ-dependent signaling results in direct antitumor activity, regulation
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of tumor microenvironment, enhancement of apoptosis and proliferation decrease. The γ-PI3k isoform is expressed in both leukemic B cells and tumor microenvironment, where it contributes to regulation of T cell and innate immune cell function [6].
In vitro dual inhibition of γ- and δ-PI3K isoforms showed a stronger effect on PI3K/Akt pathway activity, chemokine-dependent migration and adhesion than either selective PI3K-δ or PI3K-γ inhibitors [31].
In the light of promising preclinical data, duvelisib clinical development has continued until the recent approval for R/R CLL/SLL patients, based on a superior PFS and ORR, compared with ofatumumab, in the Phase III DUO trial [41].
Ofatumumab was also employed as standard treatment arm in the International Phase III RESONATE trial and compared with ibrutinib. With up to 4 years of follow-up, PFS was significantly longer in patients receiving ibrutinib compared with ofatumumab (not reached vs 8.1 month). Notably, a high-risk population was enrolled in this study. About half of the patients had received ≥3 previous therapies; a third had 17p and a third 11q deletion; overall 79/195 (41%) patients carried TP53 mutation at molecular analysis and in half of the cases this was coexistent with 17p- [46,47].
In another Phase III trial, PI3K-δ inhibitor idelalisib administered in combination with rituximab was compared with rituximab as single-agent. The study was prematurely terminated due to the superiority of idelalisib arm in terms of response rate and PFS. During the second interim analysis at the end of the blinded phase, the median PFS was still not reached in the idelalisib-R group with a 1-year PFS of 66%. Notably, this study was specifically addressed to a population with coexisting conditions precluding chemoimmunotherapy and refractory disease. Also in this trial, patients were heavily pretreated with a median of three previous lines and TP53 aberrations in about 40% of cases [3,48]. Although indirect comparison would suggest a greater efficacy of ibrutinib in respect to PI3K inhibitors, prospective trials comparing different BCR inhibitors are needed.
Similar to other BCR inhibitors, complete responses are rare with duvelisib, so its association to other agents could be promising.
In vitro duvelisib presented a meaningful synergistic activity in lymphoma cell lines when associated with dexamethasone, ibrutinib, everolimus and venetoclax [49]. In another study, venetoclax tested in ex vivo cultured CLL cells obtained from patients on duvelisib, induced greater apoptosis compared with pretreatment CLL cells from the same patients. Apoptosis was potentiated also in vitro with this combination, even in CLL cells cultured under conditions that simulate the tumor microenvironment [50]. Furthermore, given the demonstrated reduction of Tregs [16,17], and immunosuppressive myeloid cells in the tumor microenvironment [18,19], association with immune checkpoint or costimulatory antibodies is promising and potent synergy was shown in a murine model when duvelisib was combined with anti-PD-1 [51]. Based on these evidences, trials assessing the efficacy and tolerability of duvelisib in combination with other agents are warranted.
Immune-related AEs represent the main concern with PI3K inhibitors. Treg cells in fact contribute to the maintenance of peripheral tolerance to both self-antigens and the intestinal flora and contribute to the homeostatic control of T-cell numbers, allograft tolerance and the modulation of immune responses against pathogens and neoplasms. In addition, mice with T cells expressing a kinase-inactive knock-in form of p110-δ develop sponta-neous colitis [52]. As previously mentioned, PI3K-δ inhibition decreases immunosuppressive Tregs in the tumor microenvironment [16,17] and plays a critical role in the differentiation of peripheral T-helper cells into the Th1 and Th2 lineages, thus leading to immune-related AEs [53]. Despite promising antitumor activity of both approved PI3K inhibitors, high rate of treatment interruption due to toxicity suggests the need for more specific agents.
Certainly, longer observation is needed to compare the incidence of toxicity between idelalisib and duvelisib. In fact, one could speculate that dual inhibition may partly mitigate immune-related toxicities by impairing T-cell migration into sites of inflammation such as colon, lung or liver. Moreover, even if the rate of AEs was almost similar between duvelisib and idelalisib, the latter, at the time of the Phase III trial, had a shorter follow-up and this could affect the real incidence of immune-mediate long-term side effect [48].
Safety and efficacy results from idelalisib compassionate French Program were reported in 2018. In 41 CLL patients (39 R/R), idelalisib was administered for a median of nearly 6 months. Notably, AEs of special interest (defined as diarrhea/colitis, pneumonitis, liver enzyme elevation, neutropenia, infection and rash) were reported in over 90% of patients and led to permanent idelalisib discontinuation in three cases [54]. Furthermore, a large European and Australian cohort was retrospectively analyzed and showed in 14% of patients the occurrence of grade ≥3 events at a median follow-up of 133 days [55].
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On the other hand, other PI3K-targeted agents are emerging. Umbralisib is a structurally distinct next-generation PI3K-δ-selective inhibitor, which also inhibits casein kinase-1ε (CK-1ε). The favorable safety profile of umbralisib has been observed across several trials [56]. Based on preclinical data, CK-1ε inhibition might be responsible for increasing T-cell activity, thus leading to immune suppression and thereby lowering the risk of immune-mediated toxicities [57]. In a Phase I dose escalation study, patients with R/R lymphomas and CLL experienced a lower rate of grade 3–4 diarrhea and colitis than previous PI3K inhibitors and no pneumonitis, although in 8% serious AEs potentially related to treatment occurred. Furthermore, in 20 CLL patients ORR was 85% with 13.4 months median DOR [58].
Recently, a Phase I-1b trial evaluated the safety and efficacy of umbralisib associated to ibrutinib in 21 R/R CLL [59]. Notably, while grade 1–2 toxicities occurred more frequently with the combination than with ibrutinib or duvelisib as single agents, with a median follow-up of 26 months, only one case of transient grade 3 transaminitis, one grade 1 pneumonitis and two treatment-related diarrhea were reported.
In 23 CLL/SLL (treatment naive in four cases), umbralisib was administered in combination with ublituximab and ibrutinib [60]. Immune-related AEs were infrequent and included grade ≥3 diarrhea (9% of patients), grade 2 pneumonitis (two cases) and grade 3 transaminitis in one patient. No grade 4 diarrhea were recorded. Median follow-up in the safety population was 15 months.
Even if these data should be carefully interpreted as not coming from direct comparison, umbralisib seems to present a favorable safety profile compared with idelalisib or duvelisib also considering that patients’ follow-up was more than 24 months in one of the studies and therefore, covered the onset-time usually needed for the emergence of immune-related AE with PI3K inhibitors. Nevertheless, previous experience with idelalisib could have influenced clinicians’ behavior leading to early drug interruption/dose reduction or start of steroid treatment. On the other hand, mandatory prophylaxis probably limited the incidence of severe infections.
Compared with idelalisib or duvelisib, diarrhea was also less frequent and intense with copanlisib, a pan-class I PI3K inhibitor with predominant activity against the PI3K-α and PI3K-d isoforms. Noteworthy, no episodes of colitis were reported in the Phase II study. Regarding copanlisib, the different spectrum of toxicity compared with duvelisib and idelalisib may reflect the intermittent intravenous versus continuous oral administration [61,62]. Notably, while clinical development of copanlisib is at present interrupted in CLL, the drug is currently approved for patients with follicular lymphoma who have received at least two prior therapies.
Conclusion
Although considerable progress has been made in CLL treatment, the disease will eventually relapse, especially in patients with high-risk biologic features. In addition, considering the ever-increasing availability of target therapies, more patients even with multiple co-morbidity will have access to specific treatments that will need to be differentiated accordingly to biological and clinical characteristics. In view of this, the approval of new agents is welcomed and duvelisib has demonstrated to be a promising treatment able to expand CLL therapeutic armamentarium. Although the toxicity profile seems favorable compared with idelalisib, immune-related AEs represent the main reason for duvelisib treatment interruption, thus affecting survival benefit.
As novel agents tend to improve quality of response over time, it would be a desirable goal that patients might be able to continue the drug for a prolonged period. Therefore, correct management of AEs with early treatment suspension and steroids administration in case of severe toxicity could ameliorate responses and survival.
At present, during duvelisib treatment, it would be advisable for clinicians to follow the guidelines for the management of AEs with idelalisib, to administer Pneumocystis jirovecii pneumonia prophylaxis to the patients and to perform regular laboratory screening for cytomegalovirus infection [63].
Future perspective
PI3K inhibitors clinical development was consistently limited by the emergence of late-onset severe AEs, nevertheless duvelisib safety and efficacy profile needs to be better defined with longer observation.
At present, duvelisib has received the US FDA approval for CLL as third-line treatment, so probably following chemoimmunotherapy and at least one inhibitor. Mechanisms of resistance have not been described so far with either idelalisib or duvelisib and there are no prospective studies addressing the best sequencing of BCR/BCl2 inhibitors in case of CLL progression. Nevertheless, as in preclinical studies, cell lines resistant to ibrutinib showed to be still susceptible to duvelisib, this agent should be considered after ibrutinib failure and in patients not eligible for BTK inhibitors.
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Finally, at present no studies have demonstrated a superior outcome of ibrutinib combined with other agents compared with ibrutinib as single agent. This might not be true with PI3K inhibitors. In vitro studies have demonstrated a meaningful synergistic activity of duvelisib with other agents. In particular, the association with Bcl-2 inhibitors or monoclonal antibodies (MoAbs), through the retention of CLL cells in the blood, reduction of antiapoptotic signaling and providing easy access for MoAbs, seems promising. Therefore, clinical trials combining duvelisib with venetoclax or anti-CD20 MoAbs would be of great interest.
Executive summary
Duvelisib (IPI-145)
• Phosphoinositide-3-kinase (PI3K) δ and γ are two isoforms belonging to the PI3K family and preferentially expressed in leukocytes where they present distinct and nonoverlapping roles as regard immune cell function.
• Duvelisib is a first-in-class, oral, dual PI3K δ/γ inhibitor, recently approved for the treatment of relapsed or refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and relapsed or refractory follicular lymphoma. In CLL samples in vitro, dual inhibition induces apoptosis, abrogates bone marrow stromal cell-mediated survival and inhibits B-cell receptor-mediated signaling and chemotaxis in response to CXCL12.
Clinical efficacy of duvelisib in CLL/SLL
• In a Phase I study, duvelisib was administered at different dosages to patients with advanced B-cells hematologic malignancies including CLL. In CLL patients, duvelisib provided a significant survival advantage that was even more evident in the setting of previously untreated.
• The ‘DUO trial’ is a Phase III, multicenter, randomized, open-label study comparing duvelisib versus ofatumumab in 319 patients with R/R CLL/SLL. The study reached its primary end point, as duvelisib demonstrated to be superior to ofatumumab in terms of progression-free survival in all patients including high-risk cytogenetic profiles.
Safety & tolerability of duvelisib
• Consistent with previous observations with idelalisib, transaminase elevations and diarrhea resulted the most frequent nonhematologic adverse events and the most common nonhematological grade ≥3 side effect. Nevertheless, severe-immune toxicity was manageable with temporary drug interruption and steroids.
Conclusion
• Considering that complete remissions are rare and that in vitro duvelisib presented a meaningful synergistic with different agents, its use in association could be promising.
• Despite duvelisib’s considerable antitumor activity, some concerns arise regarding immune-related toxicity, suggesting the need for more specific agents. Others PI3Ks are currently under development.
Financial & competing interests disclosure
M Montillo received honoraria from Verastem, Abbvie, Gilead, Janssen, AstraZeneca and Roche. A Tedeschi received honoraria from
Janssen, Abbvie, Beigene and Sunesis. The authors have no other relevant affiliations or financial involvement with any organization
or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from
those disclosed.
No writing assistance was utilized in the production of this manuscript.
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Papers of special note have been highlighted as: • of interest; •• of considerable interest
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