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PI3K Inhibitors: Efficacy in Hematologic Malignancies and Management of Treatment-Related Adverse Events

Faculty Perspectives: PI3K Inhibitors: Efficacy in Hematologic Malignancies and Management of Treatment-Related Adverse Events - TON

Lymphomas are a heterogeneous group of malignancies that are associated with substantial morbidity and mortality. Although standard chemoimmunotherapy regimens lead to durable remissions in a substantial proportion of patients, many individuals will relapse and develop refractory disease. Therefore, a clear need exists for the development of novel therapies that are designed to treat relapsed/refractory B-cell malignancies.1,2

One recently identified therapeutic target in lymphoma is the phosphoinositide 3-kinase (PI3K) pathway. PI3Ks are highly conserved intracellular lipid kinases that mediate B-cell receptor signaling, thus regulating proliferation, growth, apoptosis, and cytoskeletal rearrangement.3 The PI3K pathway is often constitutively activated in many B-cell malignancies, with overexpression of certain PI3K isoforms in vitro known to be associated with oncogenic transformation.3,4

Several PI3K inhibitors have recently been approved for use in a variety of lymphomas, including idelalisib,5 copanlisib,6 and duvelisib,7 all of which are discussed in greater detail in this article. These PI3K inhibitors have various indications, routes of administration, and selectivities for the different PI3K isoforms.5-7 Although PI3Ks have been associated with durable responses and improvements in patient survival rates, concerns remain regarding the risk for severe and fatal adverse events linked to this class of drugs, many of which are not typical of chemoimmunotherapeutic regimens, rendering them challenging for oncologists to manage. Some of the adverse events appear to be associated with the normal functions of PI3Ks in the body (eg, hyperglycemia, neutropenia), whereas other adverse events have poorly characterized mechanisms (eg, cutaneous reactions, diarrhea, hepatotoxicity). A thorough understanding of the potential toxicities and optimal management strategies for treatment-emergent adverse events associated with PI3K inhibitors is critical for healthcare providers, including oncology nurses and pharmacists, who may encounter these events with increasing regularity as approved agents are used with more frequency and investigational agents receive approval.8,9

Mechanism of Action of Novel PI3K Inhibitors

Role of PI3K in Growth and Development of Hematologic Malignancies

The PI3K pathway is often activated in lymphomas through somatic alterations, including PIK3CA gene amplification or duplication, overexpression of p110 subunits, or inactivation of PTEN.10,11 The increased activation of PI3Ks in lymphomas leads to a higher level of Akt phosphorylation. AKT signaling (as a result of higher levels of Akt phosphorylation) and downstream pathways are involved in normal and malignant B-cell biology through regulation of B-cell proliferation, differentiation, and survival.10 The tumor suppressor FOXO3 is repressed by PI3K signaling in mantle-cell lymphoma (MCL) cell lines and primary cells. Studies have shown that inhibition of the PI3K signaling pathway in MCL alters the localization of FOXO3, resulting in decreased cell proliferation and viability. The mammalian target of rapamycin (mTOR) is another downstream target of PI3K-AKT signaling, with the PI3K-mediated upregulation of mTOR resulting in nuclear factor κB (NFκB)-dependent growth and survival.10 The role played by PI3K in cancer cell proliferation and survival is illustrated in the Figure.12

Figure

Dual Inhibition of PI3K Isoforms

The PI3K family has been categorized into 3 classes, based on substrate preference and sequence homology.3 Class I PI3Ks are the most widely recognized as playing a role in oncogenesis. PI3Kα and PI3Kβ are expressed ubiquitously in tissues, whereas PI3Kδ and PI3Kγ are expressed primarily in lymphoid tissues.3,4 Therefore, by targeting the δ and γ isoforms, PI3K signaling can be selectively blocked in lymphocytes, with fewer effects on other tissues and organs.13

Evidence suggests that dual inhibition of both the δ and γ isoforms may improve efficacy compared with inhibition of only 1 of the 2 isoforms. PI3Kδ inhibition can impair lymphocyte function by reducing proliferation and survival of malignant B-cells. PI3Kγ inhibition, in contrast, decreases the differentiation and migration of cells that are supportive to the tumor microenvironment, such as T-cells and macrophages.13-15

The role of PI3K inhibitors in disrupting the tumor microenvironment has only recently been elucidated. PI3Kδ inhibition has been shown to disrupt the interactions between the cancer cell and its protective stroma, leading to a release of malignant cells into the circulation. Once the malignant cells have left the tumor microenvironment, they no longer receive protective survival signals and are thus more susceptible to programmed cell death. Furthermore, PI3Kγ inhibition has been shown to reduce the recruitment of myeloid cells to tumor microenvironments, leading to a reduced supply of tumor-promoting cytokines and growth factors.16

Clinical Trials of PI3K Inhibitors in Hematologic Malignancies

Idelalisib

The oral PI3Kδ inhibitor idelalisib was the first PI3K inhibitor approved for use by the US Food and Drug Administration (FDA).8,17 Idelalisib was investigated in an open-label, phase 2 study in 125 patients with indolent non-Hodgkin lymphoma (NHL), including follicular lymphoma (FL), lymphoplasmacytic lymphoma, marginal-zone lymphoma (MZL), and small lymphocytic lymphoma (SLL).17 Participants either had not responded to chemoimmunotherapy or had experienced a relapse within 6 months of treatment. Idelalisib was associated with a response rate of 57%, with 6% of patients meeting the criteria for complete response. The median duration of response (DoR) with idelalisib was 12.5 months, and the median progression-free survival (PFS) was 11 months. Grade 3 and 4 adverse events included neutropenia, transaminitis, diarrhea, and pneumonia.17

In patients with relapsed chronic lymphocytic leukemia (CLL), the efficacy and safety of idelalisib were investigated in combination with rituximab in a phase 3 trial.18 Significant improvements in overall response rate (ORR) were reported with idelalisib plus rituximab compared with rituximab alone (81% vs 13%, respectively; P <.001).18 Idelalisib plus rituximab was also associated with a significantly higher rate of overall survival at 12 months versus rituximab alone (92% vs 80%, respectively; P = .02).18 Overall, >90% of participants experienced ≥1 adverse events. The most common grade ≥3 adverse events were neutropenia, thrombocytopenia, transaminitis, anemia, diarrhea, and pneumonia.18 Idelalisib was also evaluated in combination with bendamustine and rituximab in patients with relapsed or refractory CLL. Interim results from this phase 3 trial suggested that idelalisib plus bendamustine and rituximab is superior to bendamustine and rituximab alone.19

Copanlisib

Copanlisib is an intravenous pan-class I PI3K inhibitor with activity against the α and δ isoforms. The agent has been FDA approved for use in patients with relapsed or refractory FL who have received ≥2 prior systemic therapies.8,20 In a phase 2 study of copanlisib in patients with relapsed or refractory indolent lymphoma, the ORR was 59%, with 12% of patients achieving a complete response.20 The median DoR was 22.6 months, and the median PFS was 11.2 months.20 The most frequent grade ≥3 treatment-emergent adverse events associated with copanlisib use included transient hyperglycemia, transient hypertension, neutropenia, and lung infection.20

When copanlisib was evaluated among patients with indolent lymphoma (n = 33) or aggressive lymphoma (n = 51), the ORR was 43.7% in the indolent cohort and 27.1% in the aggressive cohort.21 The median DoR was 390 days and 166 days in the indolent and aggressive cohorts, respectively, and the median PFS was 294 days and 70 days, respectively. Common grade ≥3 adverse events included hypertension, neutropenia, hyperglycemia, and diarrhea.21

Duvelisib

Duvelisib, which is also known as IPI-145, is an oral inhibitor of both PI3Kδ and PI3Kγ. In a phase 3 trial of patients with relapsed or refractory CLL/SLL, duvelisib significantly improved median PFS relative to ofatumumab (13.3 months vs 9.9 months, respectively; P <.0001) and was associated with a significantly higher ORR (74% vs 45%, respectively; P <.0001).22 These results remained significant regardless of the presence of high-risk chromosome 17p13.1 deletions. Furthermore, for patients who had received at least 2 prior lines of therapy, median PFS for duvelisib was 16.4 months compared with 9.1 months for those who received ofatumumab (P <.0001).7 Grade ≥3 adverse events included neutropenia, diarrhea, pneumonia, colitis, and anemia.22

In an open-label, phase 2 study, duvelisib was evaluated in 129 patients with relapsed or refractory indolent NHL (ie, FL, SLL, and MZL). Treatment with duvelisib was associated with a median DoR of 10 months and a median PFS of 9.5 months.23 The ORR was 47.3%, and all patients experienced partial responses. The most frequently reported common grade ≥3 adverse events included neutropenia, diarrhea, anemia, and thrombocytopenia.23

Duvelisib has also been evaluated in combination with rituximab or bendamustine/rituximab in patients with NHL or CLL. The adverse event profiles of these combinations were consistent with those of single agents. ORR was 71.8%, and median PFS was 13.7 months. Although median OS has not yet been reached, the 30-month OS rate was 62%.24

PI3K Inhibitor–Related Toxicities

Although PI3K inhibitors are typically well tolerated in clinically indicated settings, severe toxicities have been reported.8 Monitoring for the most common toxicities should be routine when administering PI3K inhibitors, and clinicians should also be familiar with the less common, but equally severe, adverse events that may occur.

Hematologic Toxicities

Given the role of the PI3K pathway in the proliferation of hematopoietic cell lines, it is not surprising that PI3K inhibition is associated with hematologic toxicities (Table 1).17,18,20-22,25,26 Various cytopenias are frequently associated with the use of the PI3K inhibitors, including neutropenia, thrombocytopenia, and anemia. Neutropenia appears to occur most frequently in 30% to 56% of patients, depending on the agent and the patient population. Severe neutropenia (grade >3) has been reported in 24% to 34% of patients. Anemia has been reported in 15% to 29% of patients, with 2% to 14% of patients experiencing severe anemia. Similarly, thrombocytopenia has been reported in 14% to 26% of patients, with 2% to 12% experiencing severe thrombocytopenia.17,18,20-23,26

Table 1

Nonhematologic Toxicities

Nonhematologic toxicities associated with PI3K inhibition include colitis, diarrhea, infections, aminotransferase elevations, and cutaneous reactions (Table 2).17,18,20-23,26 Because many of these adverse events are more common among immunocompetent patients and are associated with T-cell infiltrates, they are believed to be immune-mediated.16 Regulatory T-cells (Tregs), which prevent autoimmunity and maintain self-tolerance, are believed to play a key role in PI3K inhibitor– associated immune toxicity.8,16 In a phase 2 study of patients receiving idelalisib and ofatumumab, participants who experienced toxicity had a significantly lower median Treg percentage compared with those without any toxicity (2.3% vs 5.7%, respectively; P = .03).27

Table 2

Colitis and diarrhea are relatively common adverse events associated with PI3K inhibition, with a subset of patients (between 4% and 15%) experiencing severe colitis or diarrhea. 17,18,20-23 Diarrhea can be classified as early onset (median 1.9 months after therapy initiation) or late onset (median 7.1 months following therapy initiation).28 Early-onset diarrhea is typically less severe than late-onset diarrhea, which is usually watery, lacking mucus or blood, with no cramps, and not responsive to antidiarrheal therapy.28

In a case series of severe diarrhea associated with idelalisib, T-cell infiltrates were found on histologic examination of colonic biopsy specimens. The T-cell infiltrates included Tregs and activated T-cells, suggestive of an immune etiology for the gastrointestinal symptoms associated with PI3K inhibition.29,30 Recent evidence has suggested there may also be an infectious component in idelalisib-related colitis and diarrhea.31

Transaminitis is another common toxicity that is believed to be immune-related. Among patients with elevated transaminase levels, the levels of proinflammatory cytokines CCL-3 and CCL-4 were higher than those in patients without hepatotoxicity. Furthermore, lymphocytic infiltrates have been documented in liver biopsy specimens obtained from patients with idelalisib-associated transaminitis.27 Transaminitis has been reported in 23% to 47% of patients, with a smaller proportion of patients experiencing severe transaminitis (2%-13%).17,18,20-22

Another immune-related toxicity is the increased rate of infections associated with PI3K inhibition. Lung infections, such as Pneumocystis jirovecii pneumonia (PJP),5-7,23 can be serious and result in death; other opportunistic infections, including cytomegalovirus (CMV) infection or reactivation,5,7 have been documented as well. Lung infections have been reported in ≤21% of individuals receiving PI3K inhibitors, with ≤16% experiencing serious lung infections.17,18,20-22 Among patients treated with idelalisib or duvelisib, deaths have been associated with PJP, staphylococcal pneumonia, fungal sinusitis, and other infections or sepsis.17,22,32

Noninfectious autoimmune pneumonitis also has been reported in patients receiving PI3K inhibitors. Among patients who develop treatment-emergent pneumonitis, the levels of interferon (IFN)-γ, interleukin (IL)-6, IL-7, and IL-8 increase over time.33 These proinflammatory cytokines are associated with a T-helper 1–type immune response, and IFN-γ has been reported to be a central mediator of pneumonitis.33 Pneumonitis is a less common adverse event, with any grade occurring in ≤8% of patients and grade 3 reported in ≤3% of patients.17,18,20-22

Cutaneous reactions have been reported in some patients receiving PI3K inhibitors. Common cutaneous manifestations include exfoliative dermatitis, rashes, and toxic epidermal necrolysis.8 These reactions may be caused by inappropriate immune reactions to commensal bacteria on the skin.16 Between 3% and 13% of patients receiving PI3K inhibitors experience rash, with ≤2.4% reporting severe rash.17,18,20-22

Management of PI3K Inhibitor–Related Toxicities

Early identification and management of PI3K inhibitor– related toxicities are critical components of care for patients receiving these agents. Proactive monitoring for and management of toxicities can reduce the risk for death.8 Because many of the adverse events associated with the use of PI3K inhibitors are mediated by autoimmunity, steroids are a common and often successful approach to treatment.16 The various recommendations for PI3K inhibitor treatment modification, monitoring, and supportive care in response to toxicities are shown in Table 3.5,8,28,34

Table 3

Noninfectious Diarrhea or Colitis

Severe colitis or diarrhea can be debilitating for patients and should be managed accordingly. An expert panel of 10 hematologists and 1 gastroenterologist proposed several clinical management recommendations for the monitoring and management of idelalisib-related toxicity.28 These recommendations are likely more broadly applicable to other PI3K inhibitors, given the presumable class effect of diarrhea.28 Here, we review the expert panel’s recommendations and those indicated in the prescribing information for approved PI3K inhibitors.

According to the expert panel, diarrhea that develops during PI3K inhibitor therapy should lead to an evaluation for infection, dietary factors, and medications. Diagnostic testing should include stool culture, Clostridium difficile testing, and colonoscopy in some atypical or refractory cases.28 Uncomplicated grade 1 and some grade 2 diarrhea can usually be managed with antidiarrheal therapy, such as loperamide, and diet modification.28 Grade 2 diarrhea that does not respond to antidiarrheal agents within 24 hours should be treated in the same way as more severe diarrhea cases.28 It may not be necessary to discontinue PI3K inhibitor therapy if diarrhea is responsive to antidiarrheal agents, but nonresponsive diarrhea should warrant the withdrawal of treatment.5,7,28

For more severe cases of diarrhea, oral or intravenous enteric-acting steroid therapy (eg, budesonide) should be initiated and continued until complete resolution of symptoms. 28 PI3K inhibition should be withheld and the therapy resumed at a reduced dose once the diarrhea has resolved. For recurrent, severe diarrhea, treatment should be permanently discontinued.5,7,28

Infections

Because of the increased rates of opportunistic infections reported among patients receiving PI3K inhibitor therapy, monitoring for infections should be standard practice. Furthermore, all patients receiving PI3K inhibitors should receive prophylactic trimethoprim-sulfamethoxazole or, if an individual is unable to take sulfonamides, another antibiotic to prevent PJP during treatment and after cessation of therapy, until the CD4+ T-cell count is >200 cells/μL.7,8,34

If a PJP infection of any grade is suspected in a patient receiving PI3K inhibitors, treatment should be withheld until the patient has been evaluated.5-7 Treatment should be discontinued upon confirmation of PJP but may be resumed when the infection resolves with concomitant PJP prophylaxis.5-7

Patients should be tested monthly for CMV, and, for those with clinical CMV infection or end-organ damage, PI3K inhibitor therapy should be withheld, and antiviral treatment (eg, ganciclovir or valganciclovir) should be initiated. For some patients, prophylactic antiviral treatment to prevent CMV infection or reactivation may be appropriate.7,8

If any other grade ≥3 infections occur, treatment should be discontinued until the infection has resolved. Upon resolution of the infection, treatment may be resumed at the same or a lower dose.5-7

Noninfectious Pneumonitis

Any patient who presents with pulmonary symptoms (eg, cough or dyspnea) should be examined for pneumonitis. Since multiple etiologies of pneumonitis exist, the presence of infectious agents, including PJP, should be ruled out before treating a patient for autoimmune pneumonitis. The treatment for pneumonitis is typically prednisone 1 mg/kg or another systemic steroid. Even for such relatively minor respiratory symptoms as cough, PI3K inhibitors should be withheld until pneumonitis can be ruled out. PI3K inhibitors may be resumed at a lower dose after resolution of grade 0 or 1 pneumonitis. In more severe cases of noninfectious pneumonitis, PI3K inhibitors should be permanently discontinued.5-8

Cutaneous Reactions

The severity of cutaneous reactions should be described using the Common Terminology Criteria for Adverse Events (CTCAE) published by the National Cancer Institute.8,35 For grade 1 or 2 reactions covering ≤30% of body surface area (BSA) and with no evidence of superinfection,35 it is reason- able to continue PI3K inhibitor therapy at the current dose and to treat the cutaneous reactions with emollients, antihistamines, or topical steroids7; however, the efficacy of antihistamines and steroids has not been described in the literature.36 During this time, the patient should be monitored closely for worsening symptoms.7

When cutaneous reactions are grade ≥3 (ie, covering >30% of BSA), PI3K inhibitors should be discontinued until the cutaneous reactions have been resolved.8,35 Typically, severe cutaneous reactions should be treated with topical or systemic steroids or antihistamines. PI3K inhibitor therapy may be resumed at a lower dose once the cutaneous reactions have resolved.7 For life-threatening cutaneous reactions, Stevens-Johnson syndrome, or toxic epidermal necrolysis, PI3K inhibitors should be permanently discontinued.5-7

Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) Elevations

ALT and AST levels should be monitored every 2 weeks during the first 3 months of PI3K inhibitor therapy, monthly during the next 3 months, and every 1 to 3 months for the duration of treatment. If ALT or AST levels are elevated, monitoring should occur every week until resolved. When ALT or AST levels are elevated 3 to 5 times above the upper limit of normal (ULN), PI3K inhibitors may be continued with careful monitoring; however, treatment should be discontinued if the levels reach >5 times the ULN.5 Treatment may be continued at either the same or reduced dose once resolved, provided the ALT and/or AST levels remain at <20 times the ULN.5,7

Neutropenia and Thrombocytopenia

As with AST and ALT levels, blood counts should be monitored frequently during the initial months of PI3K inhibition. In the case of mild or moderate abnormalities, monitoring should occur weekly until the abnormalities have resolved. For more severe decreases in neutrophil or platelet counts, PI3K inhibitors should be withheld until the abnormalities have resolved. Treatment may be resumed at the same dose after the first occurrence of neutropenia or thrombocytopenia, or at a lower dose following subsequent occurrences.5,7 If severe thrombocytopenia does not resolve within 21 days, treatment may be permanently discontinued.5

Conclusion

PI3K inhibitors are effective treatment options for patients with relapsed or refractory lymphomas. Many of the approved PI3K inhibitors are currently under investigation for other indications as well. Furthermore, several investigational PI3K inhibitors are currently in clinical trials, suggesting that the use of these agents will expand in the coming years. Optimal monitoring for adverse events and appropriate supportive care are key to reducing the toxic effects of these agents on patients. 8 Future studies designed to evaluate the efficacy of various supportive care regimens will be beneficial in the development of recommendations for the management of toxicities associated with PI3K inhibitors.

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Last modified: June 1, 2020