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Pharmacist Continuing Education - Immunotherapy and Management of Immune-Related Adverse Effects

01 Jun 2018 3:12 PM | Anonymous

Immunotherapy and Management of Immune-Related Adverse Effects: A Focus on the Immune Checkpoint Inhibitors

Authors: Mallory Crain, PharmD: PGY-2 Oncology Resident Barnes-Jewish Hospital and Sara K. Butler, PharmD, BCPS, BCOP: Barnes-Jewish Hospital

Program Number: 2018-04-10
Approval Dates: 6/6/18 - 9/6/18
Approved Contact Hours: One (1) CE(s) per LIVE session.

Objectives
Understand the general mechanism of immune checkpoint inhibitors and specific mechanisms of action for the individual agents.

  1. Identify immune checkpoint inhibitor agents, mechanism of action, FDA-approved indications, and dosing.
  2. Recognize common immune-related adverse effects and factors that increase patient’s risk of developing immune-related adverse effects.
  3. Identify management strategies for common immune-related adverse effects including cutaneous, gastrointestinal, endocrine, and pulmonary toxicities.
  4. Recommend monitoring and supportive care measures for medications initiated to manage immune-related adverse effects.


Background
Immunotherapy is quickly becoming a mainstay treatment option for numerous malignancies, and multiple immunotherapy agents have been approved by the US Food and Drug Administration (FDA).  In general, immunotherapy agents work by using the immune system to fight off cancer, which can be done through various mechanisms.1 The immune checkpoint inhibitors, a specific class of immunotherapy agents, upregulate the immune system by blocking proteins that inactivate the immune system.  This class of agents can be very effective against malignancies that express these inactivating proteins.2-9 

Immune Checkpoint Inhibitors
The immune checkpoint inhibitors are a group of agents that target specific proteins that help control the immune response, called the immune checkpoint proteins.  There are three different checkpoint proteins that are currently targeted by available agents: cytotoxic T-lymphocte-associated-4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed death-ligand 1 (PD-L1).  CTLA-4 and PD-1 are expressed on the surface of T-cells.  These inactivating proteins interact with CD80/CD86 and PD-L1, respectively, on tumor or antigen presenting cells.  When this interaction occurs, T-cell activation is inhibited resulting in malignant cells evading T-cell-mediated death.  Immune checkpoint inhibitors are able to block the interaction between PD-1 and PD-L1 or CTLA-4 and CD80/CD86.  When this occurs, T-cells are activated and able to fight off malignancy.2-9

There are currently six different immune checkpoint inhibitors that are FDA approved (table 1).  The first agent to gain FDA-approval was ipilimumab, the only agent that inhibits CTLA-4.10  Following ipilimumab, two PD-1 inhibitors, pembrolizumab and nivolumab, were both approved.11,12  The newest immune checkpoint inhibitors, atezolizumab, avelumab, and durvalumab, all inhibit PD-L1.13-15  All of these agents are FDA-approved for a variety of solid malignancies and Hodgkin’s lymphoma.10-15  In addition, there is a vast amount of ongoing clinical trials evaluating the immune checkpoint inhibitors for other solid and hematologic malignancies.

Introduction to Immune-Related Adverse Effects
Since immune checkpoint inhibitors result in a non-tumor-specific activation of T-cells, there is potential for immune-related adverse effects to occur.  This is a result of the immune system attacking non-tumor cells, which can cause organ damage.  The immune-related adverse effects can occur in any organ system. However, the most frequent immune-related adverse effects seen in clinical practice involve the gastrointestinal (GI) tract, endocrine glands, skin, and liver.  Although infrequent, the central nervous system, cardiovascular, and pulmonary systems can also be involved.6-9,16-19  There is some evidence supporting a higher incidence of specific immune-related adverse effects depending on the location of the primary malignancy.  For instance, pneumonitis may be more common in patients with lung cancer compared to other types of malignancy.20 

Immune-related adverse effects usually develop within the first few weeks to months of exposure to checkpoint inhibitors, but can occur at any time point, even after treatment discontinuation.  In general, prolonged treatment or higher doses have not been associated with an increased incidence of immune-related adverse effects.6-8  Ipilimumab is the exception to this since literature comparing 3 mg/kg to 10 mg/kg found increased immune-related adverse effects in the patients who received 10 mg/kg.21  In addition, patients who receive combination therapy with ipilimumab and nivolumab do have an increased frequency of immune-related adverse effects compared to monotherapy with either agent.22  There is currently conflicting evidence surrounding whether development of an immune-related adverse effect is associated with efficacy. However, patients that do not develop an immune-related adverse effect can still achieve response with immune checkpoint inhibitor therapy.8

Depending on the mechanism of the immune checkpoint inhibitor, immune-related adverse effects can occur at different frequencies (table 2).10-15 Evidence shows that patients who receive CTLA-4 inhibitors have increased grade 3 or higher immune-related adverse effects compared to PD-1 and PD-L1 inhibitors.23 The frequency is increased further when a CTLA-4 inhibitor is used in combination with a PD-1 inhibitor.22  In addition, even though PD-1 and PD-L1 inhibitors have the same mechanism for efficacy, these agents can have different safety profiles.  This is because both PD-L1 and PD-L2 interact with PD-1 to cause T-cell inactivation.  When PD-1 is inhibited by an immune checkpoint inhibitor, both PD-L1 and PD-L2 are unable bind to PD-1.  However, when just PD-L1 is blocked, PD-L2 can still bind to PD-1.24 This is thought to result in fewer immune-related adverse effects with PD-L1 inhibitors compared to PD-1 inhibitors.

Management of Immune-Related Adverse Effects
The management of immune-related adverse effects is highly dependent on the organ system involved and the severity of the adverse effect.  The severity of immune-related adverse effects is graded by the common terminology criteria for adverse events (CTCAE).25 In general, for most mild immune-related adverse effects, therapy with an immune checkpoint inhibitor can usually be continued.  For moderate to severe immune-related adverse effects, therapy usually needs to be held in addition to administration of systemic corticosteroids.  There are some situations that may require administration of other immunosuppressants such as infliximab, cyclophosphamide, or mycophenolate mofetil.6-8 Since the management of immune-related adverse effects is very dependent on the specific adverse effect and severity, below are specific recommendations for management of common immune-related adverse effects encountered in clinical practice.

Cutaneous Toxicities:
Cutaneous toxicities are reported in 30-50% of patients who receive immune checkpoint inhibitor therapy and are the earliest immune-related toxicities to present.26 These toxicities are less frequently reported with PD-1 and PD-L1 inhibitors compared to ipilimumab, but all agents have the same incidence of grade 3 or higher toxicities around 1-3%.  Skin toxicities include rash/inflammatory dermatitis, bullous dermatoses, Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), and drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome (DRESS/DIHS).  Since rash/inflammatory dermatitis is the most common immune-related skin toxicity, this is the only specific management recommendations included (table 3).  For grade 1 toxicities, the immune checkpoint inhibitor can be continued with topical emollients and/or corticosteroids applied for treatment.  For grade 2-4 toxicities, it is recommended to hold immune checkpoint inhibitor therapy and administer systemic corticosteroids at 1-2 mg/kg of (methyl)prednisolone or equivalent.  Topical emollients and corticosteroids along with oral antihistamines should also be given for grade 2-3 toxicities.6-9 

Gastrointestinal (GI) Toxicities:
GI toxicities are common immune-related adverse effects that occur with immune checkpoint inhibitor therapy.  The two main GI immune-related adverse effects are colitis and hepatitis.  Other serious GI immune-related adverse effects, such as pancreatitis, have been reported in the literature.  The incidence of these adverse effects depends on the therapy given.  In regards to colitis, 8-27% of patients may experience this adverse effect, with higher frequencies reported with dual anti-CTLA-4 and anti-PD-1 therapy and monotherapy with CTLA-4 inhibitors.  Hepatitis is much less common compared to colitis, occurring in 2-10% of patients treated with immune checkpoint inhibitor monotherapy.  Similar to colitis, the incidence increases with combination therapy up to 25-30%, with 15% of cases categorized as at least grade 3.  Colitis most often occurs within the first 5-10 weeks after immune checkpoint inhibitor initiation.  The general onset of hepatitis is similar to colitis at 6-12 weeks after immune checkpoint inhibitor initiation.9,27  Since colitis and hepatitis are both fairly common immune-related adverse effects, it is important to understand the management of each of these toxicities (tables 4 & 5). 

For colitis, unless restricted to grade 1, therapy should be held or permanently discontinued depending on the severity/grade.  In addition, patients should receive systemic corticosteroids.  In patients that have grade 3-4 colitis, infliximab should be considered if patients have persistent symptoms despite systemic corticosteroids.  Another therapy option for colitis is vedolizumab. However, this agent should be reserved to patients who are refractory to, or have contraindications to, infliximab.6-9,28-29

In patients who develop grade 1 hepatitis, immune checkpoint inhibitor therapy can be continued without administration of systemic corticosteroids.  Systemic corticosteroids should be administered in patients with at least grade 2 hepatitis.  If patients develop severe, grade 3-4 hepatitis, immune checkpoint inhibitor therapy should be permanently discontinued.  In addition, if patients have persistent symptoms after three days, mycophenolate mofetil can be added on to systemic corticosteroids.6-9,30  Infliximab should not be used in cases of hepatitis since there is concern for hepatic toxicity.31

Endocrine Toxicities:
There are a vast amount of endocrinopathies that can occur with immune checkpoint inhibitor therapy.  Some of these include hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis, and diabetes.  One important step is distinguishing between primary and secondary endocrine toxicity since it is possible that patients could have an endocrinopathy not related to immune checkpoint inhibitor therapy.6-7 Overall, clinically significant endocrine toxicities related to immune checkpoint inhibitors occur in about 10% of patients.  The incidence is mostly the same among the different immune checkpoint inhibitor agents.32 

Compared to other immune-related adverse effects, the management of endocrine toxicities differs slightly, with some of the specific management strategies reviewed below (table 6).  For most endocrinopathies, immune checkpoint inhibitors may be continued as long as the patient is asymptomatic or only has mild symptoms.  This is because most endocrine toxicities can be controlled through various supplementations and medications.6-9 An example of this is a patient with immune-related asymptomatic hypothyroidism treated with levothyroxine.  As long as patient’s hypothyroidism is controlled, the immune checkpoint inhibitor can be continued.

Pneumonitis:
Pneumonitis is an uncommon immune-related adverse effect, occurring in about 2.7% of patients. However, it is a very serious toxicity when it does occur.  Unlike most other immune-related adverse effects, pneumonitis is more common with PD-1 and PD-L1 inhibitors compared to CTLA-4 inhibitors, and the incidence increases with combination therapy.  In addition, the onset of pneumonitis can vary from two to 24 months after the initiation of therapy, with the median time to onset reported in the literature around three months.20,33  Since pneumonitis can be very severe, it is recommended to hold or permanently discontinue immune checkpoint inhibitor therapy depending on the grade (table 7).  For grades 2-4, patients should be started on empiric antibiotics and systemic corticosteroids.  In addition, if symptoms persist for 48 hours after systemic corticosteroids, additional immunosuppressant therapy is recommended.  There are a variety of agents that could be started at this time including infliximab, mycophenolate mofetil, intravenous immunoglobulin (IVIG), or cyclophosphamide.6-9

Other Immune-Related Adverse Effects:
There are numerous other immune-related adverse effects that can occur with immune checkpoint inhibitor therapy. However, for the most part, these are much less common.  In addition, all of these toxicities have fairly similar management with holding the immune checkpoint inhibitor and initiating systemic corticosteroids.  Some of the toxicities, including musculoskeletal and central nervous system toxicities that require unique management, are discussed below.  Other immune-related adverse effects seen with immune checkpoint inhibitors include nephritis, hematologic toxicities (ex. hemolytic uremic syndrome, aplastic anemia, and immune thrombocytopenia), cardiovascular toxicities (ex. myocarditis, arrhythmias, and venous thromboembolism), and ocular toxicities.6-9,16-19

Musculoskeletal toxicities have a wide range of severity.  Myalgias and arthralgias are less severe musculoskeletal toxicities and more common after immune checkpoint inhibitor therapy, occurring in up to 40% of patients.34 Inflammatory arthritis and myositis are severe immune-related adverse effects that may require additional immunosuppression, IVIG, or plasmapheresis for severe cases.  Similar to musculoskeletal toxicities, central nervous system toxicities also range in severity from neuropathy to myasthenia gravis, Guillain-Barré syndrome, and encephalitis.  For severe cases of myasthenia gravis or Guillain-Barré syndrome, IVIG or plasmapheresis is recommended with systemic corticosteroids.  When diagnosed with encephalitis, patients should receive empiric antimicrobials, and in severe cases, high-dose systemic corticosteroids (methylprednisolone 1000 mg IV) with or without IVIG.7 

Additional Treatment Considerations:
One of the main management strategies of immune-related adverse effects involves holding immune checkpoint inhibitor therapy.  As clinicians, a common question that may be asked is when therapy can be restarted.  The first step is making sure the patient’s immune-related adverse effect has resolved to at least grade 1.  The next step is assessing the corticosteroid dose.  In general, most practitioners consider prednisone 10 mg (or equivalent) daily an appropriate corticosteroid dose to resume immune checkpoint inhibitor therapy.7 

Aside from holding immune checkpoint inhibitor therapy, the other main management strategy for immune-related adverse effects is administration of systemic corticosteroids.  Systemic corticosteroids pose numerous supportive care challenges, mainly from adverse effects that require monitoring (table 8).35  In addition to monitoring of adverse effects, patients often require prophylactic medications as well, if the expected duration of systemic corticosteroids is prolonged.  Common supportive medications required include Pneumocystis jirovecii pneumonia (PJP) and GI prophylaxis with sulfamethoxazole-trimethoprim and a histamine2-receptor antagonist (H2RA) or proton pump inhibitor (PPI), respectively.7 

A common question from patients and practitioners is if corticosteroids decrease the efficacy of immune checkpoint inhibitor therapy.  Studies have shown that patients who receive corticosteroids for treatment of immune-related adverse effects have similar objective response rates, time to treatment failure, and overall survival compared to patients who did not receive corticosteroids.36,37  Therefore, evidence supports that corticosteroids do not impact the efficacy of immune checkpoint inhibitor therapy.

Conclusions
The immune checkpoint inhibitors are a class of immunotherapy agents currently used in a variety of solid malignancies and Hodgkin’s lymphoma.  Their use has been rapidly increasing with numerous clinical trials currently open for various solid and hematologic malignancies.  The immune checkpoint inhibitors increase the immune system activity through blocking the inactivating checkpoint proteins located on T-cells.  This allows the immune system to attack malignant cells, but also puts patients at risk for developing immune-related adverse effects.  Management may differ depending on the exact immune-related adverse effect and severity. However, the main management strategies involve holding immune checkpoint inhibitor therapy and administering systemic corticosteroids.  Due to the increased use of immune checkpoint inhibitors, it is likely that immune-related adverse effects will become more common in clinical practice.  Early recognition of these adverse effects and recommending appropriate management and supportive care strategies are key steps for successful resolution of immune-related adverse effects. 

Click here to download and open the Appendix

Appendix includes tables:

Table 1: Immunotherpy Agent Overview
Table 2: Incidence of Immune-Related Adverse Effects
Table 3: Management of rash/inflammatory dermatitis
Table 4: Management of colitis
Table 5: Management of hepatitis
Table 6: Management of endocrine toxicities
Table 7: Management of pneumonitis
Table 8: Immunosuppressants used for management of immune-related adverse effects


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References

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