Managing Immune-Related Adverse Events in an Oncology Clinic

Brandon Chang, PharmD, BCPS, BCOP
Ambulatory Care Pharmacist - Oncology
Kaiser Permanente Fontana Medical Center
Fontana, CA

Immunotherapy has become one of the most important break­throughs in medicine over the last decade. Specifically, immune checkpoint inhibitors (ICIs) have changed oncology practice with astonishingly robust and durable treatment responses in both the adjuvant and advanced settings.¹ ICIs are now widely used across many treatment indications with an estimated 43% of cancer pa­tients eligible for checkpoint inhibitors based on a 2019 cross-sec­tional study.² ICI therapy can lead to autoimmune toxicities known as immune-related adverse events (irAEs) and early recognition and frequent monitoring of these toxicities are crucial for patients to remain on this immunotherapy. Oncology pharmacists are uniquely positioned to identify and monitor these toxicities.

Development of the irAE Pharmacist Protocol
A team of board-certified oncology pharmacists and a post-graduate year 2 (PGY2) oncology pharmacy resident at Kaiser Permanente Zion Medical Center in San Diego developed an irAE Pharmacy Protocol in accordance with recommen­dations from National Comprehensive Cancer Network (NCCN), American Society of Clinical Oncology (ASCO), and European Society of Medical Oncology (ESMO).^3-5

The protocol included four irAEs, including immune-mediated dermatologic, hepatic, gastrointestinal and thyroid toxicities. These were chosen as adverse events that were identifiable and manageable within the institution’s scope of clinical pharmacy practice. Patients with other toxicities, such as renal and pulmo­nary toxicities were excluded in the initial study and were to be considered after initial implementation of the protocol. Pharmacist responsibilities under pilot protocol included ordering and assess­ing laboratory values, prescribing appropriate pharmacotherapy under pharmacist-physician collaboration, scheduling appropriate follow-up, and communicating pharmacotherapy changes with the primary oncologist.

At our institution, an oncology pharmacist reviews and assesses all labs prior to treatment with immune checkpoint inhibitors. Patients were identified to have checkpoint inhibitor toxicities based on abnormal laboratory values or physician workup. Also included in the study were patients 18 years or older who received at least one dose of the immune checkpoint inhibitors ipilimumab, nivolumab, pembrolizumab, durvalumab, atezolizumab or avelumab and who were subsequently identified to have one of the four pro­tocol-listed irAEs between October 1, 2018 and February 28, 2019. Patients with more than one of the four protocol-listed irAEs were still included in the study and managed by the oncology pharmacist.

Patients were excluded from the study if they were determined to have serious or life-threatening toxicities, pre-existing auto­immune disorders, were taking thyroid hormone replacement prescribed by a non-oncology physician, or were currently taking corticosteroids greater or equal to 10mg of prednisone daily or equivalent.

Results:
A total of 17 patients who received an immune checkpoint inhibitor and who were subsequently identified to have an irAE were enrolled into the irAE pharmacy protocol. Oncology pharma­cists performed a total of 101 telephone or in-clinic follow-ups with 21 new medications initiated for the treatment of irAE. The most common toxicity managed was hypothyroidism in which thyroid hormone replacement was initiated in seven patients based on abnormal thyroid stimulating hormone (TSH) and free T4 levels. Oral corticosteroids were initiated in six patients, including three patients with hepatotoxicity, two patients with rash and one patient with colitis.

There were a total of 28 medication dose adjustments. Levothyroxine dose was adjusted based on follow-up labora­tory values of TSH and free T4 measured every four to six weeks. Steroid doses were tapered or titrated depending on liver function tests in hepatitis or patient symptoms in colitis and dermatitis. Four patients had checkpoint inhibitor therapy held with only one rechallenge. Rechallenge criteria were not analyzed as part of this study.

Pre- and post-pilot physician satisfaction surveys were also distributed to help characterize the pharmacist-physician collab­oration. Questions included hours per month managing irAE and physician confidence in pharmacist management rated on a scale of 1 (strongly disagree) to 5 (strongly agree). Through a total of eight physician responses for the pre- and post-pilot surveys, the irAE pharmacist protocol saved an average of one hour physician time per month managing irAEs (3.3 hours pre-pilot to 2.3 hours post-pi­lot) and increased physician confidence in pharmacist management of irAE.⁶

Conclusion:
Our study demonstrates that pharmacist management of irAEs in an oncology clinic is both feasible and widely accepted by oncologists. Pharmacists performed close follow-up of patient symptoms and laboratory values often contacting patients multiple times per week. The results of this study led to the permanent implementation of this pharmacy service, as well as the addition of immune-mediated renal toxicity at the time of writing of the original study.

In addition to reducing physician time managing irAEs, a pharmacist-managed irAE protocol may also reduce referrals to specialists. An internal post-graduate year 1 (PGY1) residency project was conducted at the institution two years after the initial study. It found a numerically lower rate of specialist referrals in a pharmacist managed population compared with usual care. Future studies are needed to confirm these findings.

Implementing an irAE pharmacist protocol at your institution is a great way to increase rapport with your oncologists and elevate the oncology pharmacy practice within your team. To start a pharmacist-managed irAE protocol, we would recommend developing a lead oncology pharmacist with a high baseline knowledge of irAEs to create competen­cies and practical cases for the clinical staff. Then work with other specialties to form an interdisciplinary group to discuss unique cases or cases with severe toxicities. An oncology pharmacist has the knowledge and ability to lead such a group. As the widespread use of immune checkpoint inhibitors continues to increase, pharmacists will remain an important asset in the identification and management of immune checkpoint inhibitor toxicities.

REFERENCES

1. Xu C, Chen Y, Du X, et al. Comparative safety of immune checkpoint inhibitors in cancer: systematic review and network meta-analysis. BMJ 2018; 363:k4226
2. Haslam A and Prasad V. Estimation of the percentage of US patients with cancer who are eligible for and respond to checkpoint inhibitor immunotherapy drugs. JAMA Netw Open 2019;2:e192535
3. National Comprehensive Cancer Network. Management of Immunotherapy-Related Toxicities (Version 1.2020), https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf (accessed 11 May 2020)
4. Brahmer JR, Lacchetti C, Schneider BJ, et al. Management of immune-related checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guidelines. J Clin Oncol 2018;36:1714-1768
5. Haanen JBAG, Carbonnel F, Robert C, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2017;28:i119-i142
6. Le S, Chang B, Pham A & Chan A. Impact of pharmacist-managed immune checkpoint inhibitor toxicities. J Oncol Pharm Practice 2021;27(3):596-600