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CASE STUDIES & WEBINAR

Managing Patients With Lymphoma Receiving PI3K Inhibitor Therapy: Considerations for Advanced Practitioners

Presenting a new way to learn with the JADPRO Clinical Case Series!

Here's how it works:

  1. Read these 3 case studies on the AP role in managing patients with lymphoma receiving PI3K inhibitor therapy.
  2. Answer the poll next to each case to see how your colleagues are managing this patient population. You'll see results in real time.
  3. Continue your learning by watching a recording of a webinar presented by Amy Goodrich, RN, MSN, CRNP, as she delves deeper into the 3 cases and gives clinical pearls for managing patients with lymphoma receiving PI3K inhibitor therapy. Download the slides from the webinar for your reference.

Importance of Pretreatment Counseling

Clinical Pearl: Baseline symptom and bowel habit assessment improves adverse event management

Mr. B is a 70-year-old man who was diagnosed with grade II follicular lymphoma (FL) 10 years ago, when he was 60 years old. His prior therapies include rituximab plus cyclophosphamide, vincristine, and prednisone (R-CVP), bendamustine plus rituximab, and lenalidomide plus rituximab. However, his disease is progressing and requires additional therapy. His treatment team considers the phosphoinositide 3-kinase (PI3K) inhibitor options, which include idelalisib, copanlisib, duvelisib, and umbralisib (Table 1).

Table 1. Approved PI3K Inhibitors for the Treatment of FL1–5

  Idelalisib Copanlisib Duvelisib Umbralisib
Inhibited isoform Delta Alpha, delta Gamma, delta Delta (and CK1-epsilon)

Dosing and administration 150 mg by mouth twice daily 60 mg IV over 1 hour on days 1, 8, 15 of 28-day cycles 25 mg by mouth twice daily 800 mg by mouth daily

Duration Progression or unacceptable toxicity Progression or unacceptable toxicity Progression or unacceptable toxicity Progression or unacceptable toxicity

After the advanced practitioner (AP) discusses the available PI3K inhibitors with Mr. B, he chooses to receive umbralisib. In the UNITY-NHL trial, disease control rate was 80%, which included a 3.4% complete response rate, a 39% partial response rate, and a 37% stable disease rate. The median duration of response was 11.1 months. There were 43% of patients who required dose interruption, and 14% discontinued treatment due to adverse events (AEs). 6

Mr. B is prescribed 800 mg of umbralisib daily. The AP counsels him that the most common non-laboratory AEs include diarrhea, nausea, vomiting, fatigue, musculoskeletal pain, infection, and decreased appetite.6 The AP also describes the warnings and precautions associated with umbralisib, which include infection, neutropenia, diarrhea or non-infectious colitis, hepatotoxicity, severe cutaneous reactions, allergic reactions, and embryo-fetal toxicity.5

Due to an increased risk of Pneumocystis jirovecii pneumonia (PJP), prophylaxis is recommended during umbralisib treatment. In addition, consideration for prophylactic antiviral therapy to prevent cytomegalovirus (CMV) infection and/or reactivation is recommended.5 Therefore, Mr. B also starts treatment with sulfamethoxazole plus trimethoprim and will have CMV blood monitoring every month and if symptoms arise.

The AP educates Mr. B on reportable signs and symptoms of infection. In general, patients should call with any new signs or symptoms, with focus on GI events for umbralisib because the most common PI3K inhibitor side effect is diarrhea.5 Grading is done based on number of stools per day above normal. It is important to assess and document baseline bowel habits (see Table 2). Mr. B has two bowel movements per day at baseline. Most side effects will be well controlled with antiemetics, antimotility agents, or other supportive care. Frequent visits when starting therapy should be expected, and well as if any new symptoms arise.

Table 2. CTCAE Version 5.0 Grading of Diarrhea With PI3K Inhibitors7

AE Grade 1 Grade 2 Grade 3 Grade 4
Diarrhea Increase of <4 stools per day over baseline Increase of 4–6 stools per day over baseline Increase of 7 or more stools per day over baseline Life-threatening or urgent intervention indicated

The AP explains to Mr. B that dose interruptions and reductions could be possible if he develops moderate to severe side effects. He is counseled on the importance of keeping a stool log if diarrhea occurs, which would be important to help the team appropriately manage his care.

References

  1. Zelenetz AD, Gordon LI, Abramson JS, et al. B-cell lymphomas, version 4.2021. NCCN Clinical Practice Guidelines in Oncology. May 5, 2021.
  2. Gilead Sciences, Inc. Zydelig (idelalisib) prescribing information. Foster City, CA, 2020.
  3. Bayer HealthCare Pharmaceuticals, Inc. Aliqopa (copanlisib) prescribing information. Whippany, NJ, 2021.
  4. Verastem, Inc. Copiktra (duvelisib) prescribing information. Needham, MA, 2019.
  5. TG Therapeutics. Ukoniq (umbralisib) prescribing information. Edison, NJ, 2021
  6. Fowler NH, Samaniego F, Jurczak W, et al. Umbralisib, a dual PI3Kδ/CK1ε inhibitor in patients with relapsed or refractory indolent lymphoma. J Clin Oncol. 2021;39:1609-1618.
  7. U.S. Department of Health and Human Services. Common terminology criteria for adverse events (CTCAE), version 5.0, 2017.
How often do you educate patients and/or caregivers about the importance of sharing changes in bowel habits with their care team?
Not usually
At the initial visit
At every visit
Only if the patient reports a problem

Management of GI Side Effects

Clinical Pearl: Managing adverse events appropriately allows for optimal treatment response

Mrs. H is a 65-year-old female with nodal marginal zone lymphoma (MZL) who is currently receiving umbralisib as third-line therapy. She is currently in her third week of taking umbralisib and calls the office to report new diarrhea.

Mrs. H comes into the office for assessment. She reports no new medications or dietary changes. She typically has one bowel movement per day, but yesterday she experienced five loose and intermittently watery bowel movements. She reports that she is hydrating well, and the AP notes that her vital signs and labs are normal. A stool sample is sent to be evaluated for Clostridioides difficile (C. diff).

Diarrhea occurs in approximately 53% to 58% of patients receiving umbralisib, with grade 3 occurring in 9% to 10% of patients in the UNITY-NHL trial. No grade 4 diarrhea was noted in the pivotal clinical trial. There were 11% of patients who required a dose reduction, and only 2.9% discontinued umbralisib due to diarrhea. The median time to onset of any-grade diarrhea is 1 month and 75% of cases are expected to occur by 2.9 months.1

The AP determines that Mrs. H has grade 2 diarrhea. The management of diarrhea associated with PI3K inhibitors is dependent on the grade and may include dose interruption and/or supportive care (Table 1).

Table 1. Management of Umbralisib-Related Diarrhea2

Interventions Grade 1 Grade 2 Grade 3 Grade 4
Umbralisib dosing Maintain treatment Hold umbralisib until grade 1 or less Hold umbralisib until grade 1 or less, then restart at reduced dose. If recurrent, discontinue Hold umbralisib until grade 1 or less, then restart at reduced dose. If recurrent, discontinue

Diarrhea management Start antidiarrheals at first sign of abdominal cramping, loose stools, or diarrhea Continue grade 1 interventions Continue grade 1 interventions; consider enteric acting steroids and/or colonoscopy Continue grade 1 interventions; consider enteric acting steroids and/or colonoscopy

Although not well understood, the selectivity of umbralisib and inhibition of CK1 epsilon appear to preserve and improve regulatory T-cell numbers and function, which may be responsible for reducing autoimmune toxicity and improving the overall toxicity profile of umbralisib compared with first-generation PI3K inhibitors (Table 2).3,4 No patient in the pivotal UNITY-NHL clinical trial experienced autoimmune colitis.1

Table 2. Examples of Serious and/or Fatal Toxicities With PI3K Inhibitors2,5,6

  Idelalisib
First Generation
Duvelisib
First Generation
Umbralisib
Second Generation
Diarrhea/colitis 14%–20% 18% 9%–10%

Pneumonitis 4% 5% 1.4%

Hepatotoxicity 16%–18% 2%–8% 7%

Infections 21%–48% 31% 10%

To address Mrs. H’s diarrhea, the AP decides to temporarily interrupt umbralisib dosing and initiate over-the-counter antidiarrheal agents. The C. diff culture is negative. After 1 week of supportive treatment, her diarrhea improves to grade 1, and she restarts umbralisib at the full dose of 800 mg daily. She has no further worsening of diarrhea and is able to remain on umbralisib.

Despite its favorable side-effect profile, umbralisib is associated with AEs.2 Monitoring patients closely and promptly managing AEs maximizes time on therapy and allows for optimal treatment response.

References

  1. Fowler NH, Samaniego F, Jurczak W, et al. Umbralisib, a dual PI3Kδ/CK1ε inhibitor in patients with relapsed or refractory indolent lymphoma. J Clin Oncol. 2021;39:1609-1618.
  2. TG Therapeutics. Ukoniq (umbralisib) prescribing information. Edison, NJ, 2021.
  3. Maharaj K, Powers JJ, Achille A, et al. The dual PI3Kδ/CK1ε inhibitor umbralisib exhibits unique immunomodulatory effects on CLL T cells. Blood Adv. 2020;4:3072-3084.
  4. Esposito A, Viale G, Curigliano G. Safety, tolerability, and management of toxic effects of phosphatidylinositol 3-kinase inhibitor treatment in patients with cancer: a review. JAMA Oncol. 2019;5:1347-1354.
  5. Verastem, Inc. Copiktra (duvelisib) prescribing information. Needham, MA, 2019.
  6. Gilead Sciences, Inc. Zydelig (idelalisib) prescribing information. Foster City, CA, 2020.
If a patient experiences grade 2 diarrhea with umbralisib, what are your typical recommendations?
Continue umbralisib and add supportive care
Hold umbralisib and add supportive care until diarrhea resolves to grade 1 or less
Discontinue umbralisib and switch to another PI3K inhibitor, and add supportive care
I’ve never used umbralisib

Making Treatment Decisions After Prior Lines of Therapy

Clinical Pearl: Umbralisib side effects are highest with cycle 1 and reduce with subsequent cycles

Mrs. T is a 76-year-old woman with follicular lymphoma (FL) who was initially treated with rituximab monotherapy for nonsymptomatic, bulky disease. However, she achieved less than a partial response, and bendamustine was added to the rituximab for 4 cycles. After this regimen, she remained in remission for 4 years, at which point she received lenalidomide plus rituximab for progressive disease. Now, 3 years later, her disease is again progressing and she requires fourth-line therapy. Rituximab monotherapy is considered her first-line therapy, with bendamustine plus rituximab her second-line therapy.

In reviewing the National Comprehensive Cancer Network (NCCN) guidelines,1 a PI3K inhibitor or EZH2 inhibitor therapy are novel treatment options for her next line of treatment.2 EZH2 plays a critical role in the growth and survival of many tumor types, including FL, with approximately 25% of FL harboring an EZH2 mutation.3 EZH2 testing is done via next-generation sequencing (NGS) and can be performed on archival tissue or fresh tissue. EZH2 status remains constant throughout a patient’s disease course, including transformation. The NGS test results for Mrs. T show that her disease is wild type for EZH2.

Tazemetostat is currently an FDA-approved EZH2 inhibitor for FL. In its clinical trial, patients with an EZH2 mutation demonstrated a 69% response rate, whereas patients with wild-type E2H2 had a 35% response rate, with a median duration of response of 13 months.4 Dosing is oral, twice daily.

Both classes are generally well tolerated and administered until disease progression or unacceptable toxicity.

After a review of response rates, dosing schedules, and side effects, Mrs. T opts to receive umbralisib; she is aware that tazemetostat will remain an option for the future.

After umbralisib is initiated, Mrs. T sees the AP weekly during her first cycle. During weeks 1 and 2, she has no substantial side effects. However, 3 weeks after starting umbralisib, she reports fatigue and intermittent nausea without vomiting. She is taking antiemetics as needed with good relief of nausea, is able to eat and drink normally, and her weight is stable. The median time to onset for any-grade nausea with umbralisib is 0.3 months, with 75% of cases occurring by 1.5 months. Mrs. T is encouraged to continue her current management and is educated that nausea is expected in over 25% of patients during cycle 1, which reduces to under 10% by cycle 2 and under 5% for subsequent cycles (Figure 1).5

The median time to onset for any-grade fatigue is 1.0 months, with 75% of cases occurring by 2.8 months. The rate of fatigue during cycle 1 is just over 20%; by cycle 4, it reduces to 5% or less.6 Mrs. T is able to perform all of her usual activities. She states that she requires short rest periods throughout the day and occasionally naps.

By cycle 3, Ms. T rarely experiences nausea and her fatigue is nearly resolved.

References

  1. National Comprehensive Cancer Network. NCCN Guidelines. B-cell lymphomas, Version 4.2021.
  2. Zelenetz AD, Gordon LI, Abramson JS, et al. B-cell lymphomas, version 4.2021. NCCN Clinical Practice Guidelines in Oncology. May 5, 2021.
  3. von Keudell G, Salles G. 2021 The role of tazemetostat in relapsed/refractory follicular lymphoma. Ther Adv Hematol. 2021;12:20406207211015882.
  4. Morschhauser F, Tilly H, Chaidos A, et al. Tazemetostat for patients with relapsed or refractory follicular lymphoma: an open-label, single-arm, multicentre, phase 2 trial. Lancet Oncol. 2020;21(11):1433-1442.
  5. TG Therapeutics. Ukoniq (umbralisib) prescribing information. Edison, NJ, 2021.
  6. TG Therapeutics, data on file.
How do you typically counsel your patients about common adverse events associated with umbralisib, such as diarrhea and nausea?
Explain the general rates that occurred in clinical trials during cycle 1
Explain that diarrhea and nausea are possible, and that they should call the clinic if these symptoms become bothersome
Explain that although adverse events are possible, they typically resolve or are less likely after cycle 1
Ask patients to track their side effects and we discuss it at the next visit

Meet the Faculty


Amy Goodrich
RN, MSN, CRNP

The Johns Hopkins Kimmel Cancer Center
Baltimore, Maryland

Amy Goodrich, RN, MSN, CRNP, is a research associate and nurse practitioner in the hematologic malignancies program and is the research nursing manager at The Johns Hopkins Kimmel Cancer Center in Baltimore, Maryland. Amy has also published on hematologic malignancies, new therapeutics, and symptom management.


If you enjoyed this Clinical Case Series module on managing patients with FL and MZL taking PI3K inhibitors,
check back often to see more modules on new topics.

Let us know what you'd like to learn more about at editor@advancedpractitioner.com

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