What is umbralisib?
Umbralisib is an oral phosphatidylinositol-3-kinase (PI3K) inhibitor. PI3K is involved in the B-cell receptor signaling pathway that is commonly implicated in B-cell malignancies.
How does umbralisib work?
Umbralisib inhibits PI3K[delta] and CK1[epsilon], which are expressed on normal and malignant B cells and play a role in the pathogenesis of malignant cells. This inhibition results in decreased cell proliferation, CXCL12-mediated cell adhesion, and CCL19-mediated cell migration in lymphoma cell lines.
What is this approved for?
Umbralisib is FDA-approved under accelerated approval for relapsed or refractory marginal zone lymphoma (MZL) and relapsed or refractory follicular lymphoma (FL). Patients with MZL must have received at least one prior anti-CD20-based regimen. Patients with FL must have received at least three prior lines of therapy.
What is the basis for this approval?
In an open-label trial, 69 patients with relapsed or refractory MZL and 117 patients with relapsed or refractory FL received umbralisib 800 mg orally once daily until disease progression or unacceptable toxicity (J Clin Oncol 2021; doi: 10.1200/JCO.20.03433). Patients with MZL must have received at least one prior therapy including an anti-CD20 containing regimen and were excluded if they had received a prior PI3K inhibitor. Patients with FL were excluded if they had Grade 3b FL, large cell transformation, prior allogeneic transplant, a history of central nervous system involvement, and prior PI3K therapy.
After a median follow up of 28 months, the overall response rate (ORR) for MZL was 49 percent, with 16 percent achieving complete response (CR) and 33 percent achieving partial response (PR). The median time to response was 2.8 months. Median progression-free survival (PFS) and median duration of response was not reached. In the FL cohort, the ORR was 45 percent, with 5 percent achieving CR and 40 percent achieving PR. Median time to response was 4.6 months. The median PFS was 10.6 months and median duration of response was 11.1 months.
How do you administer this drug?
Umbralisib is available as a 200 mg tablet. The recommended dose is 800 mg taken by mouth once daily until progression or unacceptable toxicity. Tablets should be swallowed whole and taken with food.
Are there any pre-medications needed?
Umbralisib has minimal to low emetic risk. No routine pre-medications are recommended; however, antiemetics prior to each dose may be considered if nausea and vomiting occur.
What are the common side effects associated with umbralisib (> or =15%)?
The most common adverse events are increased creatinine, diarrhea and colitis, fatigue, nausea, neutropenia, transaminitis, musculoskeletal pain, anemia, thrombocytopenia, upper respiratory tract infection, vomiting, abdominal pain, decreased appetite, and rash.
What are the uncommon side effects associated with umbralisib (less than 20%)?
Edema, pyrexia, insomnia, urinary tract infections, dyspnea, pneumonia, sepsis, pneumonitis, and exfoliative dermatitis have been reported.
Are there any important drug interactions I should be aware of?
In vitro studies demonstrate that umbralisib is metabolized by CYP2C9, CYP3A4, and CYP1A2; inhibits CYP2C8, CYP2C9, CYP2C19, CYP3A4, and P-glycoprotein; and can also induce CYP3A4. The clinical significance of these drug interactions has not been fully characterized, and coadministration should be used cautiously.
How do I adjust the dose in the setting of renal or hepatic insufficiency?
No dose adjustments are needed in patients with mild or moderate renal dysfunction or in those with mild hepatic impairment. Umbralisib has not been studied in patients with moderate or severe hepatic impairment or severe renal dysfunction.
What should my patients know about umbralisib?
* Diarrhea or colitis occurred in about half of patients on umbralisib and is common in the first 3 months of therapy. Patients should maintain adequate hydration and contact their doctor if they are experiencing >6 stools per day over baseline, abdominal pain, or blood in the stool.
* Serious neutropenia has occurred in patients taking umbralisib. Patients should contact their doctor if they have an infection. Growth factor support, antimicrobials for prophylaxis or treatment, or dose reductions may be necessary.
* Umbralisib may cause fetal harm and pregnancy should be avoided. Effective contraception should be used during treatment and at least 1 month following the last dose of umbralisib. Breastfeeding should be avoided during treatment and at least 1 month after the last dose.
What else should I know about umbralisib?
Patients should receive prophylaxis for Pneumocystis jirovecii pneumonia while taking umbralisib. Cytomegalovirus infection prophylaxis or close monitoring should also be considered.
What useful links are available regarding umbralisib?
* Prescribing information: https://bit.ly/2YXluWT
* FDA Approval: https://bit.ly/3j5qwHw
Any ongoing clinical trials related to umbralisib?
Umbralisib is being studied in combination with chemotherapy and immunotherapy for various B-cell lymphomas. It is also under investigation for treatment of chronic lymphocytic leukemia. More information is available about these trials at http://clinicaltrials.gov.
ALEXANDRA LOVELL, PHARMD, BCOP, is Clinical Pharmacy Specialist in Leukemia at MD Anderson Cancer Center in Houston. JANELLE E. MANN, PHARMD, BCOP, is Clinical Oncology Pharmacist/ Manager, Clinical Pharmacy Services at Washington University School of Medicine, St. Louis, Mo. She serves as the Pharmacy Forum column editor. RAMASWAMY GOVINDAN, MD, Professor of Medicine; Anheuser Busch Chair in Medical Oncology; Director, Section of Medical Oncology, Division of Oncology, Washington University School of Medicine, serves as the Pharmacy Forum column physician advisor.