What is duvelisib?
Duvelisib is an oral kinase inhibitor of phosphatidylinositol 3-kinases (PI3K). It inhibits PI3K with the majority of inhibition occurring against PI3K-[delta] and PI3K-[gamma] isoforms that are present on normal and malignant B cells. It inhibits B-cell receptor signaling, chemotaxis of malignant B cells, and T-cell migration.
What is this approved for?
Duvelisib gained FDA approval for the treatment of patients with relapsed/refractory CLL/SLL after progression on at least two prior therapies and accelerated approval for patients with relapsed/refractory follicular lymphoma after progression on at least two prior therapies.
Duvelisib was evaluated for CLL/SLL in the DUO trial, a phase III trial randomizing 319 patients after at least two lines of therapy to either duvelisib 25 mg twice daily or ofatumumab. The median progression-free survival (PFS) was 13.3 months with duvelisib and 9.9 months with ofatumumab (HR 0.52; p < 0.001) in all patients and maintained in patients with high-risk chromosome 17p13q deletions or TP53 mutations (HR 0.40; p = 0.0002) (Blood 2018;132:2446-2455).
Duvelisib was evaluated in the phase II Dynamo trial for indolent non-Hodgkin lymphoma including a majority of follicular lymphoma patients. Of the 129 patients enrolled with prior progressive disease, the overall response rate with duvelisib was 46 percent, median duration of response of 9.9 months, and median PFS of 8.4 months (95% CI, 5.8-11.3) (Blood 2016;128:1218). This lead to the accelerated approval of duvelisib for follicular lymphoma.
How do you administer this drug?
Duvelisib is administered as a capsule, swallowed whole, twice daily with or without food.
Are there any premedications needed?
There are no premedications needed for duvelisib; however, supportive antimicrobial therapy is indicated. Patients should receive pneumocystis jirovecii pneumonia (PCP) prophylaxis continued until the patient's absolute CD4+ T-cell count increases to > 200 cells/microL. Prophylactic antiviral therapy should be considered to prevent CMV infection or reactivation.
What are the common side effects (>= 10%)?
* Edema, fever, fatigue, headache
* Skin rash
* Endocrine: hypophosphatemia, hyponatremia, hyperkalemia, hypoalbuminemia, hypocalcemia, hypokalemia, weight loss
* Gastrointestinal: colitis, diarrhea, increased serum lipase or amylase, nausea, abdominal pain, vomiting, mucositis
* Hematologic: neutropenia, anemia, thrombocytopenia, leukopenia, lymphocytopenia
* Hepatic: increased serum alanine aminotransferase or serum aspartate aminotransferase or alkaline phosphatase
* Infection: sepsis, serious infection
* Renal: increased serum creatinine
* Respiratory: upper respiratory tract infection, pneumonia, cough, dyspnea
What are the uncommon side effects (< 10%)?
Dermatological reactions, cytomegalovirus disease, arthralgia, pneumonitis, or PCP infection.
Are there any important drug interactions?
Duvelisib is metabolized predominately by the liver via CYP3A4 and is a moderate inhibitor of CYP3A4. Caution should be used with CYP3A4 strong inducers or inhibitors.
How do I adjust the dose in the setting of renal and hepatic insufficiency?
* There are no dosing recommendations for duvelisib in renal impairment.
* If hepatic impairment exists prior to starting duvelisib therapy, there is no dose adjustment recommended. If hepatotoxicity develops during therapy, increased monitoring should occur and if it progresses withhold therapy until recovery and then resume at the same dose. If an elevation in liver enzymes occurs again, dose reduction to 15 mg twice daily is recommended.
Practical tips
Duvelisib is available in 15-mg and 25-mg capsules. Dose reductions to 15-mg twice daily are recommended for grade 3 dermatologic toxicity, mild to moderate diarrhea not responsive to antidiarrheal therapy, colitis, pneumonitis, neutropenia, thrombocytopenia, infection, clinical CMV infection, or viremia. Duvelisib should be discontinued if PCP infection is confirmed.
What should my patients know?
Duvelisib is associated with black-box warnings for diarrhea, dermatologic toxicity, infection, and pulmonary toxicity. Patients should be counseled comprehensively about early presentation with adverse events and should be encouraged to carry around the provided wallet card explaining duvelisib therapy.
What else should I know about duvelisib?
As part of the safety monitoring for duvelisib, a REMS program is required by the FDA. Patients must receive the Safety Information Fact Sheet and be provided the Patient Safety Wallet Card explaining adverse reactions.
What useful links are available?
* http://www.verastem.com/wp-content/uploads/2018/08/prescribing-information.pdf
* https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm621503.htm
* http://www.copiktrarems.com/wp-content/pdf/COPIKTRA-REMS-Fact-Sheet.pdf
Any ongoing clinical trials?
Duvelisib is being studied in a variety of hematologic malignancies as a single agent or in combination with drugs such as venetoclax or rituximab and bendamustine. More information is available about the at https://clinicaltrials.gov.
SARA K. BUTLER, PHARMD, BCPS, BCOP, is Interim Manager of Clinical Pharmacy Services, Barnes-Jewish Hospital, St. Louis, Mo., and also serves as a Pharmacy Forum column co-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.