In a comprehensive review of idelalisib (Zydelig) treatment for patients with indolent non-Hodgkin lymphoma, Hofstra University’s Jacqueline C Barrientos concluded that the drug is a promising option in patients who have already been through earlier treatment.
Still, many questions remain to be answered and continuing research is needed to get a fuller picture of all aspects of idelalisib therapy.
The review, “Idelalisib for the treatment of indolent non-Hodgkin lymphoma: a review of its clinical potential,“ was published in OncoTargets and Therapy.
Indolent non-Hodgkin lymphoma is a class of slow-growing tumors, including the subtypes follicular lymphoma, marginal zone lymphoma, small lymphocytic lymphoma, and Waldenström macroglobulinemia, also known as lymphoplasmacytic lymphoma. The cancer often responds to treatment but is incurable, making viable maintenance treatments extremely necessary.
The slow progression of the disease can lead to situations that advance the disease after medical care. Patients are often older than 60 years of age or elderly. Because the cancer strikes most often as people age, complex treatment plans are typically needed due to the likelihoood of additional existing (comorbid) conditions such as high blood pressure and heart disease.
Idelalisib, which blocks a factor called PI3Kδ, kills cancer cells stemming from immune B-cells, and is approved in the U.S. for relapsed follicular lymphoma and small lymphocytic lymphoma, but patients need to have received at least two earlier treatment rounds. It is also approved for relapsed chronic lymphocytic leukemia — another B-cell related cancer — in combination with rituximab in cases where rituximab is deemed insufficient.
In Europe, the drug is approved as a monotherapy (alone) in adult patients with refractory follicular lymphoma, and in combination with rituximab for adults with chronic lymphocytic leukemia.
Patients who are candidates for idelalisib treatment have failed previous rounds of treatment – most frequently rituximab and chemotherapy – and have few options left. Owing to its profile, the treatment represents a reasonable option for patients who do not tolerate chemotherapy well, or who do not respond to treatment with rituximab or other cancer drugs.
The effectivity of idelalisib as both a monotherapy and in combination with rituximab or bendamustine, and rituximab and bendamustine together, has been examined by several clinical trials that led to long-term effectivity in reducing tumors and sustained or improved quality-of-life.
As a monotherapy, the drug produces a response in about 50% of patients, with a duration of approximately 12 months. In combination, the response rate is increased to 70-80% with a duration of more than two years.
The safety profile of idelalisib is considered acceptable based on data from patients treated for up to four years. The most common side effects are diarrhea, nausea, fatigue, cough, and fever.
Treatment is usually stopped for patients who experience severe diarrhea, pneumonia, and shortness of breath. More severe and sometimes fatal side effects have occurred, such as liver toxicity, inflammation of the colon or lungs, and perforation of the gut.
Patients need to be monitored for the occurrence of complications. Because diarrhea often emerges after several months of treatment, patients should call or visit the doctor if diarrhea persists for more than 24 hours.
While six ongoing clinical trials are currently investigating idelalisib both alone and in combinations for various previously treated patient groups, trials to assess the drug’s role as a first treatment option are further needed. Trials in patients with chronic lymphocytic leukemia suggest that using idelalisib combined with ofatumumab as a first-line treatment might be linked to excessive toxicity.
Therefore, preclinical studies need to focus on identifying mechanisms that lead to this kind of toxicity and to find possible markers that might be used for selecting patients who are likely to tolerate idelalisib as a first treatment.
Not enough is known about long-term outcomes of continued treatment beyond disease progression. Currently, the practice is to end treatment when disease progresses or unacceptable toxicity occurs, but no trials have evaluated if it could be safe to stop treatment in patients who have reached sufficient remission. There is also little data to guide clinicians toward safe ways of managing patients who stop responding to idelalisib.
Because of the considerable amount of targeted therapies that can be combined with idelalisib, including drugs already on the market and currently in development, it is crucial to sift through the options and determine best practice guidelines by finding which combinations can improve outcomes without increasing toxicity compared to monotherapy.