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Examining the Safety of CLL Medication

OVER THE LAST FEW years, significant advances were made in the treatment of patients with chronic lymphocytic leukemia (CLL). Several novel therapies, most of them oral, have now been approved by the Food and Drug Administration. These include Imbruvica (ibrutinib), a Bruton’s tyrosine kinase (BTK) inhibitor; Venclexta (venetoclax), a B-cell lymphoma-2 (BCL2) inhibitor; and Zydelig (idelalisib), a phosphoinositide 3-kinase (PI3K) inhibitor.
BY Nitin Jain, M.D.
PUBLISHED September 25, 2017
OVER THE LAST FEW years, significant advances were made in the treatment of patients with chronic lymphocytic leukemia (CLL). Several novel therapies, most of them oral, have now been approved by the Food and Drug Administration. These include Imbruvica (ibrutinib), a Bruton’s tyrosine kinase (BTK) inhibitor; Venclexta (venetoclax), a B-cell lymphoma-2 (BCL2) inhibitor; and Zydelig (idelalisib), a phosphoinositide 3-kinase (PI3K) inhibitor.

Zydelig inhibits an enzyme that is part of a growth signaling pathway called phosphatidylinositol 3-kinase, PI3Kδ, and is approved in combination with Rituxan (rituximab) for patients with CLL following progression after prior therapies. The approved dose of Zydelig is 150 mg, to be taken orally, twice a day. The approval was based on a phase 3 clinical trial that randomized patients with CLL who had progressed prior therapies to one of the two treatment arms: Zydelig plus Rituxan versus Rituxan alone. Participating patients had to have relapsed CLL needing treatment and were unable to tolerate standard chemo-immunotherapy due to coexisting medical conditions, reduced renal function or low blood counts from prior chemotherapy. Patients who received Zydelig plus Rituxan had higher response rate, longer progression-free survival and overall survival compared to the patients who received Rituxan alone. Zydelig is also approved for patients with follicular lymphoma who have failed at least two prior therapies.

However, its safety has come into question after an increased rate of death due to infectious complications that was reported in several first-line phase 3 trials of Zydelig in patients with CLL and non-Hodgkin lymphoma in March 2016. There was also an increased risk of Pneumocystis jiroveci pneumonia (PJP) and cytomegalovirus (CMV) infection. Based on these findings, the FDA stopped several first-line trials with the use of Zydelig.It is important for patients to know the common side effects of Zydelig, which include diarrhea, nausea, abdominal pain, vomiting, skin rash and pneumonia. The drug also activates immune cells such as cytotoxic T cells, and because of this, several immune-mediated complications have been noted. These may include inflammation and signs of injury of both the small intestine and the colon (enterocolitis), elevation of transaminases (an enzyme) in the liver (transaminitis) and inflammation of lung tissue (pneumonitis).

Severe diarrhea or colitis (grade 3 or higher) occurs in approximately 15 percent of patients treated with Zydelig alone and in approximately 20 percent of patients treated with Zydelig in combination trials. The risk of severe colitis/diarrhea is higher (up to 40 percent) in patients who had not received any prior therapy for CLL. Colonic biopsies typically show infiltrate of T cells, indicative of an immune-mediated process. It is important to note that diarrhea/colitis is generally a late event with onset typically between six to nine months after starting treatment.

Serious and/or fatal liver injury occurs in approximately 15 percent of patients who receive Zydelig.

Liver biopsies typically show infiltrate of T cells. Similar to colitis, the incidence of severe liver injury is significantly higher in previously untreated patients. In a 2016 study, the risk of liver injury with Zydelig was very high (79 percent any grade, 54 percent grade 3 or higher) in previously-untreated patients with CLL. A more robust immune system in previously-untreated patients may have contributed to the higher rate of liver injury.

Serious and/or fatal pneumonitis occurs in approximately 3 to 4 percent of patients who receive Zydelig.

Pneumonitis typically manifests with pulmonary symptoms such as cough, shortness of breath, low oxygen saturation and interstitial infiltrates on a chest X-ray or CT scan. It is important to rule out infection as cause of shortness of breath, though many times it can be difficult to discern pneumonia verse pneumonitis, given similar clinical and radiographic findings. The management of immune-mediated toxicities involves holding or completely discontinuing Zydelig, depending on the severity of the underlying toxicity, and the use of systemic steroids. Most cases are reversible; however, fatal toxicities have occurred.

Zydelig should not be used for previously-untreated patients. Patients who are taking Zydelig are recommended to take prophylaxis against PJP and for monitoring for CMV reactivation.

Overall, patients and physicians should be aware of the immune-mediated toxicities and infectious complications associated with Zydelig.
Nitin Jain, M.D., is an assistant professor in the Department of Leukemia at MD Anderson Cancer Center in Houston, Texas. He earned his medical degree from All India Institute of Medical Sciences, New Delhi in 2002 before moving to the United States where he completed his internal medicine residency training at the Medical College of Wisconsin. Jain’s clinical interests focus on new drug development for patients with leukemia, especially chronic lymphocytic leukemia and acute lymphoblastic leukemia. He is the recipient of the Sardari Lal Kalra Gold Medal in Microbiology and the Merit Award from the American Society of Clinical Oncology.
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