The PI3Kδ inhibitor idelalisib was effective in heavily pretreated patients with mantle cell lymphoma.
Major finding: The PI3Kδ inhibitor idelalisib was effective in heavily pretreated patients with mantle cell lymphoma.
Approach: The safety and efficacy of idelalisib in mantle cell lymphoma were evaluated in a phase I trial.
Impact: Further clinical testing of idelalisib in patients with mantle cell lymphoma is warranted.
Mantle cell lymphoma is an incurable B-cell malignancy with a poor prognosis. Chemotherapy is initially effective in mantle cell lymphoma, and bortezomib, lenalidomide, and ibrutinib have shown activity in patients with this disease, but remissions are often brief. Given that PI3K–AKT–mTOR signaling is often constitutively activated in mantle cell lymphoma and that the p110δ variant of the PI3K catalytic subunit (PI3Kδ) is highly expressed in B-cell malignancies, Kahl and colleagues evaluated the small-molecule PI3Kδ inhibitor idelalisib in mantle cell lymphoma in a phase I trial. Forty patients with relapsed or refractory mantle cell lymphoma who had received a median of four previous therapies received oral idelalisib daily; the primary endpoints were to assess safety and determine the dose-limiting toxicity, and secondary endpoints included assessment of the overall response rate, progression-free survival, and duration of response. Idelalisib was well tolerated in this population and most frequently caused asymptomatic alanine transaminase elevation, diarrhea, nausea, and fever. The maximum tolerated dose was not reached. The overall response rate was 40%, with 14 (35%) patients experiencing a partial response and 2 (5%) experiencing a complete response, and 19 (47.5%) patients had stable disease. Overall, lymph node size was reduced in 33 of 39 (84.6%) evaluable patients. The median duration of response was 2.7 months, and the median progression-free survival was 3.7 months. The subgroup of patients who had received fewer than 6 prior treatments had a longer median progression-free survival (8.2 months) and constituted almost all those who had response durations greater than 8 months and long-term stable disease. Together, these findings indicate that idelalisib is safe and has clinical activity in relapsed or refractory mantle cell lymphoma and support further testing of this agent alone or in combination with other therapies.