Umbralisib: A Promising Therapy for Hematologic Malignancies

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Umbralisib has shown improved isoform selectivity over currently used PI3Kδ inhibitors.
Umbralisib has shown improved isoform selectivity over currently used PI3Kδ inhibitors.

Umbralisib, a next-generation PI3Kδ inhibitor, may be a safe and effective option for patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or Hodgkin/non-Hodgkin lymphomas, according to a study published in The Lancet Oncology.1

While idelalisib, the first-in-class PI3Kδ inhibitor, showed promising activity in patients with CLL and non-Hodgkin lymphoma, the drug has a significant toxicity profile, and can induce colitis in up to 19% of patients. Umbralisib has shown improved isoform selectivity over currently used PI3Kδ inhibitors.

For this phase 1 dose-escalation study ( Identifier: NCT01767766), researchers evaluated the safety and efficacy of umbralisib in patients with CLL or Hodgkin/non-Hodgkin lymphoma who had received at least 1 prior therapy. Of 90 patients enrolled and treated, 24 had CLL, 49 had B-cell non-Hodgkin lymphoma, and 6 had another hematologic malignancy.

The median treatment duration and follow-up was 133 days; the maximum tolerated dose was 1200 mg of a micronized formulation. Six patients discontinued treatment because of adverse events (AEs) that may have been drug-related, including colitis (2%), increased liver enzymes (2%), diarrhea (1%), and fatigue (1%).

Objective responses were noted in 33 (37%) patients, 30 of whom had a partial response. Fifty-six (62%) patients, however, had a CT-scan-assessed reduction in disease burden. No patients who received less than 800 mg of the non-micronized formulation had an objective response.

Seventeen (85%) patients with CLL and 9 (53%) patients with follicular lymphoma had an objective response. Two patients with follicular lymphoma and 1 patient with Hodgkin lymphoma had a complete response.

The most common AEs were diarrhea (43%), nausea (42%), and fatigue (31%); the most common grade 3 to 4 AEs were neutropenia (13%), anemia (9%), and thrombocytopenia (7%).

The authors concluded that “the safety, activity, and pharmacological properties of umbralisib support investigations of its use as monotherapy or in combination with other novel targeted drugs for patients with haematological malignancies.”


  1. Burris III HA, Flinn IW, Patel MR, et al. Umbralisib, a novel PI3Kδ and casein kinase-1ε inhibitor, in relapsed or refractory chronic lymphocytic leukaemia and lymphoma: an open-label, phase 1, dose-escalation, first-in-human study. 2018 Feb 20. doi: 10.1016/S1470-2045(18)30082-2 [Epub ahead of print]

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