Integrated safety analysis of umbralisib, a dual PI3Kδ/CK1ε inhibitor, in relapsed/refractory lymphoid malignancies.
Matthew S DavidsOwen A O'ConnorWojciech JurczakFelipe SamaniegoTimothy S FenskePier Luigi Luigi ZinzaniManish R PatelNilanjan GhoshBruce D ChesonEnrico DerenziniDanielle M BranderJames A ReevesWanda Knopińska-PosłusznyJohn N AllanTycel PhillipsPaolo F CaimiEwa Lech-MarandaJohn M BurkeRichy AgajanianRuth PettengellLori A LeslieChan Yoon Y CheahGustavo FonsecaJames EssellJulio C ChavezJohn M PagelJeff P SharmanYanzhi HsuHari P MiskinPeter SportelliMichael S WeissIan W FlinnPublished in: Blood advances (2022)
Phosphoinositide 3-kinase-δ (PI3Kδ) inhibitors are active in lymphoid malignancies, although associated toxicities can limit their use. Umbralisib is a dual inhibitor of PI3Kδ and casein kinase-1ε (CK1ε). This study analyzed integrated comprehensive toxicity data from 4 open-label, phase 1 and 2 studies that included 371 adult patients (median age, 67 years) with relapsed/refractory non-Hodgkin lymphoma (follicular lymphoma [n = 147]; marginal zone lymphoma [n = 82]; diffuse large B-cell lymphoma/mantle cell lymphoma [n = 74]; chronic lymphocytic leukemia [n = 43]; and other tumor types [n = 25]) who were treated with the recommended phase 2 dose of umbralisib 800 mg or higher once daily. At data cutoff, median duration of umbralisib treatment was 5.9 months (range, 0.1-75.1 months), and 107 patients (28.8%) received umbralisib for ≥12 months. Any-grade treatment-emergent adverse events (AEs) occurred in 366 (98.7%) of 371 patients, with the most frequent being diarrhea (52.3%), nausea (41.5%), and fatigue (31.8%). Grade 3 or higher treatment-emergent AEs occurred in 189 (50.9%) of 371 patients and included neutropenia (11.3%), diarrhea (7.3%), and increased aminotransferase levels (5.7%). Treatment-emergent serious AEs occurred in 95 (25.6%) of 371 patients. AEs of special interest were limited and included pneumonia (29 of 371 [7.8%]), noninfectious colitis (9 of 371 [2.4%]), and pneumonitis (4 of 371 [1.1%]). AEs led to discontinuation of umbralisib in 51 patients (13.7%). Four patients (1.1%) died of AEs, none of which was deemed related to umbralisib. No cumulative toxicities were reported. The favorable long-term tolerability profile and low rates of immune-mediated toxicities support the potential use of umbralisib for the benefit of a broad population of patients with lymphoid malignancies.
Keyphrases
- end stage renal disease
- diffuse large b cell lymphoma
- ejection fraction
- newly diagnosed
- chronic kidney disease
- open label
- prognostic factors
- radiation therapy
- rheumatoid arthritis
- squamous cell carcinoma
- randomized controlled trial
- oxidative stress
- acute lymphoblastic leukemia
- clinical trial
- electronic health record
- machine learning
- big data
- multiple myeloma
- rectal cancer
- artificial intelligence
- chronic lymphocytic leukemia
- replacement therapy
- mechanical ventilation
- irritable bowel syndrome
- drug induced
- extracorporeal membrane oxygenation
- community acquired pneumonia
- clostridium difficile