PMID- 34547767
OWN - NLM
STAT- MEDLINE
DCOM- 20220106
LR  - 20220716
IS  - 2473-9537 (Electronic)
IS  - 2473-9529 (Print)
IS  - 2473-9529 (Linking)
VI  - 5
IP  - 23
DP  - 2021 Dec 14
TI  - Integrated safety analysis of umbralisib, a dual PI3Kdelta/CK1epsilon inhibitor, in 
      relapsed/refractory lymphoid malignancies.
PG  - 5332-5343
LID - 10.1182/bloodadvances.2021005132 [doi]
AB  - Phosphoinositide 3-kinase-delta (PI3Kdelta) inhibitors are active in lymphoid 
      malignancies, although associated toxicities can limit their use. Umbralisib is a 
      dual inhibitor of PI3Kdelta and casein kinase-1epsilon (CK1epsilon). 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.
CI  - (c) 2021 by The American Society of Hematology. Licensed under Creative Commons 
      Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), 
      permitting only noncommercial, nonderivative use with attribution. All other 
      rights reserved.
FAU - Davids, Matthew S
AU  - Davids MS
AD  - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
FAU - O'Connor, Owen A
AU  - O'Connor OA
AD  - Department of Medicine, University of Virginia Cancer Center, Charlottesville, 
      VA.
AD  - TG Therapeutics, Inc, New York, NY.
FAU - Jurczak, Wojciech
AU  - Jurczak W
AUID- ORCID: 0000-0003-1879-8084
AD  - Maria Sklodowska-Curie National Research Institute of Oncology, Krakow, Poland.
FAU - Samaniego, Felipe
AU  - Samaniego F
AD  - The University of Texas M.D. Anderson Cancer Center, Houston, TX.
FAU - Fenske, Timothy S
AU  - Fenske TS
AD  - Medical College of Wisconsin, Milwaukee, WI.
FAU - Zinzani, Pier Luigi
AU  - Zinzani PL
AUID- ORCID: 0000-0002-2112-2651
AD  - IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia 
      "Seragnoli," and Dipartimento di Medicina Specialistica, Diagnostica e 
      Sperimentale Universita degli Studi, Bologna, Italy.
FAU - Patel, Manish R
AU  - Patel MR
AUID- ORCID: 0000-0001-6836-2364
AD  - Florida Cancer Specialists/Sarah Cannon Research Institute, Sarasota, FL.
FAU - Ghosh, Nilanjan
AU  - Ghosh N
AD  - Levine Cancer Institute, Atrium Health, Charlotte, NC.
FAU - Cheson, Bruce D
AU  - Cheson BD
AD  - Lymphoma Research Foundation, New York, NY.
FAU - Derenzini, Enrico
AU  - Derenzini E
AD  - Onco-Hematology Division, European Institute of Oncology IRCCS, Department of 
      Health Sciences, University of Milan, Milan, Italy.
FAU - Brander, Danielle M
AU  - Brander DM
AD  - Duke University Health System, Duke Cancer Institute, Durham, NC.
FAU - Reeves, James A
AU  - Reeves JA
AD  - Florida Cancer Specialists South/Sarah Cannon Research Institute, Fort Myers, FL.
FAU - Knopinska-Posluszny, Wanda
AU  - Knopinska-Posluszny W
AD  - Gdynia Oncology Center, Gdynia, Poland.
FAU - Allan, John N
AU  - Allan JN
AUID- ORCID: 0000-0002-2088-0899
AD  - Weill Cornell Medicine, New York, NY.
FAU - Phillips, Tycel
AU  - Phillips T
AD  - University of Michigan Comprehensive Cancer Center, Ann Arbor, MI.
FAU - Caimi, Paolo F
AU  - Caimi PF
AUID- ORCID: 0000-0003-1436-0464
AD  - University Hospitals Seidman Cancer Center, Cleveland, OH.
FAU - Lech-Maranda, Ewa
AU  - Lech-Maranda E
AD  - Institute of Hematology and Transfusion Medicine, Warsaw, Poland.
FAU - Burke, John M
AU  - Burke JM
AUID- ORCID: 0000-0002-5144-6710
AD  - Rocky Mountain Cancer Centers/US Oncology Research, Aurora, CO.
FAU - Agajanian, Richy
AU  - Agajanian R
AD  - The Oncology Institute of Hope and Innovation, Downey, CA.
FAU - Pettengell, Ruth
AU  - Pettengell R
AUID- ORCID: 0000-0001-9948-660X
AD  - St. George's University of London, London, United Kingdom.
FAU - Leslie, Lori A
AU  - Leslie LA
AD  - John Theurer Cancer Center, Hackensack Meridian Health School of Medicine, 
      Hackensack, NJ.
FAU - Cheah, Chan Y
AU  - Cheah CY
AUID- ORCID: 0000-0001-7988-1565
AD  - Sir Charles Gairdner Hospital and University of Western Australia, Perth, 
      Australia.
FAU - Fonseca, Gustavo
AU  - Fonseca G
AD  - Florida Cancer Specialists North/Sarah Cannon Research Institute, St. Petersburg, 
      FL.
FAU - Essell, James
AU  - Essell J
AD  - Oncology Hematology Care, Cincinnati, OH.
FAU - Chavez, Julio C
AU  - Chavez JC
AD  - Moffitt Cancer Center, Tampa, FL.
FAU - Pagel, John M
AU  - Pagel JM
AD  - Swedish Cancer Institute, Seattle, WA.
FAU - Sharman, Jeff P
AU  - Sharman JP
AD  - Willamette Valley Cancer Institute/US Oncology Research, Eugene, OR; and.
FAU - Hsu, Yanzhi
AU  - Hsu Y
AD  - TG Therapeutics, Inc, New York, NY.
FAU - Miskin, Hari P
AU  - Miskin HP
AD  - TG Therapeutics, Inc, New York, NY.
FAU - Sportelli, Peter
AU  - Sportelli P
AD  - TG Therapeutics, Inc, New York, NY.
FAU - Weiss, Michael S
AU  - Weiss MS
AD  - TG Therapeutics, Inc, New York, NY.
FAU - Flinn, Ian W
AU  - Flinn IW
AD  - Sarah Cannon Research Institute and Tennessee Oncology, Nashville, TN.
LA  - eng
PT  - Clinical Trial, Phase I
PT  - Clinical Trial, Phase II
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Blood Adv
JT  - Blood advances
JID - 101698425
RN  - 0 (Heterocyclic Compounds, 4 or More Rings)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 38073MQB2A (umbralisib)
SB  - IM
MH  - Adult
MH  - Aged
MH  - *Heterocyclic Compounds, 4 or More Rings/adverse effects
MH  - Humans
MH  - *Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy
MH  - *Lymphoma, B-Cell, Marginal Zone/drug therapy
MH  - *Phosphoinositide-3 Kinase Inhibitors/adverse effects
MH  - Recurrence
PMC - PMC9153017
EDAT- 2021/09/22 06:00
MHDA- 2022/01/07 06:00
PMCR- 2021/12/09
CRDT- 2021/09/21 20:33
PHST- 2021/04/30 00:00 [received]
PHST- 2021/07/12 00:00 [accepted]
PHST- 2021/09/22 06:00 [pubmed]
PHST- 2022/01/07 06:00 [medline]
PHST- 2021/09/21 20:33 [entrez]
PHST- 2021/12/09 00:00 [pmc-release]
AID - 476985 [pii]
AID - 2021/ADV2021005132 [pii]
AID - 10.1182/bloodadvances.2021005132 [doi]
PST - ppublish
SO  - Blood Adv. 2021 Dec 14;5(23):5332-5343. doi: 10.1182/bloodadvances.2021005132.