PMID- 33259589
OWN - NLM
STAT- MEDLINE
DCOM- 20211207
LR  - 20230413
IS  - 1528-0020 (Electronic)
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 137
IP  - 20
DP  - 2021 May 20
TI  - Phase 2 study of the safety and efficacy of umbralisib in patients with CLL who 
      are intolerant to BTK or PI3Kdelta inhibitor therapy.
PG  - 2817-2826
LID - 10.1182/blood.2020007376 [doi]
AB  - Intolerance is the most common reason for kinase inhibitor (KI) discontinuation 
      in chronic lymphocytic leukemia (CLL). Umbralisib, a novel highly selective 
      phosphatidylinositol 3-kinase delta (PI3Kdelta)/CK1epsilon inhibitor, is active and well 
      tolerated in CLL patients. In this phase 2 trial (NCT02742090), umbralisib was 
      initiated at 800 mg/d in CLL patients requiring therapy, who were intolerant to 
      prior BTK inhibitor (BTKi) or PI3K inhibitor (PI3Ki) therapy, until progression 
      or toxicity. Primary end point was progression-free survival (PFS). Secondary end 
      points included time to treatment failure and safety. DNA was genotyped for 
      CYP3A4, CYP3A5, and CYP2D6 polymorphisms. Fifty-one patients were enrolled (44 
      BTKi intolerant and 7 PI3Kdeltai intolerant); median age was 70 years (range, 48-96), 
      with a median of 2 prior lines of therapy (range, 1-7), 24% had del17p 
      and/or TP53 mutation, and 65% had unmutated IGHV. Most common adverse events 
      (AEs) leading to prior KI discontinuation were rash (27%), arthralgia (18%), and 
      atrial fibrillation (16%). Median PFS was 23.5 months (95% CI, 13.1-not 
      estimable), with 58% of patients on umbralisib for a longer duration than prior 
      KI. Most common (>/=5%) grade >/=3 AEs on umbralisib (all causality) were neutropenia 
      (18%), leukocytosis (14%), thrombocytopenia (12%), pneumonia (12%), and diarrhea 
      (8%). Six patients (12%) discontinued umbralisib because of an AE. Eight patients 
      (16%) had dose reductions and were successfully rechallenged. These are the first 
      prospective data to confirm that switching from a BTKi or alternate PI3Ki to 
      umbralisib in this BTKi- and PI3Ki-intolerant CLL population can result in 
      durable well-tolerated responses.
CI  - (c) 2021 by The American Society of Hematology.
FAU - Mato, Anthony R
AU  - Mato AR
AUID- ORCID: 0000-0001-8724-1875
AD  - University of Pennsylvania Cancer Center, Philadelphia, PA.
FAU - Ghosh, Nilanjan
AU  - Ghosh N
AD  - Atrium Health, Charlotte, NC.
FAU - Schuster, Stephen J
AU  - Schuster SJ
AD  - University of Pennsylvania Cancer Center, Philadelphia, PA.
FAU - Lamanna, Nicole
AU  - Lamanna N
AD  - New York-Presbyterian Columbia University Medical Center, New York, NY.
FAU - Pagel, John M
AU  - Pagel JM
AD  - Swedish Cancer Institute, Seattle, WA.
FAU - Flinn, Ian W
AU  - Flinn IW
AD  - Tennessee Oncology/Sarah Cannon Research Institute, Nashville, TN.
FAU - Barrientos, Jacqueline C
AU  - Barrientos JC
AD  - Northwell Health/CLL Research and Treatment Program, New Hyde Park, NY.
FAU - Rai, Kanti R
AU  - Rai KR
AD  - Northwell Health/CLL Research and Treatment Program, New Hyde Park, NY.
FAU - Reeves, James A
AU  - Reeves JA
AD  - Florida Cancer Specialists/Sarah Cannon Research Institute, Fort Myers, FL.
FAU - Cheson, Bruce D
AU  - Cheson BD
AD  - Georgetown University Hospital Lombardi Comprehensive Cancer Center, Washington, 
      DC.
FAU - Barr, Paul M
AU  - Barr PM
AUID- ORCID: 0000-0002-9733-401X
AD  - Wilmot Cancer Institute, University of Rochester, Rochester, NY.
FAU - Kambhampati, Suman
AU  - Kambhampati S
AD  - Sarah Cannon Research Institute at Research Medical Center, Kansas City, KS.
FAU - Lansigan, Frederick
AU  - Lansigan F
AUID- ORCID: 0000-0001-6027-3359
AD  - Dartmouth-Hitchcock Medical Center, Lebanon, NH.
FAU - Pu, Jeffrey J
AU  - Pu JJ
AUID- ORCID: 0000-0001-7498-3159
AD  - Upstate Cancer Center, Syracuse, NY.
FAU - Skarbnik, Alan P
AU  - Skarbnik AP
AD  - John Theurer Cancer Center, Hackensack, NJ.
FAU - Roeker, Lindsey
AU  - Roeker L
AD  - Memorial Sloan Kettering Cancer Center, New York, NY.
FAU - Fonseca, Gustavo A
AU  - Fonseca GA
AD  - Florida Cancer Specialists/Sarah Cannon Research Institute, St. Petersburg, FL.
FAU - Sitlinger, Andrea
AU  - Sitlinger A
AUID- ORCID: 0000-0002-2231-5527
AD  - Duke University Medical Center, Durham, NC.
FAU - Hamadeh, Issam S
AU  - Hamadeh IS
AD  - Levine Cancer Institute, Gainesville, FL; and.
FAU - Dorsey, Colleen
AU  - Dorsey C
AD  - Memorial Sloan Kettering Cancer Center, New York, NY.
FAU - LaRatta, Nicole
AU  - LaRatta N
AD  - University of Pennsylvania Cancer Center, Philadelphia, PA.
FAU - Weissbrot, Hanna
AU  - Weissbrot H
AD  - University of Pennsylvania Cancer Center, Philadelphia, PA.
FAU - Luning Prak, Eline T
AU  - Luning Prak ET
AUID- ORCID: 0000-0002-9478-9211
AD  - University of Pennsylvania Cancer Center, Philadelphia, PA.
FAU - Tsao, Patricia
AU  - Tsao P
AD  - University of Pennsylvania Cancer Center, Philadelphia, PA.
FAU - Paskalis, Dana
AU  - Paskalis D
AD  - TG Therapeutics, Inc., New York, NY.
FAU - Sportelli, Peter
AU  - Sportelli P
AD  - TG Therapeutics, Inc., New York, NY.
FAU - Miskin, Hari P
AU  - Miskin HP
AD  - TG Therapeutics, Inc., New York, NY.
FAU - Weiss, Michael S
AU  - Weiss MS
AD  - TG Therapeutics, Inc., New York, NY.
FAU - Svoboda, Jakub
AU  - Svoboda J
AD  - University of Pennsylvania Cancer Center, Philadelphia, PA.
FAU - Brander, Danielle M
AU  - Brander DM
AD  - Duke University Medical Center, Durham, NC.
LA  - eng
GR  - P30 CA008748/CA/NCI NIH HHS/United States
GR  - P30 CA014236/CA/NCI NIH HHS/United States
GR  - P30 CA016520/CA/NCI NIH HHS/United States
PT  - Clinical Trial, Phase II
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Heterocyclic Compounds, 4 or More Rings)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (Piperidines)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 1X70OSD4VX (ibrutinib)
RN  - 38073MQB2A (umbralisib)
RN  - EC 2.7.1.137 (Class I Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.1.137 (PIK3CD protein, human)
RN  - EC 2.7.10.2 (Agammaglobulinaemia Tyrosine Kinase)
RN  - EC 2.7.10.2 (BTK protein, human)
RN  - JAC85A2161 (Adenine)
SB  - IM
CIN - Blood. 2021 May 20;137(20):2717-2719. PMID: 34014294
MH  - Adenine/adverse effects/analogs & derivatives/therapeutic use
MH  - Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors
MH  - Aged
MH  - Aged, 80 and over
MH  - Antineoplastic Agents/adverse effects/*therapeutic use
MH  - Cardiovascular Diseases/chemically induced
MH  - Class I Phosphatidylinositol 3-Kinases/*antagonists & inhibitors
MH  - Drug Eruptions/etiology
MH  - Drug Resistance, Neoplasm
MH  - Female
MH  - Gastrointestinal Diseases/chemically induced
MH  - Heterocyclic Compounds, 4 or More Rings/adverse effects/*therapeutic use
MH  - Humans
MH  - Kaplan-Meier Estimate
MH  - Leukemia, Lymphocytic, Chronic, B-Cell/*drug therapy/enzymology/mortality
MH  - Male
MH  - Middle Aged
MH  - Neoplasm Proteins/*antagonists & inhibitors
MH  - Piperidines/adverse effects/therapeutic use
MH  - Progression-Free Survival
MH  - Protein Kinase Inhibitors/adverse effects/*therapeutic use
PMC - PMC8574211
EDAT- 2020/12/02 06:00
MHDA- 2021/12/15 06:00
PMCR- 2022/05/20
CRDT- 2020/12/01 17:10
PHST- 2020/06/12 00:00 [received]
PHST- 2020/11/09 00:00 [accepted]
PHST- 2020/12/02 06:00 [pubmed]
PHST- 2021/12/15 06:00 [medline]
PHST- 2020/12/01 17:10 [entrez]
PHST- 2022/05/20 00:00 [pmc-release]
AID - S0006-4971(21)01044-2 [pii]
AID - 2020/BLD2020007376 [pii]
AID - 10.1182/blood.2020007376 [doi]
PST - ppublish
SO  - Blood. 2021 May 20;137(20):2817-2826. doi: 10.1182/blood.2020007376.