Effects of umbralisib: A Synthesis of Findings from 25 Studies

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Original Abstract of the Article

Major Research Findings

Umbralisib is a dual inhibitor of PI3Kδ and CK1ε that has shown promising results in treating various hematologic malignancies. 17 Umbralisib is currently in clinical trials for CLL and NHL patients. 17 In preclinical models, CK1δ/ε inhibitors have been found to block CLL development by inhibiting the non-canonical Wnt pathway. 17 Umbralisib has also shown promise in treating patients with relapsed/refractory marginal zone lymphoma, with a response rate of 55% and a 1-year progression-free survival rate of 71%. 25 It has also been approved by the FDA for treating relapsed or refractory marginal zone lymphoma and relapsed or refractory follicular lymphoma. 15

Benefits and Risks

Benefit Summary

Umbralisib is a promising therapeutic option for various hematologic malignancies, including CLL, NHL, MDS, AML, and MM. 17 It has demonstrated the ability to inhibit cell proliferation and induce apoptosis in cancer cells. 17 It is currently being evaluated in clinical trials for CLL and NHL patients. 17 Umbralisib has shown potential in treating patients with relapsed/refractory marginal zone lymphoma, exhibiting a favorable response rate and progression-free survival rate. 25 It has also been approved by the FDA for treating relapsed or refractory marginal zone lymphoma and relapsed or refractory follicular lymphoma. 15

Risk Summary

Common side effects of umbralisib include diarrhea, nausea, and fatigue. 14 More serious side effects, such as pneumonia, non-infectious colitis, and pneumonitis, have also been reported. 14 Furthermore, umbralisib may increase the risk of death or serious adverse effects when given with a specific monoclonal antibody used to treat chronic lymphocytic leukemia. 10 Umbralisib can also potentially impair T-cell function, increasing the risk of infections. 6 Therefore, caution should be exercised when using umbralisib. Patients receiving umbralisib should be closely monitored for adverse effects. 10

Comparison Across Studies

Similarities Across Studies

Multiple studies have demonstrated the potential effectiveness of umbralisib in treating various hematologic malignancies. 17 , 24 , 5 , 7 , 18 , 8 , 13 , 25 , 11 , 14 , 6 , 21 , 22 , 23 , 4 , 20 , 2 , 15 , , 12 , 19 , 1 , 9 , 3 , 16 These studies highlight umbralisib's potential as a therapeutic agent by inhibiting PI3Kδ and CK1ε, ultimately affecting B-cell proliferation and survival. 17

Differences Across Studies

Umbralisib's effectiveness and safety have been evaluated in various ways across studies, including different methods of assessment, target diseases, and study designs. 17 , 24 , 5 , 7 , 18 , 8 , 13 , 25 , 10 , 11 , 14 , 6 , 21 , 22 , 23 , 4 , 20 , 2 , 15 , , 12 , 19 , 1 , 9 , 3 , 16 Some studies have used umbralisib in combination with other drugs, while others have focused on single-agent therapy. 23 , 2 Additionally, some studies lacked a placebo control group. 12

Consistency and Contradictions Across Findings

Numerous studies suggest that umbralisib has potential as a treatment option for various hematologic malignancies. 17 , 24 , 5 , 7 , 18 , 8 , 13 , 25 , 11 , 14 , 6 , 21 , 22 , 23 , 4 , 20 , 2 , 15 , , 12 , 19 , 1 , 9 , 3 , 16 However, it's important to note that some studies lack a placebo control group. 12 Furthermore, research findings regarding umbralisib's side effects show some inconsistencies. 14 , 6

Considerations for Real-Life Application

While umbralisib shows potential in treating certain blood cancers, it is crucial to understand the associated risks. 17 , 8 , 15 Umbralisib can lead to various side effects, including diarrhea, nausea, fatigue, and more serious adverse events such as pneumonia, non-infectious colitis, and pneumonitis. 14 Additionally, combining umbralisib with certain monoclonal antibodies might increase the risk of death or severe adverse effects. 10 Patients and healthcare professionals need to be aware of these potential risks before considering umbralisib treatment. 10

Limitations of Current Research

Some limitations exist within the current body of research on umbralisib. For instance, certain studies lack a placebo control group, making it difficult to isolate the specific effects of umbralisib. 12 Furthermore, the reported side effects of umbralisib vary across different studies, highlighting the need for further investigation and consistent data. 14 , 6

Future Research Directions

Further research is essential to understand umbralisib's effectiveness and safety more comprehensively. 12 Long-term studies are needed to evaluate its long-term effectiveness and safety. 14 Additionally, research focusing on optimizing umbralisib's dosage and administration methods is essential. 13

Conclusion

Umbralisib has shown promise as a potential treatment for various hematologic malignancies. 17 , 8 , 15 However, it's crucial to remember that it can cause side effects. 14 Therefore, patients and healthcare professionals need to be fully aware of these risks before considering umbralisib treatment. 10 Further research is essential to better understand umbralisib's effectiveness and safety. 12

Literature analysis of 25 papers
Positive Content
20
Neutral Content
4
Negative Content
1
Article Type
0
0
0
11
24
1.

The dual PI3Kδ/CK1ε inhibitor umbralisib exhibits unique immunomodulatory effects on CLL T cells.

Author: MaharajKamira, PowersJohn J, AchilleAlex, Mediavilla-VarelaMelanie, GamalWael, BurgerKaren L, FonsecaRenee, JiangKun, MiskinHari P, MaryanskiDave, MonastyrskyiAndrii, DuckettDerek R, RoushWilliam R, ClevelandJohn L, SahakianEva, Pinilla-IbarzJavier

CLL treatment
improved safety profile
preserved Treg number and function
immune-mediated toxicities
impaired Treg function

This study examines the effects of PI3K inhibitors (idelalisib, duvelisib, and umbralisib) on regulatory T cells (Tregs) in normal human T cells, T cells from CLL patients, and a mouse model of CLL. The findings suggest that umbralisib's improved safety profile is due to its dual PI3Kδ/CK1ε inhibition, which preserves Treg function.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, N.I.H., ExtramuralResearch funding provided by the NIH to external research institutions and researchers.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

2.

Response-Adapted, Time-Limited Venetoclax, Umbralisib and Ublituximab for Relapsed/Refractory Chronic Lymphocytic Leukemia.

Author: HillBrian T, MaShuo, ZentClive S, BaranAndrea M, WallaceDanielle S, AdvaniAnjali S, WinterAllison M, WinterJane N, GordonLeo I, KarmaliReem, LiesveldJane L, MulfordDeborah A, RowlandChris, BuiAndrew, SportelliPeter, MiskinHari P, WeissMichael S, FriedbergJonathan W, BarrPaul M

BTK inhibitor resistance overcome
CLL response
MRD reduction
Diarrhea
Liver enzyme elevation

Venetoclax, umbralisib, and ublituximab were used as a combination therapy to treat relapsed/refractory chronic lymphocytic leukemia (CLL). This combination was safe and highly effective, with a 98% overall response rate and a 77% undetectable minimal residual disease (uMRD) rate in bone marrow at the end of treatment.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.

Language : English

3.

Metabolic and toxicological considerations for phosphoinositide 3-kinase delta inhibitors in the treatment of chronic lymphocytic leukemia.

Author: WitkowskaMagdalena, MajchrzakAgata, RobakPaweł, Wolska-WasherAnna, RobakTadeusz

Effective B-cell lymphoma treatment

PI3Kδ inhibitors, such as idelalisib, are new drugs that are used to treat B-cell malignancies. These drugs work by blocking a specific enzyme called PI3Kδ. Idelalisib is the first PI3Kδ inhibitor that has been approved for use in patients with B-cell lymphoid malignancies.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
ReviewAn article that critically examines existing research on a particular topic and summarizes the current state of knowledge in the field.

Language : English

4.

Management of Gastro-Intestinal Toxicity of the Pi3 Kinase Inhibitor: Optimizing Future Dosing Strategies.

Author: BrealClaire, BeuvonFrederic, de Witasse-ThezyThibault, DermineSolene, Franchi-RezguiPatricia, Deau-FisherBenedicte, WillemsLise, GrignanoEric, ContejeanAdrien, BouscaryDidier, FaillieJean Luc, TreluyerJean-Marc, GuerinCorinne, ChouchanaLaurent, VignonMarguerite

Cancer treatment
Colitis

This review examines the use of phosphatidylinositol 3-kinase (PI3K) inhibitors for hematological malignancies, focusing on the incidence and toxicity of PI3K inhibitor-induced colitis. It discusses the side effects reported in clinical trials and pharmacovigilance data, and provides real-world experience in managing idelalisib-induced colitis.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
ReviewAn article that critically examines existing research on a particular topic and summarizes the current state of knowledge in the field.

Language : English

5.

PI3k Inhibitors in NHL and CLL: An Unfulfilled Promise.

Author: Bou ZeidNaji, YazbeckVictor

CLL treatment
iNHL treatment
Adverse effects
Decreased survival

This mini-review revisits the clinical successes, the failures, and the promising aspect of PI3K inhibitors in the treatment of hematologic malignancies. It also presents possible ways that could benefit its successful development.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
ReviewAn article that critically examines existing research on a particular topic and summarizes the current state of knowledge in the field.

Language : English

7.

Functional Testing to Characterize and Stratify PI3K Inhibitor Responses in Chronic Lymphocytic Leukemia.

Author: YinYanping, AthanasiadisPaschalis, KarlsenLinda, UrbanAleksandra, XuHaifeng, MuraliIshwarya, FernandesStacey M, ArribasAlberto J, HilliAbdul K, TaskénKjetil, BertoniFrancesco, MatoAnthony R, NormantEmmanuel, BrownJennifer R, TjønnfjordGeir E, AittokallioTero, SkånlandSigrid S

CLL treatment
Resistance
Treatment intolerance

PI3Ki are used to treat relapsed CLL but often have side effects and resistance. This study aimed to identify actionable biomarkers to predict individual treatment responses and overcome these challenges.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, N.I.H., ExtramuralResearch funding provided by the NIH to external research institutions and researchers.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

8.

Current status of phosphoinotiside-3 kinase inhibitors in blood cancers.

Author: ShouseGeoffrey, DanilovaOlga V, DanilovAlexey V

CLL treatment
NHL treatment

PI3K inhibitors have been approved by the FDA for the treatment of NHL and CLL and are proving to be effective treatments, but they also present unique challenges in routine practice.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
ReviewAn article that critically examines existing research on a particular topic and summarizes the current state of knowledge in the field.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

9.

Adding Umbralisib and Ublituximab (U2) to Ibrutinib in Patients with CLL: A Phase II Study of an MRD-Driven Approach.

Author: RoekerLindsey E, FeldmanTatyana A, SoumeraiJacob D, FalcoVictoria, PantonGail, DorseyColleen, ZelenetzAndrew D, FalchiLorenzo, ParkJae H, StrausDavid J, Pena VelasquezCamila, LebowitzSonia, FoxYehudit, BattiatoKristen, LaudatiCarissa, ThompsonMeghan C, McCarthyElizabeth, KdirySabrina, MartignettiRosalba, TurpuseemaTeja, PurdomMichelle, PaskalisDana, MiskinHari P, SportelliPeter, LeslieLori A, MatoAnthony R

CLL treatment
Resistance
Toxicity

Ibrutinib is a transformative treatment for chronic lymphocytic leukemia (CLL), but its effectiveness is limited by toxicity and resistance. This study explores the use of an "add-on" approach with umbralisib and ublituximab in patients with detectable MRD, aiming to achieve undetectable-MRD and potentially allowing for treatment-free observation periods.

Clinical Trial, Phase IIA Phase II trial is a trial that further evaluates the efficacy and safety of a new drug or treatment, whose safety has been confirmed to some extent in a Phase I trial, in a small number of patients.
Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, N.I.H., ExtramuralResearch funding provided by the NIH to external research institutions and researchers.

Language : English

11.

PI3K Inhibitors for the Treatment of Chronic Lymphocytic Leukemia: Current Status and Future Perspectives.

Author: HusIwona, PułaBartosz, RobakTadeusz

CLL treatment
autoimmune-mediated pneumonitis
colitis
infections

Phosphoinositide 3-kinase delta (PI3Kδ) inhibitors have shown promise in treating chronic lymphocytic leukemia (CLL). Idelalisib, the first PI3Kδ inhibitor, had significant side effects. Duvelisib and umbralisib, newer PI3Kδ inhibitors, have shown improved safety profiles.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
ReviewAn article that critically examines existing research on a particular topic and summarizes the current state of knowledge in the field.

Language : English

12.

The evidence to date on umbralisib for the treatment of refractory marginal zone lymphoma and follicular lymphoma.

Author: SchweitzerJanelle, HoffmanMeghan, GrafSolomon A

Follicular lymphoma treatment
PI3K inhibitor efficacy
Drug safety concerns
Toxicity

Umbralisib, a PI3K inhibitor, is a promising treatment for relapsed/refractory indolent B-cell lymphoma (iB-NHL) with potential improved tolerability.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
ReviewAn article that critically examines existing research on a particular topic and summarizes the current state of knowledge in the field.

Language : English

14.

Integrated safety analysis of umbralisib, a dual PI3Kδ/CK1ε inhibitor, in relapsed/refractory lymphoid malignancies.

Author: DavidsMatthew S, O'ConnorOwen A, JurczakWojciech, SamaniegoFelipe, FenskeTimothy S, ZinzaniPier Luigi, PatelManish R, GhoshNilanjan, ChesonBruce D, DerenziniEnrico, BranderDanielle M, ReevesJames A, Knopińska-PosłusznyWanda, AllanJohn N, PhillipsTycel, CaimiPaolo F, Lech-MarandaEwa, BurkeJohn M, AgajanianRichy, PettengellRuth, LeslieLori A, CheahChan Y, FonsecaGustavo, EssellJames, ChavezJulio C, PagelJohn M, SharmanJeff P, HsuYanzhi, MiskinHari P, SportelliPeter, WeissMichael S, FlinnIan W

Lymphoid malignancy treatment
Colitis
Diarrhea
Fatigue
Nausea
Pneumonia
Pneumonitis

Umbralisib, a dual inhibitor of PI3Kδ and CK1ε, showed a favorable long-term tolerability profile in a study of 371 patients with relapsed/refractory non-Hodgkin lymphoma. The most frequent treatment-emergent adverse events were 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 4 patients (1.1%) died of AEs. The study supports the potential use of umbralisib for patients with lymphoid malignancies.

Clinical Trial, Phase IThe first stage of clinical trials in humans. Evaluates the safety, tolerability, and pharmacokinetics of a new drug/treatment.
Clinical Trial, Phase IIA Phase II trial is a trial that further evaluates the efficacy and safety of a new drug or treatment, whose safety has been confirmed to some extent in a Phase I trial, in a small number of patients.
Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

15.

Umbralisib: First Approval.

Author: DhillonSohita, KeamSusan J

Treatment for haematological malignancies

Umbralisib, a first-in-class dual phosphatidylinositol 3-kinase delta (PI3Kδ) and casein kinase 1 epsilon (CK1ε) inhibitor, has been approved by the FDA for the treatment of adults with relapsed or refractory marginal zone lymphoma (MZL) and follicular lymphoma (FL). Clinical studies are underway in multiple countries for other haematological malignancies.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
ReviewAn article that critically examines existing research on a particular topic and summarizes the current state of knowledge in the field.

Language : English

16.

The delta isoform of phosphatidylinositol-3-kinase predominates in chronic myelomonocytic leukemia and can be targeted effectively with umbralisib and ruxolitinib.

Author: VillaumeMatthew T, ArrateM Pia, RamseyHaley E, SunthankarKathryn I, JenkinsMatthew T, MoyoTamara K, SmithBrianna N, FischerMelissa A, ChildressMerrida A, GorskaAgnieszka E, FerrellP Brent, SavonaMichael R

CMML treatment

This study investigated the potential of co-inhibiting PI3K-δ and JAK1/2 as a treatment for chronic myelomonocytic leukemia (CMML). Preclinical data suggests that this combination therapy exhibits promising activity and warrants further investigation.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, N.I.H., ExtramuralResearch funding provided by the NIH to external research institutions and researchers.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

17.

Targeting Casein Kinase 1 (CK1) in Hematological Cancers.

Author: JanovskáPavlína, NormantEmmanuel, MiskinHari, BryjaVítězslav

Cancer treatment

This review summarizes recent developments in the understanding of biology and therapeutic potential of the inhibition of CK1 isoforms in the pathogenesis of hematological malignancies. CK1δ/ε inhibitors block CLL development in preclinical models via inhibition of WNT-5A/ROR1-driven non-canonical Wnt pathway.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
ReviewAn article that critically examines existing research on a particular topic and summarizes the current state of knowledge in the field.

Language : English

18.

Phase 2 study of the safety and efficacy of umbralisib in patients with CLL who are intolerant to BTK or PI3Kδ inhibitor therapy.

Author: MatoAnthony R, GhoshNilanjan, SchusterStephen J, LamannaNicole, PagelJohn M, FlinnIan W, BarrientosJacqueline C, RaiKanti R, ReevesJames A, ChesonBruce D, BarrPaul M, KambhampatiSuman, LansiganFrederick, PuJeffrey J, SkarbnikAlan P, RoekerLindsey, FonsecaGustavo A, SitlingerAndrea, HamadehIssam S, DorseyColleen, LaRattaNicole, WeissbrotHanna, Luning PrakEline T, TsaoPatricia, PaskalisDana, SportelliPeter, MiskinHari P, WeissMichael S, SvobodaJakub, BranderDanielle M

CLL treatment
Side effects

This phase 2 trial (NCT02742090) evaluated the efficacy and safety of umbralisib in CLL patients who were intolerant to prior BTK inhibitor (BTKi) or PI3K inhibitor (PI3Ki) therapy. 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.

Clinical Trial, Phase IIA Phase II trial is a trial that further evaluates the efficacy and safety of a new drug or treatment, whose safety has been confirmed to some extent in a Phase I trial, in a small number of patients.
Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Multicenter StudyResearch conducted in collaboration with multiple research institutions. It aims to collect a wide range of data and obtain more generalizable results.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

19.

Ex vivo blockade of PI3K gamma or delta signaling enhances the antitumor potency of adoptively transferred CD8<sup>+</sup> T cells.

Author: DwyerConnor J, ArhontoulisDimitrios C, Rangel RiveraGuillermo O, KnochelmannHannah M, SmithAubrey S, WyattMegan M, RubinsteinMark P, AtkinsonCarl, ThaxtonJessica E, NeskeyDavid M, PaulosChrystal M

Cancer treatment

Inhibiting PI3Kγ or PI3Kδ ex vivo, but not both, during T cell expansion for adoptive T cell transfer therapy increased antitumor activity in vivo. This discovery has significant clinical implications for improving the effectiveness of this therapy.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, N.I.H., ExtramuralResearch funding provided by the NIH to external research institutions and researchers.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

22.

Approved and emerging PI3K inhibitors for the treatment of chronic lymphocytic leukemia and non-Hodgkin lymphoma.

Author: KienleDirk L, StilgenbauerStephan

Targeted therapy for CLL/SLL
Targeted therapy for follicular lymphoma
Immune-mediated toxicity
Infectious toxicity

Idelalisib, a PI3K inhibitor, initially showed promise as a targeted therapy for CLL/SLL and follicular lymphoma. However, subsequent trials identified specific immune-mediated and infectious toxicity, leading to reduced use and stopped further development.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
ReviewAn article that critically examines existing research on a particular topic and summarizes the current state of knowledge in the field.

Language : English

23.

Ublituximab and umbralisib in relapsed/refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia.

Author: LunningMatthew, VoseJulie, NastoupilLoretta, FowlerNathan, BurgerJan A, WierdaWilliam G, SchreederMarshall T, SiddiqiTanya, FlowersChristopher R, CohenJonathon B, SportelliPeter, MiskinHari P, WeissMichael S, O'BrienSusan

Improved survival
Lymphoma treatment
Diarrhea
Pneumonia

A combination therapy of umbralisib, a PI3K-δ inhibitor, and ublituximab, an anti-CD20 monoclonal antibody (U2), showed promising safety and efficacy in patients with chronic lymphocytic lymphoma (CLL) or non-Hodgkin lymphoma (NHL). In a phase 1/1b study, U2 was well-tolerated, with a 46% overall response rate and a median duration of response of 20 months. The combination showed low instances of grade 3 or higher side effects like diarrhea, pneumonia, or hepatic toxicity.

Clinical Trial, Phase IThe first stage of clinical trials in humans. Evaluates the safety, tolerability, and pharmacokinetics of a new drug/treatment.
Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Multicenter StudyResearch conducted in collaboration with multiple research institutions. It aims to collect a wide range of data and obtain more generalizable results.

Language : English

24.

Exploring a Future for PI3K Inhibitors in Chronic Lymphocytic Leukemia.

Author: PatelKrish, PagelJohn M

Improved CLL treatment

PI3K inhibitors are drugs that block a key pathway in the growth of chronic lymphocytic leukemia (CLL).

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
ReviewAn article that critically examines existing research on a particular topic and summarizes the current state of knowledge in the field.

Language : English

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