Efficacy and safety of idelalisib in combination with ofatumumab for previously treated chronic lymphocytic leukaemia: an open-label, randomised phase 3 trial

Jones, Jeffrey A.; Robak, Tadeusz; Brown, Jennifer R.; Awan, Farrukh T.; Badoux, Xavier C.; Coutré, Steven; Loscertales, Javier; Taylor, Kerry; Vandenberghe, Elisabeth; Wach, Małgorzata; Wagner‐Johnston, Nina D.; Ysebaert, Loïc; Dreiling, Lyndah; Dubowy, Ronald L.; Xing, Guan; Flinn, Ian W.; Owen, Carolyn

doi:10.1016/s2352-3026(17)30019-4

Cited by 188 publications

(138 citation statements)

References 29 publications

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“…In consideration of the high levels of expression of p110δ PI3K in healthy lymphocytes (Chiu et al, ), inhibitors selectivity targeting this p110 PI3K isoform have been tested in preclinical models of Ph ‐ B‐ALL. CAL‐101 (Idelalisib) is a p110δ PI3K inhibitor whose use has been approved by the U.S. Food and Drug Administration (FDA) in combination with rituximab, an anti‐CD20 antibody, as a second‐line treatment for relapsed chronic lymphocytic leukemia (CLL) patients (Jones et al, ).…”

Section: Pi3k Inhibitorsmentioning

confidence: 99%

Targeting the phosphatidylinositol 3‐kinase/Akt/mechanistic target of rapamycin signaling pathway in B‐lineage acute lymphoblastic leukemia: An update

Simioni

Martelli

Zauli

et al. 2018

Journal Cellular Physiology

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Despite considerable progress in treatment protocols, B-lineage acute lymphoblastic leukemia (B-ALL) displays a poor prognosis in about 15-20% of pediatric cases and about 60% of adult patients. In addition, life-long irreversible late effects from chemo- and radiation therapy, including secondary malignancies, are a growing problem for leukemia survivors. Targeted therapy holds promising perspectives for cancer treatment as it may be more effective and have fewer side effects than conventional therapies. The phosphatidylinositol 3-phosphate kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) signaling pathway is a key regulatory cascade which controls proliferation, survival and drug-resistance of cancer cells, and it is frequently upregulated in the different subtypes of B-ALL, where it plays important roles in the pathophysiology, maintenance and progression of the disease. Moreover, activation of this signaling cascade portends a poorer prognosis in both pediatric and adult B-ALL patients. Promising preclinical data on PI3K/Akt/mTOR inhibitors have documented their anticancer activity in B-ALL and some of these novel drugs have entered clinical trials as they could lead to a longer event-free survival and reduce therapy-associated toxicity for patients with B-ALL. This review highlights the current status of PI3K/Akt/mTOR inhibitors in B-ALL, with an emphasis on emerging evidence of the superior efficacy of synergistic combinations involving the use of traditional chemotherapeutics or other novel, targeted agents.

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Section: Pi3k Inhibitorsmentioning

confidence: 99%

Targeting the phosphatidylinositol 3‐kinase/Akt/mechanistic target of rapamycin signaling pathway in B‐lineage acute lymphoblastic leukemia: An update

Simioni

Martelli

Zauli

et al. 2018

Journal Cellular Physiology

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“…3,4 In contrast, other studies, mostly interfering with microenvironmental Notch ligands or with proximal aspects of Notch activation in HSCs, reported roles for Notch signals in HSC regeneration after myeloablation, in suppressing myelopoiesis, as well as functions in E and Mk development. 2,[5][6][7][8] To date, these discrepant findings await a cohesive explanation.…”

Section: Ivan Maillard and Warren S Pear | University Of Pennsylvaniamentioning

confidence: 99%

“…Idelalisib, an oral phosphoinositide 3-kinase (PI3K) isoform d selective inhibitor, has been approved in combination with rituximab or ofatumumab for the treatment of relapsed/refractory CLL. 3,8 In spite of its significant activity, one-third of patients progressed while on treatment, whereas ;50% discontinued idelalisib owing to adverse events, with the survival after discontinuation being less than 3 months. 9 The ideal salvage therapy for CLL patients failing idelalisib therapy has not been defined.…”

mentioning

confidence: 99%

Venetoclax after idelalisib: relevant progress for CLL

Bosch

Hallek

2018

Blood

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play an important role in increasing the survival and resistance of many oncogenic kinase-driven leukemic cells to targeted kinase inhibition.Although glutaminolysis contributes a significant proportion of the energy requirements for FLT3-ITD 1 cells under FLT3 inhibitory stress, it is not the only metabolic pathway that is functioning. The CRISPR screen by Gallipoli et al reveals that several other genes associated with metabolic pathways demonstrate significant synergistic lethality with quizartinib. These include genes involved in fatty acid synthesis (MECR) and phosphatidylinositol metabolism (PLCH1). Thus, further investigation, similar to that performed here, is warranted in future studies to uncover the role of these other metabolic pathways in providing energy and promoting survival of FLT3-ITD 1 AML cells during FLT3 inhibition.

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“…Rates of toxicities (total %/grade ≥3%) including neutropenia (64/60), transaminitis (61/21), and diarrhea (38/9) were also higher in the idelalisib plus BR arms compared to placebo plus BR arms (55/47, 32/3, and 23/2, respectively). Finally, an open-label, randomized phase III trial compared idelalisib plus ofatumumab to ofatumumab monotherapy in relapsed/refractory CLL [56]. Median PFS was doubled in the idelalisib/ofatumumab group (16.3 months vs. 8.0 months), but serious infections, opportunistic infections, and treatment-related deaths (22 deaths vs. 6 deaths) were more common in the group receiving idelalisib.…”

Section: Pi3kα and Pi3kδ Inhibitors In Clinical Development For Thmentioning

confidence: 99%

“…A phase I study of idelalisib combined with ofatumumab in up-front CLL found that 79% of enrolled patients experienced any grade transaminase elevation, with 54% experiencing grade ≥3 transaminase elevation [60]. A steroid-responsive pneumonitis and rash have also been reported in patients on idelalisib [50,56,60]. Multiple lines of clinical evidence support the hypothesis that an autoimmune mechanism underlies these toxicities.…”

Section: Pi3kα and Pi3kδ Inhibitors In Clinical Development For Thmentioning

confidence: 99%

PI3Kδ-selective and PI3Kα/δ-combinatorial inhibitors in clinical development for B-cell non-Hodgkin lymphoma

Lampson

Brown

2017

Expert Opinion on Investigational Drugs

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Introduction Phosphatidylinositol-3-kinase (PI3K) inhibitors comprise a novel class of agents that are effective for the treatment of chronic lymphocytic leukemia (CLL) and indolent non-Hodgkin lymphoma (iNHL). The demonstrated efficacy and subsequent FDA approval of the prototypical PI3Kδ inhibitor idelalisib has led to development of multiple compounds targeting this pathway. Areas Covered We review the hypothesized therapeutic mechanisms of PI3K inhibitors, including abrogation of tonic signaling from the B cell receptor, blockade of pro-survival signals from the microenvironment, and enhancement of anti-tumor immunity. We examine toxicities of idelalisib, including bacterial infections and sepsis (possibly secondary to drug-induced neutropenia), opportunistic infections (possibly attributable to on-target inhibition of T cell function), and organ toxicities such as transaminitis and enterocolitis (possibly autoimmune, secondary to on-target inhibition of p110δ in regulatory T cells). We then summarize PI3K inhibitors that have entered clinical trials for the treatment of lymphoma, focusing on agents with significant selectivity for PI3Kα and PI3Kδ. Expert Opinion PI3K inhibitors, particularly those that target p110δ, have robust efficacy in the treatment of CLL and iNHL. However, in comparison to other novel agents, idelalisib has infectious and autoimmune toxicities that have limited its use. Outside of clinical trials, the use of PI3K inhibitors should be restricted to CLL patients who have progressed on ibrutinib or iNHL patients who have progressed on two prior therapies. Whether newer PI3K inhibitors will demonstrate differentiated toxicity profiles in comparable patient populations while retaining efficacy remains to be seen.

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Efficacy and safety of idelalisib in combination with ofatumumab for previously treated chronic lymphocytic leukaemia: an open-label, randomised phase 3 trial

Cited by 188 publications

References 29 publications

Targeting the phosphatidylinositol 3‐kinase/Akt/mechanistic target of rapamycin signaling pathway in B‐lineage acute lymphoblastic leukemia: An update

Targeting the phosphatidylinositol 3‐kinase/Akt/mechanistic target of rapamycin signaling pathway in B‐lineage acute lymphoblastic leukemia: An update

Venetoclax after idelalisib: relevant progress for CLL

PI3Kδ-selective and PI3Kα/δ-combinatorial inhibitors in clinical development for B-cell non-Hodgkin lymphoma

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