A phase 2 study of idelalisib plus rituximab in treatment-naïve older patients with chronic lymphocytic leukemia

O’Brien, Susan; Lamanna, Nicole; Kipps, Thomas J.; Flinn, Ian W.; Zelenetz, Andrew D.; Burger, Jan A.; Keating, Michael J.; Mitra, Siddhartha; Holes, Leanne; Yu, Albert S.; Johnson, David M.; Miller, Langdon L.; Kim, Yeon-Hee; Dansey, Roger; Dubowy, Ronald L.; Coutre, Steven

doi:10.1182/blood-2015-03-630947

Cited by 228 publications

(215 citation statements)

References 35 publications

(41 reference statements)

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“…Rapamycin potently inhibits mTOR, and is FDA approved for its immunosuppressant properties, and more recently to treat lymphangioleiomyomatosis (LAM) (164,165). Other developed inhibitors currently in clinical trials include targeting of either specific class I PI3-kinase isoforms, or so-called 'pan-PI3K' inhibitors (166)(167)(168). Despite some preclinical promise, using PI3K-pathway drugs as a monotherapy often leads to acquired resistance (168)(169)(170).…”

Section: Development Of Ras Inhibitors and Current Anti-ras Modalitiesmentioning

confidence: 99%

Regulation of Ras signaling and function by plasma membrane microdomains

Goldfinger

Michael

2017

BST

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Section: Development Of Ras Inhibitors and Current Anti-ras Modalitiesmentioning

confidence: 99%

Regulation of Ras signaling and function by plasma membrane microdomains

Goldfinger

Michael

2017

BST

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“…15,18 O'Brien et al presented the first clinical trial of idelalisib with rituximab for the initial therapy of CLL in patients with a median age of 71 years, 42% of whom had advanced-stage disease. 15 The overall The effectiveness of idelalisib is particularly striking in patients with high-risk cytogenetic abnormalities like 17p deletion and in older CLL patients in whom chemoimmunotherapy is apparently less well-tolerated. Among the highest-risk TP53-mutated patients (n= 9), the overall response rate is 100% and none have progressed, consistent with the known excellent activity of idelalisib in relapsed patients in this high risk group (Figure 2).…”

Section: Idelalisib In Chronic Lymphoid Leukemiamentioning

confidence: 99%

“…5,6,[8][9][10][11][12][13][14][15][16][17] Recently published mature results of the initial treatment of CLL with idelalisib plus rituximab demonstrated that the combination is extremely effective with manageable toxicity in older CLL patients. 15,18 O'Brien et al presented the first clinical trial of idelalisib with rituximab for the initial therapy of CLL in patients with a median age of 71 years, 42% of whom had advanced-stage disease. 15 The overall The effectiveness of idelalisib is particularly striking in patients with high-risk cytogenetic abnormalities like 17p deletion and in older CLL patients in whom chemoimmunotherapy is apparently less well-tolerated.…”

Section: Idelalisib In Chronic Lymphoid Leukemiamentioning

confidence: 99%

Idelalisib at the Crossroads of B-Cell Lymphoproliferative Disorders.

Aksu¹

2016

UHOD

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Phosphatidylinositol 3-kinases (PI3Ks) are considered as lipid kinases that are very active in the pathobiology of lymphoproliferative disorders (LPDs). Idelalisib, a selective inhibitor of the delta isoform of PI3K, provides significant clinical efficacy and has an acceptable side-effect profile in the treatment of B-LPDs. The aim of this review is to outline the pharmacobiological basis of idelalisib that is located at the crossroads of B-LPDs. The PI3K signaling pathway with downstream targets including Akt is involved in hematologic malignancies and lymphomas. Idelalisib has been most widely studied in chronic lymphoid leukemia (CLL) and B-lymphoma. The activity of idelalisib in high-risk FL with early relapse following front line immunochemotherapy was recently shown. The unique immunological toxicity pattern of idelalisib was also decribed in this review. Further clinical investigations will help for the better selection of the subsets of the patients with B-LPD that would be best candidates for the clinical utilization of idelalisib. Other indications such as marginal zone lymphoma, mantle cell lymphoma, Waldenstrom's Macroglobulinemia and other B-cell disorders could likely to be expanded. Future clinical and experimental data combined with the next-generation genomics strategies and personalized medicine for the treatment of malignant disorders will enlightened us for better placement of idelalisib in the treatment algorithm of the patients.

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“…Grade 3-4 toxicities in the idelalisib and rituximab arm were neutropenia (34%), thrombocytopenia (10%), elevated transaminases (5%), diarrhea (4%), and pyrexia (3%). Other trials with idelalisib include-idelalisib and rituximab in frontline setting [100], with ofatumumab, bendamustine, and rituximab.…”

Section: Idelalisib (Previously Gs-1101 or Cal-101)-p110 Pi3kd Inhibitormentioning

confidence: 99%

Chronic lymphocytic leukemia (CLL)—Then and now

Kanti

Jain²

2016

American J Hematol

134

108

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The field of chronic lymphocytic leukemia (CLL) has witnessed considerable change since the time clinical staging was introduced in clinical practice in 1975. Over the years, the prognostication in CLL has expanded with the addition in late 90s of mutational status of variable region of immunoglobulin heavy chain (IGHV), and chromosomal analyses using fluorescent in situ hybridization (FISH). More recently, stereotypy of BCR (B cell receptor) and whole exome sequencing (WES) based discovery of specific mutations such as NOTCH1, TP53, SF3B1, XPO-1, BIRC3, ATM, and RPS15 further refined the current prognostication system in CLL. In therapy, the field of CLL has seen major changes from oral chlorambucil and steroids prior to 1980s, to chemo-immunotherapy (CIT) with fludarabine, cyclophosphamide, rituximab (FCR) to the orally administered targeted therapeutic agents inhibiting kinases in the B cell receptor (BCR) signaling pathway such as Ibrutinib (BTK inhibitor) and Idelalisib (p110 PI3Kd inhibitor) and novel anti-CD20 mAb's (monoclonal antibodies) such as obinutuzumab. This progress is continuing and other targeted therapeutics such as Bcl2 antagonists (Venetoclax or ABT-199) and finally chimeric antigen receptor against T cells (CART) are in the process of being developed. This review is an attempt to summarize the major benchmarks in the prognostication and in the therapy of CLL. The topic allocated to us by Dr Ayalew Tefferi and Dr Carlo Brugnara is very appropriate to reminisce what our understanding of chronic lymphocytic leukemia (CLL) was in 1976 and how rapidly have the advances occurring in this field affected the patients with CLL. It is a disease of progressive accumulation of lymphocytes. CLL lymphocytes are morphologically indistinguishable from a normal mature lymphocyte CLL lymphocytes are functionally inert and perhaps as a direct consequence, their life-span is longer than of normal lymphocytes. It was also believed that CLL lymphocytes are not rapidly proliferating. CLL is a disease of elderly population In some cases, chronic lymphocytic leukemia (CLL) closely resembled leukemic Brill Symmers disease (leukemic form of follicular lymphoma). In an elegant study on 88 patients, the temporal profile of the clinical course of CLL was described by Galton et al.[1] Disease progression was assessed in relation to lymphadenopathy, splenomegaly and bone marrow infiltration. CLL was considered as an immunoproliferative disorder with low immunoglobulin levels, striking response to therapy with steroids and exaggerated skin reaction to arthropod bites. Management of CLL (then in 1976)Most clinicians recognized that at the time of initial diagnosis, patients with CLL, generally, were free of disease-related symptoms. Therefore, virtually all patients were followed on a wait-and-watch regimen, withholding any cytotoxic therapy. When, on clinical grounds, initiation of any therapy was considered appropriate, oral alkylating agents such as chlorambucil with/without steroids [3,4] or cyclophosphamide [5] with or...

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A phase 2 study of idelalisib plus rituximab in treatment-naïve older patients with chronic lymphocytic leukemia

Cited by 228 publications

References 35 publications

Regulation of Ras signaling and function by plasma membrane microdomains

Regulation of Ras signaling and function by plasma membrane microdomains

Idelalisib at the Crossroads of B-Cell Lymphoproliferative Disorders.

Chronic lymphocytic leukemia (CLL)—Then and now

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