Randomized phase 2 study of obinutuzumab monotherapy in symptomatic, previously untreated chronic lymphocytic leukemia

Byrd, John C.; Flynn, Joseph M.; Kipps, Thomas J.; Boxer, Michael; Kolibaba, Kathryn S.; Carlile, David; Fingerle-Rowson, Guenter; Tyson, Nicola; Hirata, Jamie; Sharman, Jeff P.

doi:10.1182/blood-2015-03-634394

Cited by 75 publications

(50 citation statements)

References 29 publications

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“…However, FISH indicated 72% of cells with split RARA signals, suggesting a variant RARA translocation. Karyotype and metaphase FISH studies revealed 45,X,-Y,t(3;17)(q26;q21)[8]/46,XY [5] (Figure 1B-C) but the expected TBLR1-RARA fusion previously identified in t(3;17) was absent. No mutations in FLT3, NPM1, CEBPA, DNMT3A, RUNX1, K/NRAS, WT1, or IDH1/2 were detected.…”

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confidence: 95%

“…[1][2][3][4] Obinutuzumab has also demonstrated impressive clinical activity in CLL as a single agent and in combination. 5,6 First results from an ongoing phase 1b trial with both compounds suggest a venetoclax dose of 400 mg. 7 In the phase 3 CLL14 trial, patients with previously untreated CLL and coexisting medical conditions as assessed by a cumulative illness rating scale (CIRS) total score .6 and/or an estimated creatinine clearance ,70 mL/min were randomized to receive either 6 cycles of chlorambucil plus obinutuzumab plus 6 cycles of chlorambucil or 6 cycles of venetoclax plus obinutuzumab plus 6 cycles of venetoclax (NCT02242942). Here, we report the safety and efficacy results of the run-in phase of the CLL14 trial.…”

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confidence: 99%

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Venetoclax and obinutuzumab in chronic lymphocytic leukemia

Fischer

Al‐Sawaf

Fink

et al. 2017

Blood

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111

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confidence: 95%

mentioning

confidence: 99%

Venetoclax and obinutuzumab in chronic lymphocytic leukemia

Fischer

Al‐Sawaf

Fink

et al. 2017

Blood

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111

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“…Obinutuzumab was recently approved by the Food and Drug Administration (FDA) for use in combination with chlorambucil for the treatment of patients with previously untreated CLL. In a dose response trial [106], 2,000 mg obinutuzumab produced better CR rates and manageable toxicities compared to 2,000 mg in previously untreated patients. Another trial, GALTON trial [91], combined obinutuzumab with chemotherapy-fludarabine, cyclophosphamide (FC) or with bendamustine (B) in a phase 1-2 clinical trial in patients with relapsed CLL.…”

Section: Obinutuzumab (G; Previously Ga-101)mentioning

confidence: 98%

Chronic lymphocytic leukemia (CLL)—Then and now

Kanti

Jain²

2016

American J Hematol

137

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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“…50,51 High rates of CR/CRi were observed in patients receiving 2,000 mg dose of obinutuzumab when compared with those receiving the standard dose of 1,000 mg (67% versus 49%). CR or CR with incomplete cytopenia response Table 3.…”

Section: Obinutuzumabmentioning

confidence: 99%

Monoclonal Antibodies in Chronic Lymphocytic Leukemia

2016

Lymphoma and Chronic Lymphocytic Leukemias

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Monoclonal antibodies (MoAbs) play a pivotal role in the treatment of chronic lymphocytic leukemia (CLL). Rituximab, a MoAb against CD20, was initially used as a single agent in the treatment of CLL before being incorporated into newer combination regimens. Integration of rituximab into chemotherapy regimens has led to an improvement in the response rate and overall survival when used in frontline therapy. Despite this, CLL remains an incurable disease, and treatment of relapsed CLL, particularly after failure of purine analog-based regimens, remains challenging. Technological advances relating to development of chimeric and humanized MoAbs are supporting the role of antibody-based regimens for many diseases, including CLL. Currently, MoAbs represent an integral component of CLL therapy. The antitumor efficacy of many therapeutic MoAbs can be potentially improved upon by their use in combination with new targeted therapy agents.

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Randomized phase 2 study of obinutuzumab monotherapy in symptomatic, previously untreated chronic lymphocytic leukemia

Abstract: Key Points Obinutuzumab monotherapy demonstrates an increased ORR with 2000 mg over 1000 mg, but no difference in progression-free survival. No meaningful difference was observed in the overall safety profile across the 2 treatment arms.

Cited by 75 publications

References 29 publications

Venetoclax and obinutuzumab in chronic lymphocytic leukemia

Venetoclax and obinutuzumab in chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL)—Then and now

Monoclonal Antibodies in Chronic Lymphocytic Leukemia

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