The GAIA (CLL13) trial: An international intergroup phase III study for frontline therapy in chronic lymphocytic leukemia (CLL).

Julia, Von Tresckow; Cu, Niemann; Kater, Arnon P.; Bahlo, Jasmin; FÃ1⁄4rstenau, Moritz; Fink, Anna‐Maria; Gregor, Michael; Thornton, Patrick; Tadmor, Tamar; Fischer, Kirsten; Ritgen, Matthias; Kreuzer, Karl; Eldering, Eric; Stilgenbauer, Stephan; Oers, Marinus van; Geisler, Christian H.; Hallek, Michael; Eichhorst, Barbara

doi:10.1200/jco.2018.36.15_suppl.tps7582

Cited by 8 publications

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“…The side effects of FCR, such as hematological toxicity and infectious complications, are well documented [ 36 , 37 ], making it a feasible treatment choice only for young, fit patients because dose reductions in FCR, which are an often used approach to minimize the drug-related toxicity of FCR, result in reduced efficacy [ 38 , 39 ]. Although FCR is still a reasonable treatment option for a small proportion of CLL patients, recent trials such as the CLL-13 trial by the German CLL Study Group (GCLLSG) [ 40 ] or the FLAIR trial [ 41 ] are challenging CIT and are probably shifting the standard of care to targeted agents even more. In addition, FCR had a higher mortality than expected in recent phase 3 trials [ 42 ].…”

Section: Chemoimmunotherapymentioning

confidence: 99%

“…The efficacy of venetoclax in younger, fit patients still needs to be proven. This question will probably be answered by the CLL13 trial (NCT02950051), which compares CIT (FCR or BR) vs. various combinations of venetoclax (Ve), rituximab (R), obinutuzumab (G) and ibrutinib (I) (RVe vs. GVe vs. GIVe) in treatment-naïve, fit CLL patients without del(17p) or TP53 mutation [ 40 ].…”

Section: Bcl2 Inhibitorsmentioning

confidence: 99%

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Current Treatment Options in CLL

Bewarder

Stilgenbauer

Thurner

et al. 2021

Cancers

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After impressive developments in recent years with the rise of new targeted agents, chemoimmunotherapy (CIT) only plays a minor role in the treatment of patients with chronic lymphocytic leukemia (CLL). Inhibitors of the Bruton tyrosine kinase (BTK), such as ibrutinib or more recently acalabrutinib, are highly effective, even in poor-risk or chemo-refractory patients. Venetoclax, an inhibitor of the anti-apoptotic BCL2 protein and, to a lesser extent, phosphoinositide-3 kinase (PI3K) delta inhibitors, add to the armamentarium of targeted agents for the treatment of CLL. Furthermore, anti-CD20 monoclonal antibodies are used very successfully either alone or in combination with BTK, BCL2 or PI3K inhibitors. Despite these advances, there is still an ongoing pursuit for new therapeutic approaches in the treatment of CLL. An even bigger challenge poses the determination of the optimal combination and sequence of those drugs. Here, we give an overview of current treatment options in CLL, weighing the advantages and disadvantages of each approach in the light of different clinical settings.

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Section: Chemoimmunotherapymentioning

confidence: 99%

Section: Bcl2 Inhibitorsmentioning

confidence: 99%

Current Treatment Options in CLL

Bewarder

Stilgenbauer

Thurner

et al. 2021

Cancers

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“…All venetoclax regimens will be administered for 1-year. 18 An ongoing phase III trial (ECOG EA9161) will compare ibrutinib-obinutuzumab versus ibrutinib-obinutuzumab-venetoclax (for 19 cycles) in younger treatment-naïve patients [ ClinicalTrials.gov identifier: NCT03701282]. The phase III Alliance A041702 trial will similarly assess ibrutinib-obinutuzumab versus ibrutinib-obinutuzumab-venetoclax in previously untreated older patients with CLL.…”

Section: Novel Agents and Novel-novel Combinations Is Three Really Amentioning

confidence: 99%

The evolving role of Bruton’s tyrosine kinase inhibitors in chronic lymphocytic leukemia

Gordon

Danilov

2021

Therapeutic Advances in Hematology

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Ibrutinib, the first in class of the oral covalent Bruton tyrosine kinase (BTK) inhibitors, has profoundly changed the treatment landscape of chronic lymphocytic leukemia (CLL). The phase III RESONATE and RESONATE-2 trials first demonstrated the superiority of ibrutinib over ofatumumab in the relapsed/refractory setting and over chlorambucil in older patients with de novo disease. The phase III ECOG–ACRIN trial extended these results to young, fit patients, demonstrating a significant survival advantage to ibrutinib plus rituximab over fludarabine, cyclophosphamide, and rituximab. Similarly, the Alliance trial demonstrated the superiority of ibrutinib over bendamustine with rituximab as frontline in elderly patients. Challenges with ibrutinib include toxicity, development of resistance, and need for indefinite therapy. The second generation BTK inhibitor acalabrutinib may cause less off-target toxicity. The ELEVATE TN trial demonstrated the superiority of acalabrutinib with or without obinutuzumab over chlorambucil and obinutuzumab as frontline therapy for elderly or comorbid patients. Promising early results from the phase II CAPTIVATE and CLARITY trials, which combined ibrutinib with venetoclax, suggest a future role for minimal residual disease (MRD) testing to determine treatment duration. The ongoing phase III GAIA/CLL13, ECOG EA9161, Alliance A041702, CLL17, and [ClinicalTrials.gov identifier: NCT03836261] trials will assess various combinations of ibrutinib/acalabrutinib, venetoclax, and anti-CD20 antibodies. These trials will answer key questions in the treatment of CLL: should novel agents in CLL be used in combination or sequentially? What is the best frontline agent? Can treatment be safely stopped with BTK inhibitors? Can undetectable MRD be used to determine treatment duration? In this review, we will discuss these and other aspects of the evolving role of BTK inhibition in CLL.

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“…The phase III CLL13 trial (GAIA), an international four arm study for physically fit patients, is testing chemotherapy-free frontline therapy for previously untreated patients without del(17p). The trial is fully enrolled and tested with standard chemotherapy (FCR/BR), venetoclax plus rituximab (RVe), venetoclax plus obinutuzumab (GVe) and venetoclax plus ibrutinib, and obinutuzumab (GIVe) with MRD and PFS as co-primary endpoints [80].…”

Section: Combination Trials Of Bcr Inhibitors and Bcl2 Inhibitorsmentioning

confidence: 99%

Revolution of Chronic Lymphocytic Leukemia Therapy: the Chemo-Free Treatment Paradigm

Scheffold

Stilgenbauer

2020

Curr Oncol Rep

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Purpose of Review Over the last years, targeted anticancer therapy with small molecule inhibitors and antibodies has much replaced chemoimmunotherapy, which has been the gold standard of care for patients with chronic lymphocytic leukemia (CLL). Here we give an overview of novel targeted agents used in therapy of chronic lymphocytic leukemia, as well as efforts to overcome resistance development, focusing on approved drugs since they gained high relevance in clinical practice. Recent Findings Novel agents moved to the forefront as a treatment strategy of CLL due to their outstanding efficacy, almost irrespectively of the underlying genetic features. Inhibition of Bruton's tyrosine kinase (BTK), a key molecule in the B cell receptor pathway, achieved dramatic efficacy even in poor-risk and chemo-refractory patients. Further success was accomplished with venetoclax, which specifically inhibits anti-apoptotic BCL2 and induces apoptosis of CLL cells. Summary Inhibition of BTK or BCL2 is very effective and induces prolongation of progression-free and overall survival. Approved combination treatments such as venetoclax or ibrutinib with obinutuzumab show high responses rates and long remission durations. However, evolution and selection of subclones with continuous treatment leads to resistance towards these novel drugs and disease relapse. Hence, comparison of sequential treatment with combinations and discontinuation of therapy are important aspects which need to be investigated. Keywords Chronic lymphocytic leukemia. BCR signaling. BTK inhibitor. Venetoclax. BCL2 inhibitors This article is part of the Topical Collection on Leukemia

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The GAIA (CLL13) trial: An international intergroup phase III study for frontline therapy in chronic lymphocytic leukemia (CLL).

Cited by 8 publications

References 0 publications

Current Treatment Options in CLL

Current Treatment Options in CLL

The evolving role of Bruton’s tyrosine kinase inhibitors in chronic lymphocytic leukemia

Revolution of Chronic Lymphocytic Leukemia Therapy: the Chemo-Free Treatment Paradigm

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