Safety and Efficacy of a Combination of Venetoclax (GDC-0199/ABT-199) and Obinutuzumab in Patients with Relapsed/Refractory or Previously Untreated Chronic Lymphocytic Leukemia - Results from a Phase 1b Study (GP28331)

Flinn, Ian W.; Brunvand, Mark W.; Choi, Michael Y.; Dyer, Martin J.S.; Gribben, John G.; Hillmen, Peter; Jones, Jeffrey A.; Li, Yan; Mobasher, Mehrdad; Vosganian, Gregory; Kipps, Thomas J.

doi:10.1182/blood.v126.23.494.494

Cited by 31 publications

(18 citation statements)

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“…The reason for long-term or indefinite ibrutinib therapy is that during treatment with BTK inhibitor monotherapy, achieving U-MRD status is very rare, which makes MRD analysis of limited utility and likely necessitates indefinite maintenance therapy to prevent relapse. ( 17 – 20 , 27 ) In contrast, in the first-line setting, venetoclax plus obinutuzumab( 28 ), venetoclax plus ibrutinib( 29 ) and venetoclax plus ibrutinib and obinutuzumab( 30 ) achieved high rates of U-MRD. As U-MRD is now attainable with novel therapeutic combination strategies, we believe it will have increasing relevance as a therapeutic endpoint for the broader population of patients with CLL, particularly where the intent is to give time-limited treatment.…”

Section: Discussionmentioning

confidence: 99%

Serial minimal residual disease (MRD) monitoring during first-line FCR treatment for CLL may direct individualized therapeutic strategies

et al. 2018

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Achieving undetectable MRD (U-MRD) status after chemoimmunotherapy predicts longer progression-free and overall survival. The predictive factors and timing of relapse in patients with U-MRD and value of interim MRD analysis are ill-defined. This was a prospective study of 289 patients with CLL treated first-line with FCR. MRD analysis was performed after course 3 (C3) and at end-of-therapy (EOT) in bone marrow using 4-color flow cytometry (sensitivity 10−4). Eighteen percent of patients had U-MRD after C3 and 48% at EOT. U-MRD status at EOT was associated with longer PFS (median NR vs 38mo, p<0.001). MRD level (≤1% vs. >1%) after C3 predicted greater likelihood of U-MRD status at EOT (64% vs. 9%, p<0.001). PFS was significantly longer for patients with MRD ≤1% vs. >1% after C3 (median 73mo vs 41mo, p<0.001), but similar for <0.01% vs. 0.01–1%. Interim MRD status may therefore be used for risk stratification and to individualize therapy. Eighty-five patients with U-MRD status at EOT had yearly blood MRD monitoring; MRD re-emerged in 38/85, a median of 48mo after EOT and preceded clinical progression by a median of 24 months, which may allow development of early intervention strategies.

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Section: Discussionmentioning

confidence: 99%

Serial minimal residual disease (MRD) monitoring during first-line FCR treatment for CLL may direct individualized therapeutic strategies

et al. 2018

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“…Combining venetoclax with a second generation CD20 targeting monoclonal antibody that has greater efficacy than rituximab, such as obinutuzumab, may result in even longer PFS. Phase 1b (NCT01685892) and phase 3 (NCT02242942) trials of venetoclax combined with obintuzumab in patients with CLL are ongoing …”

Section: Discussionmentioning

confidence: 99%

Relationship between venetoclax exposure, rituximab coadministration, and progression‐free survival in patients with relapsed or refractory chronic lymphocytic leukemia: demonstration of synergy

Freise

Jones

Menon

et al. 2016

Hematological Oncology

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Venetoclax is indicated at a dosage of 400 mg daily (QD) for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion who have received at least 1 prior therapy. Ongoing trials are evaluating venetoclax in combination with CD20 targeting monoclonal antibodies, such as rituximab. The objective of this research was to characterize the relationship between venetoclax exposures and progression-free survival (PFS) and to evaluate the effect of rituximab coadministration on PFS in patients with relapsed or refractory (R/R) CLL/small lymphocytic lymphoma (SLL). A total of 323 patients from 3 clinical studies of venetoclax, with and without rituximab coadministration, were pooled for the analyses. A time-variant relative risk survival model was used to relate plasma venetoclax concentrations and rituximab administration to PFS. Demographics and baseline disease characteristics were evaluated for their effect on PFS. A concentration-dependent effect of venetoclax on PFS and a prolonged synergistic effect of 6 cycles of concomitant rituximab were identified. The 17p deletion chromosomal aberration was not identified to affect the PFS of patients treated with venetoclax. A venetoclax dose of 400 mg daily QD was estimated to result in a substantial median PFS of 1.8 years (95% confidence interval [CI], 1.7-2.1), whereas the addition of 6 cycles of rituximab was estimated to increase the median PFS to 3.9 years (95% CI, 2.8-5.6). The analysis demonstrates a concentration-dependent effect of venetoclax on PFS and also a synergistic effect with rituximab. Combining venetoclax with the CD20 targeting monoclonal antibody rituximab in R/R CLL/SLL patients provides substantial synergistic benefit compared with increasing the venetoclax monotherapy dose.

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“…Trials evaluating obinutuzumab combinations with alternative agents in a broader population of patients with CLL are already underway (Table ). Preliminary results with ibrutinib and venetoclax have been promising (Davids et al , ; Flinn et al , ; Jain et al , ; Michallet et al , ; Rogers et al , ) and it will be interesting to see if these advantages continue to translate into clinical superiority over rituximab (Table ).…”

Section: Discussionmentioning

confidence: 99%

A tale of two antibodies: obinutuzumab versus rituximab

2018

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While rituximab has dramatically improved outcomes for patients with CD20 malignancies for two decades, responses are not universal and resistance can develop. Obinutuzumab was developed to potentiate activity and overcome resistance. Pre-clinical data suggests obinutuzumab is superior to rituximab at effecting B cell depletion; however recent phase III clinical trial results have been mixed. The decision of which antibody to employ will probably be further complicated by the approval of a subcutaneous preparation of rituximab and several anti-CD20 biosimilars. Clinicians are now challenged with deciding whether to switch to obinutuzumab in approved settings, accepting the potential for increased toxicity and probable increased cost. The benefit conferred by obinutuzumab over rituximab may be context-specific and vary based on histological subtype and immune integrity. This comprehensive review will explore the preclinical differences, investigate the proposed pathogenesis of rituximab resistance, compare the employed dosing strategies and interrogate available clinical results to help inform practice.

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Safety and Efficacy of a Combination of Venetoclax (GDC-0199/ABT-199) and Obinutuzumab in Patients with Relapsed/Refractory or Previously Untreated Chronic Lymphocytic Leukemia - Results from a Phase 1b Study (GP28331)

Cited by 31 publications

References 0 publications

Serial minimal residual disease (MRD) monitoring during first-line FCR treatment for CLL may direct individualized therapeutic strategies

Serial minimal residual disease (MRD) monitoring during first-line FCR treatment for CLL may direct individualized therapeutic strategies

Relationship between venetoclax exposure, rituximab coadministration, and progression‐free survival in patients with relapsed or refractory chronic lymphocytic leukemia: demonstration of synergy

A tale of two antibodies: obinutuzumab versus rituximab

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