Chlorambucil plus ofatumumab versus chlorambucil alone in previously untreated patients with chronic lymphocytic leukaemia (COMPLEMENT 1): a randomised, multicentre, open-label phase 3 trial

Hillmen, Peter; Robak, Tadeusz; Janssens, Ann; Babu, K Govind; Kłoczko, Janusz; Grosicki, Sebastian; Doubek, Michael; Panagiotidis, Panagiotis; Kimby, Eva; Schuh, Anna; Pettitt, Andrew R.; Boyd, Thomas E.; Montillo, Marco; Gupta, Ira; Wright, Oliver; Dixon, Iestyn; Carey, Jodi; Chang, Che Shoa; Lisby, Steen; McKeown, Astrid; Offner, Fritz

doi:10.1016/s0140-6736(15)60027-7

Cited by 305 publications

(257 citation statements)

References 36 publications

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“…The network of evidence for analysis of TDs included three RCTs (RESONATE-2 [13], COMPLEMENT1 [19] and CLL11 [12]). The random-effects NMA showed that patients receiving ibrutinib experienced fewer TDs than those in other treatment groups, with ORs (and probabilities of being better [i.e., associated with fewer discontinuations]) ranging from 0.…”

Section: Safety Outcomes: Overall Front-line Populationmentioning

confidence: 99%

“…As both age and mutation status are prognostic indicators and potential treatment-effect-modifiers in CLL [6], analyses were conducted, where data permitted, on the subgroups of patients aged ≥65 years, those with unmutated IgVH, those with del11q mutation and those without del17p mutation. Some or all outcomes of interest for the four subgroups were available from four RCTs: RESONATE-2 [13], CLL11 [12], COMPLEMENT1 [19] and Knauf et al [23]. Pairwise comparisons were conducted for ibrutinib versus Obi-Chl, R-Chl, Ofa-Chl and bendamustine, respectively, and effects were tested in the subgroups for which data were available.…”

Section: Regression Analyses For Survival Outcomes Using Chlorambucilmentioning

confidence: 99%

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Front-line treatment of patients with chronic lymphocytic leukemia: a systematic review and network meta-analysis

Fahrbach

Dorman

et al. 2018

J. Comp. Eff. Res.

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Aim:A systematic literature review and network meta-analysis were conducted to determine the relative efficacy and safety of interventions for treatment-naive chronic lymphocytic leukemia patients, as comparative evidence is scarce. Materials & methods: Relative treatment effects of progression-free survival, overall survival and safety outcomes were estimated via network meta-analysis based on data identified via systematic literature review. Results: Ibrutinib was superior in all pairwise comparisons for progressionfree survival (probability to be better [P] range: overall population: 69-100%; fludarabine-ineligible population: 69-100%) and overall survival (P range: overall: 89-100%; fludarabine-ineligible: 91-100%) and had the highest probability of being best for all outcomes. Conclusion: Ibrutinib provides superior benefit in survival and safety compared with other front-line treatments of chronic lymphocytic leukemia. Chronic lymphocytic leukemia (CLL) is the most common hematologic malignancy in western countries and occurs mainly in older people. Overall, 4.2 per 100,000 population per year develop the condition, a figure that rises to over 30 per 100,000 per year among those aged over 80 years [1]. The overall 5-year survival rate for people with CLL is 83%, although survival varies widely according to disease stage [2]. Treatment for CLL has evolved rapidly over the past two decades, with the addition of CD20-targeted antibodies, B-cell lymphoma-2 (BCL-2)-targeted treatment and B-cell receptor-targeted treatment resulting in improved outcomes [3][4].As indicated by both the European Society for Medical Oncology (ESMO) and the National Comprehensive Cancer Network [1,5], there are various management options for CLL, and treatment choices must account for key patient and disease characteristics known to affect therapeutic outcomes. These include patient age [6], fitness/comorbidities [7] and molecular cytogenetics [6,8]. Generally, for fit patients with advanced, symptomatic disease, the so-called 'full-dose fludarabine-based' regimen of fludarabine + cyclophosphamide + rituximab (FCR) is recommended [1]. However, for elderly patients and/or those with significant comorbidities, FCR is associated with significant risk of myelosuppression and severe infection [9]. Options are further limited if these individuals also have cytogenetic characteristics associated with poor outcomes from current treatments (such as 17p or 11q deletion, or absence of IgVH mutation). For these patients, ESMO and National Comprehensive Cancer Network guidelines recommend ibrutinib monotherapy [1,5,9].Given the range of CLL treatment options for people with differing levels of fitness, and the dearth of head-tohead clinical trials comparing front-line treatments, there remains considerable uncertainty regarding the optimal regimen for each patient group. The objectives of the presented systematic literature review (SLR) and network meta-analyses (NMAs) were therefore to determine the relative efficacy and safety of intervention...

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Section: Safety Outcomes: Overall Front-line Populationmentioning

confidence: 99%

Section: Regression Analyses For Survival Outcomes Using Chlorambucilmentioning

confidence: 99%

Front-line treatment of patients with chronic lymphocytic leukemia: a systematic review and network meta-analysis

Fahrbach

Dorman

et al. 2018

J. Comp. Eff. Res.

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“…Type I and II anti-CD20 antibodies are capable of recruiting FcR-expressing cells to mediate ADCC and phagocytosis directed against CD20 ϩ cells (16). Importantly, both type I and II antibodies have been approved for clinical use based on their activities against various CD20 ϩ B-lymphomas or B cell-mediated autoimmune diseases (17,18). As shown in this study, 2B8T2M retains rituximab-like CDC against CD20 ϩ FIGURE 9.…”

Section: Discussionmentioning

confidence: 67%

A Novel Fusion of ALT-803 (Interleukin (IL)-15 Superagonist) with an Antibody Demonstrates Antigen-specific Antitumor Responses

Liu

Kong

Han

et al. 2016

Journal of Biological Chemistry

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Edited by Luke O'Neill IL-15 and its receptor ␣ (IL-15R␣IL-15, a four-helix, common ␥ chain (␥ C ) 2 cytokine, is a critical factor for the development, proliferation, and activation of natural killer (NK) cells and CD8 ϩ T cells (1, 2). IL-15 is co-expressed with its ␣ chain receptor (IL-15R␣) by antigen-presenting cells, and the two proteins form a complex on the cell surface that is transpresented to NK and T cells bearing the IL-2R␤␥ C complex (2). IL-15 binds to IL-15R␣ at high affinity, and IL-15R␣ functions as a chaperone and conformational stabilizer to enhance the interaction between IL-15 and IL-2R␤␥ C (2). We identified a novel IL-15 variant carrying an asparagineto-aspartic acid mutation at amino acid 72 (N72D) that exhibits superior binding to IL-2R␤␥ C on immune cells and increased immunostimulatory activity (3). Our previous studies have demonstrated that this IL-15 variant, when associated with a soluble IL-15R␣ sushi domain fusion to IgG1 Fc (IL15R␣SuFc), could form a heterodimeric complex, IL-15N72D⅐ IL-15R␣SuFc (designated ALT-803), that also exhibits increased binding activity to the IL-2R␤␥ C complex, enhanced capacity to stimulate NK and T cells, and has a longer biological half-life compared with native IL-15 (4). In various animal models, ALT-803 acts as a potent immunostimulant that is capable of simultaneously activating the innate and adaptive arms of the immune system to elicit both rapid and long-lasting protective responses against neoplastic challenges (5). Moreover, ALT-803, in combination with checkpoint blockade or therapeutic antibodies, is effective in reducing the tumor burden and prolonging survival in mouse tumor models (6, 7). To make ALT-803-based molecules more specific and efficient in combating disease, we converted ALT-803 into a targeted immunotherapeutic agent by genetically fusing it with singlechain antibodies (scFv) at the N termini of IL-15N72D and IL-15R␣SuFc proteins. In this study, we used the anti-CD20 scFv as the target recognition domain to demonstrate that ALT-803 is a versatile, functional scaffold for creating diseasetargeted immunostimulatory molecules. This novel single fusion protein approach was also found to improve the antibody-dependent cellular cytotoxicity (ADCC) and apoptotic functions of the anti-CD20 therapeutic antibody rituximab.

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“…As probabilidades de transição entre os estados de saú-de (1L e 2L) foram baseadas nas curvas de TPPT dos estudos clínicos CLL11 e COMPLEMENT 1 (Goede et al, 2015a;Goede et al, 2015b;Hillmen et al, 2015) (Figura 2). As curvas de TPPT para GClb e RClb foram obtidas diretamente por meio das curvas publicadas do estudo.…”

Section: Métodosunclassified

“…Já a curva de Clb foi projetada pela premissa de riscos proporcionais por meio da aplicação do inverso do hazard ratio (HR) (0,24; IC 95% 0,17-0,34; p < 0,0001) à curva de RClb, na ausência de uma curva publicada para o comparador (Paloni, 2016). O mesmo vale para a curva de OClb que foi extrapolada por meio da aplicação do HR (0,49; IC 95% 0,36-0,67; p < 0,0001) à curva de Clb (Hillmen et al, 2015). As curvas TPPT de todos os regimes de tratamento foram consideradas para o cálculo de número de pacientes em 1L e 2L.…”

Section: Métodosunclassified

Obinutuzumabe no tratamento de pacientes com leucemia linfoide crônica, não elegíveis à dose completa de fludarabina: análise de impacto orçamentário baseado no tempo para a próxima terapia

Fraga¹,

Ho²,

Fogliatto³

et al. 2017

JBES

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Chlorambucil plus ofatumumab versus chlorambucil alone in previously untreated patients with chronic lymphocytic leukaemia (COMPLEMENT 1): a randomised, multicentre, open-label phase 3 trial

Cited by 305 publications

References 36 publications

Front-line treatment of patients with chronic lymphocytic leukemia: a systematic review and network meta-analysis

Front-line treatment of patients with chronic lymphocytic leukemia: a systematic review and network meta-analysis

A Novel Fusion of ALT-803 (Interleukin (IL)-15 Superagonist) with an Antibody Demonstrates Antigen-specific Antitumor Responses

Obinutuzumabe no tratamento de pacientes com leucemia linfoide crônica, não elegíveis à dose completa de fludarabina: análise de impacto orçamentário baseado no tempo para a próxima terapia

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