Phase 1b study of obinutuzumab, ibrutinib, and venetoclax in relapsed and refractory chronic lymphocytic leukemia

Rogers, Kerry A.; Huang, Ying; Ruppert, Amy S.; Awan, Farrukh T.; Heerema, Nyla A.; Hoffman, Corinne; Lozanski, Gerard; Maddocks, Kami J.; Moran, Mollie E.; Reid, Mark A.; Lucas, Margaret S.; Woyach, Jennifer A.; Whitlow, W. Thomas; Jones, Jeffrey A.; Byrd, John C.

doi:10.1182/blood-2018-05-853564

Cited by 99 publications

(67 citation statements)

References 17 publications

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“…Ongoing studies are investigating venetoclax-obinutuzumab and other venetoclax combinations as doublets or triplets in CLL, including a phase 1b/2 study of venetoclaxobinutuzumab-ibrutinib. 38 Preliminary results for 12 patients with R/R CLL showed a high ORR (92%) and deep remissions (all 12 patients became uMRD in PB or BM), consistent with our findings for venetoclax-obinutuzumab; however, longer follow-up is needed to determine longer-term outcomes. 38 Ibrutinib-venetoclax has also shown promising clinical activity in the frontline treatment of CLL in early data from the phase 2 CAPTIVATE study.…”

Section: Despite the Study Population Including A High Proportion Of supporting

confidence: 88%

Phase 1b study of venetoclax-obinutuzumab in previously untreated and relapsed/refractory chronic lymphocytic leukemia

Flinn

Gribben

Dyer

et al. 2019

Blood

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Key points [2 key points maximum, up to 140 characters, including spaces]: 1. Dose finding established venetoclax 400 mg combined with obinutuzumab; this regimen had an acceptable safety profile in R/R and 1L CLL. [138 ch] 2. Venetoclax-obinutuzumab elicited high response rates with deep remissions in R/R and 1L CLL, irrespective of cytogenetic risk factors. [137 ch] Abstract This single-arm, open-label, phase 1b study evaluated the maximum tolerated dose (MTD) of venetoclax when given with obinutuzumab and its safety and tolerability in patients with relapsed/refractory (R/R) or previously untreated (1L) chronic lymphocytic leukemia. Venetoclax dose initially was escalated (100-400 mg) in a 3+3 design to define the MTD combined with standard-dose obinutuzumab. Patients received venetoclax (Schedule A) or obinutuzumab (Schedule B) first to compare safety and determine dose/schedule for expansion. Venetoclax-obinutuzumab was administered for 6 cycles, followed by venetoclax monotherapy until disease progression (R/R) or fixed-duration 1 year of treatment (1L). 50 R/R and 32 1L patients were enrolled. No dose-limiting toxicities were observed. Safety, including incidence of tumor lysis syndrome (TLS), did not differ between schedules (2 laboratory TLS per schedule). Schedule B and 400 mg dose of venetoclax was chosen for expansion. The most common grade 3-4 adverse event was neutropenia (R/R, 58% of patients; 1L, 53%).Rates of grade 3-4 infections were 29% (R/R) and 13% (1L); no fatal infections occurred in 1L. All infusion-related reactions were grade 1-2, except for 2 grade 3 events. No clinical TLS was observed. Overall best response rate was 95% (CR/CRi, 37%) in R/R and 100% (CR/CRi, 78%) in 1L patients. Rate of undetectable (<10 -4 ) minimal residual disease (MRD) in peripheral blood for R/R and 1L patients respectively was 64% and 91%

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Section: Despite the Study Population Including A High Proportion Of supporting

confidence: 88%

Phase 1b study of venetoclax-obinutuzumab in previously untreated and relapsed/refractory chronic lymphocytic leukemia

Flinn

Gribben

Dyer

et al. 2019

Blood

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“…This progress in CLL therapy has encouraged additional efforts to use more than two highly effective targeted agents, thereby testing the concept that a deeper response might allow discontinuation of all treatment . A recent phase 1b study demonstrates that combination therapy with obinutuzumab, ibrutinib, and venetoclax is feasible in patients with CLL …”

Section: Can We Improve the Efficacy Of Ibrutinib Through Combinationmentioning

confidence: 99%

“…59 A recent phase 1b study demonstrates that combination therapy with obinutuzumab, ibrutinib, and venetoclax is feasible in patients with CLL. 15 Other active agents such as phosphoinositide-3-kinase (PI3K)…”

Section: Can We Improve the Depth Of Response Using Ibrutinib In Comentioning

confidence: 99%

“…Three recent landmark trials have suggested in turn, that ibrutinib alone or in combination with an anti‐CD20 monoclonal antibody would become the new standards of care for upfront therapy of CLL . However, while many issues still remain unsolved with ibrutinib, (including the fact that only a relatively small proportion of patients achieve complete remission (CR), emergence of resistant clones, the need for continuous therapy and drug toxicities), second‐generation BTK inhibitors have already aroused considerable interest and have gathered momentum …”

Section: Introductionmentioning

confidence: 99%

“…have already aroused considerable interest and have gathered momentum. [13][14][15] This review focuses on the effectiveness of ibrutinib in relapsed/ refractory (R/R) patients as well as in the frontline setting and takes into account the fact that the therapeutic landscape of CLL is rapidly changing under the pressure of recent progress in the understanding of the biology of this disease.…”

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Ibrutinib in the treatment of chronic lymphocytic leukemia: 5 years on

Molica

Matutes

Tam

et al. 2019

Hematological Oncology

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A major revolution in the treatment of chronic lymphocytic leukemia (CLL) began with the approval of ibrutinib, a first‐in‐class oral inhibitor of Bruton tyrosine kinase (BTK), for the treatment of relapsed/refractory (R/R) and/or TP53 mutated patients with CLL. However, 5 years later, some issues relating to this disorder still remain including the fact that with ibrutinib only a relatively small proportion of patients achieve complete remission and that ibrutinib‐resistant CLL clones can develop in about 20% of patients. In addition, therapy must still be given continuously, and toxicities leading to drug discontinuation occur in about 30% of patients. In the meantime second‐generation BTK inhibitors have already aroused considerable interest and gathered momentum. A possible strategy to overcome some of these obstacles is to combine ibrutinib with other targeted agents especially in high‐risk disease, such as previously treated refractory patients or those with TP53 aberrations or complex karyotypes, in whom rapid eradication of disease is most desirable. Therapy with single agent ibrutinib should be part of a sequential approach for patients with low risk disease, especially in older patients (aged >70 years) with a higher burden of comorbidities. Long‐term results of ongoing studies combining Ibrutinib with (chemo)‐immunotherapy or other targeted agents are eagerly awaited. Future clinical trials are indeed still needed to provide answers to these open questions.

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Apatinib enhances chemosensitivity of ABT‐199 in diffuse large B‐cell lymphoma

Shen

et al. 2022

Molecular Oncology

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To investigate the effect of Apatinib (an inhibitor targeting VEGFR-2) enhances chemosensitivity of ABT-199 on diffuse large B-cell lymphoma (DLBCL). Viability assay and flow cytometric assay for determining apoptosis, cell cycle, mitochondrial membrane potential, reactive oxygen species and immunoblotting were used to explore the combination effect in DLBCL cell lines, DLBCL patient samples, and DLBCL mouse models. RNA sequencing assay helped identify mechanisms of ABT-199 plus Apatinib. The results show that ABT-199 combined with Apatinib inhibited cell proliferation, reduced colony-forming capacity, and induced apoptosis and cell cycle arrest in DLBCL cells. Mechanistically, the combination therapy inhibited tumour cell growth and promoted tumour cell death by regulating EDN1 and MAPK-related pathways and activating the intrinsic apoptotic pathway. The effect of the combination therapy was also validated in primary DLBCL blasts and xenograft mouse models. Our findings indicate that Apatinib enhances the chemosensitivity of ABT-199 and might serve as a promising therapeutic strategy for DLBCL.

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Phase 1b study of obinutuzumab, ibrutinib, and venetoclax in relapsed and refractory chronic lymphocytic leukemia

Abstract: Key Points Cytoreduction with obinutuzumab and ibrutinib followed by the addition of venetoclax has acceptable safety with no tumor lysis syndrome. This combination has preliminary activity including complete remissions with undetectable residual disease in relapsed or refractory CLL.

Cited by 99 publications

References 17 publications

Phase 1b study of venetoclax-obinutuzumab in previously untreated and relapsed/refractory chronic lymphocytic leukemia

Phase 1b study of venetoclax-obinutuzumab in previously untreated and relapsed/refractory chronic lymphocytic leukemia

Ibrutinib in the treatment of chronic lymphocytic leukemia: 5 years on

Apatinib enhances chemosensitivity of ABT‐199 in diffuse large B‐cell lymphoma

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