A phase 2 study of the BH3 mimetic BCL2 inhibitor navitoclax (ABT-263) with or without rituximab, in previously untreated B-cell chronic lymphocytic leukemia

Kipps, Thomas J.; Eradat, Herbert; Grosicki, Sebastian; Catalano, John; Cosolo, W; Dyagil, Iryna; Yalamanchili, Sreeni; Chai, Akiko; Sahasranaman, Srikumar; Punnoose, Elizabeth A.; Hurst, Deborah; Pylypenko, Halyna

doi:10.3109/10428194.2015.1030638

Cited by 154 publications

(110 citation statements)

References 28 publications

(38 reference statements)

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“…However, CLL cells in vivo appear to be substantially more resistant to the cytotoxic effects of these drugs, as evidenced by the relatively low complete response rates observed in recent clinical trials. 12,14,38 The greater resistance of CLL cells in vivo is believed to be caused by survival signals that the leukemic cells receive in the lymph node microenvironment, which induce changes in the expression of apoptosis-regulatory proteins not directly targeted by these drugs. 39 The existence of such signals is further supported by observations from ongoing clinical trials with ABT-199 in CLL, which demonstrate frequent presence of residual disease in lymph nodes of patients that are otherwise minimal residual disease-negative in the peripheral blood or bone marrow.…”

Section: Discussionmentioning

confidence: 99%

BCR signaling inhibitors differ in their ability to overcome Mcl-1–mediated resistance of CLL B cells to ABT-199

Bojarczuk

Sasi

Gobessi

et al. 2016

Blood

102

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Key Points• BCR signals induce resistance in CLL cells by upregulating Mcl-1.• SYK inhibitors prevent BCRmediated Mcl-1 induction more effectively than BTK or PI3Kd inhibitors.The Bcl-2 antagonist has demonstrated promising clinical activity in patients with chronic lymphocytic leukemia (CLL). ABT-199 is strongly cytotoxic against unstimulated peripheral blood CLL cells in vitro but is much less effective against CLL cells that have received survival signals from the microenvironment. In particular, stimulation of CLL cells with CD40L results in substantial resistance mediated by induction of the antiapoptotic Bcl-2 family proteins Bcl-xL and Bfl-1. In this study, we investigated whether resistance to ABT-199 can be conferred by B-cell receptor (BCR) stimulation, which is another important survival signal from the leukemic microenvironment. We show that sustained BCR stimulation results in significant ABT-199 resistance, which correlates with induction of the antiapoptotic protein Mcl-1 and less consistently with downregulation of proapoptotic Bmf, Hrk, and Bim EL . A major role for Mcl-1 in conferring ABT-199 resistance is additionally supported by knockdown and enforced expression experiments with primary CLL cells. We further show that SYK, BTK, and phosphatidylinositol 3-kinase d (PI3Kd) inhibitors significantly downregulate Mcl-1, but with different efficacy. Complete Mcl-1 downregulation was consistently achieved only with SYK inhibitors R406 and GS-9973 (entospletinib), whereas the BTK inhibitor ibrutinib and the PI3Kd inhibitor idelalisib in more than half of the cases had only a partial effect. The greater ability of SYK inhibitors to downregulate Mcl-1 correlated with their greater capacity to block BCR-mediated inactivation of GSK-3, a major negative regulator of Mcl-1. The finding that BCR signaling inhibitors differ in their ability to target Mcl-1 is relevant for the design of clinical trials combining these agents with ABT-199. (Blood. 2016;127(25):3192-3201)

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Section: Discussionmentioning

confidence: 99%

BCR signaling inhibitors differ in their ability to overcome Mcl-1–mediated resistance of CLL B cells to ABT-199

Bojarczuk

Sasi

Gobessi

et al. 2016

Blood

102

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“…Although rituximab has modest single-agent activity in chronic lymphocytic leukaemia and small lymphocytic lymphoma, 8,9 when combined with chemotherapy, it improves the proportion of patients who achieve an overall response, progression-free survival, and overall survival. 10,11 Combining rituximab with an earlier BCL2 inhibitor, navitoclax, proved tolerable and highly active in patients with relapsed or refractory lymphoid malignancies, 12 including chronic lymphocytic leukaemia, 13 establishing the proof-of-principle and safety of this approach.…”

Section: Introductionmentioning

confidence: 98%

Venetoclax plus rituximab in relapsed or refractory chronic lymphocytic leukaemia: a phase 1b study

Seymour

Brander

et al. 2017

The Lancet Oncology

302

246

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Summary Background Selective BCL2 inhibition with venetoclax has substantial activity in patients with relapsed or refractory chronic lymphocytic leukaemia. Combination therapy with rituximab enhanced activity in preclinical models. The aim of this study was to assess the safety, pharmacokinetics, and activity of venetoclax in combination with rituximab. Methods Adult patients with relapsed or refractory chronic lymphocytic leukaemia (according to the 2008 Modified International Workshop on CLL guidelines) or small lymphocytic lymphoma were eligible for this phase 1b, dose-escalation trial. The primary outcomes were to assess the safety profile, to determine the maximum tolerated dose, and to establish the recommended phase 2 dose of venetoclax when given in combination with rituximab. Secondary outcomes were to assess the pharmacokinetic profile and analyse efficacy, including overall response, duration of response, and time to tumour progression. Minimal residual disease was a protocol-specified exploratory objective. Central review of the endpoints was not done. Venetoclax was dosed daily using a stepwise escalation to target doses (200–600 mg) and then monthly rituximab commenced (375 mg/m2 in month 1 and 500 mg/m2 in months 2–6). Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for adverse events version 4.0. Protocol-guided drug cessation was allowed for patients who achieved complete response (including complete response with incomplete marrow recovery) or negative bone marrow minimal residual disease. Analyses were done per protocol for all patients who commenced drug and included all patients who received at least one dose of venetoclax. Data were pooled across dose cohorts. Patients are still receiving therapy and follow-up is ongoing. The trial is registered at ClinicalTrials.gov, number NCT01682616. Findings Between Aug 6, 2012, and May 28, 2014, we enrolled 49 patients. Common grade 1–2 toxicities included upper respiratory tract infections (in 28 [57%] of 49 patients), diarrhoea (27 [55%]), and nausea (25 [51%]). Grade 3–4 adverse events occurred in 37 (76%) of 49 patients; most common were neutropenia (26 [53%]), thrombocytopenia (eight [16%]), anaemia (seven [14%]), febrile neutropenia (six [12%]), and leucopenia (six [12%]). The most common serious adverse events were pyrexia (six [12%]), febrile neutropenia (five [10%]), lower respiratory tract infection, and pneumonia (each three [6%]). Clinical tumour lysis syndrome occurred in two patients (resulting in one death) who initiated venetoclax at 50 mg. After enhancing tumour lysis syndrome prophylaxis measures and commencing venetoclax at 20 mg, clinical tumour lysis syndrome did not occur. The maximum tolerated dose was not identified; the recommended phase 2 dose of venetoclax in combination with rituximab was 400 mg. Overall, 42 (86%) of 49 patients achieved a response, including a complete response in 25 (51%) of 49 patients. 2 year estimates for progression-free survival and ongoing resp...

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“…In early clinical testing, navitoclax displayed single-agent activity against relapsed/refractory lymphoid malignancies 10, 51 , especially CLL. Adding navitoclax to the monoclonal anti-CD20 antibody rituximab improved both response rate and progression-free survival in previously untreated CLL compared to rituximab alone 52 . This hypersensitivity of CLL was thought to reflect frequent deletion of genes on chromosome 13q14 encoding miR15A and miR16A, two microRNAs that normally inhibit BCL2 expression 53, 54 .…”

Section: Current Status Of Bh3 Mimeticsmentioning

confidence: 97%

Mitochondrial apoptosis and BH3 mimetics

2016

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The BCL2-selective BH3 mimetic venetoclax was recently approved for the treatment of relapsed, chromosome 17p-deleted chronic lymphocytic leukemia (CLL) and is undergoing extensive testing, alone and in combination, in lymphomas, acute leukemias, and solid tumors. Here we summarize recent advances in understanding of the biology of BCL2 family members that shed light on the action of BH3 mimetics, review preclinical and clinical studies leading to the regulatory approval of venetoclax, and discuss future investigation of this new class of antineoplastic agent.

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A phase 2 study of the BH3 mimetic BCL2 inhibitor navitoclax (ABT-263) with or without rituximab, in previously untreated B-cell chronic lymphocytic leukemia

Cited by 154 publications

References 28 publications

BCR signaling inhibitors differ in their ability to overcome Mcl-1–mediated resistance of CLL B cells to ABT-199

BCR signaling inhibitors differ in their ability to overcome Mcl-1–mediated resistance of CLL B cells to ABT-199

Venetoclax plus rituximab in relapsed or refractory chronic lymphocytic leukaemia: a phase 1b study

Mitochondrial apoptosis and BH3 mimetics

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