Efficacy of venetoclax monotherapy in patients with relapsed, refractory mantle cell lymphoma after Bruton tyrosine kinase inhibitor therapy

Eyre, Toby A.; Walter, Harriet S.; Iyengar, Sunil; Follows, George; Cross, Matt; Fox, Christopher P.; Hodson, Andrew; Coats, Josh T.; Narat, Santosh; Morley, Nick; Dyer, Martin J. S.; Collins, Graham P.

doi:10.3324/haematol.2018.198812

Cited by 109 publications

(73 citation statements)

References 15 publications

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“…This initial report paved the way for landmark clinical trials of ibrutinib in MCL and other B‐cell NHLs . Our group has been involved in various clinical trials with ibrutinib, acalabrutinib, venetoclax (a Bcl2 inhibitor), and their combinations with anti‐CD20 monoclonal antibodies (mAb), rituximab, or with obinutuzumab. Furthermore, we are characterizing ibrutinib, acalabrutinib, and venetoclax‐refractory MCL and championing the CAR‐T cell clinical trials (Zuma‐2) in MCL in the United States.…”

Section: Advances In the Treatment Of MCLmentioning

confidence: 99%

“…Results from the ibrutinib with venetoclax combination trial were described above in the ibrutinib section. Venetoclax has great potential in MCL treatment, even among patients who have progressed on BTK inhibitors (53% ORR) . Of late, a few studies have reported venetoclax‐resistant mutations in CLL, and the mechanism of venetoclax resistance is being studied in MCL.…”

Section: Advances In the Treatment Of MCLmentioning

confidence: 99%

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Mantle cell lymphoma: 2019 update on the diagnosis, pathogenesis, prognostication, and management

2019

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Unprecedented advances in our understanding of the pathobiology, prognostication, and therapeutic options in mantle cell lymphoma (MCL) have taken place in the last few years. Heterogeneity in the clinical course of MCL—indolent vs aggressive—is further delineated by a correlation with the mutational status of the variable region of immunoglobulin heavy chain, methylation status, and SOX‐11 expression. Cyclin‐D1 negative MCL, in situ MCL neoplasia, and impact of the karyotype on prognosis are distinguished. Apart from Ki‐67% and morphology pattern (classic vs blastoid/pleomorphic), the proliferation gene signature has helped to further refine prognostication. Studies focusing on mutational dynamics and clonal evolution on Bruton's tyrosine kinase (BTK) inhibitors (ibrutinib, acalabrutinib) and/or Bcl2 antagonists (venetoclax) have further clarified the prognostic impact of somatic mutations in TP53, BIRC3, CDKN2A, MAP3K14, NOTCH2, NSD2, and SMARCA4 genes. In therapy, long‐term follow‐up on chemo‐immunotherapy studies has demonstrated durable remissions in some patients; however, long‐term toxicities, especially from second cancers, are a serious concern with chemotherapy. The therapeutic options in MCL are constantly evolving, with dramatic responses from nonchemotherapeutic agents (ibrutinib, acalabrutinib, and venetoclax). Chimeric antigen receptor therapy and combinations of nonchemotherapeutic agents are actively being studied and our focus is shifting toward making the treatment of MCL chemotherapy‐free. Still, MCL remains incurable. The following aspects of MCL continue to pose a challenge: disease transformation, role of the cytokine‐microenvironmental milieu, incorporation of positron emission tomography‐computerized tomography imaging, minimal residual disease in the prognosis, circulating tumor DNA testing for clonal evolution, predicting resistance to BTK inhibitors, and optimal management of patients who progress on BTK/Bcl2 inhibitors. Next‐generation clinical trials should incorporate nonchemotherapeutic agents and personalize the treatment based upon the genomic profile of individual patient. Recent advances in the field of MCL are reviewed.

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Section: Advances In the Treatment Of MCLmentioning

confidence: 99%

Section: Advances In the Treatment Of MCLmentioning

confidence: 99%

Mantle cell lymphoma: 2019 update on the diagnosis, pathogenesis, prognostication, and management

2019

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“…In patients with ibrutinib‐resistant RRMCL, the optimal therapeutic approach remains a matter of debate. Recently, Eyre et al observed an ORR of 53% (18% CR, 35% PR) to venetoclax monotherapy in patients with RRMCL that was pretreated with ibrutinib, and among the patients who were primarily resistant to ibrutinib, the ORR to venetoclax was 38% …”

Section: Resultsmentioning

confidence: 99%

Obinutuzumab and venetoclax induced complete remission in a patient with ibrutinib‐resistant non‐nodal leukemic mantle cell lymphoma

Zhou

Steinhardt

Düll

et al. 2020

European J of Haematology

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We herein report the case of a 73‐year‐old male patient who was diagnosed with leukemic non‐nodal MCL. This patient had received six cycles of bendamustine, which resulted in a transient remission, and a second‐line therapy with ibrutinib, which unfortunately failed to induce remission. We started a treatment with single‐agent obinutuzumab at a dose of 20 mg on day 1, 50 mg on day 2‐4, 330 mg on day 5, and 1000 mg on day 6. The laboratory analysis showed a rapid decrease of leukocyte count. Four weeks later, we repeated the treatment with obinutuzumab at a dose of 1000 mg q4w and started a therapy with venetoclax at a dose of 400 mg qd, which could be increased to 800 mg qd from the third cycle. This combination therapy was well tolerated. The patient achieved a complete remission (CR) after three cycles of obinutuzumab and venetoclax. To date, the patient has a progression‐free survival of 17 months under ongoing obinutuzumab maintenance q4w. This is the first report about obinutuzumab and venetoclax induced CR in rituximab‐intolerant patient with an ibrutinib‐resistant MCL. This case suggests that obinutuzumab‐ and venetoclax‐based combination therapy might be salvage therapy in patients with ibrutinib‐resistant MCL.

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“…2 Venetoclax is a potent selective oral inhibitor of the BCL2 antiapoptotic protein, with demonstrated efficacy in relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) 3,4 and mantle cell lymphoma. 5,6 In contrast, 2 cases of R/R T-PLL treated with venetoclax monotherapy demonstrated only moderate and transient activity. 7 There are no other published in vivo data on the use of venetoclax in T-PLL.…”

Section: Introductionmentioning

confidence: 98%

Dual dependence on BCL2 and MCL1 in T-cell prolymphocytic leukemia

Smith

Lomas²,

Constantine

et al. 2020

Blood Advances

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Efficacy of venetoclax monotherapy in patients with relapsed, refractory mantle cell lymphoma after Bruton tyrosine kinase inhibitor therapy

Cited by 109 publications

References 15 publications

Mantle cell lymphoma: 2019 update on the diagnosis, pathogenesis, prognostication, and management

Mantle cell lymphoma: 2019 update on the diagnosis, pathogenesis, prognostication, and management

Obinutuzumab and venetoclax induced complete remission in a patient with ibrutinib‐resistant non‐nodal leukemic mantle cell lymphoma

Dual dependence on BCL2 and MCL1 in T-cell prolymphocytic leukemia

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