Avadomide plus obinutuzumab in patients with relapsed or refractory B-cell non-Hodgkin lymphoma (CC-122-NHL-001): a multicentre, dose escalation and expansion phase 1 study

Michot, Jean‐Marie; Bouabdallah, Réda; Vitolo, Umberto; Doorduijn, Jeanette K.; Salles, Gilles; Chiappella, Annalisa; Zinzani, Pier Luigi; Bijou, Fontanet; Kersten, Marie José; Sarmiento, R.; Mosulen, Silvia; Méndez, Camila; Uttamsingh, Shailaja; Pourdehnad, Michael; Hege, Kristen; Chen, Tianlei; Klein, Christian; Hagner, Patrick R.; Nikolova, Zariana; Ribrag, Vincent

doi:10.1016/s2352-3026(20)30208-8

Cited by 26 publications

(26 citation statements)

References 29 publications

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“…Avadomide combined with obinutuzumab shows similar tolerability to R2 with a high (76%) ORR in FL and 47% of patients achieving a CR. 140 Other IMiDs/cereblon E3 ligase modulators like iberdomide (CC-220) and CC-99282 are being further investigated to determine their activity in lymphoma.…”

Section: Immunotherapy: Emerging Directionmentioning

confidence: 99%

Chemotherapy-Free Management of Follicular and Marginal Zone Lymphoma

Ollila¹,

Olszewski²

2021

CMAR

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Many patients with follicular (FL) or marginal zone lymphoma (MZL) are not eligible to receive immunochemotherapy due to advanced age or comorbidities. Recent innovations in the treatment of these indolent lymphomas provide options for multiple lines of chemotherapy-free management. More research is needed to determine which older patients are best served by a chemotherapy-free approach in the context of geriatric vulnerabilities. In the first line, regardless of disease burden, rituximab monotherapy can provide high rates of disease control with minimal toxicity, while judicious use of brief maintenance extends the duration of response. Radioimmunotherapy using ibritumomab tiuxetan is an effective and safe post-rituximab consolidation for older patients who have <25% bone marrow involvement. The combination of rituximab and lenalidomide, although "chemotherapy-free", does not improve tolerability over immunochemotherapy. However, studies support lower doses and shorter duration of lenalidomide exposure as a means to improve safety without materially compromising efficacy for older individuals. Extranodal MZL can often be effectively controlled with low-dose radiation therapy, and splenic MZL has excellent outcomes with rituximab monotherapy. For many patients with relapsed FL/ MZL, simple retreatment with anti-CD20 antibodies will prove sufficient. Other currently available options for relapsed/refractory disease include ibritumomab tiuxetan, lenalidomide with rituximab, umbralisib as a potentially less toxic PI3K inhibitor, ibrutinib (for MZL), and tazemetostat (for FL, especially with EZH2 mutation). Emerging data with novel forms of immunotherapy (antibody-drug conjugates like polatuzumab vedotin or loncastuximab tesirine; T-cell-engaging bispecific antibodies like mosunetuzumab or epcoritamab; and chimeric antigen receptor CAR T-cells like axicabtagene ciloleucel) suggest that immune-directed approaches can produce very high and potentially durable responses in FL/MZL with limited toxicities, further obviating the need for chemotherapy.

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Section: Immunotherapy: Emerging Directionmentioning

confidence: 99%

Chemotherapy-Free Management of Follicular and Marginal Zone Lymphoma

Ollila¹,

Olszewski²

2021

CMAR

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“…CC-122 is now in phase 1/2 trials for hematological malignancies, including DLBCL and MM [ 29 ]. The most common treatment-emergent adverse events (TEAEs) are neutropenia, thrombocytopenia and anemia [ 21 , 22 , 114 – 116 ]. CC-220 has shown significant efficacy in systemic lupus erythematosus (SLE) and relapsed/refractory MM (RRMM) and now under phase 1/2 studies [ 24 , 117 ].…”

Section: Conclusion and Perspectivementioning

confidence: 99%

“…Lenalidomide also has therapeutic activity in myelodysplastic syndrome (MDS) with deletion of chromosome 5q (del(5q)) [ 10 , 11 ], mantle cell lymphoma (MCL) [ 12 – 15 ] and chronic lymphocytic leukemia (CLL) [ 16 – 18 ]. New generations of IMiDs, including CC-122 (avadomide) [ 19 – 22 ], CC-220 (iberdomide) [ 23 , 24 ], CC-885 [ 25 , 26 ], CC-92480 [ 27 ] and CC-90009 [ 28 ] (Fig. 1 ), are being evaluated for their potential to treat diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), MM and acute myeloid leukemia (AML) [ 29 , 30 ].…”

Section: Introductionmentioning

confidence: 99%

Key regulators of sensitivity to immunomodulatory drugs in cancer treatment

Wang

Gao

2021

Biomark Res

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Immunomodulatory drugs (IMiDs) include thalidomide, lenalidomide, and pomalidomide, which have shown significant efficacy in the treatment of multiple myeloma (MM), myelodysplastic syndrome (MDS) with deletion of chromosome 5q (del(5q)) and other hematological malignancies. IMiDs hijack the CRL4CRBN ubiquitin ligase to target cellular proteins for ubiquitination and degradation, which is responsible for their clinical activity in MM and MDS with del(5q). However, intrinsic and acquired resistance frequently limit the efficacy of IMiDs. Recently, many efforts have been made to explore key regulators of IMiD sensitivity, resulting in great advances in the understanding of the regulatory networks related to this class of drugs. In this review, we describe the mechanism of IMiDs in cancer treatment and summarize the key regulators of IMiD sensitivity. Furthermore, we introduce genome-wide CRISPR-Cas9 screenings, through which the regulatory networks of IMiD sensitivity could be identified.

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“…More recently, avadomide (CC-122) a next generation CELMoD, has demonstrated promising clinical activity in R/R DLBCL patients as a single-agent. Avadomide has also been well-tolerated in combination therapy with anti-CD20 monoclonal antibodies including obinutuzumab [22]. Avadomide exhibits its antitumor effects by binding to the same protein target, cereblon (CRBN), as IMiDs, however, preclinical and clinical data suggest that its direct cell autonomous activity (anti-proliferative and direct tumor cytotoxicity), as well as its immunostimulatory effects are superior to that of lenalidomide [23,24].…”

Section: Introductionmentioning

confidence: 99%

Immunomodulatory Drugs for the Treatment of B Cell Malignancies

Ioannou

Jain

Ramsay

2021

IJMS

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Accumulating evidence suggests that the tumor microenvironment (TME) is involved in disease progression and drug resistance in B cell malignancies, by supporting tumor growth and facilitating the ability of malignant cells to avoid immune recognition. Immunomodulatory drugs (IMiDs) such as lenalidomide have some direct anti-tumor activity, but critically also target various cellular compartments of the TME including T cells, NK cells, and stromal cells, which interfere with pro-tumor signaling while activating anti-tumor immune responses. Lenalidomide has delivered favorable clinical outcomes as a single-agent, and in combination therapy leads to durable responses in chronic lymphocytic leukemia (CLL) and several non-Hodgkin lymphomas (NHLs) including follicular lymphoma (FL), diffuse large B cell lymphoma (DLBCL), and mantle cell lymphoma (MCL). Recently, avadomide, a next generation cereblon E3 ligase modulator (CELMoD), has shown potent anti-tumor and TME immunomodulatory effects, as well as promising clinical efficacy in DLBCL. This review describes how the pleiotropic effects of IMiDs and CELMoDs could make them excellent candidates for combination therapy in the immuno-oncology era—a concept supported by preclinical data, as well as the recent approval of lenalidomide in combination with rituximab for the treatment of relapsed/refractory (R/R) FL.

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Avadomide plus obinutuzumab in patients with relapsed or refractory B-cell non-Hodgkin lymphoma (CC-122-NHL-001): a multicentre, dose escalation and expansion phase 1 study

Cited by 26 publications

References 29 publications

Chemotherapy-Free Management of Follicular and Marginal Zone Lymphoma

Chemotherapy-Free Management of Follicular and Marginal Zone Lymphoma

Key regulators of sensitivity to immunomodulatory drugs in cancer treatment

Immunomodulatory Drugs for the Treatment of B Cell Malignancies

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