Combination of CD20xCD3 Bispecific Antibodies with Ibrutinib and Lenalidomide Shows Efficacy in Relapsed/ Refractory CNS Lymphoma

Poor prognosis still remains in R/R CNS lymphoma although remarkable progress has been made with the introduction of CART cell therapies and bispecific antibodies CD20xCD3. Recently, some data showed that glofitamab penetrates the blood-brain barrier and induces response in patients with R/R CNS lymphoma. Lenalidomide and Ibrutinb separately have been previouly used for the treatment of nGC DLBCL and R/R CNS lymphoma and showed encouraging response. Lenalidomide has been proven to increase CD3 bispecific antibody and to induce CD8+ T cell cytotoxicity and expansion in R/R myeloma. Ibrutinib therapy also can reinvigorate CD8+ T cells. We hypothetised that the combination of Ibrutinib, lenalidomide and bispecific antibodies could show efficacy in R/R CNS lymphoma patients. We report the cases of 4 patients treated with this combination between January and July 2024 in our institution : 3 using Glofitamab and 1 treated with Epcoritamab. All patients received Ibrutinib 560mg per day from Day 1 continuously and lenalidomide 25mg from Day 1 to Day 10 of each cycle. Three patients received Obinutuzumab 1000mg as pretreatment at Day-7 then Glofitamab as step up doses at Day 8 and Day 15 and then 30mg from cycle 2. One patient received Epcoritamab as step doses 0,16mg at Day 1, 0,8mg at Day 8 and then 48mg from Day 15 cycle 1. Patient 1 is a female aged 51 years old. She was diagnosed DLBCL nGC stage IV, IPIaa=3 on January 2023 and received 4 cycles of Rituximab Doxorubicine Cyclophophamide Vinblastin Bleomycin and Prednisone (R ACVBP) and a maintenance with High Dose (HD) methotrexate and 4 cycles of Rituximab Ifosfamide Etoposide. A complete response was obtained at the end of treatment (EOT). She relapsed 3 months after with CNS localization only ; she received CART cell therapy after bridging therapy by radiotherapy. There was no reponse after 1 month. Thus she received a combination of Glofitamab Lenalidomide and Ibrutinib. Cerebral MRI perfomed after 2 cycles showed an encouraging good partial response. The treatment is still on going. Patient 2 is a male aged 42 years old and was diagnosed PCNSL on September 2023. He received in first line 2 cycles of MATRIX (Methotrexate,Cytarabine,Rituximab, Thiotepa) and had a partial response after 2 cycles assessed by cerebral MRI. Due to acute renal failure induced by HD methotrexate, he received only rituximab and cytarabine at thrid cycle, but relapsed right after this cycle. He was treated by CART cell therapy (Axi cel) with a bridging therapy by rituximab Ibrutinib and lenalidomide. He relapsed 1 month after the CART cell infusion assessed by cerebral MRI. A combination of Glofitamab Lenalidomide and Ibrutinib was decided and started on April 2024. After 3 cycles, MRI showed a complete response. The treatment is on going. Patient 3 is a female aged 71 years old and was diagnosed DLBCL nGC triple hit stade IV IPIaa=3 on January 2023. She received 6 cycles of R CHOP in first line and a complete metabolic response was obtained at EOT. She relapsed 2 months later with a CNS lymphoma and without any nodal involvement. CART cells therapy (Axi cel) was performed after a bridging therapy by Rituximab cytarabine and HD methotrexate. She relapsed 3 months later, assessed by cerebral MRI. She received Epcoritamab Lenalidomide and Ibrutinib, 1 cycle completed, and Day 1 of cycle 2. A cerebral CT scan was performed and showed a good partial response after Cycle 2 Day 1. Unfortunately, due to altered condition, she was not able to continue the treatment and she died 1 month later. Patient 4 is male aged 68 and was diagnosed DLBCL NOS EBV+ on 2019 stage IV IPIaa=2. He was successfully treated by RCHOP. A cerebral relapse occured 4 years later, assessed by MRI. He was treated in second line by Rituximab Cytarabine and HD Methotrexate. He responded well at 2 cycles but relapsed after 3 cycles. He then received Glofitamab Ibrutinb and Lenalidomide 1 cycle. Cerebral MRI is pending after 2 cycles, we will update the result during the ASH meeting. In conclusion, in our knowledge, this is the first time a combination of bispecfic antibodies CD20xCD3 with lenalidomide and Ibrutinib is been reported in R/R CNS lymphoma and show efficacy. More data and a longer follow up are needed to assess the efficacy of this combination but it may represent a good alternative treatment for this poor prognosis disease, especially after CART cell therapy.