Ibrutinib, rituximab, and lenalidomide in unfit or frail patients aged 75 years or older with de novo diffuse large B-cell lymphoma: a phase 2, single-arm study

Xu, Pengpeng; Shi, Zi-Yang; Qian, Ying; Cheng, Shu; Zhu, Yue; Jiang, Libin; Li, Jianfeng; Fang, Hai; Huang, Huizhen; Yi, Hongmei; Ouyang, Bin-Sheng; Wang, Li; Zhao, Wei‐Li

doi:10.1016/s2666-7568(22)00123-4

Cited by 16 publications

(16 citation statements)

References 31 publications

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“…In fact, following R-miniCHOP the 24-months disease free survival was reported to be slightly less than 60% (vs. 74% for R-DEVEC) [ 5 ]. Furthermore, two recent trials based on Rituximab-lenalidomide [ 11 ] and Rituximab-lenalidomide-ibrutinib(iR2) [ 12 ] combinations, respectively, reported a 12-months PFS of 55%, [ 11 ] and a 24-months PFS of 53%, respectively. We acknowledge these comparisons, although intriguing, remain speculative.…”

Section: Discussionmentioning

confidence: 99%

“…Conversely, ongoing clinical trials based on immunomodulators [ 8 ], new monoclonal antibodies [ 9 ] and small molecules targeting pathogenetic pathways [ 10 ] will hopefully help a shift towards therapeutic schedules defined as chemo-free, in vulnerable DLBCL. As a matter of fact, results from a few phase II trials, based on chemo-free combinations, have already reported encouraging data [ 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

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Remarkable Remission Rate and Long-Term Efficacy of Upfront Metronomic Chemotherapy in Elderly and Frail Patients, with Diffuse Large B-Cell Lymphoma

Bocci

Pelliccia

Orlandi

et al. 2022

JCM

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The upfront treatment of very elderly and frail patients with diffuse large B-cell lymphoma (DLBCL) is still a matter of debate. Herein, we report results of the metronomic all-oral DEVEC [prednisolone/deltacortene®, vinorelbine (VNR), etoposide (ETO), cyclophosphamide] combined with i.v. rituximab (R). This schedule was administered as a first line therapy in 22 elderly/frail DLBCL subjects (median age = 84.5 years). In 17/22 (77%) patients, the Elderly-IPI-score was high. After a median follow-up of 24 months, 15 patients had died: seven (50%) for causes unrelated to DLBCL or its treatment, six (40%) for progression, and two (13%) for multiorgan failure. Six treatment-pertinent serious-adverse-events occurred. At the end of induction, 14/22 (64%) achieved complete remission; overall survival and event-free survival at 24 months were both 54% (95% CI = 32–72%), while the time to progression was 74% (95% CI = 48–88%). Furthermore, antiproliferative and proapoptotic assays were performed on DLBCL/OCI-LY3 cell-line using metronomic VNR and ETO and their combination. Both metronomic VNR and ETO had concentration-dependent antiproliferative (IC50 = 0.036 ± 0.01 nM and 7.9 ± 3.6 nM, respectively), and proapoptotic activities in DLBCL cells. Co-administration of the two drugs showed a strong synergism (combination index < 1 and dose reduction index > 1) against cell proliferation and survival. This low-dose schedule seems to compare favourably with intravenous-CHEMO protocols used in the same subset. Indeed, the high synergism shown by metronomic VRN+ETO in in vitro studies, explains the remarkable clinical responses and it allows significant dose reductions.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Remarkable Remission Rate and Long-Term Efficacy of Upfront Metronomic Chemotherapy in Elderly and Frail Patients, with Diffuse Large B-Cell Lymphoma

Bocci

Pelliccia

Orlandi

et al. 2022

JCM

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“…For the intermediate-and high-risk patients, chemotherapy-free agents that have shown potential in DLBCL, including bi-specific antibodies, immunomodulatory agents, targeted agents and CAR-T based therapy could be considered in a clinical trial setting, either alone or in combination with R-CHOP. [46][47][48][49][50] In conclusion, we have developed and externally validated the Geriatric Prognostic Index (GPI) suited for older (≥70 years) DLBCL patients who are considered candidates for curative treatment with R-CHOP. The GPI combines GA variables with well-established prognostic factors in DLBCL.…”

Section: Discussionmentioning

confidence: 99%

The Geriatric Prognostic Index: a clinical prediction model for survival of older diffuse large B-cell lymphoma patients treated with standard immunochemotherapy

Isaksen¹,

Galleberg²,

Mastroianni³

et al. 2023

haematol

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International prognostic Index (IPI) is the most widely used clinical prediction model for diffuse large B-cell lymphoma (DLBCL) patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP), but may be suboptimal in older patients. We aimed to develop and externally validate a clinical prediction model for older, R-CHOP treated DLBCL patients by examining geriatric assessment and lymphoma-related parameters in real-world cohorts. A population-based training set of 365 R-CHOP treated DLBCL patients ≥70 years was identified through the Cancer Registry of Norway. The external test set consisted of a population-based cohort of 193 patients. Data on candidate predictors was retrieved from the Cancer Registry and through review of clinical records. Cox regression models for 2-year overall survival (OS) were used for model selection. Activities of daily living (ADL), Charlson Comorbidity index (CCI), age, sex, albumin, stage, ECOG and LDH were identified as independent predictors and combined into a Geriatric prognostic index (GPI). The GPI demonstrated good discrimination (optimism-corrected C-index 0.752), and identified a low-, intermediate- and high-risk group with significantly different survival (2-year OS 94%, 65%, 25%). At external validation, the continuous and grouped GPI demonstrated good discrimination (C-index 0.727, 0.710) and the GPI groups had significantly different survival (2- year OS 95%, 65%, 44%). Both the continuous and grouped GPI showed better discrimination than IPI, R-IPI and NCCN-IPI (C-index 0.621, 0.583, 0.670) We have developed and externally validated the GPI for older DLBCL patients treated with RCHOP that outperformed IPI, R-IPI and NCCN-IPI. A web-based calculator is available at https://wide.shinyapps.io/GPIcalculator/.

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“…Moreover, BTK expression correlated positively with higher international prognostic index (IPI), and worse outcome after treatment with rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). A chemotherapy-free regimen was studied in a phase 2 trial with the BTKi ibrutinib, combined with lenalidomide and rituximab (iR2) ( 75 ). In a group of 30 treatment-naïve unfit or frail patients over 75 years of age, the ORR was 66.7% with 56.7% of CRs.…”

Section: Zanubrutinib In Other Lymphoid Malignanciesmentioning

confidence: 99%

Zanubrutinib for the treatment of lymphoid malignancies: Current status and future directions

Wolska-Washer

Robak

2023

Front. Oncol.

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Zanubrutinib (BGB-3111, Brukinsa®, BeiGene) is a next-generation irreversible inhibitor of Bruton’s tyrosine kinase (BTK), developed by BeiGene in 2012 for the treatment of B-cell malignancies. It was designed to minimize off-target inhibition of TEC- and EGFR-family kinases. Zanubrutinib is more selective than ibrutinib for BTK versus EGFR, FGR, FRK, HER2, HER4, ITK, JAK3, LCK, BLK and TEC. In addition, compared to ibrutinib, zanubrutinib has improved oral absorption and better target occupancy. Zanubrutinib demonstrated a lower incidence of off-target toxicities and reduced severity than ibrutinib. Moreover, zanubrutinib is similar to acalabrutinib, with less activity against TEC and ITK. The preliminary phase 1 results suggest that zanubrutinib has clinical activity and the drug is well tolerated in patients with B-cell lymphoid malignancies. Recent clinical trials have found it to demonstrate excellent efficacy and good tolerability in patients with chronic lymphocytic leukemia (CLL), Waldenstrom macroglobulinemia (WM) and mantle cell lymphoma (MCL). In recent phase 3 studies, zanubrutinib was compared with ibrutinib in patients with relapsed/refractory (R/R) MW and RR CLL. In both trials, zanubrutinib was found to demonstrate clinically meaningful advantages in safety and tolerability over ibrutinib; in particular, it was associated with a lower risk of atrial fibrillation/flutter and major bleeding events. In the recent SEQUOIA study, comparing zanubrutinib with bendamustine and rituximab (BR) in patients with previously untreated CLL, zanubrutinib significantly improved progression-free survival versus BR, with an acceptable safety profile consistent with previous studies. Zanubrutinib also demonstrated good activity and tolerability in patients with R/R MCL, marginal zone lymphoma and follicular lymphoma. Trials examining the efficacy and safety of the combination of zanubrutinib with obinutuzumab venetoclax and other drugs are ongoing. This review summarizes the clinical efficacy and safety of zanubrutinib in lymphoid malignancies.

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Ibrutinib, rituximab, and lenalidomide in unfit or frail patients aged 75 years or older with de novo diffuse large B-cell lymphoma: a phase 2, single-arm study

Cited by 16 publications

References 31 publications

Remarkable Remission Rate and Long-Term Efficacy of Upfront Metronomic Chemotherapy in Elderly and Frail Patients, with Diffuse Large B-Cell Lymphoma

Remarkable Remission Rate and Long-Term Efficacy of Upfront Metronomic Chemotherapy in Elderly and Frail Patients, with Diffuse Large B-Cell Lymphoma

The Geriatric Prognostic Index: a clinical prediction model for survival of older diffuse large B-cell lymphoma patients treated with standard immunochemotherapy

Zanubrutinib for the treatment of lymphoid malignancies: Current status and future directions

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