Abstract
Individual variations in concentrations of rituximab in different B cell non-Hodgkin’s lymphoma subtypes and their relevance to efficacy were still unclear. From 2016 to 2021, a prospective clinical trial was conducted, and 510 samples with 6 uncommon subtypes of B-cell lymphoma were enrolled to examine the pharmacokinetic behaviour of rituximab and its impact on clinical outcomes, including complete response (CR), progression-free survival (PFS) and overall survival (OS). Considerable variability was observed in the rituximab trough concentration in the first cycle (C1-trough, 1.16–55.52 μg/ml) in patients with different lymphoma subtypes. Patients with “double-hit” lymphoma (4.01 ± 0.77 μg/ml) or mantle cell lymphoma (MCL; 15.65 ± 16.45 μg/ml) had much lower C1-trough and worse outcomes. Great individual variation in the C1-trough existed among patients with mucosa-associated lymphoma (MALT), and the high C1-trough observed in patients treated with the RB regimen was associated with a better response than was obtained with R-CHOP (38.41 ± 14.13 μg/ml vs 15.49 ± 8.80 μg/ml, p = 0.0029). Despite the high aggressiveness of the cancer, Burkitt lymphoma patients receiving intensive chemotherapy had the highest C1-trough (28.85 ± 9.35 μg/ml) and maintained long-term PFS. The C1-trough in patients with mixed, unclassifiable B-cell lymphoma was close to 20 μg/ml, and these patients had acceptable outcomes. Overall, a low rituximab C1-trough was associated with adverse consequences, including persistent progression, early recurrence and a short OS, however, some high-risk factors appeared to be balanced by the presence of a high C1-trough. Basal levels of circulating CD19+ lymphocytes differed between and within patients with diverse lymphoma subtypes and were negatively correlated with C1-trough. Therefore, the traditional doses of rituximab are inadequate for patients with “double-hit” lymphoma and MCL. Increasing the initial rituximab dose according to the disease, high-risk factors and even the baseline CD19+ lymphocyte count will be new methods to optimize therapeutic regimens for patients with different lymphoma subtypes.
Highlights
Since its initial approval in 1997, rituximab has improved the prognosis of all B-cell derived lymphoproliferative diseases, especially B-cell malignancies (Pierpont et al, 2018), including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt lymphoma, high-grade B-cell lymphoma, mantle cell lymphoma (MCL), mucosa-associated lymphoma (MALT), and chronic lymphocytic leukaemia (CLL), etc (Salles et al, 2017)
This study reported the pharmacokinetic properties of rituximab in patients with 6 different subtypes of lymphoma, all of which represent small groups of tumours, and to our knowledge, the rituximab pharmacokinetics in some subtypes have never been reported
Considerable variability in the initial rituximab trough concentration was observed in patients with different lymphoma subtypes, and a low C1-trough was associated with adverse consequences, some high-risk factors appear to be balanced by the presence of a high C1-trough
Summary
Since its initial approval in 1997, rituximab has improved the prognosis of all B-cell derived lymphoproliferative diseases, especially B-cell malignancies (Pierpont et al, 2018), including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt lymphoma, high-grade B-cell lymphoma, mantle cell lymphoma (MCL), mucosa-associated lymphoma (MALT), and chronic lymphocytic leukaemia (CLL), etc (Salles et al, 2017). One MCL patient showed approximately 4-fold higher clearance than patients with DLBCL and FL in Yonezawa’s study (Yonezawa et al, 2019) All these studies are invaluable and inspired us to focus on the variations in pharmacokinetics of rituximab in different B cell lymphoma histological type. For individuals with chronic lymphocytic leukaemia, the recommended rituximab dose is 500 mg/m2, because in that disorder, cells express lower levels of CD20, and the disease is associated with higher levels of free circulating CD20 antigen than other B-cell non-Hodgkin’s lymphoma (O’Brien et al, 2001). A prospective pharmacokinetics study was conducted in patients with 6 uncommon lymphoma subtypes to more closely examine the concentration-outcome relationship and the related influencing factors to obtain evidence that can be used to individualize rituximab regimens
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