Real World Outcomes of Adult Patients with Diffuse Large B-Cell Lymphoma Receiving Fixed Dose Intravenous Rituximab in the Philippine General Hospital

Introduction. Diffuse large B-cell lymphoma (DLBCL) is the most frequent type of aggressive non-Hodgkin lymphoma (NHL). The backbone of therapy includes rituximab at a dose of 375 mg/m ² however, the rationale for which is not explained in pharmacokinetic studies but has been the set dose for succeeding clinical trials. In limited-resource settings, standard regimen or fixed dose adaptations of certain cancer medicines are common. This study investigated the clinical profile and treatment outcomes of patients who received fixed dose intravenous (IV) rituximab of 500 mg per cycle for DLBCL.

Methods. This study was a retrospective cohort conducted through review of records of adults diagnosed with DLBCL given fixed dose IV rituximab of 500mg at the University of the Philippines - Philippine General Hospital from January 1, 2015 to December 31, 2019. Clinical characteristics, stage, international prognostication index (IPI), body surface area dosing, response assessment, and overall survival (OS) and progression-free survival (PFS) were recorded. The computed sample size was 110 patients however, all patients within the period of observation were included.

Results. One hundred thirty-two adult patients with DLBCL were identified of which, 77 received a rituximab-based regimen, and 71 received fixed dose IV rituximab of 500mg and were included in the study. Table 1 summarizes the baseline demographic and clinical characteristics of the participants. The mean age was 46 years old with a slight male predominance. Eighty percent of patients received a dose below 350 mg/m ². Fifty-one percent of patients had bulky and advanced stage of disease. Thirty-nine percent of patients presented with B symptoms. Eighty-two percent had one or no comorbidities on consult. Sixty-six percent had a low-risk IPI of 0 or 1, 30% with a low-intermediate risk IPI of 2, and 4% with a high-intermediate risk IPI of 3. Ninety percent of patients received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (RCHOP). The mean number of doses of rituximab received was 6 and patients received treatment at a mean interval of 1 month from diagnosis. Notably, only three patients underwent immunohistochemistry studies to determine the subtype of DLBCL. All three were found to have activated B cell as the cell of origin.

Table 2 summarizes the distribution of outcomes in relation to average dose received. Of the original 71 who received fixed-dose Rituximab, 25 patients had no documentation of objective response assessment. Thirty or 43% showed complete response and 20% showed progressive disease. Complete response was documented across dose ranges from 250 to 400 mg/m ² however, 77% of complete responders received a dose lower than 350 mg/m ². Conversely, 79% of patients with progressive disease received a dose lower than 350 mg/m ². There were no noted significant associations between these outcomes and the average dose range of rituximab received based on Fisher's exact test. This finding is also illustrated in Figure 1, which is a boxed plot diagram of the range of dose received across clinical outcomes. Because of the limited number of patients and sparse distribution of outcomes, a Cox proportional hazard model could not be made. Table 3 shows the distribution of characteristics across clinical outcomes. Age and follow-up time were significantly different across the three groups. No difference was found for the other clinical variables. A Kaplan-Meier survival plot could not be constructed due to the high lost to follow-up rate, with 66% of patients being lost to follow-up at time of analysis.

Discussion and Conclusions. The study identified the high use of fixed dose IV rituximab in our hospital rather than the recommended dosing of 375 mg/m ². These patients showed comparable initial response rates of fixed dose rituximab in adult patients with DLBCL compared to response rates from previous RCTs, however long-term response rates were not evaluable. The study was not able to demonstrate the durability of response, given the lack of data and high lost to follow-up rate. At the time of analysis, the use of subcutaneous (SC) rituximab has not progressed in the treatment center, and the prohibitive cost of both IV and SC rituximab has affected its optimal use. Pharmacokinetic modeling and longer-term cohorts of fixed-dose studies may provide more robust data to support the use of fixed-dose treatment strategies.

Figure 1

View largeDownload slide

Figure 1

View largeDownload slide

Close modal