Comparison of Standard-Dose Versus Fixed-Dose Rituximab for Non-Malignant, Immune-Mediated Hematologic Disorders

Background: Rituximab (RTX) is a chimeric monoclonal antibody that targets the B-cell antigen CD20 and is FDA-approved to treat both hematologic malignancies and autoimmune disorders like Rheumatoid Arthritis. RTYX has reported efficacy and is routinely used in the treatment of thrombotic thrombocytopenic purpura [TTP], immune thrombocytopenic purpura [ITP], acquired hemophilia A [AHA], and autoimmune hemolytic anemia [AIHA], although not FDA approved for these classical hematology indications. Autoimmune rheumatological disorders are treated with a fixed-dose (FD) RTX paradigm (1,000 mg IV every two weeks x two doses) because their lower total lymphocyte mass likely requires a lower RTX dose for efficacy when compared to the standard dose (SD) used for hematologic malignancies (375 mg/m² IV every week x four weeks). The optimal RTX dosing to treat TTP, ITP, AHA, and AIHA is not established. During the COVID-19 pandemic, the UNC Classical Hematology group transitioned to FD RTX given demonstrated efficacy in autoimmune disorders, its simplicity, fewer infusion visits, and lower cost. This study was designed to evaluate the safety and efficacy of SD RTX versus FD RTX for the treatment of autoimmune hematological disorders.

Methods: This was a single-center retrospective study of adult patients treated with SD or FD RTX for an acute episode of TTP, ITP, AIHA, or AHA between April 1, 2017 and April 1, 2023 (UNC IRB 23-1347). Eligible subjects were identified using the Carolina Data Warehouse for Health (CDW-H). Exclusion criteria included treatment with RTX in the previous year, active malignancy, HIV, HBV or HCV, history of solid organ or hematopoietic cell transplant, or were pregnant or breastfeeding. The primary outcome was complete response (CR) rates at 6 and 12 months. Complete response was defined follows: TTP: platelets >150x10⁹/L and normalizing LDH for 2 consecutive days; ITP: platelets > 100x10⁹/L; AIHA: Hgb >11 g/dL (female) or >12 g/dL (male), and normalization of hemolysis markers (LDH, haptoglobin); AHA: FVIII activity ≥70% and a negative FVIII inhibitor titer. Secondary outcomes included time to CR, partial response (PR) rates at 6 and 12 months, relapse rates at 6 and 12 months, and incidence of adverse reactions. All inferential statistical testing was two-sided with an alpha level of 0.05 (P<0.05) required to infer statistical significance. Fisher’s exact test was used for categorical data and an unpaired t-test or the non-parametric Mann-Whitney test was used to analyze continuous variables, as appropriate. A log-rank test was used for time to complete and partial responses. All statistical testing was performed in GraphPad Prism v10.1 (GraphPad, San Diego, CA).

Results: Among 225 potentially eligible patients identified by CDW-H, 112 subjects were included in the study (SD RTX, n=69; FD RTX, n=43). Patient clinical and demographic characteristics were well-balanced between the two study groups, with the exception of concomitant caplacizumab use, which was higher in the FD RTX group (n=7 [16%] vs. n=3 [4%]; P=0.04). For the primary endpoint, a significant difference was not observed in composite CR rate, CR rates at 6 months (SD RTX n=50 [72%] vs. FD RTX n=33 [77%]; P=0.66), or CR rates at 12 months (SD RTX n=54 [78%] vs. FD RTX n=35 [81%]; P=0.81). Composite PR rates were not significantly different between the two groups at 6 months (P>0.99) and 12 months (P=0.66). Relapse rates were generally low and not significantly different between the SD RTX and FD RTX groups at 6 months (n=7 [10%] vs. n=3 [7%]; P=0.74) nor at 12 months (n=10 [14%] vs. n=3 [7%]; P=0.37). Finally, incidence of adverse events were also low and significant differences were not observed between the two groups for infusion-related reactions (n=9 [13%] vs. n=4 [9%]; P=0.76) and neutropenia (n=2 [3%] vs. n=3 [7%]; P=0.37).

Conclusions: FD RTX was a similar in efficacy and safety to SD RTX in the treatment of non-malignant, immune-mediated hematologic disorders. FD RTX offers several benefits including the convenience of fewer infusions visits, and reduced costs and healthcare burden. In the absence of prospective randomized trials comparing these tow regimen, which are unlikely to be conducted, our data support adopting FD RTX as the preferred regimen for the treatment of autoimmune hematological disorders.