Protective Effect of Rituximab Against Lymphoma Risk In HIV-Associated Multicentric Castleman Disease

Abstract 2869

Human Immunodeficiency Virus (HIV)-associated multicentric Castleman disease (HIV-MCD) is a rare lymphoproliferative disorder occurring in patients co-infected with HHV-8. Long-term prognosis remains severe mainly because of the high incidence of aggressive HHV-8 associated non-Hodgkin lymphoma (NHL). Chemotherapy is usually the first line therapy in active HIV-MCD. Most patients remain dependent on chemotherapy. Recent studies have demonstrated that rituximab allows to resume chemotherapy in most patients. However, effect of rituximab on long-term incidence of lymphoma is unknown.

All consecutive patients with HIV-MCD from the national HIV-lymphoproliferative cohort (Clinical site, Saint-Louis Hospital, Paris, France) were enrolled in combination antiretroviral therapy (cART) era. Patients with NHL within the 2 months prior or following rituximab were excluded from analysis. Patients treated with rituximab received 4 infusions, 375 mg per m² at weekly intervals. Primary objective of the study was to compare incidence of NHL between patients who received rituximab (rituximab group) and who did not received rituximab (control group). Secondary objectives were to compare overall survival and to describe tolerance to rituximab. Survival and NHL incidence was estimated using Kaplan-Meier method and tested with log-rank test.

115 patients with HIV-MCD were included in the HIV-lymphoproliferative cohort until november, 2009. Patients were followed for a mean period of 3 years. 7 patients received rituximab as part of LNH therapy and were excluded from analysis. 33 patients (29%) received rituximab as part of MCD therapy. In rituximab group at MCD diagnosis, mean age was 41 years, 24 patients (73%) received antiretroviral therapy, HIV viral load was undetectable (< 500 c/ml) in 10 patients (30%), median CD4 cell count was 233 × 10⁶/L [IQR, 101–368], median nadir CD4 was 160 × 10⁶/L [IQR, 61–194], 14 patients (42%) had an history of Kaposi sarcoma (KS) before rituximab therapy, which was in complete remission or stable at time of rituximab therapy. All 33 patients received chemotherapy as first line MCD treatment: etoposide (n=27), vinblastine (n=4), anthracyclines (n=2). The median period from MCD diagnosis to rituximab therapy was 7.7 months [IQR, 4.6–23.8]. All but 2 patients received the 4 scheduled infusions. These 2 patients discontinued rituximab after the second infusion; one died at day 15 from progressive MCD and the other one discontinued for investigation of rectal tumor. 4 patients received a second course of 4 rituximab infusions for MCD relapse, after a median period of 19.5 months (IQR, 15 to 23).

The 3-years probability of developing lymphoma was 0.04% [95%CI,0.01-0.99] in rituximab group (n=33) and 23% [95%CI,14-34] in control group (n=74) (P=0.001). The only lymphoma in rituximab group occurred 22 months after rituximab therapy and patient died. In rituximab group, the median overall survival was 15.7 years compared to 5.2 years in control group (P=0.0007). During total follow-up, 5 patients (15%) died in rituximab group and 28 patients (38%) died in control group. Causes of death in rituximab group was MCD attack (n=1), lymphoma (n=1), acute myeloid leukemia (n=1), infection (n=1), cardiovascular disease (n=1).

No severe adverse event was observed during rituximab infusions. Within the first year following rituximab therapy, 9 patients (27%) developed mild to moderate infections; pneumonia (n=2), herpes reactivation (n=2), enterocolitis (n=2), dacryocystitis (n=1), folliculitis (n=1), staphylococcus catheter-related infection (n=1). Transient grade 3 neutropenia occurred in 2 patients (6%). Exacerbation of KS was observed in 4 out of the 15 patients with prior history of KS (4, 4, 7, 36 months after rituximab therapy, respectively), and required specific treatment in 2 patients.

Despite improvement in overall survival of HIV-MCD in cART era, risk for developing lymphoma remains high (23% at 3 years). Rituximab seems to induce long-term protection against lymphoma risk, with only one patient developing lymphoma during the 3-year follow-up period in our cohort.