Rituximab for KSHV-associated multicentric castleman disease: A phase II safety/efficacy trial

Abstract Objectives: HIV-associated multicentric Castleman disease (MCD) has recently been recognized as an important emerging comorbidity in Africa for people living with HIV on antiretroviral therapy (ART). Rituximab is the standard first-line treatment for MCD internationally but has not been prospectively evaluated in Africa where safety and efficacy may differ from high-income countries, and where mortality for patients with MCD not receiving rituximab is high. Methods: We report results from a phase 2 clinical trial completed at the National Cancer Centre in Malawi with enrollment April 2021-June 2024 and censoring June 2025. Eligible participants were adults with histologically confirmed, KSHV-positive MCD, ECOG performance status ≤3, who required MCD therapy on the basis of: 1) fever, 2) lymphadenopathy or splenomegaly, and 3) malaise, weakness, hemoglobin <10 g/dL, or platelets <100 x 109/L. Eligible participants received four weekly doses of rituximab 375 mg/m2 while high-risk participants (hemoglobin <8 g/dL or ECOG performance status >2) also received four weekly doses of etoposide 100 mg/m2. The primary outcome was safety as determined by grade ≥3 non-hematologic adverse events within twelve weeks of initiation of therapy; secondary outcomes included all adverse events, radiological response, clinical response, progression free survival (PFS), and overall survival (OS). Changes in quality of life over time were also assessed using the Patient-Reported Outcomes Measurement Information System (PROMIS) Global Physical and Mental Health scales at baseline, 12 weeks, and at relapse. Clinical response was defined as resolution of signs and symptoms that made them eligible for treatment and for the study as delineated above (ie symptoms and cytopenias). Results: We screened sixteen patients and enrolled fifteen participants with MCD; there was one screen failure due to high creatinine. Eleven participants (73%) had newly diagnosed disease, while four (27%) had relapsed disease after chemotherapy. Median age was 41 and ten (66%) were male. Fourteen (93%) were people living with HIV of whom thirteen (93%) were on ART prior to enrollment. All presented with B symptoms and lymphadenopathy. Median hemoglobin was 8.9 g/dL (range 6-11) and nine (60%) participants had high-risk MCD. Nine (64%) participants had undetectable HIV RNA, five (36%) detectable <200 copies/mL, and one (7%) elevated HIV RNA. At 12 weeks radiological response assessment, ten (67%) achieved complete response of measurable lymphadenopathy, hepatomegaly or splenomegaly, four (27%) had a partial response and one (7%) had refractory disease. The clinical response at 12 weeks, twelve (79%) achieved complete response of the presenting symptoms, one (7%) had a partial response, one (7%) had stable disease and one (7%) with progressive disease. Median follow up was 1.9 years (range 1.1-4.0). PFS at one year was 80% and at two years was 48%. OS at one year was 87% and at two years was 87%. Grade ≥3 hematologic adverse events were observed in five (33%) participants; two anemia (13%) and three neutropenia (20%). There were no grade ≥3 non-hematologic adverse events. There was one participant death within twelve weeks due to anemia from refractory MCD and an additional death at three months after enrollment due to anemia from relapsed MCD. Median PROMIS Physical Health at baseline was 14 (range 6-20), 19.5 (range 15-20) at 12 weeks, and 13 (range 7-16) in the five patients who relapsed with higher scores relaying better QoL with possible score range 4-20. Median PROMIS Mental Health scores were as follows: baseline 14 (range 5-19), 12 weeks 20 (range 20-20), and at relapse 13 (range 9-16) with higher scores relaying better QoL with possible score range 4-20. Conclusions: This is the first prospective trial for MCD in Africa. Rituximab appears safe and efficacious in prolong survival and quality of life but efficacy appears lower at two years than in comparable studies from high-income countries. Further studies are needed to understand possible reasons for lower efficacy, which may include population, health system, and disease factors. Correlative studies are planned to further elucidate potentially unique MCD immunobiology features in Africa. Access to rituximab should be expanded for this population and alternative therapies are needed for patients who do not respond.