Adding Rituximab to Corticosteroids and Cyclosporine A in Patients With cGVHD Improves ORR

Standard firstline treatment for chronic graft-versus-host disease (cGVHD) includes corticosteroids and cyclosporine A, but disease control often requires long-term immunosuppressive treatment, which impairs patients’ immune function and increases the risk of opportunistic infection.

In a multicenter, prospective, phase II study, Florent Malard, MD, PhD, from the Centre de Recherche en Transplantation et Immunologie at the Université de Nantes in France, evaluated whether adding the anti-CD20 monoclonal antibody rituximab to standard frontline therapy could improve overall response rates (ORRs) and enable patients to more quickly and effectively taper corticosteroid use. Their results were published in Blood.

The study included 24 adult patients (median age = 47 years; range = 23-63 years) who were newly diagnosed with cGVHD following first allogeneic hematopoietic cell transplantation (alloHCT) for a hematologic malignancy. Patients were excluded if they had acute GVHD; had cGVHD not requiring systemic immunosuppressive therapy; received prednisone at doses of ≥1 mg/kg/day; had cGVHD following donor lymphocyte infusion; or had uncontrolled systemic infection associated with an increased risk of death within one month.

Six patients (25%) had myeloid malignancies and 18 (75%) had lymphoid malignancies. Ten donors (42%) received alloHCT from human leukocyte antigen-matched siblings, nine (37%) from matched unrelated donors, and five (21%) from mismatched unrelated donors. Cells were derived from bone marrow in five alloHCTs (21%).

“Based on our findings, targeting B cells [with rituximab] appears to be an effective therapeutic strategy for firstline treatment of cGVHD.”

–Florent Malard, MD, PhD

Four patients had previously received rituximab to treat their underlying malignancy. Per study protocol, once patients were diagnosed with cGVHD requiring systemic therapy, they received rituximab 375 mg/m2 weekly for four consecutive weeks, as well as cyclosporine A and corticosteroids 1 mg/kg/day. Patients who achieved a complete remission (CR; defined as complete disappearance of any sign of cGVHD) after the first cycle of rituximab did not continue treatment; those who achieved a partial response (PR; defined as improvement in ≥1 organ or site without progression in any other organ or site) were eligible to receive another cycle of rituximab eight weeks after the first rituximab infusion.

The median time from alloHCT to cGVHD diagnosis was 5.9 months (range = 2.4-32.7 months), and patients were followed for a median of 6.7 months (range = 4.2-33.6 months) after alloHCT. Most patients had severe (n=15; 62%) or moderate cGVHD (n=7; 29%), and two (8%) had mild cGVHD.

By one year after first rituximab administration, 20 patients had responded to treatment, for an ORR (primary endpoint) of 83 percent, including seven CRs (29%) and 13 PRs (54%). Treatment failure (defined as a lack of CR or PR at week 6, requirement of another therapy before week 6, or death before week 6) was reported in two patients (8%). The cumulative incidence of non-relapse mortality was 14 percent (n=3).

Eight patients received only one course of rituximab because of CR (n=5), resistance (n=2), or study withdrawal related to cGVHD progression under treatment (n=1). Two-thirds of patients received a second course of rituximab, and four (25%) experienced an improvement from PR to CR.

At last follow-up, three patients remained in CR, whereas two lost CR but remained in PR. Another patient who did not initially respond to rituximab and did not receive a second rituximab course achieved a PR at three months without additional treatment and remained in PR at last follow-up.

Eleven non-hematologic serious adverse events (AEs) were reported: sepsis (n=3), lung infection (n=2), sinus infection (n=1), progressive multifocal leukoencephalopathy (PML; n=1), hyperglycemia (n=1), acute renal failure (n=1), thrombotic microangiopathy (n=1), and transient global amnesia (n=1). All non-hematologic serious AEs resolved, except in the patient with PML, who died. Two other patients died during follow-up because of underlying disease relapse and infection. Hematologic AEs included grade 3/4 lymphopenia (n=12; 50%) and grade 3/4 neutropenia (n=5; 21%).

Of the 23 patients who were evaluable at three months after first rituximab infusion, 19 (83%) could safely decrease corticosteroid use by 30 percent or more, including two patients (9%) who discontinued corticosteroids entirely. At one year, four patients (21%) had reduced corticosteroid use by 30 percent or more and 14 (74%) were off corticosteroids entirely.

“Based on our findings, targeting B cells [with rituximab] appears to be an effective therapeutic strategy for firstline treatment of cGVHD,” the authors wrote. As the researchers expected, PD-L1hi-naïve B cells, which are involved in cGVHD pathophysiology, were significantly decreased at cGVHD diagnosis but were increased after B-cell depletion with rituximab (2.4% vs. 6.7%; p=0.01). “The increase in naïve B cells goes along with an increase in PD-L1hi B cells in patients without cGVHD,” the authors reported.

“[These] results suggest that [the] addition of rituximab may be effective [and provide] a framework for a possible new mechanism of action of rituximab in the setting of cGVHD, mediated through PD-L1hi B cells and T follicular helper cells,” the authors concluded. However, “this hypothesis remains to be confirmed in a randomized, prospective, phase III clinical trial.”

The study is limited by its small patient population and lack of a comparator arm.

Corresponding authors report financial relationships with Roche, manufacturer of one of the drugs included in this trial.

Reference

Malard F, Labopin M, Yakoub-Agha I, et al. Rituximab-based first line treatment for chronic GVHD after allogeneic SCT: results of a phase 2 study. Blood. 2017 September 1. [Epub ahead of print]

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