B and T cells in chronic graft-versus-host disease and graft-versus-leukemia - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 311

The effects of IL-2 as cGVHD therapy could potentially be enhanced if
administered following donor Treg infusion or concurrent with drugs such
as rapamycin that selectively inhibit Tcon activity, and combination strate-
gies such as this warrant further study.

TARGETING B CELLS

As further evidence of a B-cell role in the pathogenesis of cGVHD, ritux-
imab, an anti-CD20 monoclonal antibody, has shown promise in treating
steroid-refractory cGVHD [69-77] . Initial interest in the use of rituximab
for the treatment of cGVHD grew out of a small case series that demon-
strated improvement in cGVHD in patients treated with rituximab for
autoimmune cytopenias. This was subsequently confirmed by larger,
dedicated studies, and a meta-analysis of published rituximab studies in
patients with steroid-resistant cGVHD revealed an overall response rate of
66%, with responses observed for disease involving the skin, oral mucosa,
liver, and lung [69,71-76] . Although one study demonstrated a specific
decrease in Y-encoded mHAs in recipients of sex-mismatched transplants,
the kinetics of clinical response after rituximab treatment would suggest
that responses often occur before antibody titers could be affected [71] .
Rituximab, which results in profound B-cell depletion, may therefore
be helpful against both antibody-dependent and antibody-independent
B-cell mechanisms of cGVHD.

315

Patients with cGVHD who did and did not respond to rituximab were evalu-
ated at serial time points following rituximab therapy for BAFF levels and
B-cell numbers [136] . B cells did not begin to recover until 2 years follow-
ing therapy and at this time patients who responded to rituximab had sig-
nificantly lower BAFF levels, higher B-cell numbers, and lower BAFF/B-cell
ratios than did patients who did not respond to rituximab. This suggested
that depleting the B-cell compartment may work to treat cGVHD both by
making B cells unavailable for the pathogenesis of the disease and by allow-
ing for B-cell reconstitution in a new, potentially more tolerant, immune
environment that could allow for the achievement of normal B-cell homeo-
stasis. Based on these results and the observation that patients with non-
Hodgkin's lymphoma who received rituximab peritransplant had lower
rates of cGVHD than historical controls, it is currently being investigated as
a prophylaxis against the development of cGVHD.

The success of anti-BAFF agents, such as monoclonal antibodies against
BAFF and the BAFFR, makes them potentially attractive candidates for the
treatment of cGVHD. Belimumab, an anti-BAFF monoclonal antibody, has
been FDA approved for the treatment of systemic lupus erythematosus
based on the encouraging results of the BLISS-52 trial. This trial demon-
strated prolonged remissions with decreased risk of disease flares, deeper
reductions in steroid dosing, and larger decreases in autoantibody titers
in patients who received belimumab compared to those receiving placebo
in conjunction with standard induction therapy for a lupus flare [81] . The
similarities between the dynamics of BAFF elevations and B-cell numbers
in patients with cGVHD compared to patients with autoimmune diseases
suggest that agents such as belimumab could be promising in the treatment
of cGVHD and warrant clinical investigation.