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Oct. 29, 2002 (New Orleans) — Rituximab (Rituxan,
Genentech Inc.) appears to be well tolerated and significantly depletes
B lymphocytes in patients with systemic lupus erythematosus (SLE),
according to the findings of a phase I/II trial.
Jennifer H. Anolik, MD, PhD, from the University of
Rochester School of Medicine, New York, and colleagues presented
their findings here Sunday at the American College of Rheumatology
(ACR) 66th Annual Scientific Meeting.
According to the researchers, because B cell abnormalities
contribute to the pathogenesis of SLE, depletion of B cells by rituximab
may have "lasting clinical benefit."
Rituximab is a monoclonal antibody approved for use
in certain types of CD20-positive non-Hodgkin's lymphomas. CD20
is primarily expressed on immature and mature B cells but not on
plasma cells or T cells; thus, rituximab may be less immunosuppressive
than other treatment regimens, the authors suggest.
Dr. Anolik and colleagues investigated the safety,
tolerability, and preliminary clinical efficacy of rituximab in
the treatment of 18 patients with SLE, all of whom had clinically
active but non-organ threatening SLE (Systemic Lupus Activity Measure
[SLAM] score >/= 6).
Of the 18 patients, six received one infusion of 100
mg/m2 (low dose); six received one infusion of 375 mg/m2 (medium
dose); and six patients received four weekly doses of 375 mg/m2
(full dose).
Three of the 12 patients in the low- and medium-dose
groups developed elevated human anti-chimera antibody (HACA) titers
at 2 months. Patients receiving the full dose are still being evaluated.
According to the researchers, the clinical significance
of high HACA titers is unclear, but they may be associated with
increased risk of infusion-related reaction or increased clearance
of rituximab.
"We have not seen the immediate reactions to infusion
that have been a major problem in patients with lymphomas," the
researchers point out. But serious infections were seen in two patients
with baseline leucopenia, one of whom had a history of similar infection
in the past.
In the 16 evaluated subjects, the 10 patients with
good B-cell depletion had a significant improvement in SLAM score
(P=.0004 at 3 months). Clinical responses were most prominent for
macositis, "acute" skin lesions, and alopecia. However, in the subset
of six subjects who depleted poorly, the SLAM score did not change.
Overall, serologies did not significantly improve.
In particular, anti-dsDNA titers did not decrease (with one exception),
even in subjects who depleted well for prolonged periods of time
(six to nine months). "This suggests that anti-dsDNA plasma cells
can be long-lived or depletion of autoreactive B cells in incomplete,"
the authors point out.
Dr. Anolik told Medscape that the reason for including
the low and medium doses was to evaluate safety. "But the high dose
does appear to be safe and it is probably the necessary dose," she
said.
"We observe high levels of antibodies against the
rituximab and we think that with future studies this will probably
need to be used in combination with other immunosuppressive treatments,"
she said.
One of the many rheumatologists crowded around the
poster presentation described the findings as "extremely promising,"
and he pointed out that it is the largest trial to date on this
subject.
"Rituximab is a treatment with established efficacy
in related disorders — it is not new — and we would expect that
it would work in SLE," said the rheumatologist and professor from
the University of Michigan, Ann Arbor, who requested that he not
be identified.
He also pointed out that the safety of rituximab suggests
that it would be easily incorporated into SLE regimens.
The trial was investigator-initiated but received
corporate support; the principal investigator is a paid consultant
for Genentech Inc.
A related study is reported in the October issue of
Arthritis & Rheumatism. Maria J. Leandro and colleagues from University
College in London, U.K., treated six patients with SLE resistant
to standard chemotherapy with a combination of rituximab, cyclophosphamide,
and high-dose oral corticosteroids over two weeks. One patient was
lost to follow-up but the remaining five all improved at six months
and no significant adverse effects were observed. Based on the study
results, the investigators believe that a formal controlled trial
is justified.
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