BALTIMOREThe monoclonal antibody rituximab (Rituxan) may be
effective in purging in vivo autografts for indolent lymphoma, and
post-transplant may serve as adjuvant immunotherapy, according to
research presented at the ASH meeting.
A study from Johns Hopkins Oncology Center in Baltimore suggests that
rituximab, already approved for the treatment of relapsed or
refractory low-grade or follicular, CD20-positive B-cell
non-Hodgkins lymphoma, may have broader applicability in
Two Years Experience
For about 2 years, rituximab has been used at Johns Hopkins for in
vivo purging of peripheral blood stem cells (PBSC) before autologous
transplant for non-Hodgkins lymphoma. This approach is based on
rituximabs activity in patients with low-grade lymphoma and its
ability to deplete peripheral blood of lymphocytes and
theoretically also of lymphoma cells, explained Ian W. Flinn,
MD, Assistant Professor of Oncology there.
Tumor contamination of the PBSC graft was measured with lymphoma
colony formation and/or polymerase chain reaction (PCR). Dr. Flinn
said that using rituximab as a purge has cleared peripheral blood of
all detectable lymphoma cells by PCR assay in a small series of patients.
We were looking for a new purging method, he said.
It seemed that by giving the patient the antibody rather than
by treating the graft after the cells were collected, you could
prevent the mobilization of tumor cells.
Results from Two Trials
Dr. Flinn presented the combined results from two trials involving 51
patients, most with follicular lymphoma. The trials were similar in
design, except in the second trial, a number of patients were
CD34-selected for tumor depletion if at least 5 x 106 CD34+ cells/kg
(twice the number needed for transplant) were collected. In these 19
patients, the investigators were able to determine purging efficacy
with and without the additional CD34-selection, he explained.
The logic is that with positive and negative selection, you are
better able to purge the graft. However, with ex vivo technique many
CD34 cells are lost and transplantation may not be possible, he
pointed out. Rituximab does not interfere with stem cell mobilization
and thus there are more stem cells available for CD34 selection.
Patients received 375 mg/m² of rituximab on day 1 of
mobilization, followed by cyclophosphamide (Cytoxan, Neosar) 2.5 g/m²
on day 4, and either G-CSF 10 µ/kg starting on day 5 or GM-CSF
10 µ/kg on days 5 to 11 and G-CSF 10 µ/kg starting on day
10 through the last day of apheresis. Stem cells were collected using
a high-volume apheresis procedure.
The preparative regimen consisted of either cyclophosphamide and
total body irradiation or busulfan (Myleran) and cyclophosphamide in
patients with prior radiotherapy. Post-transplant, patients in the
first study received one dose of rituximab and patients in the second
study received four doses.
Forty-six of the 51 patients were successfully mobilized (median 10.6
x 106 CD34+/kg, range of 2.24 x 106 to 59.5 x 106 CD34+/kg), and most
of these required only one high-volume apheresis.
We found that the majority of patients undergoing in vivo
purging were free of lymphoma by colony forming assay, but there was
an incremental increase in these numbers [depleted] after CD34
selection, Dr. Flinn reported.
Thirteen of 19 patients were lymphoma-free before CD34 selection, and
17 of 19 after CD34 selection. Seven patients whose lymphomas were
positive for either t(11;14) or t(14;18) received grafts that were
not CD34 selected. Only one of these grafts was PCR-positive for lymphoma.
So far it looks as if the use of both techniques is the
best, Dr. Flinn noted. But there are still several
questions: are we giving the optimal dose of rituximab before stem
cell mobilization to get the best purge possible prior to transplant?
You might give three to four doses of Rituxan prior to mobilization,
and this might produce a better purge and CD34 selection might not be
needed, he proposed.
CD34 selection is labor intensive and expensive.
Furthermore, some studies have found that there are a
population of CD34 cells that are positive for t(14;18). Therefore,
grafts that are only CD34 selective may still contain neoplastic
cells, Dr. Flinn said.