MIAMI BEACHBone marrow and peripheral blood stem cell
transplants after high-dose chemotherapy are becoming more widely
used, but there is no standard method of purging graft material to
remove tumor cells prior to transplant.
In vitro approaches have included chemical methods, CD34 selection,
and a cocktail of monoclonal antibodies used to treat graft material
before it is reinfused.
Two studies presented at ASH suggest that it may be possible to do
in vivo purging in patients with non-Hodgkins
lymphoma using the anti-CD20 monoclonal antibody rituximab (Rituxan).
Ian W. Flinn, MD, reported that a rituximab-based combination is
a well-tolerated regimen that successfully depletes stem cell grafts
of CD20+ cells, provides rapid engraftment, and is associated with
little added toxicity.
Dr. Flinn and his colleagues at Johns Hopkins studied rituximab for
in vivo purging and as post-transplant adjuvant immunotherapy in NHL.
Their goals were to reduce contamination of the stem cell graft with
lymphoma and to reduce residual disease remaining in the patient
after high-dose therapytwo causes of relapse after autologous transplant.
Our problem was that we had reached the maximum tolerance of
our preparative regimens. We were looking for some sort of adjuvant
as a nontoxic way of adding to the protocol, he said.
In this protocol, patients first receive rituximab; then, to mobilize
stem cells, cyclophosphamide and G-CSF are given 3 days after
rituximab. Stem cells are collected, the patient receives a
preparative regimen, and the stem cells are reinfused. Once the
patient has recovery of platelets and neutrophils, another rituximab
dose is given, Dr. Flinn said.
No CD20+ Cells Detected
In this preliminary report, stem cells were successfully mobilized in
21 of 22 patients. Fifteen patients required only one apheresis. No
CD20+ cells were detectable by flow cytometry in any of the grafts.
However, he said, quantitative PCR will need to be
done to further evalute purging.
Rituximab was very well tolerated, with a very low rate of
infusion-related side effects, he said. That may be because our
candidates for transplant had only minimal residual disease.
Toxicities include one patient who developed pancytopenia and
subsequently died; two with zoster; and one with thrombocytopenia who
responded rapidly to steroids.
In our next trial, we will be giving four doses of rituximab
after transplant rather than one, Dr. Flinn said. We will
also be using GM-CSF as adjuvant therapy post-transplant. GM-CSF may
increase antibody-dependent cellular cytotoxicity.
R. K. Gupta, MD, and colleagues at St. Bartholomews Hospital,
London, reported that PCR analysis for the t(14;18) translocation in
patients with recurrent follicular lymphoma showed similar purging
following rituximab. This translocation can be found in up to 80% of
patients with follicular lymphoma and is used as a surrogate marker,
particularly in minimal residual disease.
Dr. Gupta monitored minimal residual disease in 58 patients treated
with rituximab in a large UK trial. Prior to rituximab treatment, 31
patients (53%) were PCR positive for the t(14:18) marker in lymph
node tissue (13 patients) and/or bone marrow (12 patients) and/or
peripheral blood (20).
Follow-up bone marrow and blood samples (obtained a month after the
last rituximab infusion) were available in 28 of these patients.
Overall, 17 (61%) became PCR negative after treatment. Of the 13
nonresponders, 7 (54%) became PCR negative. Partial remissions
occurred in 15 patients; 10 of 15 (67%) who became PCR negative had a
PR vs 5 of 11 (45%) who remained PCR positive.
This suggests that rituximab is very effective in decreasing or
eliminating CD20+ cells, including follicular lymphoma cells, in
marrow or blood irrespective of clinical response, he said.
Although obtaining a PCR-negative state does not reflect
clinical outcome, rituximab may be useful as a means of in vivo purging.