NANTES, FranceThe anti-CD20 monoclonal antibody rituximab
(Rituxan) produced a 69% overall response rate in patients with
B-cell post-transplant lymphoproliferative disease (PTLD), according
to a retrospective analysis presented at the ASH meeting by Noël
Milpied, MD, of the Centre Hospitalier Regional et Universitaire de
Nantes. The analysis also showed that rituximab is effective in both
solid organ and bone marrow transplant recipients (see Table 1).
A catastrophic and often fatal complication of organ transplantation,
PTLD occurs in 5% to 7% of lung transplant patients, with a mortality
rate of up to 70%. Standard treatment has been able to reduce
immunosuppression, but this increases the risk of transplant
rejection. Anti-B-cell monoclonal antibodies are being been tested as
an alternative to reducing immunosuppression.
Activity in B-Cell PLTD
Researchers observed the activity of rituximab in 32 post-transplant
patients8 liver, 8 kidney, 4 heart, 3 lung, 1 heart-lung, 1
liver-kidney, 1 kidney-pancreas, and 6 bone marrowwith B-cell
PTLD treated in 14 transplant centers in France. Median age was 34
years (range 3 to 67 years).
Immunosuppressive therapy had been tapered in 27 patients, but Dr.
Milpied said in an interview that tapering immunosuppressive therapy
made no apparent difference in response to rituximab He emphasized,
however, that only five patients were treated without previous
reduction of immunossupressive therapy. Most important in my
opinion, he said, is that in the vast majority of the
patients, the immunosuppressive therapy was still ongoing at the time
of therapy with rituximab even though it was at lower doses.
First-Line and Salvage Therapy
Rituximab was used as first-line therapy in 30 patients and as
salvage therapy in 2 patients. The median time from PTLD diagnosis to
rituximab treatment was 14 days. Patients were treated with infusions
of 375 mg/m². Numbers of infusions ranged from 2 to 8. Most
patients (26) received 4 infusions.
The overall response rate (ORR) was 69%, which included 20 (63%)
complete responses (CR), and 2 (6%) partial responses (PR). The
median time to response was 54 days (range 1 to 148 days.) Median
follow-up was 10 months, at which point 22 patients were alive,
including 18 still in CR.
Data Raise Concern
Due to the relatively low number of patients in each category,
I did not find significant prognostic factor for the response to
rituximab, Dr. Milpied stated. However, the response rate
was only 50% in patients who developed B-cell PTLD more than 1 year
after the transplant, compared to 80% in patients developing such
disease 1 year or less after the transplant. Although not
significant, these data raise a concern regarding the efficacy of
this therapy in late B-cell PTLD. This will be assessed in the
prospective trial which is about to begin, he added.
Dr. Milpied said that 4 of the 22 responders relapsed but remain
alive after salvage therapy. Five patients died, including three of
infections, one of transplant rejection, and one of pulmonary
fibrosis. Five of the 10 patients who did not respond to rituximab
died of PTLD, and 5 remain alive after salvage chemotherapy.
In my opinion, the most important thing to understand about
this retrospective analysis is that rituximab can be very effective
in PTLD with very little toxicity compared to chemotherapy, Dr.
Milpied said. In this regard, provided the disease expresses
the CD20 antigen, the use of this monoclonal antibody should be the
first attempt to treat the disease if there is no improvement after
tapering the immunosuppressive regimen (when possible). Such a
treatment does not preclude the use of chemotherapy in case of no
response or progression of the disease despite rituximab. Thus, it
may offer a chance of cure at a very little toxic cost.
Similar results had been reported by British researchers, who
reported two complete remissions and one non-response in three
patients with diffuse large B-cell PTLD after lung transplantation
(Cook RC, Connors JM, et al. Lancet 354:1698, 1999).
There is already, at least in France, a wide use of rituximab
in this setting, Dr. Milpied said. I believe that the
most important barrier to overcome is to convince the medical
community that this treatment is really effective and to identify the
types of cases in which it will not be effective. This will be
achieved through the prospective trial which will allow us to
eliminate bias necessarily present in a retrospective analysis. The
second barrier to widespread use is the cost of this treatment.
However, this point should be evaluated in view of the cost of
standard chemotherapy with its complications in such patients.