Rituximab Proves Useful Against Post-Transplant Lymphoproliferative Disease and Is Less Toxic

NANTES, France—The 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 patients—8 liver, 8 kidney, 4 heart, 3 lung, 1 heart-lung, 1 liver-kidney, 1 kidney-pancreas, and 6 bone marrow—with 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.

 Overcoming Barriers

“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.”