Response: Choice of conditioning for allogeneic transplantation in follicular lymphoma: nonmyeloablative or high-dose chemotherapy?

We appreciate Dr van Besien's interest in our study,¹  which demonstrated nonmyeloablative conditioning could result in long-term remissions in 83% of patients with relapsed follicular lymphoma, and possible cure, via a graft-versus-lymphoma. These encouraging results were achieved in a group of patients who were a decade older than the patients conditioned with myeloablative regimens and reported in a registry study by van Besien et al.²  Our patients were also heavily pretreated with intensive modern chemotherapeutic regimens, including 19% that had recurred after prior autologous stem cell transplantation. In these patients the use of high-dose chemotherapy for conditioning was both prohibitive in terms of toxicity and unlikely to result in significant benefit, given the intensity of their prior therapy. Our regimen resulted in only 11% grade II to IV acute graft-versus-host disease (GVHD), substantially lower than the 40% risk of acute GVHD reported by the registry after myeloablative conditioning.² 

In the 1990s, patients with recurrent follicular lymphoma were considered for high-dose chemotherapy and allogeneic transplantation if they were young (< 60 years), with good organ function and a Zubrod performance status of 2 or lower. We have previously reported our single center experience in patients who had recurrent disease and who met those criteria.³  The mortality rate at day 100 was 34% in these younger patients with good performance status, irrespective of whether they had sensitive or refractory disease at the time they underwent transplantation.

In analyzing the information provided Dr van Besien and his colleagues regarding the outcome after high-dose chemotherapy and allogeneic transplantation, we must consider its limitations. The patients' ages, within the groups who had chemosensitive disease or good performance status, were not provided. In addition, information about prior treatments was not included. In the registry's original report,²  it appears that 48% of patients were transplanted in “early disease status,” which was defined as transplantation in first or second complete remission or in first relapse. One may argue then that these patients did not necessarily need an allogeneic transplant at all; yet despite the good-risk features, 30% to 40% of patients died within 100 days.

We are surprised that Dr van Besien continues to advocate high dose conditioning chemotherapy for patients with follicular lymphoma. His group coauthored a recent paper arguing against the presence of a graft-versus-lymphoma effect, a conclusion we believe was in part related to lack of information regarding the clinical details of a substantial portion of the patients studied.⁴  We continue to believe that our results using nonmyeloablative conditioning, along with observations that follicular lymphoma patients can respond to donor lymphocyte infusions alone, strongly argue in favor of an effective graft-versus-malignancy effect in follicular lymphoma.

How about patients with refractory disease? We believe that a focus on high-dose chemotherapy in the refractory setting is unlikely to be successful. Instead, various strategies are currently under investigation to improve the outcome after nonmyeloablative transplantation. This includes the incorporation of novel agents into the conditioning regimen to increase efficacy without additional toxicity, or by enhancing graft-versus-lymphoma effects through tumor-specific immunization or posttransplant immunomodulation. We have recently published preliminary data to suggest that the addition of radioimmunotherapy to the fludarabine, cyclophosphamide, and rituximab preparative regimen may be helpful in treating patients with refractory follicular lymphoma.⁵  The study is still open and we are soliciting referrals from the community and other centers.