Allogeneic Hematopoietic Cell Transplantation for Patients with Follicular Non-Hodgkin Lymphoma

Allogeneic HCT (alloHCT) represents the only treatment modality with curative potential for patients with advanced FL. In contrast to AHCT, alloHCT utilizes the graft-vs.-lymphoma effect mediated by donor T cells to eradicate minimal residual disease and ameliorates potential tumor cell contamination in the graft. Although no randomized trials have been performed, several studies have consistently reported a lower risk of relapse compared to AHCT. But the TRM associated with myeloablative alloHCT has invariably offset the benefit conferred by lower relapse rates. An International Bone Marrow Transplant Registry (IBMTR) report compared the outcomes of 904 patients with FL who underwent either myeloablative alloHCT (n=176), purged AHCT (n=131), or unpurged AHCT (n=597). The risk for relapse was 54 percent lower in the allogeneic recipients (p<.001) and 26 percent lower in recipients of purged autografts (p=.04) than in recipients of unpurged autografts¹³ . Few relapses occurred in the allogeneic group after one year, as opposed to a continuous relapse pattern in the autologous patients. However, the risk of TRM was 4.4 times higher after alloHCT than after AHCT (p<.001), resulting in comparable five-year probabilities of OS (52 percent after allogeneic, 62 percent after purged autologous, and 55 percent after unpurged autologous). In another large registry series from Europe, the outcomes of 1,185 patients with NHL who underwent myeloablative alloHCT (including 231 patients with indolent NHL) were compared to the results of 14,687 AHCT recipients¹⁴ . As in the IBMTR study, the relapse risk was significantly lower among the allogeneic recipients, but OS was compromised due to the prohibitive TRM of 38 percent at four years.

Reduced-intensity conditioning (RIC) incorporates a less intensive preparative regimen and relies more on the immunotherapeutic effects of the allograft to confer anti-tumor activity rather than the cytoreduction of high-dose chemotherapy. The goal of RIC is to induce adequate immune suppression of the recipient to allow engraftment, but the level of cytoreduction varies among the numerous RIC regimens depending on the dosage of chemotherapy or radiation administered.

With followup ranging from one to three years, several studies utilizing various RIC regimens with matched related and unrelated donors have reported DFS and OS ranging from 65-84 percent and 73-85 percent, respectively, with TRM reported from 10-18 percent^15-19 . Table 1 lists these trials. Interestingly, patient ages ranged from 18-73 years, and all studies included patients who had failed prior AHCT and/or who had been heavily pretreated. The most promising data employing RIC alloHCT is from the M.D. Anderson Cancer Center. Twenty patients with relapsed indolent NHL (including 18 follicular patients) who had matched sibling donors received RIC with fludarabine and cyclophosphamide + high-dose rituximab. Twelve patients were in second or greater CR at the time of transplantation. The CR rate was 100 percent after transplantation. DFS and OS at two years were both ~84 percent. The incidences of grade II-IV acute graft-vs.-host disease (GVHD) and chronic GVHD were 20 percent and 64 percent, respectively. Only one patient died from a treatment-related complication. These results were recently updated with a total accrual of 47 patients²⁰ . With a median followup of 34 months, the three-year DFS, OS, and risk of progression were 88 percent, 85 percent, and 3 percent, respectively. These encouraging data support the existence of a graft-vs.-lymphoma effect, although longer followup is necessary to confirm a true plateau in survival.

A recent analysis from the IBMTR confirmed the increasing utilization of RIC regimens for FL patients²¹ . In 1997, less than 10 percent of matched sibling allogeneic transplants reported to the registry employed RIC regimens with this percentage, increasing to 80 percent by 2002. In this report, the outcomes of 120 myeloablative recipients were compared to 85 RIC recipients. Interestingly, PFS, OS, and TRM did not differ between the two groups. The three-year PFS and OS were 65 percent and 55 percent, and 70 percent and 64 percent, respectively. However, relapse/progression was higher in the RIC group, 21 percent vs. 9 percent (p=.03). It should be noted that nearly one-third of patients had chemotherapy-resistant disease and that the RIC recipients had an older median age (50 years vs. 45 years) and a longer time from diagnosis to transplantation (34 vs. 24 months). Chemosensitivity and recipient performance status were better predictors of outcome than conditioning regimen utilized.

Although relapse/progression occurs significantly less often after myeloablative alloHCT compared to AHCT, this modality cannot be routinely recommended due to prohibitive TRM. However, younger patients beyond first remission or who have exhausted all other options may better tolerate and benefit from such a regimen. RIC regimens have shown promising results and have broadened eligibility of alloHCT to older patients and patients who have failed prior AHCT. The advent of prognostic indices such as the Follicular Lymphoma International Prognostic Index (FLIPI) and gene-expression profiling may allow earlier identification of patients who could benefit from alloHCT sooner rather than later^22-23 .