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Reduced‐intensity conditioning allogeneic stem cell transplantation for patients with chemoresistant or relapsed follicular lymphoma

Patients with recurrent advanced stage follicular lymphoma (FL) have a poor prognosis (median survival 4–5 years) with limited therapeutic options. Conventional allogeneic stem cell transplantation (allo-SCT) was suggested to be a curative option for FL. However, the benefit of standard myeloablative allo-SCT is usually offset by high transplantrelated mortality (TRM) (Peniket et al, 2003). Reducedintensity conditioning (RIC) allo-SCT generated some interesting results in patients with FL and were related to a potent graft-versus-lymphoma (GVL) effect (Khouri et al, 2001; Marks et al, 2002; Faulkner et al, 2004). Here, we report our experience in eight FL patients who received RIC allo-SCT in progressive and/or chemoresistant disease. All donors were human leucocyte antigen (HLA)-identical siblings. Details of the patients’ characteristics, transplant procedures, graft-versus-host disease (GVHD) features and outcome are summarised in Table I. Of note, four patients had relapsed after autologous SCT (ASCT) and three had chemoresistant disease at the time of allo-SCT. After RIC allo-SCT, sustained engraftment of neutrophils and platelets was achieved in all patients. With a median follow-up of 19 (range, 7–85) months, the cumulative incidence of TRM was 25% (95% confidence interval, 3–65%, Patients 2 and 3). These two patients died of chronic GVHD (cGVHD), and were in complete remission (CR) at time of death. The cumulative incidence of grade 2 to 4 acute GVHD (aGVHD) was 62% (five patients), and seven out of eight patients (87%) developed cGVHD (six extensive and one limited). Objective disease responses were observed concomitantly or after GVHD onset, without any additional chemotherapy. Interestingly, of the three patients who were chemoresistant at the time of allo-SCT (Patients 2, 5 and 6), two experienced CR after grade 2 aGVHD (Patients 2 and 6). One of them is still in CR 19 months after allo-SCT (Patient 6), whereas the other died in CR at 7 months from cGVHD (Patient 2). One patient experienced disease recurrence at 8 months, after ciclosporin A taper, and received a donor lymphocyte infusion (DLI) at 10 months, which induced CR (Patient 8). In two other patients, disease progressions occurred after allo-SCT (Patients 1 and 5), at 8 and 42 months, but both are still alive after salvage chemotherapy. Patient 5 was allografted in chemoresistant progressive disease and did not experience GVHD, neither after immunosuppression withdrawal, nor after DLI. Interestingly, Patient 1 responded to salvage ESHAP (etoposide, methylprednisolone, cytarabine, cisplatin)-type chemotherapy combined with radiotherapy at 42 months, and achieved a sustainable CR (though this patient had previously failed ASCT). Eighty-five months later, this patient is still alive in CR. Patients with chemoresistant FL or who failed ASCT have limited therapeutic options. Because of its potential to reduce TRM, RIC allo-SCT has arisen as an attractive modality in patients with FL. However, the role of RIC allo-SCT in this disease remains a matter of debate (Bierman et al, 2003). In the myeloablative setting, allo-SCT failed to demonstrate superior survival when compared with purged ASCT, and neither acute nor cGVHD appeared to significantly reduce the relapse risk (van Besien et al, 2003). In this study, a potent GVL effect can be suggested, as six patients experienced an objective response concomitantly to GVHD, or after DLI. In contrast, one patient did not develop signs of GVHD, and relapsed shortly after allo-SCT. The alkylating agent (busulfan) contained in the RIC regimen is unlikely to explain disease control, because the majority of patients had failed multiple chemotherapy regimens including ASCT with high-dose alkylating agents. Despite its obvious limitations, mainly due to its small size, this study indicated that RIC allo-SCT is feasible and may be a therapeutic option for those patients with chemoresistant disease and/or who have relapsed after ASCT, as a significant GVL effect can be achieved in this particular population.