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- Design and methods
The role of haematopoietic stem cell transplantation (HSCT) in relapsed follicular lymphoma remains controversial. This study analysed 126 patients with relapsed, advanced stage follicular lymphoma who received BEAM (BCNU [carmustine], cytarabine, etoposide, melphalan)-alemtuzumab allogeneic HSCT (BEAM-allo) (n = 44) or BEAM-autologous HSCT (BEAM-auto) (n = 82). The BEAM-allo group had a younger median age (48 years vs. 56 years, P < 0·001) but received a higher median number of therapies pretransplant (P = 0·015) compared with the BEAM-auto group. There was a higher non-relapse mortality (NRM) in the BEAM-allo group compared with the BEAM-auto group at 1 year (20% vs. 2%, P = 0·001). Older age and heavily pretreated patients were associated with a higher NRM and poorer survival in the BEAM-allo group. There was, however, a significantly lower relapse rate (20% vs. 43%, P = 0·01) at 3 years with BEAM-alemtuzumab, with no relapses after 2 years, compared with a continued pattern of relapse in the autologous group. No difference in overall survival (OS) (P = 0·99) or disease-free survival (DFS) (P = 0·90) was identified at 3 years, whereas a plateau in OS and DFS with crossing of the survival curves in favour of BEAM-allo group was observed. Furthermore, the ability to re-induce remissions with donor leucocytes provides additional benefit in favour of allogeneic HSCT.
Follicular lymphoma is typically characterized by an indolent course with recurrent relapses, progressive shortening in the duration of remission and a median survival of 8–9 years (Johnson et al, 1995; Hunault-Berger et al, 2002). Despite modest improvements in progression-free survival (PFS) with monoclonal antibodies and combination chemotherapy, the disease remains incurable with conventional agents. In particular, patients with advanced stage follicular lymphoma or those with high grade transformation show poor survival with standard therapy (Horning & Rosenberg, 1984; Gallagher et al, 1986). Improved PFS was reported with the use of autologous haematopoietic stem cell transplantation (auto-HSCT) in first remission, but no survival advantage over standard chemotherapy has been demonstrated(Lenz et al, 2004; Deconinck et al, 2005). Furthermore, the only randomized study (Chemotherapy, Unpurged-, Purged-stem cell [CUP] trial) performed in relapsed/refractory disease reports both an improved PFS and overall survival (OS) but suffered slow recruitment and contained small patient numbers (Schouten et al, 2003). A major obstacle to the success of auto-HSCT is the high incidence of relapse that becomes apparent on longer follow-up, reported between 43% and 88% (Ratanatharathorn et al, 1994; Verdonck et al, 1997; Mijovic et al, 1998; van Besien et al, 2003). In addition, an excess of secondary malignancies has been reported by several groups following the use of auto-HSCT (Freedman et al, 1999; Micallef et al, 2000; Howe et al, 2003; Deconinck et al, 2005).
Allogeneic HSCT (allo-HSCT) offers curative potential in patients with advanced stage follicular lymphoma. Non-myeloablative or reduced-intensity conditioned (RIC) allo-HSCT is associated with lower regimen-related toxicity as compared with myeloablative regimens, whilst maintaining the ability to harness the graft-versus-lymphoma (GvLy) effect (Jones et al, 1991; van Besien et al, 1997; Mandigers et al, 1998, 2003; Cull et al, 2000; Khouri et al, 2001; Martino et al, 2001; Branson et al, 2002; Ho et al, 2003; Faulkner et al, 2004; Morris et al, 2004; Valcarcel et al, 2005; Vigouroux et al, 2007). Mortality resulting from graft-versus-host disease (GvHD) and infectious complications remain as a significant problem. Alemtuzumab is a humanized monoclonal antibody to the panlymphoid antigen CD52, which results in a low incidence of chronic GvHD (7–17%) compared with non-T-cell-depleted regimens (59–64%) (Cull et al, 2000; Khouri et al, 2001; Perez-Simon et al, 2002; Faulkner et al, 2004). Higher relapse rates seen with the use of T-cell depletion initially raised concern. In two preliminary reports of alemtuzumab for lymphoma, a relapse rate of 44% was reported with a fludarabine-based regimen and 10% when used in conjunction with BEAM conditioning, which compared with 0–3% for non-T-cell-depleted regimens (Khouri et al, 2001; Perez-Simon et al, 2002; Faulkner et al, 2004; Morris et al, 2004). The OS was, however, comparable for all studies, at 73–84%, irrespective of T-cell depletion and heterogeneous disease groups, at a short follow-up of up to 2 years.
BEAM (BCNU [carmustine], cytarabine, etoposide, melphalan) is commonly used as conditioning for auto-HSCT in lymphoproliferative disorders with low transplant-related toxicity (Chopra et al, 1993; Bastion et al, 1995; Mills et al, 1995). The addition of alemtuzumab as part of an allogeneic regimen, with its associated stable donor engraftment, minimal GvHD and modest relapse rates is encouraging (Faulkner et al, 2004). Here, we report the outcome of 126 patients with advanced stage follicular lymphoma, who either received autologous transplantation using BEAM conditioning (BEAM-auto) or allogeneic HSCT incorporating BEAM-alemtuzumab (BEAM-allo).
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- Design and methods
The majority of patients with advanced stage follicular lymphoma are currently managed with either combination chemotherapy +/−addition of anti-CD20 monoclonal antibody (rituximab) or high-dose therapy with autologous stem cell rescue. Improved PFS but no survival advantage was reported following the use of high-dose therapy with autologous stem cell rescue when compared with standard chemotherapy alone in previously untreated patients with advanced stage follicular lymphoma (Deconinck et al, 2005). Allogeneic HSCT is considered as a potential curative option for advanced stage lymphoma; however, is only offered to those with relapsed disease as a result of the high regimen-related toxicity. A previous report demonstrates a low incidence of NRM and GvHD with the use of BEAM-alemtuzumab conditioning in a variety of lymphoproliferative disorders (Faulkner et al, 2004). Here, we directly compared the outcome of patients with advanced stage follicular lymphoma who received BEAM conditioning either in an autologous setting or as allogeneic conditioning in combination with alemtuzumab.
We acknowledge that, because of the retrospective nature of this paper, the two groups were not matched for age and prior chemotherapy regimens. Despite a younger median age in the BEAM-allo group, they were more heavily pretreated and were more likely to be resistant to initial salvage chemotherapy than patients who received auto-HSCT. Irrespective of this difference, patients who received BEAM-alemtuzumab conditioning had a higher NRM but significantly lower relapse rate than the BEAM-auto group. Older age and heavily pretreated patients sustained higher regimen-related toxicity, with worse outcome reflected in poorer DFS and OS following BEAM-allo HSCT. The use of volunteer unrelated donors or HLA-mismatched donors did not significantly adversely affect outcome. However, all patients who received HLA-mismatched transplants were heavily pretreated and demonstrated incomplete response to conventional chemotherapy, with, at best, partial remission in six patients, progressive disease in one patient and high-grade transformation in two patients. Details on the International Prognostic Index (IPI) and the follicular lymphoma IPI were unavailable because of the retrospective nature of the study. Current treatment options for patients with relapsed follicular lymphoma are limited, particularly if they have failed mobilization of autologous stem cells. Heavily pretreated patients and older age are both associated with an increased frequency of co-morbidity. Formal assessment of co-morbidity score pretransplant may improve risk stratification in those poor prognostic patients as described recently in the myeloid setting (Sorror et al, 2005; Parimon et al, 2006).
Relapse rates of up to 44% have been reported following the use of T-cell-depleted regimens for lymphoproliferative disorders (Morris et al, 2004). The present study found a relapse rate of 20% at 3 years in the alemtuzumab arm compared with 43% in the autologous group. Indeed the pattern of relapse was quite different between the two groups. A plateau was reached at 2 years in the BEAM-allo group, whereas a continuous pattern of relapse was seen in the autologous group with the 5-year relapse rate reaching 56%. These observations are consistent with a GvLy effect in the BEAM-allo group. No significant difference in the relapse rate was observed within the allo-HSCT group on comparison of 50 mg vs. 100 mg of alemtuzumab. Furthermore, Campath-1H (alemtuzumab) may indeed have a direct anti-lymphoma effect, as low-grade B-cell non-Hodgkin lymphoma (NHL) is known to express CD52 antigen (Salisbury et al, 1994; Rodig et al, 2006). However, in a phase II study of Campath-1H for previously treated low-grade NHL, a partial remission rate of just 14% was achieved in B-cell NHL with a short median time to progression of 4 months (Lundin et al, 1998). These data suggest that the GvLy effect is the most important factor in maintaining remission following BEAM-allo HSCT.
A potential advantage of allogeneic HSCT is the ability to re-induce remissions in the event of relapse or falling donor chimaerism with the use of donor leucocytes, with a low incidence of associated GvHD. Complete remission was achieved in four of six patients who relapsed (three morphological and one molecular) following BEAM-alemtuzumab conditioning, further demonstrating the GvLy effect of allo-HSCT. A state of stable mixed chimaerism with no evidence of relapse was observed in a small proportion of patients (n = 7), suggesting that achievement of full donor chimaerism is not an essential goal. However, rapidly falling donor chimaerism, seen in four patients, was associated with disease relapse and required rapid intervention with DLI.
The comparison of patients who received BEAM-auto with BEAM-alemtuzumab conditioning demonstrated no significant difference in the 3-year PFS or OS. Nonetheless, a plateau was observed following BEAM-allo HSCT with respect to relapse, DFS and OS, with crossing of the survival curves in favour of allo-HSCT despite them being more heavily pretreated. Longer follow-up may enable the identification of a true survival advantage over autologous HSCT. Furthermore, the use of alemtuzumab resulted in a low incidence of GvHD, with no patient in this study developing grade III or IV acute GvHD and only three patients developing chronic extensive GvHD.
A disadvantage of the use of alemtuzumab is the high incidence of viral complications in the post-transplant period as reported by other groups (Chakrabarti et al, 2002a,b,c). Up to 50% of patients in this study developed a viral complication following BEAM-allo conditioning incorporating alemtuzumab. CMV reactivation was the most common finding with a third of patients requiring pre-emptive treatment. Despite this, the mortality from viral illness was low, with only one death as a result of CMV pneumonitis and two resulting from adenovirus infection. Both patients with adenovirus infection also had graft failure at the time of death. Routine monitoring and prompt treatment of patients with anti-viral agents prevent mortality in the majority of cases.
In conclusion, this study demonstrated comparable outcome of patients with relapsed advanced stage follicular lymphoma treated with either BEAM-auto or BEAM-allo HSCT. Longer follow-up will determine whether the reduced relapse risk and plateau in OS observed in the BEAM-alemtuzumab group will translate into a survival benefit over autologous HSCT. Improved patient selection through the use of prognostic scoring systems (Follicular Lymphoma International Prognostic Index) and the use of co-morbidity scores may better predict outcome following HSCT.