Discussion

CLL will not affect life expectancy, although the disease is incurable with conventional treatment. However, in patients with advanced-stage disease or with adverse prognostic factors, survival time is considerably reduced (1-4,37-40). The prognostic factors are the same in younger and older patients (2). The disease can be treated with conventional chemotherapy (31,41-49), but most of the responses observed with different regimens are partial remission.

Fig. 7. Allotransplantations after reduced conditioning regimens for CLL (P. Dreger): time to best response. Data from EBMT database.

More recently, fludarabine (50-56), 2-chlorodeoxyadenosine, and deoxycoformycin (57-60) have been shown to achieve complete remission in previously treated CLL patients, and randomized comparisons between fludarabine and other regimens (61) have demonstrated that fludarabine produces more complete responses but is without benefit in terms of overall survival. The median time to progression for responders to fludarabine was 31 mo, and for refractory patients the median survival was only 48 wk (32). Some interesting results were observed with the association of fludarabine and other agents (62,63) or after using Campath-IH (64). Nevertheless, all these therapeutic approaches have not yet cured CLL, hence the consideration of innovative dose-intensive therapies.

Allotransplantation adds immunotherapeutic effects to cytotoxic effects and may thus be a curative treatment for CLL, as we and other authors have demonstrated (5,6,7,13). Moreover, the sensitivity to donor lymphocyte infusions suggests an important role of the GVL effect for the success of alloT (13,14,16,17). Nevertheless, even in highly experienced centers, the TRM has been reported to be as high as 30-40% (5-7,13), which is clearly higher than after alloT for standard indications (65). The causes of these discouraging results are not completely clear, but patient age, selection of poor-risk patients with advanced disease and extensive pretreatment, and the CLL-associated incompetence of the immune system may all contribute to the high TRM observed. The demonstration in this disease of the GVL effect (16,17) and, in parallel, the recent development of conditioning regimens with reduced intensity (18,25-27,36) may help to make it possible to propose allogeneic SCT to a larger number of CLL patients, even older patients. TRM after a reduced intensity regimen is much lower than after a myeloablative-conditioning regimen (21-23,36).

In contrast to allogeneic transplantation, the number of autotransplantations for CLL has dramatically increased over the past few years (13,66). Because of mobilization of PBSCs and other improvements in supportive therapy, the mortality of the procedure is now well below 10%. High-dose radiochemotherapy followed by autologous SCT can induce or maintain long-term complete remissions at the molecular level, as has been shown in various studies (8,9). With this strategy, it was demonstrated that the persistence of the tumor-specific PCR signal after autografting is strongly predictive for subsequent disease recurrence, whereas patients achieving molecular remission are not at risk for short-term relapse (28). In the vast majority of published stem cell transplantations for CLL, the myeloablative regimen included TBI. The rationale behind this is that CLL cells—like other indolent lymphatic neoplasms—are sensitive to irradiation. Thus, TBI/cyclophosphamide still appears to be the gold standard for autografting of patients with CLL, and we have demonstrated the significantly favorable impact of a TBI-containing regimen on outcome after autotransplantation. Two other parameters significantly influenced outcome after autotransplantation: being in CR or very good PR before transplantation and having a short interval between diagnosis and autotransplantation.

Although the outcome of patients after autotransplantation is characterized by an 3-yr overall survival of more than 75% and thus is generally better than that after allotransplantation, in most series, a steady decline of the event-free survival curve was observed owing to continuous relapses occurring up to 5 yr after transplantation, and it is still not clear whether autografting can be curative in at least certain subsets of patients with CLL. In spite of sophisticated purging technologies (34,35), only a little information on the clinical benefit of ex vivo B-cell depletion is available, meaning that clear-cut evidence for the usefulness of purging of CLL autografts is still lacking. Because of their favorable engraftment kinetics, mobilized PBPCs have now replaced bone marrow as the principal source of stem cells for autotransplantation (65). Very preliminary data indicate that the mobilization efficacy of more intensive protocols such as the Dexa-BEAM regimen appears better than classic cyclophosphamide plus G-CSF combinations (8), but many other variables could influence PBSC mobilization in this disease (29,33).

In conclusion, hematopoietic stem cell transplantations could be proposed in CLL, but we need more prospective studies to determine the real place of allotransplantation, particularly after reduced-intensity conditioning and timing of autotransplantation throughout the history of the disease. In the light of all observed results, we would nevertheless make the following recommendations for SCT in CLL: (1) fludarabine should be used during therapy before allotransplantation and pilot studies should be developed of allotransplantations after reduced-intensity conditioning regimen; (2) a TBI-containing conditioning regimen should be used before autotransplantation; (3) the interval between CLL diagnosis and autotransplantation should be short; and (4) patients should be in CR or very good PR before autotransplantation.

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