Results of a randomized trial comparing high-dose chemotherapy plus Auto-SCT and R-FC in CLL at diagnosis

Abstract

The importance of early therapy intensification in B-cell CLL (B-CLL) patients remains to be defined. Even though several studies have been published, no randomized trials comparing directly autologous stem cell transplant (ASCT) and the accepted conventional therapy (that is, rituximab, fludarabine and CY; R-FC) have been reported so far. To assess the benefit of a first-line aggressive therapy, we designed a multicenter, randomized, phase 3 trial comparing R-FC and high-dose chemotherapy supported by ASCT in patients under 65 years of age, with stage B(II) or C B-CLL. Primary end point was CR: 96 patients were enrolled (48 in each arm). On an intent-to-treat basis, the CR rates in the ASCT and R-FC arms were 62.5% and 58%, respectively. After 5 years of follow-up, PFS was 60.4% in the ASCT arm and 65.1% in the R-FC arm, time to progression 65.8 and 70.5%, and overall survival 88% vs 88.1%, respectively. Our trial demonstrates, for the first time in a randomized manner, that frontline ASCT does not translate into a survival advantage when compared with benchmark chemoimmunotherapy in B-CLL patients; the possibility of its clinical benefit in certain subgroups remains uncertain. Keywords: B-CLL; high-dose chemotherapy; autologous transplantation INTRODUCTION B-CLL is the most common form of leukemia in adults in western countries and it is characterized by the slow, albeit continous, accumulation of mature B lymphocytes in peripheral blood, BM and lymphoid organs. Although the median age of 70 years at diagnosis does not allow intensive chemotherapy regimens and achieving a prolonged disease control is the best option, at least 30% of the patients are younger than 65 years, 1 thus deserving a more aggressive approach. Several groups reported results with standard-dose chemotherapy or with intensive therapeutic regimens: the evidence is that R-FC chemoimmunotherapy is to be considered the gold standard for B-CLL treatment, while more aggressive approaches do not translate into a survival advantage. 2 However, in spite of the large number of reports, 3,4 randomized trials comparing R-FC and autologous stem cell transplant (ASCT) are still lacking while there is recent evidence supporting the use of R-FC in the front-line setting. 5 Since ASCT appears to be a reasonably safe procedure, and ASCT trials performed so far are difficult to compare for differences in myeloablative regimens, use of MoAbs, graft purging and type of chemotherapy, 6-9 we started a multicenter, randomized, phase 3 trial comparing R-FC and highdose chemotherapy supported by ASCT in patients under 65 years of age, with stage B(II) or C B-CLL in 2005. The aim was to study

High-dose therapy and autologous hematopoietic cell transplantation as front-line consolidation in chronic lymphocytic leukemia: a systematic review

“…21 This benefit is possibly explained by the fact that mini-CHOP and, subsequently, fludarabine monotherapy, as prescribed, were suboptimal therapies in CLL, hence patients randomized to the observation arm were at an inherent disadvantage when compared with those who received HDT/auto-HCT and benefited from the consolidation. 21 This argument is supported by findings from Magni et al 20 who showed that HDT/auto-HCT failed to show improvement in responses, PFS and OS when compared with a contemporary chemoimmunotherapy regimen, consisting of fludarabine, cyclophosphamide and rituximab. Interestingly, the European intergroup randomized trial comparing autografting with observation demonstrated a benefit in lowering risk of relapse as well as improved EFS in the HDT/auto-HCT arm despite the fact that 73% of the subjects in the transplant arm did not receive rituximab as part of the initial regimen.…”

“…Brion et al 19 reported two deaths attributed to secondary AML in 39 subjects who were treated with HDT-auto-HCT. None of the subjects who received HDT/auto-HCT in the study by Magni et al 20 were reported to have developed AML/ MDS; it is possible this could be explained by a relatively short follow-up. The relatively low incidence of secondary AML/MDS from these studies 19-21 compared with 9-12% incidence reported in a previous systematic review by our group 10 is probably explained by the fact that the latter patients were offered HDT/ auto-HCT in the relapsed disease setting, suggesting an increased risk of leukemogenesis as a result of cumulative exposure to multiple lines of chemotherapy in this pre-treated group in addition to using TBI as part of the preparative regimen; and/or perhaps by a smaller rate of events in the present analysis (eight AML/MDS cases in 274 autografted patients), possibly related to a relatively short follow-up as previously stated.…”

“…Four randomized controlled trials, which included a total of 600 subjects, were eligible for inclusion. 11,[19][20][21] Selection process of studies is reported in Figure 1.…”

“…10,11,16,[17][18][19][20][21] Use of HDT/auto-HCT as a consolidative strategy following front-line therapy has been evaluated in the context of a randomized controlled trial by several investigators. Accordingly, we performed a systematic review aiming at evaluating the totality of evidence pertaining to the efficacy (or lack thereof) of this approach in newly diagnosed CLL.…”

Long-term Outcomes in Patients with Chronic Lymphocytic Leukemia Treated with Standard Therapy

“…Autologous transplantation of stem cells does not offer substantial advantages when compared against new pharmacological treatment On the contrary, allogeneic transplantation is still to be considered for refractory diseases de novo, given the long-term efficacy of new drugs remains unknown [26,27].…”