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Allograft and preemptive immuneintervention in CLL
A
B
C
Figure 4. Impact of minimal residual disease negative (MRD ) status achieve- neg
ment on post transplant outcome according to the Mantel-Byar method illus- trated by Simon-Makuch plots (MRD status as a time-dependent event). (A) overall survival, (B) progression-free survival and (C) cumulative incidence of relapse.
mixed chimerism or renal failure. The immune-intervention related toxicity was low, with only two cases of GvHD occurring after CsA withdrawal or DLI applied as per pro- tocol.
In an Intent-To-Treat analysis, the primary end-point of M12 MRDneg status has been achieved in 64 % of the 42 transplanted patients and in 79% of the 34 patients who actually had a M12 MRD evaluation. This result favorably compares with both prospective10 and retrospective11-14 stud- ies reporting 48% to 71% MRDneg status at 6 to 12 months after HSCT.10-14 Particularely our results are in line with one large single-center retrospective analysis of 77 allografted CLL patients submitted to immune modulation based on MRD evaluation.6 In this latter study M12 MRD clearance was achieved in 56% overall and 84% of all patients evalu- able for M12 MRD status and the 3-year relapse incidence was 26%. Our data argue for the benefit of an early pre- emptive immune-intervention based on MRD evaluation. Thus, early CsA withdrawal applied in D90 MRDpos patients translated into MRDneg status at M12 in 69% of them. Moreover, most patients with D90 MRDpos status and GvHD, spontaneously switched to MRDneg at M12, high- lighting the role of allogeneic reaction in the control of the disease. Conversely, in this context of early preemptive immune-intervention we failed to show a benefit of DLI to convert MRD from positive to negative, but three of five patients were already in clinical progression at the time of infusion. Finally, considering the non-randomized nature of
the trial, our data suggest that a MRD-driven CsA with- drawal can provide durable MRD clearance, improve GvHD leukemia effect and avoid progression.
In several studies, the M12 MRDneg status was associated with lower incidence of relapse.13-15,39 As half of the progres- sion occurred before M12 in our series, we chose to analyze the impact of MRD using MRD as a time dependent vari- able. We confirm here the strong correlation between an MRDneg status achievement regardless of time point and both low progression and better PFS. Interestingly, we also show that MRDneg status achievement translates into better survival. The impressive post-transplant OS closed to 90% at 3 years in this high-risk CLL population could also be explained by the possibility opened to physician of treating post-allograft relapses with ibrutinib. It should also be noted that the three patients who died from CLL-related cause had Richter's syndrome, including two escaping ther- apy with ibrutinib.
These data lead us to propose early additional therapy in patients who display an MRDpos status despite either MRD- driven CsA withdrawal or chronic GvHD, or in the rare patients who could experience disease despite MRDneg status achievement. Recent reports show the efficacy of ibrutinib in post-HSCT CLL relapse without limiting toxicity or GvHD, as also observed in our series.40,41 This treatment should be evaluated preemptively in patients who fail to achieve negative MRD after CsA cessation.
In conclusion, this report shows the feasibility of MRD-
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