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O. Tournilhac et al.
A
B
C
D
Figure 3. Patterns of minimal residual disease response of the 39 patients who engrafted and were alive after 1 month. Pattern A: patients with pre-transplant min- imal residual disease negative (MRDneg) status (n=6), Pattern B: patients who converted to MRDneg within 3 months post-transplant without any immune-intervention
neg
pos
number of allogeneic HSCT for CLL has considerably decreased since 2015, both in the United States27 and Europe.28 BCR and BCL-2 inhibitors allow control of relapsed CLL with a response duration exceeding those reported after immunochemotherapy.29,30 However, relapses are the rule, particularly in patients with adverse molecu- lar31,32 and/or complex karyotype.33,34 For such patients, CAR-T cells are also a hope.35,36 However, while this new option is very promising in several hematological diseases, in the 134 highly pre-treated CLL reported to date, the com- plete response rate remains 20 to 30%, with a median PFS of 18% at 18 months.37 This approach is associated with significant acute toxicity, but does not present, in contrast to allogeneic HSCT, a risk of GvHD. Hence, long-term results in large cohorts of CLL patients treated by CAR-T cells are currently needed, and allogeneic HSCT is still a valid option in CLL for selected patients.38
We report the first trial evaluating prospectively an approach of post-transplantation MRD-driven immune- intervention for CLL. M12 MRDneg associated with a reduced risk of relapse and an improvement of disease-free survival, was chosen as the primary endpoint.10-14 We hypothesized that early CsA tapering potentially followed by DLI in case of a post-transplantation MRDpos status could increase the incidence of MRDneg status at M12 and as a con- sequence could reduce the risk of relapse. Conversely, for
patients with a post-transplantation MRDneg status, CsA administration would be extended for a longer period to reduce the risk of chronic GvHD.
In order to minimize severe GvHD incidence, we selected the same ATG containing conditioning regimen as previous- ly evaluated in a large multicenter study performed in a sim- ilar age population.18 Overall, in this population with a medi- an age close to 60 years, we observed less than 25% exten- sive cGvHD which appears lower than in previous series of HSCT in CLL and can be considered very acceptable in the context of allogeneic treatment of high-risk diseases.7-10
Moreover, only four deaths were related to either GvHD or infection and the 2-year NRM less than 10%, favorably compares with those varying from 17% to 27% reported in the main series of reduced intensity conditioning transplant in CLL.7-10 In this trial low NRM highly contribute to impres- sive 3-year OS close to 90%.
We show that post-transplantation MRD-driven immune-intervention is feasible in the setting of a multicen- ter trial. MRD evaluation was centralized and performed by a sensitive method of high-resolution ten-color flow cytom- etry. Results were available within 48 hours, allowing a rapid adaptation of the immunosuppressive therapy. Immune-intervention was conducted in accordance to the protocol in 83% of the evaluable patients; in the remaining patients CsA was withdrawn earlier due to graft-failure,
upon immune-intervention (cyclosporine A [CsA] withdrawal only) or graft-versus-host disease (GvHD) (n=16)
(n=11). Pattern C : patients who converted to MRD
Pattern D: patients who remained MRD positive (MRD
(n=7). Solid blue line: negativity limit of MRD (<0.01%). UD : undetectable MRD (MRD < limit of detection [LOD]).
) during follow-up despite immune-intervention (CsA withdrawal and donor lymphocyte infusion [DLI]) or GvHD
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