RIC Allogeneic Stem Cell Transplantation for High Risk CLL Followed By Preemptive MRD-Based Immunointervention - Intermediate Results from the Phase II ICLL03 Ricac-Pmm Trial (FILO & SFGM-TC French intergroup)

Introduction Reduced intensity conditioning (RIC) allogeneic stem cell transplantation (ASCT) remains a valuable and potentially curative strategy in high-risk CLL. Post-ASCT relapse remains an important (30-40%) cause of failure, predicted by persisting positive minimal residual disease (MRD) at 12m post-ASCT. ASCT is also associated with a toxic mortality and with the burden of chronic graft versus host disease (cGVHD). We evaluated the efficacy and safety of a preemptive immunointervention (PrIm) based on serial MRD assessment in high-risk CLL. (NCT01849939)

Methods Main inclusion criteria were (1) EBMT criteria for ASCT, (2) CLL in PR/CR, (3) mass ≤5cm, (4) age ≤70, (5) SORROR score ≤2 and (6) HLA donor (10/10). RIC regimen included fludarabine 120 mg/m2, IV busulfan 6.4 mg/kg, rabbit ATG 5mg/kg and CsA prophylaxy. Centralized 10-color flow cytometry blood MRD was assessed before and at M1, M2, M3, M4, M5, M6, M9 and M12 post-ASCT. MRD[-] was defined by blood detection <10e-4 at 2 consecutive time-points, confirmed (if possible) on bone marrow aspiration. PrIm algorithm, applied from D30 to M12, considered IWCCL response criteria, blood MRD and GVHD occurrence/severity. PrIm comprised tutored CsA early (≤4-5m), standard (6m) or late (7m) tapering and discontinuation (T&D). Early CsA T&D was followed in case of failure to achieve MRD[-] by 1-3 increasing DLI doses (1, 5 or 10x10e6 CD3/kg). Primary end point was the rate of MRD[-] at M12. Chimerism was assessed in parallel on full blood and on sorted CD3+ cells and was not a part of PrIm decision.

Results As of 2015, August the 1^st, the 43 planned inclusions have been done. Before their last line prior to ASCT, pts had: (a) presence of a del(17p) in 1^st line (n=24) or in relapse (n=3), (b) absence of del(17p) but relapse ≤2y post fludarabine-based combination (n=14) or post-autologous transplantation (n=1). At time of transplantation, 11/43 (26%) had achieved CR, 28/43 (65%) had achieved PR, 2/43 (5%) had SD with 2 unknown status. Six patients had undetectable MRD (limit of detection: 5x10^-6). For the 37 other patients, the median pre-ASCT MRD level was 2.35%(0.014 to 70%).

The results of these 43 pts will be available in December 2015. This abstract describes the outcome of the 30 first consecutive pts including 26 pts evaluable [alive with ≥12m post-ASCT follow-up] and 4 pts non evaluable [death at M10 (n=1; sepsis) and at M8 (n=1 GVHD), EBV induced lymphoproliferation (n=1) and immediate graft rejection (n=1)], all included in the ITT analysis. In the 29 pts with full engraftment, the full blood chimerism at 3m and 12m was 99.1[62.1 ;99.8] and 99.5[59.4 ;99.9], and the T-cell specific chimerism was 99.2[5.2;99.8] and 99.6[21.1;99.8], with 30% and 25% >95% donor derived CD3+ cells respectively. MRD evolution followed different patterns (Table 1). At the M3 checkpoint, among evaluable patients, 10 were already MRD[-], and 16 were still MRD[+]. Then 10 pts became MRD[-] and 6 remained MRD[+]. This approach achieved 67% blood MRD[-] at M12 (ITT). When early CSA T&D had failed DLI done in 6 pts did not achieve MRD negativity. Finally, 6 pts (20%) remained MRD[+] at 12m.

At 12m FU, the rate of Gr≥2 aGVHD was (11/30) 37% (consecutive to early CsA T&D in 2 pts and to early CsA T&D followed by DLI in 1 pt) and the rate of extensive cGVHD was (5/29) 17% (consecutive to CsA T&D in 1 pt). Hence we observed the occurrence of Gr≥2 aGVHD and extensive cGVHD in 2/8 and 1/8 pts after early CsA T&D. We also observed one case of Gr≥2 aGVHD among the 6 pts who had early CsA T&D followed by DLI. Eighteen severe adverse events were reported, including the 2 aforementioned deaths. These events were not related to the study procedure (PrIm).

Discussion These preliminary data highlight the feasibility, safety and efficacy of a standardized PrIm strategy in high-risk CLL. As DLI appears to have limited impact when CsA T&D fails, the preemptive use of new agents should be considered at this point for persistent MRD[+] after 3-6m post-ASCT.