Efficacy of minimal residual disease driven immune-intervention after allogeneic hematopoietic stem cell transplantation for high-risk chronic lymphocytic leukemia: results of a prospective multicenter trial

Abstract

Allogeneic hematopoietic stem cell transplantation (HSCT) remains a potentially curative and useful strategy in high-risk relapsing CLL. Minimal Residual Disease (MRD) assessment at 12 months post-HSCT is predictive of relapse. This phase 2 study aimed to achieve M12 MRD negativity (MRDneg) using MRD-driven immune-intervention (Md-PII) algorithm based on serial flow-cytometry blood MRD, involving cyclosporine tapering followed if failure by donor lymphocytes infusions. Patients had high-risk CLL according to 2006 EBMT consensus, in complete or partial response with lymphadenopathy < 5 cm and comorbidity score ≤ 2. Donors were HLA-matched sibling or matched unrelated (10/10). Forty-two enrolled patients with either 17p deletion (front-line, n=11; relapse n=16) or other high-risk relapse (n=15) received reduced intensity-conditioning regimen before HSCT and were submitted to Md-PII. M12-MRDneg status was achieved in 64% versus 14.2% before HSCT. With a median follow-up of 36 months (range, 19-53), 3-year overall survival, non-relapse mortality and cumulative incidence of relapse are 86.9% (95%CI, 70.8-94.4), 9.5% (95%CI, 3.7-23.4) and 29.6% (95%CI, 17.3-47.7). Incidence of 2-year limited and extensive chronic graft versus host disease (cGVHD) is 38% (95%CI, 23-53) and 23% (95%CI, 10-36) including 2 cases post Md-PII. Fifteen patients converted to MRDneg either after CsA withdrawal (n=12) or after cGVHD (n=3). As a time-dependent variable, MRDneg achievement at any time-point correlates with reduced relapse (HR=0.14 [0.04-0.53], p=0.004) and improvement of both progression free (HR=0.18 [0.06-0.6], p<0.005) and overall (HR: 0.18 [0.03-0.98], p=0.047) survival. These data highlight the value of MRD-driven immune-intervention to induce prompt MRD clearance in the therapy of CLL.

Figure 1.

Post-transplant outcome of the 42 chronic lymphocytic leukemia transplanted patients. Kaplan-Meier estimates of (A) overall survival, (B) progressionfree survival. Calculated probability of (C) non relapse mortality and (D) cumulative incidence of relapse after hematopoietic stem cell transplantation.

Figure 2.

Post-transplantation minimal residual disease evaluation. At 12 months (M12), 27 of 42 (64%) patients were minimal residual disease negative (MRD_neg), 7 of 42 (17%) patients remained MRD positive (MRDpos), 8 of 42 (19%) patients were not evaluable because either prior early toxic death (n=4) and 4 of 42 patients (9.5%) or other reasons including graft rejection (n=2), Eppstein-Barr virus lymproliferation (n=1) and early relapse (n=1).

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 minimal residual disease negative (MRD_neg) status (n=6), Pattern B: patients who converted to MRD_neg within 3 months post-transplant without any immune-intervention (n=11). Pattern C : patients who converted to MRDneg upon immune-intervention (cyclosporine A [CsA] withdrawal only) or graft-versus-host disease (GvHD) (n=16) Pattern D: patients who remained MRD positive (MRDpos) during follow-up despite immune-intervention (CsA withdrawal and donor lymphocyte infusion [DLI]) or GvHD (n=7). Solid blue line: negativity limit of MRD (<0.01%). UD : undetectable MRD (MRD < limit of detection [LOD]).

Figure 4.

Impact of minimal residual disease negative (MRDneg) status achievement on post transplant outcome according to the Mantel-Byar method illustrated by Simon-Makuch plots (MRD status as a time-dependent event). (A) overall survival, (B) progression-free survival and (C) cumulative incidence of relapse.