Page 98 - 2021_07-Haematologica-web

O. Tournilhac et al.
9.5% (95% CI: 3.7-23.4) and 29.6% (95% CI: 17.3-47.7). Incidence of 2-year limited and extensive chron- ic graft versus host disease (cGVHD) is 38% (95% CI: 23-53) and 23% (95% CI: 10-36) including two cases post Md-PII. Fifteen patients converted to MRDneg either after cyclosporine A withdrawal (n=12) or after cGvHD (n=3). As a time-dependent variable, MRDneg achievement at any time-point correlates with reduced relapse (Hazard ratio [HR] 0.14 [range, 0.04-0.53], P=0.004) and improvement of both progres- sion free (HR 0.18 [range, 0.06-0.6], P<0.005) and overall (HR 0.18 [range, 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 (clinicaltrials gov. Identifier: NCT01849939).
Introduction
Until recently, patients with refractory chronic lympho- cytic leukemia (CLL) or who relapse early after purine analogs and rituximab-based chemoimmunotherapy or those harboring 17p deletion (del(17p)) and/or TP53 muta- tions were considered high-risk patients with reduced over- all survival (OS). Better understanding of the molecular and genetic aspects of CLL brought novel and highly active strategies such as targeting kinases downstream of the B- cell receptor (BCR) pathway.1-3 These therapies have pro- fondly modified the CLL therapeutic landscape, thanks to improved efficacy and better tolerability. However, the dis- ease is still incurable and allogeneic hematopoietic stem cell transplantation (HSCT) remains a valid option in selected high-risk patients.4,5
Prospective studies have shown that allogeneic HSCT can offer long progression free survival (PFS) and even a cure in 35% to 45% of high-risk patients. Reduced intensity conditioning (RIC) HSCT can be proposed to older patients and patients with comorbidities who represent the bulk of the CLL population. However disease recurrence, recorded in 22% to 46% patients, is still a major issue.6-9 Pre-trans- plantation refractoriness and bulky disease is associated with higher risk of post-transplantation progression.9,10 The level of post-transplantation minimal residual disease (MRD) is widely associated with the risk of further progres- sion. In several studies, a negative MRD (MRDneg) status at 6 to 12 months translated into a progression incidence below 10%.11-14 Moreover, the MRDneg status may be reached by post-transplantation immunomodulation such as cyclosporine A (CsA) tapering or donor lymphocyte infu- sion (DLI).15 These data led us to conduct a prospective study evaluating an approach of RIC HSCT followed by a preemptive MRD-driven immune-intervention with the aim to achieve a MRDneg status at 12 months post-transplan- tation.
Methods
Study design
The ICLL03 RICAC-PMM (Reduced Intensity Conditioning Allogeneic Transplantation for CLL with Preemptive MDR Management), a joint FILO (French Innovative Leukemia Organization) and SFGM-TC (Société Francophone de Greffe de Moelle et de Thérapie Cellulaire) multicenter phase II trial evalu- ated the efficacy and safety of a preemptive immune-intervention based on MRD assessment in high-risk CLL. Eligible patients were 18 to 70 years old, with CLL (Matutes score 4 or 5) or lymphocytic lymphoma, and high-risk features according to the 2006 European Society for Blood and Marrow Transplantation (EBMT) consen- sus16 (see Online Supplementary Appendix). Patients had to be in complete or partial response with lymphadenopathy <5 cm and a
comorbidity score ≤ 2. Donors were HLA-matched sibling or unre- lated (10/10).17 All responsible Institutional Review Boards in accordance with the Declaration of Helsinki approved the proto- col including the study-specific informed consent form. The study was declared to the French Authorities (reference ID-RCB 2011- A00906-35) and registered on clinicaltrials gov. Identifier: NCT01849939.
Transplantation modalities
Conditioning regimen was fludarabine, 30 mg/m2/day, from day (D) D-5 to D-1, intravenous busulfan 3.2 mg/kg/day from D- 4 to D-3 and ATG (thymoglobuline) 2.5 mg/kg/day from D-3 to D-2.18 Stem cell source was G-CSF mobilized peripheral blood cells. Graft-versus-host disease (GvHD) prophylaxis was based on CsA with a short course of methotrexate in case of minor donor/recipient ABO mismatch.
Response and minimal residual disease evaluation
Response evaluation was performed according to 2008 iwCLL criteria including computed tomography scan (CT-scan)19 before and 3 months (M3), 6 months (M6) and 12 months (M12) after transplantation.
MRD analysis was centrally performed on blood and/or bone
marrow by 10-color multiparameter flow cytometry.20-22 MRD neg
definition was <1 CLL cell detectable per 10,000 leukocytes
) definition was ≥1 CLL cell detectable per 10,000 leukocytes. Clusters of <20 events were considered as undetectable MRD (UD). Blood MRD evaluation was planned before transplantation, then monthly until M6, at M9 and M12. Once achieved, the blood MRDneg status was confirmed 1 month
later in both blood and bone marrow.
Preemptive immune-intervention
Preemptive immune-intervention was applied in the absence of significant GvHD, defined by either acute GvHD (aGVHD) ≥ grade 2 or extensive chronic GvHD (cGvHD). The algorithm based on response and blood MRD assessment included accelera- tion of CsA tapering and withdrawal followed in case of failure by escalating DLI. The algorithm also included extension of CsA treatment in case of early achievement of MRD status (Online Supplementary Appendix; Figure A)
Chimerism and graft-versus-host disease assessment Chimerism studies were performed on peripheral blood at M1, M2, M3, M6, and M12 post HSCT by multiplex fluorescent poly- merase chain reaction using Short Tandem Repeat analysis. (Online Supplementary Appendix). The diagnosis of GvHD was
made according to published criteria.23,24
Trial objectives and statistical analysis
The primary objective was to evaluate the efficacy of a pre- emptive immune-intervention to achieved MRDneg at M12. The probabilities of OS, and PFS were calculated using the Kaplan- Meier estimator. The probability of non-relapse mortality
(<1.10-4).19 MRD (MRD pos
1868
haematologica | 2021; 106(7)