Claude Lemarie

Antithymocyte Globulin in Reduced-Intensity Conditioning Regimen Allows a High Disease-Free Survival Exempt of Long-Term Chronic Graft-versus-Host Disease

Nonmyeloablative (NMA) regimens allow the use of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients considered unfit for standard myeloablative conditioning (MAC) regimens using high-dose alkylating agents with or without total body irradiation (TBI). Reduced-intensity conditioning (RIC) regimens, based on fludarabine (Flu), busulfan (Bu), and rabbit antithymocyte globulin (r-ATG), represent an intermediate alternative between NMA and MAC regimens. This platform was subsequently optimized by the introduction of i.v. Bu and the use of 5 mg/kg r-ATG, based on the hypothesis that these modifications would improve the safety of RIC allo-HSCT. Here we report a study conducted at our institution on 206 patients, median age 59 years, who underwent allo-HSCT after conditioning with Flu, 2 days of i.v. Bu, and 5 mg/kg r-ATG (FBx-ATG) between 2005 and 2012. The prevalence of grade III-IV acute graft-versus-host disease (GVHD) was 9%, and that of extensive chronic GVHD was 22%. Four-year nonrelapse mortality (NRM), relapse, and overall survival (OS) rates were 22%, 36%, and 54%, respectively. NRM tended to be influenced by comorbidities (hematopoietic cell transplantation-specific comorbidity index [HCT-CI] <3 versus HCT-CI ≥3: 18% versus 27%; P = .075), but not by age (<60 years, 20% versus ≥60 years, 25%; P = .142). Disease risk significantly influenced relapse (2 years: low, 8%, intermediate, 28%, high, 34%; very high, 63%; P = .017). Both disease risk (hazard ratio [95% confidence interval]: intermediate, 2.1 [0.8 to 5.2], P = .127; high, 3.4 [1.3 to 9.1], P = .013; very high, 4.0 [1.1 to 14], P = .029) and HCT-CI (hazard ratio [95% confidence interval]: HCT-CI ≥3, 1.7 (1.1 to 2.8), P = .018) influenced OS, but age and donor type did not. The FBx-ATG RIC regimen reported here is associated with low mortality and high long-term disease-free survival without persistent GVHD in both young and old patients. It represents a valuable platform for developing further post-transplantation strategies aimed at reducing the incidence of relapse, particularly in the setting of high-risk disease.

A conditioning platform based on fludarabine, busulfan, and 2 days of rabbit antithymocyte globulin results in promising results in patients undergoing allogeneic transplantation from both matched and mismatched unrelated donor

Conditioning regimen including fludarabine, intravenous busulfan (Bx), and 5 mg/kg total dose of rabbit antithymocyte globulin (r‐ATG) (FBx‐ATG) results in low incidence of graft‐versus‐host disease (GVHD) and non‐relapse mortality (NRM) after allogeneic hematopoietic stem cell transplantation (Allo‐HSCT) from HLA‐matched related or unrelated donors (MUD). However, whether this platform produces similar results in the setting of one mismatch unrelated donor (MMUD) Allo‐HSCT is not known. We retrospectively analyzed patients aged less than 65 years who were diagnosed with hematological malignancies and received FBx‐ATG regimen prior to Allo‐HSCT from MUD (N = 74) or MMUD (N = 40). We compared outcome of MUD versus MMUD patients. There was no difference in the cumulative incidence of grades II–IV acute GVHD (MUD: 34% vs. MMUD: 35%, P = 0.918), but MMUD patients developed more grade III–IV acute GVHD (MUD: 5% vs. MMUD: 15%, P = 0.016). The cumulative incidences of overall chronic GVHD (MUD: 33% vs. MMUD: 22%, P = 0.088) and extensive chronic GVHD (MUD: 20% vs. MMUD: 19%, P = 0.594) were comparable. One‐year NRM was similar in both groups (MUD: 16% vs. MMUD: 14%, P = 0.292); similarly, progression‐free survival (MUD: 59% vs. MMUD: 55%, P = 0.476) and overall survival (MUD: 63% vs. MMUD: 61%, P = 0.762) were not different between both groups. With a median follow up of 24 months, 35 of 74 MUD patients (47%) and 19 of 40 MMUD patients (48%) were free of both disease progression and immunosuppressive treatment. We conclude that the FBx‐ATG regimen results in low incidences of NRM and GVHD in both MUD and the MMUD recipients. Am. J. Hematol. 89:83–87, 2014.

A new single-platform method for the enumeration of CD34+ cells

Guidelines for flow cytometric enumeration of CD34(+) hematopoietic stem cells (HSC) recommend the use of a single-platform assay. The SCE kit has recently been commercialized by BD Biosciences. Results obtained with this newly available kit were compared with CD34(+) cell enumerations obtained in parallel with already commercialized diagnostic kits; fresh peripheral blood, apheresis, cord blood (CB) and bone marrow (BM) samples, as well as thawed apheresis and CB samples, were assayed. The SCE kit produced data for CD34(+) enumeration that correlate well with data produced with the older assays (r(2) > or = 0.9). Practical advantages were the ability to enumerate viable CD34 cells in all kinds of HSC products, the absence of bead pipetting (which decreases results precision) and a gating strategy complying with international recommendations. A major disadvantage was the absence of specific software for data analyses and presentation of results.

Disease status is a more reliable predictive factor than histology in lymphoma patients after reduced-intensity conditioning regimen and allo-SCT

We analyzed 113 patients with lymphoma who underwent allogeneic transplantation with reduced-intensity conditioning (allo-RIC) regimens at a single institution, from February 2001 through November 2009, searching for factors predictive of the outcome. At the time of transplantation, 60% of patients were in CR, 29% in PR and 11% had progressive or stable disease. At a median follow-up of 34 months (confidence interval (CI) 17–45), the 3-year OS and PFS were 59% (CI 48–68%) and 51% (CI 41–61%), respectively. The 100-day and 2-year nonrelapse mortalities (NRM) were 6% and 28% (CI 20–35%), respectively. Grade II–IV acute GVHD (aGVHD) incidence was 38%, and the global incidence of chronic GVHD was 33%. In univariate analysis, OS was influenced by disease status before allo-RIC; aGVHD negatively affected on survival. Similarly, PFS was influenced only by disease status. Histological subtype did not affect OS or PFS. We conclude that disease status at the time of transplantation significantly influences survival in patients receiving allo-RIC for lymphoma, whereas histological subtype does not. This reinforces the need to administer more effective debulking treatments to lymphoma patients, for optimal benefit of allogeneic immune recognition of minimal residual disease, independently from lymphoma histology.

Prophylactic donor lymphocyte infusion after allogeneic stem cell transplantation for high-risk AML.

Prophylactic donor lymphocyte infusion after allogeneic stem cell transplantation for high-risk AML

Killer Cell Immunoglobulin-Like Receptor–Ligand Mismatch in Donor versus Recipient Direction Provides Better Graft-versus-Tumor Effect in Patients with Hematologic Malignancies Undergoing Allogeneic T Cell–Replete Haploidentical Transplantation Followed by Post-Transplant Cyclophosphamide

We evaluated the impact of unidirectional donor versus recipient killer cell immunoglobulin-like receptor (KIR)-ligand mismatch (KIR-Lmm) on the outcomes of T cell-replete haploidentical stem cell transplantation (Haplo-SCT) with post-transplant cyclophosphamide (PT-Cy) in a cohort of 144 patients treated for various hematologi diseases. We separately analyzed 81 patients in complete remission (CR group) and 63 with active disease (no CR group) at the time of Haplo-SCT. One-third of patients in each group had KIR-Lmm. In the no CR group, KIR-Lmm was associated with a significantly lower incidence of relapse (hazard ratio, .21; P = .013) and better progression-free survival (hazard ratio, .42; P = .028), with no significant increase in graft-versus-host disease incidence or nonrelapse mortality. In contrast, in the CR group no benefit of KIR-Lmm was observed. Our results encourage considering KIR-Lmm as an additional tool to improve donor selection for T cell-replete Haplo-SCT with PT-Cy, especially in patients with high-risk diseases.

An intra-patient comparison of blood cell separators Spectra and Optia in patients and donors undergoing blood mononuclear cell collections at a single institution for subsequent autologous or allogeneic hematopoietic cell transplantation reveals comparable collection efficiencies.

An intra-patient comparison of blood cell separators Spectra and Optia in patients and donors undergoing blood mononuclear cell collections at a single institution for subsequent autologous or allogeneic hematopoietic cell transplantation reveals comparable collection efficiencies

Accreditation and regulations in cell therapy

Advances in stem cell biology and immunology raise hopes for new developments in regenerative medicine as well as cell‐based immune intervention, with potential applications in many medical disciplines. Emerging from the medical practices of organ, tissue and cell transplantations over several decades, the development of cellular therapies nowadays enter a new era in which the industry may take cell manufacturing activities away from academic facilities, using complex procedures for cell engineering and large‐scale production at centralized facilities. Recent changes in regulations push towards this historical transition; however, a pragmatic analysis of met and unmet clinical needs, as well as of specific procedural and organizational aspects that govern human cell procurement and processing suggest that a significant role will remain for academic facilities in the near future. Taking advantage of the large experience in the field of haematopoietic stem cell transplantation, we here review actual and potential consequences of regulatory changes in these medical practices, with a focus on the unique system for quality management that has been established in Europe and the United States of America to address specific risks associated with these therapeutic procedures.

HLA-Matched Sibling versus Unrelated versus Haploidentical Related Donor Allogeneic Hematopoietic Stem Cell Transplantation for Patients Aged Over 60 Years with Acute Myeloid Leukemia: A Single-Center Donor Comparison

Haploidentical related donor (HRD) allogeneic hematopoietic stem cell transplantation (allo-HSCT) was developed as a valid option for the treatment of acute myeloid leukemia (AML) in the absence of a matched donor. However, many investigators are reluctant to consider the use of this alternative in elderly patients, anticipating high morbidity. Here, we report a single-center comparison of HRD versus matched sibling donor (MSD) and unrelated donor (UD) allo-HSCT for patients with AML aged ≥60 years. Ninety-four patients (MSD: n = 31; UD: n = 30; HRD: n = 33) were analyzed. The median age was 65 (range, 60 to 73) years. We observed a higher cumulative incidence of grade 3 to 4 acute graft-versus-host disease (GVHD) after UD allo-HSCT (MSD versus UD versus HRD: 3% versus 33% versus 6%, respectively; P = .006). Two-year cumulative incidence of moderate or severe chronic GVHD was 17%, 27%, and 16% in the MSD, UD, and HRD groups, respectively (P = .487). No difference was observed in the 2-year cumulative incidence of relapse or nonrelapse mortality (NRM) (relapse: MSD versus UD versus HRD: 32% versus 25% versus 25%, respectively; P = .411; NRM: MSD versus UD versus HRD: 19% versus 27% versus 24%, respectively; P = .709). At 2 years, progression-free survival, overall survival, and GVHD- and relapse-free survival were 48%, 50%, and 39%, respectively, in the MSD group; 48%, 51%, and 23%, respectively, in the UD group; and 50%, 52%, and 32%, respectively, in the HRD group, without statistically significant differences between the groups. We conclude that HRD allo-HSCT is highly feasible and no less efficient than MSD or UD allo-HSCT in patients with AML aged ≥60 years. Thus, the absence of a HLA-identical donor should not limit the consideration of allo-HSCT for the treatment of AML.

New developments in the use of apheresis to collect haematopoietic cells for cell transplantation and cell therapies

Currently, there is renewed interest in apheresis as a tool to collect blood mononuclear cells. Several manufacturers have introduced a new generation of cell separators. Historical applications, that is the collection of autologous or allogeneic hematopoietic stem and progenitor cells for ‘bone marrow transplantation’, witness new developments: introduction of new agents that mobilize stem cells help deal with ‘poor mobilizers’ and streamline the collection process, algorithms based on robust measurement of circulating and collected CD34+ cells allow to tailor the collection procedure to better suit donors and recipients’ needs. Furthermore, new forms of cellular therapies are being developed, with potential applications as additions, substitutes or unrelated to conventional hematopoietic stem cell transplantation. These are mostly immune therapies that will be manufactured from blood mononuclear cells; these will be efficiently engineered only when the collected cell product meets predefined specifications that are likely to be different and more stringent than they are for the collection of minimally manipulated autologous or allogeneic blood grafts. Thus, healthcare professionals who perform or supervise apheresis will need to update and upgrade their skills and competencies in the near future.