Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 110
Filter
1.
Bone Marrow Transplant ; 58(5): 526-533, 2023 05.
Article in English | MEDLINE | ID: mdl-36774432

ABSTRACT

Allogeneic hematopoietic stem cell transplantation (HSCT) is still needed for many children with very high-risk acute leukemia. An HLA-haploidentical family donor is a suitable option for those without an HLA-matched donor. Here we present outcomes of a novel HLA-haploidentical HSCT (haplo-HSCT) strategy with adoptive immunotherapy with thymic-derived CD4+CD25+ FoxP3+ regulatory T cells (Tregs) and conventional T cells (Tcons) performed between January 2017 and July 2021 in 20 children with high-risk leukemia. Median age was 14.5 years (range, 4-21), 15 had acute lymphoblastic leukemia, 5 acute myeloid leukemia. The conditioning regimen included total body irradiation (TBI), thiotepa, fludarabine, cyclophosphamide. Grafts contained a megadose of CD34+ cells (mean 12.4 × 106/Kg), Tregs (2 × 106/Kg) and Tcons (0.5-1 × 106/Kg). All patients achieved primary, sustained full-donor engraftment. Only one patient relapsed (5%). The incidence of non-relapse mortality was 15% (3/20 patients). Five/20 patients developed ≥ grade 2 acute Graft versus Host Disease (aGvHD). It resolved in 4 who are alive and disease-free; 1 patient developed chronic GvHD (cGvHD). The probability of GRFS was 60 ± 0.5% (95% CI: 2.1-4.2) (Fig. 6), CRFS was 79 ± 0.9% (95% CI: 3.2-4.9) as 16/20 patients are alive and leukemia-free. The median follow-up was 2.1 years (range 0.5 months-5.1 years). This innovative approach was associated with very promising outcomes of HSCT strategy in pediatric patients.


Subject(s)
Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Leukemia, Myeloid, Acute , Humans , Child , Adolescent , Immunotherapy, Adoptive/adverse effects , Hematopoietic Stem Cell Transplantation/adverse effects , Graft vs Host Disease/etiology , Leukemia, Myeloid, Acute/complications , Hematopoietic Stem Cells , Transplantation Conditioning/adverse effects
3.
Ann Oncol ; 27(12): 2251-2257, 2016 12.
Article in English | MEDLINE | ID: mdl-28007754

ABSTRACT

BACKGROUND: To evaluate long-term outcome of myeloablative allogeneic stem cell transplantation (allo-SCT) (MAC) versus reduced-intensity allo-SCT (RIC) in patients with relapsed/refractory Hodgkin's lymphoma (HL) in recent years. PATIENTS AND METHODS: A total of 312 patients (63 MAC and 249 RIC) with relapsed/refractory HL who received allo-SCT between 2006 and 2010 and were reported to the EBMT Database were included in the study. RESULTS: With a median follow-up for alive patients of 56 (26-73) months, there were no significant differences in non-relapse mortality (NRM) between MAC and RIC. Relapse rate (RR) was somewhat lower in the MAC group (41% versus 52% at 24 months, P = 0.16). This lower RR translated into a marginal improvement in event-free survival (EFS) for the MAC group (48% versus 36% at 24 months, P = 0.09) with no significant differences in overall survival (73% for MAC and 62% for RIC at 24 months, P = 0.13). Multivariate analysis after adjusting for disease status at the time of allo-SCT showed that the use of MAC was of borderline statistical significance for predicting a lower RR and EFS [HR 0.7, 95% CI (0.5-1.0), P = 0.1] and [HR 0.7, 95% CI (0.5-1.0), P = 0.07], respectively, after allo-SCT. CONCLUSIONS: With modern transplant practices, the NRM associated with MAC for HL has strongly decreased, resulting into non-significant improvement of EFS because of a somewhat better disease control compared with RIC transplants. The intensity of conditioning regimens should be considered when designing individual allo-SCT strategies or clinical trials in patients with relapsed/refractory HL.


Subject(s)
Graft vs Host Disease/epidemiology , Hodgkin Disease/therapy , Neoplasm Recurrence, Local/therapy , Stem Cell Transplantation/methods , Transplantation, Homologous/methods , Adult , Aged , Bone Marrow , Disease-Free Survival , Female , Graft vs Host Disease/etiology , Graft vs Host Disease/pathology , Hodgkin Disease/pathology , Humans , Male , Neoplasm Recurrence, Local/pathology , Retrospective Studies , Stem Cell Transplantation/adverse effects , Transplantation Conditioning , Transplantation, Homologous/adverse effects , Treatment Outcome
5.
Leukemia ; 30(2): 447-55, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26293645

ABSTRACT

Haploidentical hematopoietic stem cell transplants (HSCTs) are increasingly used, but it is unknown whether they have a stronger graft-versus-leukemia (GVL) effect. We analyzed 10 679 acute leukemia patients who underwent HSCT from an HLA-matched sibling donor (MSD, n=9815) or a haploidentical donor (⩾2 HLA-antigen disparity, n=864) between 2007 and 2012, reported to the European Group for Blood and Marrow Transplantation. In a Cox regression model, acute and chronic graft-versus-host disease (GVHD) was added as time-dependent variables. There was no difference in probability of relapse between recipients of haploidentical and MSD grafts. Factors of importance for relapse after T-cell-replete grafts included remission status at HSCT, Karnofsky score ⩽80, acute GVHD of grade II or higher and chronic GVHD (P<10(-5)). Patients with post-transplant cyclophosphamide (n=194) had similar outcome as other T-cell-replete haploidentical transplants (n=369). Non-relapse mortality was significantly higher in the haploidentical group compared with that in MSD patients (P<10(-5)). Leukemia-free survival was superior in the MSD patients receiving T-cell-replete (P<10(-5)) or T-cell-depleted grafts (P=0.0006). The risk of relapse was the same in acute leukemia patients who received haploidentical donor grafts as in those given MSD transplants, suggesting a similar GVL effect.


Subject(s)
Graft vs Leukemia Effect , Haplotypes , Histocompatibility Testing , Leukemia/therapy , Adolescent , Adult , Aged , Aged, 80 and over , Child , Child, Preschool , Hematopoietic Stem Cell Transplantation , Humans , Infant , Leukemia/mortality , Middle Aged , Proportional Hazards Models , Recurrence
6.
Bone Marrow Transplant ; 50 Suppl 2: S63-6, 2015 Jun.
Article in English | MEDLINE | ID: mdl-26039211

ABSTRACT

Relapse is still the major cause of failure of allogeneic stem cell transplantation in high-risk acute leukemia patients. Indeed, whoever the donor and whatever the transplantation strategy, post-transplant relapse rates are ~30%, which is hardly satisfactory. The present phase 2 study analyzed the impact of adoptive immunotherapy with naturally occurring FoxP3+ T-regulatory cells (2 × 10(6) per kg) and conventional T lymphocytes (1 × 10(6) per kg) on prevention of GvHD and leukemia relapse in 43 high-risk adults undergoing full-haplotype mismatched transplantation without any post-transplant immunosuppression. Ninety-five percent of patients achieved full-donor type engraftment. Only 6/41 patients (15%) developed ⩾ grade II acute GvHD. Specific CD4(+) and CD8(+) for opportunistic pathogens emerged significantly earlier than after standard T-cell-depleted haplo-transplantation. The probability of disease-free survival was 0.56. At a median follow-up of 46 months (range 18-65 months), only 2/41 evaluable patients have relapsed. The cumulative incidence of relapse was significantly lower than in historical controls (0.05 vs 0.21; P = 0.03). These results demonstrate that the immunosuppressive potential of Tregs can be used to suppress GvHD without loss of the benefits of GvL activity. Humanized murine models provided insights into the mechanisms underlying separation of GvL from GvHD.


Subject(s)
Adoptive Transfer , Graft vs Host Disease , HLA Antigens , Hematopoietic Stem Cell Transplantation , Leukemia , T-Lymphocytes, Regulatory/transplantation , Acute Disease , Adolescent , Adult , Aged , Allografts , Disease-Free Survival , Female , Follow-Up Studies , Graft vs Host Disease/mortality , Graft vs Host Disease/prevention & control , Humans , Leukemia/mortality , Leukemia/therapy , Male , Middle Aged , Recurrence , Survival Rate
7.
Bone Marrow Transplant ; 50(8): 1037-56, 2015 Aug.
Article in English | MEDLINE | ID: mdl-25798672

ABSTRACT

This is the sixth special report that the European Society for Blood and Marrow Transplantation regularly publishes on the current practice and indications for haematopoietic SCT for haematological diseases, solid tumours and immune disorders in Europe. Major changes have occurred in the field of haematopoietic SCT over the last years. Cord blood units as well as haploidentical donors have been increasingly used as stem cell sources for allo-SCT, thus, augmenting the possibility of finding a suitable donor for a patient. Continuous refinement of conditioning strategies has also expanded not only the number of potential indications but also has permitted consideration of older patients or those with co-morbidity for a transplant. There is accumulating evidence of the role of haematopoietic SCT in non-haematological disorders such as autoimmune diseases. On the other hand, the advent of new drugs and very effective targeted therapy has challenged the role of SCT in some instances or at least, modified its position in the treatment armamentarium of a given patient. An updated report with revised tables and operating definitions is presented.


Subject(s)
Autoimmune Diseases/therapy , Donor Selection/methods , Hematologic Neoplasms/therapy , Hematopoietic Stem Cell Transplantation/methods , Neoplasms/therapy , Tissue Donors , Allografts , Autografts , Europe , Female , Hematopoietic Stem Cell Transplantation/standards , Humans , Male
8.
Bone Marrow Transplant ; 50(2): 173-80, 2015 Feb.
Article in English | MEDLINE | ID: mdl-25387090

ABSTRACT

Over the past 15 years, SCT has emerged as a promising treatment option for patients with severe autoimmune diseases (ADs). Mechanistic studies recently provided the proof-of-concept that restoration of immunological tolerance can be achieved by haematopoietic SCT in chronic autoimmunity through eradication of the pathologic, immunologic memory and profound reconfiguration of the immune system, that is, immune 'resetting'. Nevertheless, a number of areas remain unresolved and warrant further investigation to refine our understanding of the underlying mechanisms of action and to optimize clinical SCT protocols. Due to the low number of patients transplanted in each centre, it is essential to adequately collect and analyse biological samples in a larger cohort of patients under standardized conditions. The European society for blood and marrow transplantation Autoimmune Diseases and Immunobiology Working Parties have, therefore, undertaken a joint initiative to develop and implement guidelines for 'good laboratory practice' in relation to procurement, processing, storage and analysis of biological specimens for immune reconstitution studies in AD patients before, during and after SCT. The aim of this document is to provide practical recommendations for biobanking of samples and laboratory immune monitoring in patients with ADs undergoing SCT, both for routine supportive care purposes and investigational studies.


Subject(s)
Autoimmune Diseases/therapy , Biological Specimen Banks/standards , Hematopoietic Stem Cell Transplantation , Preservation, Biological/standards , Congresses as Topic , Hematopoietic Stem Cell Transplantation/methods , Hematopoietic Stem Cell Transplantation/standards , Humans , Practice Guidelines as Topic , Severity of Illness Index , Societies, Medical
9.
Bone Marrow Transplant ; 49(6): 744-50, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24637898

ABSTRACT

In all, 661 of 680 centers in 48 countries reported 37 818 hematopoietic SCT (HSCT) in 33 678 patients (14 165 allogeneic (42%), 19 513 autologous (58%)) in the 2012 survey. Main indications were leukemias, 10 641 (32%; 95% allogeneic); lymphoid neoplasias, 19 336 (57%; 11% allogeneic); solid tumors, 1630 (5%; 3% allogeneic); and nonmalignant disorders, 1953 (6%; 90% allogeneic). There were more unrelated donors than HLA-identical sibling donors (54% versus 38% (8% being mismatched related donor HSCT)). Cord blood was almost exclusive in allogeneic transplants (5% of total). Since 2011, the highest increases in allogeneic HSCT were for AML in CR1 (12%) and for myeloproliferative neoplasm (15%). For autologous HSCT the main increases were for plasma cell disorders (7%), non-Hodgkin lymphoma (4%) and autoimmune disease (50%). There were 4097 pediatric patients <18 years of age receiving HSCT, 2902 received an allogeneic and 1195 an autologous HSCT. Overall, 69% of allogeneic and 64% of autologous HSCT were performed in dedicated pediatric centers and the remainder in combined adult and pediatric centers. Distributions of diseases, donor types and stem cell source for all patients and pediatric patients in particular are shown. A percentage of centers fulfilling the annual required criteria for patient numbers for JACIE accreditation are provided.


Subject(s)
Hematopoietic Stem Cell Transplantation/trends , Adult , Allografts , Autografts , Bone Marrow Transplantation/statistics & numerical data , Bone Marrow Transplantation/trends , Child , Cord Blood Stem Cell Transplantation/statistics & numerical data , Cord Blood Stem Cell Transplantation/trends , Data Collection , Europe , Hematopoietic Stem Cell Transplantation/statistics & numerical data , Humans , Tissue Donors
10.
Bone Marrow Transplant ; 48(9): 1161-7, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23584439

ABSTRACT

In all, 651 from 680 centers in 48 countries reported 35 660 hematopoietic SCT (HSCT) in 32 075 patients (13 470 allogeneic (42%), 18 605 autologous (58%)) to the 2011 survey. Main indications were: leukemias; 10 113 (32%; 94% allogeneic); lymphoid neoplasias; non-Hodgkin's lymphoma, Hodgkin's lymphoma, plasma cell disorders; 18 433 (57%; 12% allogeneic); solid tumours; 1573 (5%; 5% allogeneic); and non-malignant disorders; 1830 (6%; 92% allogeneic). There were more unrelated donors than HLA identical sibling donors (54% versus 39%); proportion of peripheral blood as stem cell source was 99% for autologous and 73% for allogeneic HSCT. Cord blood was only used in allogeneic transplants (6% of total). In the past 10 years, the overall number of transplants has increased by 53%. Allogeneic HSCT have doubled (from 7272 to 14 549) while, autologous have increased by 32% and continue to increase by about 1100 HSCT per year since 2001. In the past 2 years, an increase of >2000 HSCT per year was seen. Transplant activity is shown by team size. For allogeneic HSCT, we show use of reduced-intensity conditioning versus myeloablative conditioning across Europe and use of post-transplant donor lymphocyte infusions with considerable variation across different countries.


Subject(s)
Hematopoietic Stem Cell Transplantation/statistics & numerical data , Hematopoietic Stem Cell Transplantation/trends , Europe , History, 21st Century , Humans , Transplantation, Autologous , Transplantation, Homologous
11.
Int J Immunogenet ; 40(1): 2-10, 2013 Feb.
Article in English | MEDLINE | ID: mdl-23279968

ABSTRACT

The International Histocompatibility Working Group is a collaborative international effort to understand the HLA and non-HLA genetics of the transplantation barrier. The Working Group is comprised of experts in the fields of histocompatibility and immunogenetics, hematopoietic cell transplantation and outcomes research. Data for 25 855 unrelated donor transplants were submitted in support of research studies for the 16th International Histocompatibility Workshop. Active investigation is in progress in seven key areas: the impact of HLA matching, role of race and ethnicity, identification of permissible HLA mismatches, haplotype-associated determinants, minor histocompatibility antigens, immune response genes and KIR genetics. New hypotheses for the 16th workshop were developed for immunogenetic studies in cord blood and haploidentical-related donor transplantation.


Subject(s)
Graft vs Host Disease , HLA Antigens , Hematopoietic Stem Cell Transplantation , Histocompatibility , Graft vs Host Disease/genetics , Graft vs Host Disease/immunology , HLA Antigens/genetics , HLA Antigens/immunology , Humans , Immunogenetics
12.
Bone Marrow Transplant ; 47(7): 906-23, 2012 Jul.
Article in English | MEDLINE | ID: mdl-22543746

ABSTRACT

A total of 654 centers from 48 countries were contacted for the 2010 survey. In all, 634 centers reported a total of 33 362 hematopoietic SCT (HSCT) with 30 012 patients receiving their first transplant (12 276 allogeneic (41%) and 17 736 autologous (59%)). Main indications were leukemias: 9355 (31%; 93% allogeneic), lymphoid neoplasias specifically Non Hodgkin's lymphoma, Hodgkin's lymphoma and plasma cell disorders: 17 362 (58%; 12% allogeneic), solid tumors: 1585 (5%; 6% allogeneic) and non-malignant disorders: 1609 (6%; 88% allogeneic). There were more unrelated donors than HLA-identical sibling donors (53% versus 41%); the proportion of peripheral blood as stem cell source was 99% for autologous and 71% for allogeneic HSCT. Cord blood was primarily used in allogeneic transplants (6% of total) with three autologous cord blood HSCT being reported. The number of transplants has increased by 19% since 2005 (allogeneic 37% and autologous 9%) and continued to increase by about 1100 HSCT per year since 2000. Patterns of increase were distinct and different. The data show the development of transplantation in Europe since 1990, with the number of patients receiving a HSCT increasing from 4200 to over 30 000 annually. The most impressive trend seen is the steady increase of unrelated donor transplantation, in parallel to the availability of unrelated donors through donor registries.


Subject(s)
Bone Marrow Transplantation/statistics & numerical data , Hematopoietic Stem Cell Transplantation/statistics & numerical data , Europe , Humans , Neoplasms/surgery
13.
Bone Marrow Transplant ; 47(9): 1196-200, 2012 Sep.
Article in English | MEDLINE | ID: mdl-22139067

ABSTRACT

In adults, one-haplotype-mismatched haematopoietic SCT (haploidentical HSCT) is associated with slow immune recovery due to decaying thymic function and extensive T-cell depletion of the graft. Although essential for preventing GVHD, T-cell depletion underlies the major reasons for transplant failure: leukemia relapse and infections, with infection-related mortality accounting for about 40% of non-leukemic deaths. Adoptive T-cell therapy would be helpful for these patients but to administer it without causing GVHD, alloreactive T cells need to be eliminated from donor T lymphocytes before infusion. In a preclinical study, to address this problem, we determined the efficacy of photodynamic purging of alloreactive T cells, by investigating combinations of parameters in order to achieve maximum allodepletion, preservation of T-regulatory cells and of pathogen and leukemia-specific T-cell responses in donor-vs-recipient MLR. We also needed to identify an optimal method to quantify the Ag-specific T-cell repertoires. Optimal procedures were identified. In particular, we compared limiting-dilution analyses (LDA) of proliferating T cells with H(3)-thymidine incorporation by bulk T cells and with flow cytometry CD25 expression, which is accepted as a T-cell activation marker. This study demonstrated that LDA is a reliable, predictable and sensitive method for measuring alloreactive, pathogen- and leukemia-specific T-cell frequencies.


Subject(s)
Hematopoietic Stem Cell Transplantation/methods , Immunotherapy, Adoptive/methods , Lymphocyte Activation/immunology , Lymphocyte Depletion/methods , Cohort Studies , Epitopes, T-Lymphocyte/immunology , Haplotypes/immunology , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Photochemotherapy/methods , T-Lymphocytes/immunology
14.
Bone Marrow Transplant ; 45(11): 1607-10, 2010 Nov.
Article in English | MEDLINE | ID: mdl-20173785

ABSTRACT

We studied killer-cell Ig-like receptor (KIR)/natural killer (NK)-cell group-2-Ag repertoires on donor-derived NK cells in 28 patients after haploidentical SCT in the first 6 months after SCT and correlated results with EFS. The reconstitution hierarchy of potentially alloreactive, single KIR+ NK cells was the following: HLA-C1 binding>HLA-Bw4 binding>HLA-C2 binding. The differences in reconstitution kinetics of the three potentially alloreactive NK cell subsets prompted an updated analysis of EFS in AML patients transplanted from haploidentical donors in our center. This analysis showed that in haploidentical transplantation for AML, HLA-C group 1 mismatching in the graft vs host direction not only provides a survival advantage over non-NK-alloreactive (KIR ligand-matched) transplants (5-year EFS 67±10% vs 17±5%) but, indeed, also provides the best EFS compared with C2 (35±10%) or Bw4 KIR ligand mismatches (44±17%). In conclusion, we show that the kinetics with which single KIR-expressing NK cells are generated after haploidentical SCT differ between individual KIR receptors and seem to influence survival after haploidentical SCT.


Subject(s)
Hematopoietic Stem Cell Transplantation/methods , Killer Cells, Natural/immunology , Receptors, KIR/immunology , Haploidy , Humans , Killer Cells, Natural/cytology , Killer Cells, Natural/transplantation , Transplantation Conditioning/methods , Transplantation, Homologous
15.
Bone Marrow Transplant ; 45(2): 219-34, 2010 Feb.
Article in English | MEDLINE | ID: mdl-19584824

ABSTRACT

The European Group for Blood and Marrow Transplantation regularly publishes special reports on the current practice of haematopoietic SCT for haematological diseases, solid tumours and immune disorders in Europe. Major changes have occurred since the first report was published. HSCT today includes grafting with allogeneic and autologous stem cells derived from BM, peripheral blood and cord blood. With reduced-intensity conditioning regimens in allogeneic transplantation, the age limit has increased, permitting the inclusion of older patients. New indications have emerged, such as autoimmune disorders and AL amyloidosis for autologous HSCT and solid tumours, myeloproliferative syndromes and specific subgroups of lymphomas for allogeneic transplants. The introduction of alternative therapies, such as imatinib for CML, has challenged well-established indications. An updated report with revised tables and operating definitions is presented.


Subject(s)
Hematologic Diseases/therapy , Hematopoietic Stem Cell Transplantation , Immune System Diseases/therapy , Neoplasms/therapy , Adolescent , Adult , Aged , Amyloidosis/therapy , Bone Marrow Transplantation , Child , Clinical Protocols , Europe , Hodgkin Disease/therapy , Humans , Infant , Leukemia/therapy , Lymphoma, Non-Hodgkin/therapy , Middle Aged , Myeloproliferative Disorders/therapy , Severe Combined Immunodeficiency/therapy , Transplantation Conditioning , Transplantation, Autologous , Transplantation, Homologous
16.
Tissue Antigens ; 69 Suppl 1: 17-24, 2007 Apr.
Article in English | MEDLINE | ID: mdl-17445157

ABSTRACT

Deciphering the role of human leukocyte antigen (HLA), killer immunoglobulin like receptor, and immune response genes in a model as complex as unrelated donor hematopoietic cell transplantation is a challenge. The allelic diversity of these genes is shaped by the race and ethnicity of transplant donors and recipients. Coupled with the genetic polymorphism is the complexity of clinical phenotypes of transplant populations: donor and recipient demographic characteristics and the regimens used by transplant physicians to prepare patients for transplantation and to prevent and treat graft-vs-host disease (GVHD). Furthermore, GVHD is itself a complex disease shaped by both genes and 'environment'. How does one begin to deconstruct the genetic barrier to understand risk factors important to transplant outcome? To begin with, population-based studies, particularly retrospective ones, benefit from adequate sample sizes to measure genetic effects. The more homogeneous the population for variables that influence clinical endpoints, the higher the likelihood that a real genetic effect can be uncovered. Even so, the feasibility of studies can be hampered if genotype and clinical data are not both complete and precise. For studies of HLA, diversity of alleles and antigens contributed by ethnically different transplant populations is an asset, because not only can a broader range of HLA mismatches be studied but they provide the opportunity for side-by-side analyses that may yield clues as to why transplant outcomes differ between populations.


Subject(s)
HLA Antigens/genetics , Hematopoietic Stem Cell Transplantation , Immunogenetics , Graft vs Host Disease/immunology , HLA Antigens/immunology , Humans , Major Histocompatibility Complex , Polymorphism, Genetic , Transplantation Tolerance/genetics , Transplantation Tolerance/immunology
17.
Cytotherapy ; 8(6): 554-8, 2006.
Article in English | MEDLINE | ID: mdl-17148031

ABSTRACT

In haplo-identical hematopoietic transplantation, donor vs. recipient natural killer (NK) cell alloreactivity derives from a mismatch between donor NK clones bearing inhibitory killer cell Ig-like receptors (KIR) for self-HLA class I molecules and their HLA class I ligands (KIR ligands) on recipient cells. When faced with mismatched allogeneic targets, these NK clones sense the missing expression of self-HLA class I alleles and mediate alloreactions. KIR ligand mismatches in the GvH direction trigger donor vs. recipient NK cell alloreactions, which improve engraftment, do not cause GvHD and control relapse in AML patients . The mechanism whereby alloreactive NK cells exert their benefits in transplantation has been elucidated in mouse models. The infusion of alloreactive NK cells ablates (i) leukemic cells, (ii) recipient T cells that reject the graft and (iii) recipient DC that trigger GvHD, thus protecting from GvHD.


Subject(s)
Hematopoietic Stem Cell Transplantation/standards , Histocompatibility Antigens Class I/immunology , Host vs Graft Reaction , Killer Cells, Natural/immunology , Transplantation, Homologous/immunology , Animals , Clone Cells , Disease Models, Animal , Graft vs Host Disease , Haploidy , Histocompatibility Antigens Class I/genetics , Humans , Immunotherapy, Adoptive , Mice
19.
Int J Hematol ; 76 Suppl 1: 165-8, 2002 Aug.
Article in English | MEDLINE | ID: mdl-12430847

ABSTRACT

PREMISE: Since March 1993, 133 patients with high-risk acute leukemia (66 AML, 67 ALL) have received a megadose of T-cell depleted hematopoietic stem cells. The 1993-95 conditioning protocol included TBI, thiotepa, ATG and CY for 36 patients who received an inoculum made up of lectin-separated bone marrow and PBPCs. After 1995, to minimise the extra-hematological toxicity of the conditioning and eliminate GvHD, we substituted fludarabine for CY in the conditioning and PBPCs were depleted of T-cells by a positive selection of the CD34+ cells using CellPro (n=44 patients) or, since January 1999, CliniMacs (n = 53 patients). A later modification to the protocol in January 1999 was the suspension of post transplant G-CSF. WORK IN PROGRESS: We report here the results in the last 53 acute leukemia patients all of whom were transplanted under our modified protocol. Ages ranged from 9 to 62 years with a median of 38 years for the 33 patients with AML and 23 for the 20 with ALL. All were at high risk because 25 were actually in relapse at transplant, 16 were in second or later CR and even the 12 patients in CR1 were at high risk because of the unfavourable prognostic features. Overall 52/53 patients (98%) engrafted. The TBI-Fludarabine-based conditioning was well tolerated even in the 14 patients between 45 and 62 years of age. There was no veno-occlusive disease of the liver and the incidence of severe mucositis was low. Even though no post-transplant immunosuppressive therapy was given, acute GvHD grade > or = II occurred in only 4 cases and only one progressed to chronic GvHD. Overall, 16 patients (30%) have died of non-leukemic causes. Relapses occurred mainly in patients who were already in relapse at transplant (12/25). Only 3 of the 28 who were in any CR at transplant have so far relapsed. As our group has already shown, donor-vs-recipient NK cell alloreactivity exerts a specific graft-vs-AML effect in the absence of GvHD. In fact, leukemia relapse was largely controlled in AML recipients whose donor was NK alloreactive, with only 2 out of 16 relapsing. To date, 13 of 18 AML (72%) and 5 of 10 ALL (50%) who were in any CR at transplant, survive disease-free while 4 of the 15 patients (16%) in relapse at transplant survive. The probability of event-free survival for patients transplanted in CR is 60% in the 18 AML patients and 38% in the 10 ALL. The probability of EFS was significantly better in the 16 AML patients whose transplant included donor vs recipient NK cell alloreactivity than in those whose transplant did not (70% vs 7%). In conclusion, given our current results, the most suitable candidate for the full haplotype mismatched transplant should be in early stage disease and selection of an NK alloreactive donor is recommended.


Subject(s)
Haplotypes/immunology , Leukemia/therapy , Peripheral Blood Stem Cell Transplantation/methods , Vidarabine/analogs & derivatives , Acute Disease , Adolescent , Adult , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/toxicity , Child , Disease-Free Survival , Histocompatibility , Humans , Killer Cells, Natural/immunology , Killer Cells, Natural/transplantation , Leukemia/complications , Leukemia/mortality , Middle Aged , Peripheral Blood Stem Cell Transplantation/mortality , Retrospective Studies , Transplantation Conditioning/adverse effects , Transplantation Conditioning/methods , Treatment Outcome , Vidarabine/administration & dosage , Vidarabine/toxicity , Whole-Body Irradiation
20.
Cytotherapy ; 4(4): 343-6, 2002.
Article in English | MEDLINE | ID: mdl-12396834

ABSTRACT

BACKGROUND: Allogeneic hematopoietic transplantation relies on T-cell alloreactions for engraftment and the GvL effect. In HLA haplotype-mismatched transplants, extensive T-cell depletion of the graft is essential to prevent GvHD. This raises the question of whether mismatched transplants exert any GvL effect, and whether it will ever be possible to reduce the intensity of preparative regimens. Natural killer (NK) cells are negatively regulated by MHC Class I-specific inhibitory receptors. Mismatched transplants may therefore trigger NK-cell alloreactivity. METHODS: The effects of NK-cell alloreactivity were evaluated in clinical transplantation and in murine transplant models. RESULTS: In clinical hematopoietic stem-cell transplants, HLA Class I disparities driving NK-cell alloreactions in the GvH direction eliminate AML relapse and graft rejection, while protecting patients from GvHD. In murine MHC mismatched transplant models, the pre-transplant infusion of donor-versus-recipient alloreactive NK cells conditioned the recipients to BMT, and reduced GvHD. DISCUSSION: NK-cell alloreactivity may thus provide a novel, powerful tool for enhancing the efficacy and safety of allogeneic hematopoietic transplantation.


Subject(s)
Hematologic Neoplasms/therapy , Hematopoietic Stem Cell Transplantation , Immunity, Innate , Animals , Disease Models, Animal , Genes, MHC Class I , Graft vs Host Disease/immunology , HLA Antigens/immunology , Hematologic Neoplasms/immunology , Humans , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Transplantation, Homologous
SELECTION OF CITATIONS
SEARCH DETAIL
...