. .. Historique, 2.1. Les premiers essais chez l'Homme

. Principe and . .. Csh,

.. .. Aspects,

C. .. Le, Allo réactivité et effet « GvL

. .. Allo-csh, Complications les plus fréquentes de l

. .. Déficit, Les conflits immunologiques post-greffe (Cf. Annexe 4)

.. .. Le,

L. .. Gvhd-aigüe,

L. .. Gvhd-chronique,

(. La-maladie-veino-occlusive and .. .. Mvo)-du-foie,

. .. Les-complications-tardives,

:. .. Choix-du-donneur,

C. .. Sources-de-greffon-de,

. .. Moelle-osseuse, Sang de cordon ombilical ou unité de sang placentaire

. .. Conditionnement-myéloablatif-standard,

E. Thomas, Bone-marrow transplantation (first of two parts), N. Engl. J. Med, vol.292, pp.832-843, 1975.

E. D. Thomas, One hundred patients with acute leukemia treated by chemotherapy, total body irradiation, and allogeneic marrow transplantation, Blood, vol.49, pp.511-533, 1977.

P. L. Weiden, Antileukemic effect of graft-versus-host disease in human recipients of allogeneic-marrow grafts, N. Engl. J. Med, vol.300, pp.1068-1073, 1979.

E. D. Thomas, H. L. Lochte, W. C. Lu, and J. W. Ferrebee, Intravenous infusion of bone marrow in patients receiving radiation and chemotherapy, N. Engl. J. Med, vol.257, pp.491-496, 1957.

J. Dausset, The major histocompatibility complex in man, Science, vol.213, pp.1469-1474, 1981.

J. Dausset and H. Brecy, Identical nature of the leucocyte antigens detectable in monozygotic twins by means of immune iso-leuco-agglutinins, Nature, vol.180, p.1430, 1957.

G. Mathe, Transfusions and grafts of homologous bone marrow in humans after accidental high dosage irradiation

, Rev. Fr. Etud. Clin. Biol, vol.4, pp.226-238, 1959.

G. Mathe, J. L. Amiel, L. Schwarzenberga, and M. Schneider, Adoptive Immunotherapy of Acute Leukemia: Experimental and Clinical Results, Cancer Res, vol.7

M. M. Bortin, A compendium of reported human bone marrow transplants, Transplantation, vol.9, pp.571-587, 1970.

R. Storb, R. B. Epstein, T. C. Graham, and E. D. Thomas, Methotrexate regimens for control of graftversus-host disease in dogs with allogeneic marrow grafts, Transplantation, vol.9, pp.240-246, 1970.

R. B. Epstein, R. Storb, H. Ragde, and E. D. Thomas, Cytotoxic typing antisera for marrow grafting in littermate dogs, Transplantation, vol.6, pp.45-58, 1968.

E. D. Thomas, Marrow transplantation for acute nonlymphoblastic leukemia in first remission, N. Engl. J. Med, vol.301, pp.597-599, 1979.

A. Fefer, Disappearance of Ph1-positive cells in four patients with chronic granulocytic leukemia after chemotherapy, irradiation and marrow transplantation from an identical twin

. Engl, J. Med, vol.300, pp.333-337, 1979.

R. L. Powles, Mismatched family donors for bone-marrow transplantation as treatment for acute leukaemia, Lancet Lond. Engl, vol.1, pp.612-615, 1983.

P. G. Beatty, Marrow transplantation from related donors other than HLA-identical siblings, N. Engl. J. Med, vol.313, pp.765-771, 1985.

R. Szydlo, Results of allogeneic bone marrow transplants for leukemia using donors other than HLA-identical siblings, J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol, vol.15, pp.1767-1777, 1997.

R. Storb, Methotrexate and cyclosporine compared with cyclosporine alone for prophylaxis of acute graft versus host disease after marrow transplantation for leukemia, N. Engl. J. Med, vol.314, pp.729-735, 1986.

F. R. Appelbaum, Hematopoietic-Cell Transplantation at 50, N. Engl. J. Med, vol.357, pp.1472-1475, 2007.

, for the European Society for Blood and Marrow Transplantation (EBMT) et al. The EBMT activity survey report 2017: a focus on allogeneic HCT for nonmalignant indications and on the use of non-HCT cell therapies, 2019.

P. Martin, Greffe de cellules souches hématopoïétiques et prévention de la maladie du greffon contre l'hôte, Actual. Pharm. Hosp, vol.5, p.15, 2009.

M. L. Sorror, Comorbidity-Age Index: A Clinical Measure of Biologic Age Before Allogeneic Hematopoietic Cell Transplantation, J. Clin. Oncol, vol.32, pp.3249-3256, 2014.

M. L. Sorror, How I assess comorbidities before hematopoietic cell transplantation, Blood, vol.121, pp.2854-2863, 2013.

P. Loiseau, HLA Association with Hematopoietic Stem Cell Transplantation Outcome: The Number of Mismatches at HLA-A, -B, -C, -DRB1, or -DQB1 Is Strongly Associated with Overall Survival, Biol. Blood Marrow Transplant, vol.13, pp.965-974, 2007.

J. Klein and A. Sato, The HLA system. First of two parts, N. Engl. J. Med, vol.343, pp.702-709, 2000.

J. Klein and A. Sato, The HLA system. Second of two parts, N. Engl. J. Med, vol.343, pp.782-786, 2000.

S. G. Marsh, Nomenclature for factors of the HLA system, Tissue Antigens, vol.75, pp.291-455, 2010.

S. G. Marsh, & for the WHO Nomenclature Committee for Factors of the HLA System. Nomenclature for factors of the HLA system, HLA, vol.88, pp.70-73, 2016.

S. Y. Choo, The HLA system: genetics, immunology, clinical testing, and clinical implications, Yonsei Med. J, vol.48, pp.11-23, 2007.

C. Lind, Next-generation sequencing: the solution for high-resolution, unambiguous human leukocyte antigen typing, Hum. Immunol, vol.71, pp.1033-1042, 2010.

P. L. Weiden, Antileukemic effect of chronic graft-versus-host disease: contribution to improved survival after allogeneic marrow transplantation, N. Engl. J. Med, vol.304, pp.1529-1533, 1981.

M. M. Horowitz, Graft-Versus-Leukemia Reactions After Bone Marrow Transplantation, vol.8

D. Maraninchi, The Lancet, vol.330, pp.175-178, 1987.

H. Kolb, Graft-Versus-Leukemia Effect of Donor Lymphocyte Transfusionsin Marrow Grafted Patients, vol.11

J. H. Falkenburg, Complete Remission of Accelerated Phase Chronic Myeloid Leukemia by Treatment With Leukemia-Reactive Cytotoxic T Lymphocytes, vol.9

J. Michalek, Definitive separation of graft-versus-leukemia-and graft-versus-host-specific CD4+ T cells by virtue of their receptor loci sequences, Proc. Natl. Acad. Sci, vol.100, pp.1180-1184, 2003.

M. Mohty and D. Olive, Peut-on séparer GVH et GVT après greffe de cellules souches hématopoïétiques allogéniques ? médecine/sciences 19, pp.540-541, 2003.

S. Cooley, Donor selection for natural killer cell receptor genes leads to superior survival after unrelated transplantation for acute myelogenous leukemia, Blood, vol.116, pp.2411-2419, 2010.

L. Ruggeri, Role of Natural Killer Cell Alloreactivity in HLA-Mismatched Hematopoietic Stem Cell Transplantation, vol.8

L. Ruggeri, Effectiveness of Donor Natural Killer Cell Alloreactivity in Mismatched Hematopoietic Transplants, Science, vol.295, pp.2097-2100, 2002.

M. Tomblyn, Guidelines for preventing infectious complications among hematopoietic cell transplant recipients: a global perspective, Bone Marrow Transplant, vol.44, pp.453-455, 2009.

R. E. Billingham, The biology of graft-versus-host reactions, Harvey Lect, vol.62, pp.21-78, 1966.

T. A. Gooley, Reduced Mortality after Allogeneic Hematopoietic-Cell Transplantation, N. Engl. J. Med, vol.363, pp.2091-2101, 2010.

H. Glucksberg, Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors, Transplantation, vol.18, pp.295-304, 1974.

P. A. Rowlings, IBMTR Severity INDEX FOR GRADING ACUTE GRAFT-VERSUS-HOST DISEASE: RETROSPECTIVE COMPARISON WITH GLUCKSBERG GRADE, Br. J. Haematol, vol.97, pp.855-864, 1997.

J. Cahn, Prospective evaluation of 2 acute graft-versus-host (GVHD) grading systems: a joint Société Française de Greffe de Moëlle et Thérapie Cellulaire (SFGM-TC), Dana Farber Cancer Institute (DFCI), and International Bone Marrow Transplant Registry (IBMTR) prospective study, Blood, vol.106, pp.1495-1500, 2005.

P. D. Ziakas, F. N. Zervou, I. M. Zacharioudakis, and E. Mylonakis, Graft-versus-host disease prophylaxis after transplantation: a network meta-analysis, PloS One, vol.9, p.114735, 2014.

M. T. Van-lint, Early treatment of acute graft-versus-host disease with high-or low-dose 6-methylprednisolone: a multicenter randomized trial from the Italian Group for Bone Marrow Transplantation, Blood, vol.92, pp.2288-2293, 1998.

M. Mielcarek, Effectiveness and safety of lower dose prednisone for initial treatment of acute graft-versus-host disease: a randomized controlled trial, Haematologica, vol.100, pp.842-848, 2015.

N. Dhédin and J. Vernant, Allogreffe de cellules souches hématopoïétiques : réalisation et complications, EMC -Hématologie, vol.5, pp.1-19, 2010.

M. E. Flowers, Comparative analysis of risk factors for acute graft-versus-host disease and for chronic graft-versus-host disease according to National Institutes of Health consensus criteria, Blood, vol.117, pp.3214-3219, 2011.

G. Socié and J. Ritz, Current issues in chronic graft-versus-host disease, Blood, vol.124, pp.374-384, 2014.

A. H. Filipovich, National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. Diagnosis and Staging Working Group Report

, Biol. Blood Marrow Transplant, vol.11, pp.945-956, 2005.

M. H. Jagasia, National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The, Diagnosis and Staging Working Group Report. Biol. Blood Marrow Transplant, vol.21, p.1, 2014.

H. M. Schoemans, EBMT?NIH?CIBMTR Task Force posizon statement on standardized terminology & guidance for graft-versus-host disease assessment, Bone Marrow Transplant, vol.53, pp.1401-1415, 2018.

F. Obut, V. Kasinath, and R. Abdi, Post-bone marrow transplant thrombotic microangiopathy, Bone Marrow Transplant, vol.51, pp.891-897, 2016.

S. Jodele, Abnormalities in the alternative pathway of complement in children with hematopoietic stem cell transplant-associated thrombotic microangiopathy, Blood, vol.122, 2003.

J. Labrador, Risk factors for thrombotic microangiopathy in allogeneic hematopoietic stem cell recipients receiving GVHD prophylaxis with tacrolimus plus MTX or sirolimus, Bone Marrow Transplant, vol.49, pp.684-690, 2014.

S. Changsirikulchai, Renal Thrombotic Microangiopathy after Hematopoietic Cell Transplant: Role of GVHD in Pathogenesis, Clin. J. Am. Soc. Nephrol. CJASN, vol.4, pp.345-353, 2009.

J. A. Coppell, Hepatic veno-occlusive disease following stem cell transplantation: incidence, clinical course, and outcome, Biol. Blood Marrow Transplant. J. Am. Soc. Blood Marrow Transplant, vol.16, pp.157-168, 2010.

C. C. Barker, J. D. Butzner, R. A. Anderson, R. Brant, and R. S. Sauve, Incidence, survival and risk factors for the development of veno-occlusive disease in pediatric hematopoietic stem cell transplant recipients, Bone Marrow Transplant, vol.32, pp.79-87, 2003.

S. Corbacioglu, Defibrotide for the Treatment of Hepatic Veno-Occlusive Disease: Final Results From the International Compassionate-Use Program, Biol. Blood Marrow Transplant. J. Am. Soc. Blood Marrow Transplant, vol.22, pp.1874-1882, 2016.

P. Richardson, S. Aggarwal, O. Topaloglu, K. F. Villa, and S. Corbacioglu, Systematic review of defibrotide studies in the treatment of veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS), Bone Marrow Transplant, 2019.

L. Gragert, HLA Match Likelihoods for Hematopoietic Stem-Cell Grafts in the U, S. Registry. N. Engl. J. Med, vol.371, pp.339-348, 2014.

I. Yakoub-agha, Allogeneic Marrow Stem-Cell Transplantation From Human Leukocyte Antigen-Identical Siblings Versus Human Leukocyte Antigen-Allelic-Matched Unrelated Donors (10/10) in Patients With Standard-Risk Hematologic Malignancy: A Prospective Study From the French Society of Bone Marrow Transplantation and Cell Therapy, J. Clin. Oncol, vol.24, pp.5695-5702, 2006.

V. Gupta, Comparable survival after HLA-well-matched unrelated or matched sibling donor transplantation for acute myeloid leukemia in first remission with unfavorable cytogenetics at diagnosis, Blood, vol.116, pp.1839-1848, 2010.

L. Luznik, HLA-Haploidentical Bone Marrow Transplantation for Hematologic Malignancies Using Nonmyeloablative Conditioning and High-Dose

, Biol. Blood Marrow Transplant, vol.14, pp.641-650, 2008.

S. J. Lee, High-resolution donor-recipient HLA matching contributes to the success of unrelated donor marrow transplantation, Blood, vol.110, pp.4576-4583, 2007.

M. Michallet, Allogreffes de cellules souches hématopoïétiques, Transfus. Clin. Biol, vol.18, pp.235-245, 2011.

M. A. Pulsipher, Acute toxicities of unrelated bone marrow versus peripheral blood stem cell donation: results of a prospective trial from the National Marrow Donor Program, Blood, vol.121, pp.197-206, 2013.

, for the European Society for Blood and Marrow Transplantation (EBMT) et al. Hematopoietic stem cell transplantation in Europe 2014: more than 40 000 transplants annually, Bone Marrow Transplant, vol.51, pp.786-792, 2016.

H. Bonig and T. Papayannopoulou, Hematopoietic stem cell mobilization: updated conceptual renditions, Leukemia, vol.27, pp.24-31, 2013.

C. Okafor, Introduction and overview of therapeutic apheresis, J. Clin. Apheresis, vol.25, pp.240-249, 2010.

A. Ruggeri, A. Paviglianiti, E. Gluckman, and V. Rocha, Impact of HLA in cord blood transplantation outcomes, HLA, vol.87, pp.413-421, 2016.
URL : https://hal.archives-ouvertes.fr/hal-01290435

J. N. Barker, A. Scaradavou, and C. E. Stevens, Combined effect of total nucleated cell dose and HLA match on transplantation outcome in 1061 cord blood recipients with hematologic malignancies, Blood, vol.115, pp.1843-1849, 2010.

V. Rocha and E. Gluckman, Eurocord-Netcord registry and European Blood and Marrow Transplant group. Improving outcomes of cord blood transplantation: HLA matching, cell dose and other graft-and transplantation-related factors, Br. J. Haematol, vol.147, pp.262-274, 2009.

A. Bacigalupo, DEFINING THE INTENSITY OF CONDITIONING REGIMENS : working definitions

, Blood Marrow Transplant. J. Am. Soc. Blood Marrow Transplant, vol.15, pp.1628-1633, 2009.

H. J. Deeg and B. M. Sandmaier, Who is fit for allogeneic transplantation?, Blood, vol.116, pp.4762-4770, 2010.

E. D. Thomas, Stem cell transplantation: Past, present and future, Stem Cells, vol.12, pp.539-544, 1994.

H. J. Deeg, Acute and delayed toxicities of total body irradiation, Int. J. Radiat. Oncol. ? Biol. ? Phys, vol.9, pp.1933-1939, 1983.

G. W. Santos, Marrow transplantation for acute nonlymphocytic leukemia after treatment with busulfan and cyclophosphamide, N. Engl. J. Med, vol.309, pp.1347-1353, 1983.

P. J. Tutschka, E. A. Copelan, and J. P. Klein, Bone marrow transplantation for leukemia following a new busulfan and cyclophosphamide regimen, Blood, vol.70, pp.1382-1388, 1987.

G. Socie, Busulfan plus cyclophosphamide compared with total-body irradiation plus cyclophosphamide before marrow transplantation for myeloid leukemia: long-term follow-up of 4 randomized studies, Blood, vol.98, pp.3569-3574, 2001.

E. A. Copelan, Better leukemia-free and overall survival in AML in first remission following cyclophosphamide in combination with busulfan compared with TBI, Blood, vol.122, pp.3863-3870, 2013.
URL : https://hal.archives-ouvertes.fr/hal-00979459

M. A. Kharfan-dabaja, Comparing i.v. BU dose intensity between two regimens (FB2 vs FB4) for allogeneic HCT for AML in CR1: a report from the Acute Leukemia Working Party of EBMT, Bone Marrow Transplant, vol.49, pp.1170-1175, 2014.

H. J. Deeg, Conditioning with targeted busulfan and cyclophosphamide for hemopoietic stem cell transplantation from related and unrelated donors in patients with myelodysplastic syndrome, Blood, vol.100, pp.1201-1207, 2002.

L. B. Grochow, Pharmacokinetics of busulfan: correlation with veno-occlusive disease in patients undergoing bone marrow transplantation, Cancer Chemother. Pharmacol, vol.25, pp.55-61, 1989.

S. P. Dix, Association of busulfan area under the curve with veno-occlusive disease following BMT, Bone Marrow Transplant, vol.17, pp.225-230, 1996.

H. P. Bhagwatwar, S. Phadungpojna, D. S. Chow, and B. S. Andersson, Formulation and stability of busulfan for intravenous administration in high-dose chemotherapy, Cancer Chemother

. Pharmacol, , vol.37, pp.401-408, 1996.

A. Nagler, Allogeneic hematopoietic SCT for adults AML using i.v. BU in the conditioning regimen: outcomes and risk factors for the occurrence of hepatic sinusoidal obstructive syndrome

, Bone Marrow Transplant, vol.49, pp.628-633, 2014.

A. Kashyap, Intravenous versus oral busulfan as part of a busulfan/cyclophosphamide preparative regimen for allogeneic hematopoietic stem cell transplantation: Decreased incidence of hepatic venoocclusive disease (HVOD), HVOD-related mortality, p.100

, Biol. Blood Marrow Transplant, vol.8, pp.493-500, 2002.

A. Nagler, Allogeneic hematopoietic stem-cell transplantation for acute myeloid leukemia in remission: comparison of intravenous busulfan plus cyclophosphamide (Cy) versus total-body irradiation plus Cy as conditioning regimen--a report from the acute leukemia working party of the European group for blood and marrow transplantation, J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol, vol.31, pp.3549-3556, 2013.

M. Mohty, Reduced-intensity versus conventional myeloablative conditioning allogeneic stem cell transplantation for patients with acute lymphoblastic leukemia: a retrospective study from the European Group for Blood and Marrow Transplantation, Blood, vol.116, pp.4439-4443, 2010.

C. Bredeson, Prospective cohort study comparing intravenous busulfan to total body irradiation in hematopoietic cell transplantation, Blood, vol.122, pp.3871-3878, 2013.

M. Mohty, Predictive factors and impact of full donor T-cell chimerism after reduced intensity conditioning allogeneic stem cell transplantation, Haematologica, vol.92, pp.1004-1006, 2007.

B. Gyurkocza, Nonmyeloablative Allogeneic Hematopoietic Cell Transplantation in Patients With Acute Myeloid Leukemia, J. Clin. Oncol, vol.28, pp.2859-2867, 2010.

C. Schmid, Long-term survival in refractory acute myeloid leukemia after sequential treatment with chemotherapy and reduced-intensity conditioning for allogeneic stem cell transplantation, Blood, vol.108, pp.1092-1099, 2006.

S. Slavin, Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases, Blood, vol.91, pp.756-763, 1998.

P. Corradini, Effect of age and previous autologous transplantation on nonrelapse mortality and survival in patients treated with reduced-intensity conditioning and allografting for advanced hematologic malignancies, J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol, vol.23, pp.6690-6698, 2005.

S. Tauro, Allogeneic Stem-Cell Transplantation Using a Reduced-Intensity Conditioning Regimen Has the Capacity to Produce Durable Remissions and Long-Term Disease-Free Survival in Patients With High-Risk Acute Myeloid Leukemia and Myelodysplasia, J. Clin. Oncol, vol.23, pp.9387-9393, 2005.

D. Blaise, Randomized study of 2 reduced-intensity conditioning strategies for human leukocyte antigen-matched, related allogeneic peripheral blood stem cell transplantation: prospective clinical and socioeconomic evaluation, Cancer, vol.119, pp.602-611, 2013.

T. Kim, Clinical impact of anti-thymocyte globulin on survival and graft-versus-host disease in patients undergoing human leukocyte antigen mismatched allogeneic stem cell transplantation, Korean J. Intern. Med, 2019.

R. Devillier, The increase from 2.5 to 5 mg/kg of rabbit anti-thymocyte-globulin dose in reduced intensity conditioning reduces acute and chronic GVHD for patients with myeloid malignancies undergoing allo-SCT, Bone Marrow Transplant, vol.47, pp.639-645, 2012.

S. O. Ciurea and B. S. Andersson, Busulfan in Hematopoietic Stem Cell Transplantation. Biol. Blood Marrow Transplant, vol.15, pp.523-536, 2009.

D. Blaise, Low non-relapse mortality and long-term preserved quality of life in older patients undergoing matched related donor allogeneic stem cell transplantation: a prospective multicenter phase II trial, Haematologica, vol.100, pp.269-274, 2015.
URL : https://hal.archives-ouvertes.fr/hal-02167058

M. Aoudjhane, Comparative outcome of reduced intensity and myeloablative conditioning regimen in HLA identical sibling allogeneic haematopoietic stem cell transplantation for patients older than 50 years of age with acute myeloblastic leukaemia: a retrospective survey from the Acute Leukemia Working Party (ALWP) of the European group for Blood and Marrow Transplantation (EBMT), vol.9

S. M. Luger, Similar outcomes using myeloablative vs reduced-intensity allogeneic transplant preparative regimens for AML or MDS, Bone Marrow Transplant, vol.47, pp.203-211, 2012.

A. Shimoni, Intravenous Busulfan Compared with Treosulfan-Based Conditioning for Allogeneic Stem Cell Transplantation in Acute Myeloid Leukemia: A Study on Behalf of the Acute Leukemia Working Party of European Society for Blood and Marrow Transplantation, Biol. Blood Marrow Transplant. J. Am. Soc. Blood Marrow Transplant, vol.24, pp.751-757, 2018.
URL : https://hal.archives-ouvertes.fr/hal-02143555

B. S. Andersson, Bu-Flu) Compares Favorably with i.v. Busulfan and Cyclophosphamide (i.v. BuCy2) as Pretransplant Conditioning Therapy in AML/MDS, Biol. Blood Marrow Transplant, vol.14, pp.672-684, 2008.

G. Alatrash, Myeloablative reduced-toxicity i.v. busulfan-fludarabine and allogeneic hematopoietic stem cell transplant for patients with acute myeloid leukemia or myelodysplastic syndrome in the sixth through eighth decades of life, Biol. Blood Marrow Transplant. J. Am. Soc. Blood Marrow Transplant, vol.17, pp.1490-1496, 2011.

A. Rambaldi, Busulfan plus cyclophosphamide versus busulfan plus fludarabine as a preparative regimen for allogeneic haemopoietic stem-cell transplantation in patients with acute myeloid leukaemia: an open-label, multicentre, randomised, phase 3 trial, Lancet Oncol, vol.16, pp.1525-1536, 2015.

A. Terenzi, Efficacy of fludarabine as an immunosuppressor for bone marrow transplantation conditioning: preliminary results, Transplant. Proc, vol.28, p.3101, 1996.

G. B. Mcdonald, Cyclophosphamide metabolism, liver toxicity, and mortality following hematopoietic stem cell transplantation, Blood, vol.101, pp.2043-2048, 2003.

H. Liu, Busulfan plus fludarabine as a myeloablative conditioning regimen compared with busulfan plus cyclophosphamide for acute myeloid leukemia in first complete remission undergoing allogeneic hematopoietic stem cell transplantation: a prospective and multicenter study, J. Hematol. Oncol.J Hematol Oncol, vol.6, p.15, 2013.

M. Mohty, Reduced-toxicity conditioning with fludarabine, once-daily intravenous busulfan, and antithymocyte globulins prior to allogeneic stem cell transplantation: Results of a multicenter prospective phase 2 trial: Reduced-Toxicity Conditioning Allo-SCT, Cancer, vol.121, pp.562-569, 2015.

A. Galaup and A. Paci, Pharmacology of dimethanesulfonate alkylating agents: busulfan and treosulfan, Expert Opin. Drug Metab. Toxicol, vol.9, pp.333-347, 2013.

J. A. Hartley and B. W. Fox, Cross-linking between histones and DNA following treatment with a series of dimethane sulphonate esters, Cancer Chemother. Pharmacol, vol.17, pp.56-62, 1986.

G. Vassal, Dose-dependent Neurotoxicity of High-Dose Busulfan in Children: A Clinical and Pharmacological Study

A. Seber, X. O. Shu, T. Defor, S. Sencer, and N. Ramsay, Risk factors for severe hemorrhagic cystitis following BMT, Bone Marrow Transplant, vol.23, pp.35-40, 1999.

M. Kondo, S. Kojima, K. Kato, and T. Matsuyama, Late-onset hemorrhagic cystitis after hematopoietic stem cell transplantation in children, Bone Marrow Transplant, vol.22, pp.995-998, 1998.

O. Ringdén, Increased risk of chronic graft-versus-host disease, obstructive bronchiolitis, and alopecia with busulfan versus total body irradiation: long-term results of a randomized trial in allogeneic marrow recipients with leukemia. Nordic Bone Marrow Transplantation Group, Blood, vol.93, pp.2196-2201, 1999.

A. Haddow and G. M. Timmis, Myleran in chronic myeloid leukaemia; chemical constitution and biological action, Lancet Lond. Engl, vol.264, pp.207-208, 1953.

D. A. Galton and M. Till, Myleran in chronic myeloid leukaemia, Lancet Lond. Engl, vol.268, pp.425-430, 1955.

M. Hassan, H. Ehrsson, and P. Ljungman, Aspects Concerning Busulfan Pharmacokinetics and Bioavailability. Leuk. Lymphoma, vol.22, pp.395-407, 1996.

M. Hassan, Busulfan bioavailability. Blood, vol.84, pp.2144-2150, 1994.

J. S. Mccune, J. P. Gibbs, and J. T. Slattery, Plasma Concentration Monitoring of Busulfan: Does It Improve Clinical Outcome?, Clin. Pharmacokinet, vol.39, pp.155-165, 2000.

M. Hassan, Cerebrospinal fluid and plasma concentrations of busulfan during high-dose therapy, Bone Marrow Transplant, vol.4, pp.113-114, 1989.

H. Ehrsson and M. Hassan, Binding of busulfan to plasma proteins and blood cells, J. Pharm. Pharmacol, vol.36, pp.694-696, 1984.

M. Czerwinski, J. P. Gibbs, and J. T. Slattery, Busulfan conjugation by glutathione S-transferases alpha, mu, and pi, Drug Metab. Dispos. Biol. Fate Chem, vol.24, pp.1015-1019, 1996.

L. Johnson, Glutathione S-transferase A1 genetic variants reduce busulfan clearance in children undergoing hematopoietic cell transplantation, J. Clin. Pharmacol, vol.48, pp.1052-1062, 2008.

R. Elhasid, Influence of glutathione S-transferase A1, P1, M1, T1 polymorphisms on oral busulfan pharmacokinetics in children with congenital hemoglobinopathies undergoing hematopoietic stem cell transplantation, Pediatr. Blood Cancer, vol.55, pp.1172-1179, 2010.

S. Kim, Influence of GST gene polymorphisms on the clearance of intravenous busulfan in adult patients undergoing hematopoietic cell transplantation, Biol. Blood Marrow Transplant. J. Am. Soc. Blood Marrow Transplant, vol.17, pp.1222-1230, 2011.

V. Michaud, Impact of GSTA1 Polymorphisms on Busulfan Oral Clearance in Adult Patients Undergoing Hematopoietic Stem Cell Transplantation, Pharmaceutics, vol.11, 2019.

J. Zwaveling, Glutathione S-transferase polymorphisms are not associated with population pharmacokinetic parameters of busulfan in pediatric patients, Ther. Drug Monit, vol.30, pp.504-510, 2008.

E. Goekkurt, Pharmacogenetic analysis of liver toxicity after busulfan/cyclophosphamidebased allogeneic hematopoietic stem cell transplantation, Anticancer Res, vol.27, pp.4377-4380, 2007.

F. Versace, A novel method for quantification of sulfolane (a metabolite of busulfan) in plasma by gas chromatography-tandem mass spectrometry, Anal. Bioanal. Chem, vol.404, pp.1831-1838, 2012.

M. Hassan, Pharmacokinetic and metabolic studies of high-dose busulphan in adults, Eur. J. Clin. Pharmacol, vol.36, pp.525-530, 1989.

I. El-serafi, Gas chromatographic-mass spectrometry method for the detection of busulphan and its metabolites in plasma and urine, J. Chromatogr. B Analyt. Technol. Biomed. Life

. Sci, , pp.98-105, 2013.

M. Hassan and H. Ehrsson, Urinary metabolites of busulfan in the rat, Drug Metab. Dispos. Biol. Fate Chem, vol.15, pp.399-402, 1987.

N. Krivoy, E. Hoffer, Y. Lurie, Y. Bentur, and J. Rowe, Busulfan Use in Hematopoietic Stem Cell Transplantation: Pharmacology, Dose Adjustment, Safety and Efficacy in Adults and Children

, Drug Saf, vol.3, pp.60-66, 2008.

M. B. Regazzi, Disposition of high-dose busulfan in pediatric patients undergoing bone marrow transplantation, Clin. Pharmacol. Ther, vol.54, pp.45-52, 1993.

K. S. Baker, Busulfan pharmacokinetics do not predict relapse in acute myeloid leukemia, Bone Marrow Transplant, vol.26, pp.607-614, 2000.

M. Hassan, Pharmacokinetics of high-dose busulphan in relation to age and chronopharmacology, Cancer Chemother. Pharmacol, vol.28, pp.130-134, 1991.

H. Ehrsson, M. Hassan, M. Ehrnebo, M. Beran, . Busulfan et al., Clin. Pharmacol. Ther, vol.34, pp.86-89, 1983.

M. Hassan, The role of busulfan in bone marrow transplantation, Med. Oncol. Northwood Lond

. Engl, , vol.16, pp.166-176, 1999.

B. S. Andersson, Busulfan systemic exposure relative to regimen-related toxicity and acute graft-versus-host disease: Defining a therapeutic window for i.v. BuCy2 in chronic myelogenous leukemia, Biol. Blood Marrow Transplant, vol.8, pp.477-485, 2002.

J. T. Slattery, Marrow Transplantation for Chronic Myeloid Leukemia: The Influence of Plasma Busulfan Levels on the Outcome of Transplantation, vol.7

J. T. Slattery, Graft-rejection and toxicity following bone marrow transplantation in relation to busulfan pharmacokinetics, Bone Marrow Transplant, vol.16, pp.31-42, 1995.

M. Geddes, High Busulfan Exposure Is Associated with Worse Outcomes in a Daily i.v. Busulfan and Fludarabine Allogeneic Transplant Regimen, Biol. Blood Marrow Transplant, vol.14, pp.220-228, 2008.

M. Bornhauser, Conditioning with fludarabine and targeted busulfan for transplantation of allogeneic hematopoietic stem cells, Blood, vol.102, pp.820-826, 2003.

A. M. Bolinger, Target dose adjustment of busulfan in pediatric patients undergoing bone marrow transplantation, Bone Marrow Transplant, vol.28, pp.1013-1018, 2001.

H. P. Bhagwatwar, S. Phadungpojna, D. S. Chow, and B. S. .-l.-&-andersson, Formulation and stability of busulfan for intravenous administration in high-dose chemotherapy, Cancer Chemother. Pharmacol, vol.37, pp.401-408, 1996.

J. A. Russell, Once-daily intravenous busulfan given with fludarabine as conditioning for allogeneic stem cell transplantation: Study of pharmacokinetics and early clinical outcomes, Biol. Blood Marrow Transplant, vol.8, pp.468-476, 2002.

M. De-lima, Once-daily intravenous busulfan and fludarabine: clinical and pharmacokinetic results of a myeloablative, reduced-toxicity conditioning regimen for allogeneic stem cell transplantation in AML and MDS, Blood, vol.104, pp.857-864, 2004.

B. S. Andersson, Fludarabine with pharmacokinetically guided IV busulfan is superior to fixed-dose delivery in pretransplant conditioning of AML/MDS patients, Bone Marrow Transplant, vol.52, pp.580-587, 2017.

I. H. Bartelink, Once-daily intravenous busulfan with therapeutic drug monitoring compared to conventional oral busulfan improves survival and engraftment in children undergoing allogeneic stem cell transplantation, Biol. Blood Marrow Transplant. J. Am. Soc. Blood Marrow Transplant, vol.14, pp.88-98, 2008.

L. B. Grochow, Busulfan disposition: the role of therapeutic monitoring in bone marrow transplantation induction regimens, Semin. Oncol, vol.20, p.26, 1993.

S. Chunduri, Comparable kinetics of myeloablation between fludarabine/full-dose busulfan and fludarabine/melphalan conditioning regimens in allogeneic peripheral blood stem cell transplantation, Bone Marrow Transplant, vol.38, pp.477-482, 2006.

V. Gandhi, W. Plunkett, C. Cellular, and . Pharmacology-of-fludarabine, Clin. Pharmacokinet, vol.41, pp.93-103, 2002.

M. Mohty, Mechanisms of action of antithymocyte globulin: T-cell depletion and beyond, Leukemia, vol.21, pp.1387-1394, 2007.

A. Bacigalupo, Antithymocyte globulin for graft-versus-host disease prophylaxis in transplants from unrelated donors: 2 randomized studies from Gruppo Italiano Trapianti Midollo Osseo (GITMO), Blood, vol.98, pp.2942-2947, 2001.

J. Storek, M. Mohty, and J. J. Boelens, Rabbit anti-T cell globulin in allogeneic hematopoietic cell transplantation, Biol. Blood Marrow Transplant. J. Am. Soc. Blood Marrow Transplant, vol.21, pp.959-970, 2015.

M. Mohty, Antithymocyte globulins and chronic graft-vs-host disease after myeloablative allogeneic stem cell transplantation from HLA-matched unrelated donors: a report from the
URL : https://hal.archives-ouvertes.fr/hal-00849647

, Leukemia, vol.24, pp.1867-1874, 2010.

G. Socié, Chronic graft-versus-host disease: long-term results from a randomized trial on graft-versus-host disease prophylaxis with or without anti-T-cell globulin ATG-Fresenius, Blood, vol.117, pp.6375-6382, 2011.

A. Ravinet, Impact of Thymoglobulin by Stem Cell Source (Peripheral Blood Stem Cell or Bone Marrow) After Myeloablative Stem Cell Transplantation From HLA 10/10-Matched Unrelated Donors: A Report From the Société Française de Greffe de Moelle et de Thérapie Cellulaire, Transplantation, vol.100, pp.1732-1739, 2016.

R. Crocchiolo, Two days of antithymocyte globulin are associated with a reduced incidence of acute and chronic graft-versus-host disease in reduced-intensity conditioning transplantation for hematologic diseases, Cancer, vol.119, pp.986-992, 2013.

J. L. Ferrara, R. Levy, and N. J. Chao, Pathophysiologic mechanisms of acute graft-vs.-host disease, Biol. Blood Marrow Transplant. J. Am. Soc. Blood Marrow Transplant, vol.5, pp.347-356, 1999.

D. Couriel, H. Caldera, R. Champlin, and K. Komanduri, Acute graft-versus-host disease: Pathophysiology, clinical manifestations, and management, Cancer, vol.101, pp.1936-1946, 2004.

H. Wallen, Ablative allogeneic hematopoietic cell transplantation in adults 60 years of age and older, J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol, vol.23, pp.3439-3446, 2005.

J. B. Langenhorst, Fludarabine exposure in the conditioning prior to allogeneic hematopoietic cell transplantation predicts outcomes, Blood Adv, vol.3, pp.2179-2187, 2019.

P. Chevallier, Results from a clofarabine-busulfan-containing, reduced-toxicity conditioning regimen prior to allogeneic stem cell transplantation: the phase 2 prospective CLORIC trial, Haematologica, vol.99, pp.1486-1491, 2014.
URL : https://hal.archives-ouvertes.fr/hal-01325352

P. Chevallier, Clofarabine versus fludarabine-based reduced-intensity conditioning regimen prior to allogeneic transplantation in adults with AML/MDS, Cancer Med, vol.5, pp.3068-3076, 2016.
URL : https://hal.archives-ouvertes.fr/hal-01818593

A. El-jawahri, Phase II Trial of Reduced-Intensity Busulfan/Clofarabine Conditioning with Allogeneic Hematopoietic Stem Cell Transplantation for Patients with Acute Myeloid Leukemia, Myelodysplastic Syndromes, and Acute Lymphoid Leukemia, Biol. Blood Marrow Transplant. J. Am

. Soc, Blood Marrow Transplant, vol.22, pp.80-85, 2016.

N. Vey and D. Blaise, Cellules NK et hémopathies malignes, 2012.

M. Mohty, Revised diagnosis and severity criteria for sinusoidal obstruction syndrome/veno-occlusive disease in adult patients: a new classification from the European Society for Blood and Marrow Transplantation, Bone Marrow Transplant, vol.51, pp.906-912, 2016.

A. L. Myers, Clarifying busulfan metabolism and drug interactions to support new therapeutic drug monitoring strategies: a comprehensive review, Expert Opin. Drug Metab

. Toxicol, , vol.13, pp.901-923, 2017.

, CONTEXTE : Les conditionnements à intensité réduite (RIC) combinant la fludarabine

. Busulfan, ATG sont couramment utilisés chez les patients d'âge avancé et/ou avec de nombreuses comorbidités, non éligibles à un conditionnement myéloablatif (MAC) standard (c.à-d. BuCy ou CyTBI12). Bien que la mortalité sans rechute (NRM) ait été considérablement diminuée après le RIC, la rechute demeure un enjeu majeur

. Materiels and . Methodes, Nous avons comparé les résultats de patients âgés de plus de, p.55

, ans atteints d'hémopathies malignes inclus dans un essai prospectif monocentrique à un seul bras (BxPK : NCT02483325) évaluant la faisabilité de doses de Busulfan guidées par PK dans un schéma de conditionnement myéloablatif

, Busulfan IV (260 mg/m²) et ATG (5 mg/kg), mg/m²)

, Le rapport des risques de BxPK par rapport à Bx2 a été ajusté en fonction de l'âge, du DRI, du type de donneur et de l'HCT-CI. RÉSULTATS Nous avons analysé 83 patients consécutifs (BxPK : n=27 ; Bx2 : n=56) sans différence significative dans les caractéristiques de base entre les deux groupes de conditionnement, L'objectif principal était la survie sans progression à 2 ans (PFS), pp.55-70

, les donneurs HLA-identique 10/10 non apparentés ont été utilisés pour 15 (56%) et 37 (66%) patients, respectivement, vol.493, p.0

L. Était, , vol.3

, 67%) et 28 (50%) patients, respectivement, vol.232, p.0

, DRI était élevé chez, vol.5, p.5

, AUC médiane du Busulfan à J-2 (après ajustement) était de 5 287 µmol, p.3326

, Les mucites de grade 3-4 (BxPK vs Bx2 : 52 % vs 11 %, p < 0,001) et les nausées (BxPK vs Bx2 : vs Bx2 : 15% vs 11%, p = 0,810), rénales (BxPK vs Bx2 : 0% vs 1,8%, p = 1) et digestives (BxPK vs, vol.2, p.11

I. La-gvhd-aigüe-de-grade and . Bxpk, BxPK vs Bx2 : 41 % vs 29 %, p = 0,058) alors qu'aucune différence n'a été observée en termes de GvHD chronique à 2 ans (BxPK vs Bx2 : 41 % vs 36 %, Ces tendances ont été confirmées par des analyses multivariées, vol.547, pp.9-60

, Aucune différence significative n'a été observée entre la PFS à 2 ans (BxPK vs Bx2 : 62 % vs 51 %, p = 0,391) et l'OS (BxPK vs Bx2 : 70 % vs 61 %, vol.859, p.0

, Mots clefs : Greffe allogénique de cellules souches hématopoïétiques ; conditionnement a intensité réduite, conditionnement a toxicité réduite