Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Human leukocyte antigen wikipedia , lookup
Psychoneuroimmunology wikipedia , lookup
Lymphopoiesis wikipedia , lookup
Innate immune system wikipedia , lookup
Cancer immunotherapy wikipedia , lookup
Polyclonal B cell response wikipedia , lookup
Adoptive cell transfer wikipedia , lookup
Immunosuppressive drug wikipedia , lookup
X-linked severe combined immunodeficiency wikipedia , lookup
Leukemia (2002) 16, 424–426 2002 Nature Publishing Group All rights reserved 0887-6924/02 $25.00 www.nature.com/leu MEETING REPORT Workshop on haploidentical stem cell transplantation: Chicago, Illinois, USA, 18-19 November 2000 IR Walker McMaster University Medical Centre, Hamilton, Ontario, Canada Leukemia (2002) 16, 424–426. DOI: 10.1038/sj/leu/2402385 Regimens Haplo-identical donors are a source of hematopoietic stem cells, along with cord blood, for those 20% of individuals for whom a fully matched donor is unavailable. Transplant experience with these donors over the last 15 years has demonstrated feasibility, but the incidences of graft-versus-host disease (GVHD) and graft rejection have been significantly higher, and the survival lower, than with matched donors. An important lesson from this early experience, not to be forgotten, is that disease-free survival is better when patients are transplanted in remission rather than relapse, something to bear in mind when assessing this procedure in the future. The Chicago and Perugia meetings signaled a new momentum, stimulated by the recent results from the basic research of Reisner’s group at the Weizmann Institute in Israel, and the later application of their techniques to humans, which culminated in the excellent clinical results in adults from Martelli’s group at Perugia, and in children from Handgretinger’s group at Tübingen, and O’Reilly’s group in New York. Preparative regimens are now more specific, and there are automated cell selection devices available which provide large number of purified stem cells virtually devoid of T lymphocytes. At the Chicago meeting a number of new groups reported pilot studies, demonstrating the practicality of the new approaches. In the United States progress is hindered by lack of the cell selection devices which are freely available in Europe and Canada. Nevertheless, a few groups from the United States have been able to complete pilot studies using FDA approved protocols. The main lessons from the Chicago meeting were: (1) that the successful use of haplo-identical donors solves the problem of donor availability for virtually all individuals who have blood relatives; (2) that such donors are immediately available; (3) that with modern techniques, which make possible large doses of stem cells markedly depleted of T lymphocytes, both graft rejection and GVHD are virtually eliminated; (4) that the preparative regimens have low toxicity; and (5) that, most surprisingly for T cell-depleted grafts, the relapse rate for advanced myeloid leukemia is low. It would appear that the Holy Grail of transplantation, graft-versus-leukemia (GVL) effect without GVHD, is a realistic concept, and that it may be occurring in this setting. Not all is rosy, however; immune reconstitution is very slow, leading to a drawn out period of immunodeficiency, lasting typically up to 1 year before CD4+ helper cells are greater than 200 × 109/l. It is this aspect which is limiting the success of haploidentical donor transplantation and on which most of developmental research needs to focus. A more detailed analysis follows. Most centers use regimens similar or identical to those used by the groups at New York, Perugia and Tübingen incorporating, in various combinations, radiation, busulfan, melphalan, cyclophosphamide, fludarabine, thiotepa and anti-thymocyte globulin. Anti-thymocyte globulin, having been demonstrated by O’Reilly’s group to reduce the risk of rejection, is a moreor-less constant feature of all regimens. Post-transplant administration of G-CSF is unnecessary as engraftment is almost universally rapid without it; in fact, as the Perugia group has shown, G-CSF may adversely affect immune reconstitution. Correspondence: I Walker, McMaster University Medical Centre, 1200 Main Street West, Hamilton, Ontario, Canada L8N 3Z5; Fax: +1-905-521-4971 Graft preparation Older techniques using partially T cell-depleted grafts followed by post-transplant immunosuppression have been largely abandoned in favor of markedly T cell-depleted grafts, typically containing ⬍5 × 104/kg T cells. Though no absolute threshold of T cell numbers exists for GVHD to occur, it is rare with this level of T cell depletion, and post-transplant immunosuppression is not needed. Another feature of present protocols is a high CD34+ cell dose, the aim being to provide ⭓10 × 106/kg recipient body weight. A high cell dose was previously demonstrated by Reisner’s group, in mice, to overcome graft rejection induced by T cell depletion, even across major histocompatibility complex (MHC) barriers. This megadose therapy appears to induce specific tolerance, eliminating recipient cells having anti-donor activity, but not eliminating third-party reactivity. Recent work suggests the presence of ’veto’ cells (see Rachamim N et al).1 Overall outcome and relapse The main cause of death in patients transplanted for advanced acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) has been opportunistic infection, but in ALL relapse has also been common. Overall outcomes for those transplanted in stable complete remission (CR1 and CR2) are very much better than for those transplanted in advanced stage (relapse and ⭓CR2), although some spectacular salvages of relapsed and resistant cases have occurred. Outcome for non-malignant indications (eg metabolic disease and severe combined immunodeficiency (SCID)) is also excellent. Graft rejection has been uncommon, and success of re-engraftment is high. The relapse rate in AML is surprisingly low, given the advanced stage of disease transplanted in these series and the historically high relapse rate with T cell depletion in transplants using matched donors. Relapse is particularly uncommon where the direction of killer inhibitory receptor (KIR) typing is favorable (more below). Relapse of ALL is higher, Workshop on haploidentical stem cell transplantation IR Walker and overall survival lower, than in AML, and transplantation of patients with ALL in relapse is futile – there is no indication of GVL except in the 20% of cases where the malignant cells express the adhesion molecule LFA-1. Prevention of infection Practices regarding prophylaxis varies, but use of cotrimoxazole and acyclovir is universal, as is some kind of fungal prophylaxis. Herpes simplex virus (HSV) infections may be unusually severe and prolonged. Practices regarding cytomegalovirus (CMV) prophylaxis vary, both preemptive and prophylactic approaches being used. A battery of polymerase chain reaction (PCR) tests for Epstein–Barr virus (EBV), CMV, Aspergillus, Candida, adenovirus, done weekly, is suggested. The use of newly emerging agents, such as cidofovir, merits consideration whenever opportunistic infection occurs. Donor lymphocyte infusions These are being considered both for speeding immunological recovery and increasing GVL. However, unmanipulated lymphocytes are considered hazardous with respect to precipitating fatal GVHD; the experimental approach pursued by the Perugia group selects lymphocyte clones which lack anti-host cytotoxicity. With respect to prevention of infections, the Perugia group is also selecting lymphocyte clones with cytotoxicity to Aspergillus and CMV. The clinical efficacy of these interesting approaches remains to be proven. GM-CSF is being used as a supplement to lymphocyte infusions where infection is the focus. Future considerations include infusions of interleukin 2 (IL-2) and natural killer (NK) cells. Anti-thymocyte globulin (ATG) Features of the typical preparative regimens include low toxicity profiles and an emphasis on immunosuppression; ATG has been included universally. ATG is necessary for prevention of rejection but its need for preventing GVHD, in the setting of marked T cell depletion, is doubtful. While it is given for its effects on the recipient’s lymphocytes, its long half-life allows for a prolonged post-transplant effect on the recovering immune system, an unwanted effect. ATG is now blamed for much of the prolonged post-BMT immunosuppression through its effect on the graft. As evidence, O’Reilly from Memorial Sloan-Kettering showed instructive data from the experience of transplanting patients with SCID. GVHD is not seen in the absence of ATG administration provided that T cell depletion is at a high level. On the other hand, the main adverse influences on immunological recovery in SCID patients have been increasing age and the use of rabbit ATG (horse ATG gives little post-transplant immune suppression). Surprisingly, T cell depletion has little effect on speed of immunological recovery when matched unrelated donor (MUD) transplants with and without T cell depletion are compared. Buffet and colleagues at SangStat showed data suggesting that giving ATG on days −10 to −7 rather than on days −5 to −2 shortens post-transplant anti-lymphocyte activity from 4 to 6 weeks to less than 2 weeks; this seems well worth investigating in the haplo-transplant setting. The role of NK activity in preventing relapse and rejection 425 The Perugia group have shown a strong relation between favorable KIR typing (specific incompatibility) and risk of relapse and graft rejection.2 They recommend that donors be chosen on this basis. The basic concept is best illustrated by contrasting NK activity (’innate’ immunity) with T cell activity (’adaptive’ immunity). T cell activity is ’switched on’ by specific recognition, that is, the default state is ’switched off’. By contrast, NK activity is ’switched on’ and NK cells will attack any cell unless its killer inhibitory receptor recognizes specific HLA class I groups on the target surface and is thereby ’switched off’. Thus a person’s own NK cell activity is ’switched off’ by his/her own HLA class I receptors. NK activity may remain on when, for example, CMV causes down-regulation of a cell’s HLA class I. In haplo-transplants, there may be clones of donor NK cells which may fail to be switched off because one recipient haplotype may express HLA class I antigens which are not recognized by the donor NK cell KIR. KIR receptors recognize groups of HLA alleles, so that just because donor and recipient differ in HLA class I does not mean they are incompatible; for example, a KIR will recognize Cw 1, 3, 7 and 9 as all being compatible and capable of being switched off by them. Alternatively, this same KIR will not recognize Cw 2, 4, 5 and 6 and the NK clone may remain activated. Published data from the Perugia group indicate that specific KIR typing may not be necessary and that accurate information can be obtained by studying the donor and recipient HLA class I typings. It is clear that haploidentical donor transplantation has arrived, but what is the way forward? There are a variety of problems to be investigated, particularly with respect to immune reconstitution such as timing of ATG and add-back of lymphocyte sub-populations, but firstly, how good is the procedure right now, and how does it compare with cord blood and, dare we ask, MUD transplants? What is a physician to do with a patient who needs a transplant in a hurry and there is no matched family member? Conventional wisdom would say proceed to a search of unrelated donor registries. But, can the physician afford to await the results of a registry search and the time it takes to choose and secure donor marrow; maybe yes, but maybe no. Also, what is there to be gained by using unrelated donor marrow; might a haplodonor transplant have just as much chance of success, and, after all, is the donor immediately available? Is it a reasonable question to ask given the short experience? That yes, it is appropriate to ask the question, is indicated by a sub-analysis of the Perugia results. The long-term survival of those patients with AML who were in complete remission at the time of transplant is 50–70% depending on whether the entire cohort, or only those transplanted with the latest protocol, is considered. These figures, although needing validation, are surely the equal of those of transplantation using unrelated donors. Is it possible that the high prevalence of opportunistic infections following haploidentical donor transplantation owes as much to the very advanced disease stage at which many of the patients have been transplanted as to the procedure itself? These are provocative questions and the aforesaid arguments are hypothesis-generating only; in truth, data are not available to help the physician right now. To answer the question one approach might be to compare outcomes using haploidentical donors at various stages of disease, and with outcomes with unrelated donors, using the International Bone Marrow Transplant Registry (IBMTR) and the European Group for Blood and Marrow Transplantation (EBMT) registry. The comparisons Leukemia Workshop on haploidentical stem cell transplantation IR Walker 426 should be on transplants performed prospectively, as results in any new procedure will improve with experience, and past transplants will have been performed on the ’learning curve’. Haploidentical donor transplantation, therefore, has great potential for those patients lacking matched donors, but much of what we learn may also be useful for fully matched transplants. For example, the Perugia3 and New York4 groups have published excellent results in matched sibling transplants with the use of ’mega-dose’/T cell-depleted grafts and with the addition of ATG and thiotepa, all borrowed from the ’haplo’ experience. Despite severe T cell depletion of the grafts, posttransplant relapse of leukemia has been low, particularly in AML. Why this is so is also a question worth addressing. References 1 Rachamim N, Gan J, Segall H, Krauthgamer R, Marcus H, Berrebi A, Martelli M, Reisner Y. Tolerance induction by ‘megadose’ hem- Leukemia atopoietic transplants: donor-type human CD34 stem cells induce potent specific reduction of host anti-donor cytotoxic T lymphocyte precursors in mixed lymphocyte culture. Transplantation 1998; 65: 1386–1393. 2 Ruggeri L, Capanni M, Casucci M, Volpi I, Tosti A, Perruccio K, Urbani E, Negrin RS, Martelli MF, Velardi A. Role of natural killer cell alloreactivity in HLA-mismatched hematopoietic stem cell transplantation. Blood 1999; 94: 333–339. 3 Aversa F, Terenzi A, Carotti A, Felicini R, Jacucci R, Zei T, Latini P, Aristei C, Santucci A, Martelli MP, Cunningham I, Reisner Y, Martelli MF. Improved outcome with T-cell-depleted bone marrow transplantation for acute leukaemia. J Clin Oncol 1999; 17: 1545–1550. 4 Papadopoulos EB, Carabasi MH, Castro-Malaspina H, Childs BH, Mackinnon S, Boulad F, Gillio AP, Kernan NA, Small TN, Szabolcs P, Taylor J, Yahalom J, Collins NH, Bleau SA, Black PM, Heller G, O’Reilly R, Young JW. T-cell-depleted allogeneic bone marrow transplantation as postremission therapy for acute myelogenous leukemia: freedom from relapse in the absence of graft-versus-host disease. Blood 1998; 91: 1083–1090.