Journal of Hematology - Supplements - Haematologica

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haematologica 2000; 85(supplement to n. 11):26-29 original paper Cord blood transplantation in childhood FRANCO LOCATELLI, GIOVANNA GIORGIANI, EUGENIA GIRALDI, CLAUDIA CASTELNOVI, PAOLA STROPPA, MARIA ESTER BERNARDO, FEDERICO BONETTI, RITA MACCARIO Oncoematologia Pediatrica, IRCCS Policlinico San Matteo, Università di Pavia, Italy The first allogeneic umbilical cord blood transplant (UCBT) was successfully performed in 1988 to treat a boy with Fanconi's anemia; the umbilical cord blood donor was his HLA identical sister. 1 Twelve years later, this patient is doing well with full donor hematopoietic and lymphoid reconstitution. Since then, our knowledge of the biological characteristics of umbilical cord blood cells has increased, emphasizing the advantages of using umbilical cord blood stem cells for transplantation. Simultaneously, umbilical cord blood banks have been established world-wide for both related and unrelated umbilical cord blood transplants, 2-4 with more than 40,000 units currently available and more than 1,500 UCBT having been performed mainly in children and less frequently in adults, for either malignant or non malignant disorders. Several reports on these transplants have been published in the last 5 years. 5-10 The main practical advantages of using umbilical cord blood as an alternative source of stem cells are the relative ease of procurement, the absence of risks to donor, the reduced risk of transmitting viral infections (Cytomegalovirus, Epstein-Barr virus, etc.) and, especially for transplant from unrelated donors, the prompt availability of cryopreserved samples. The use of stored cord blood units is certainly capable of reducing the time required to perform an allogeneic transplant of hematopoietic stem cells, which at present can be estimated at an average of 4-5 months for bone marrow transplantation (BMT) from unrelated individuals. On average, the time that elapses between opening the search and identifying a unit of placental blood usable to perform the transplant is no more than 20 days. This reduction is of particular interest for patients affected by acute leukemia or by life-threatening diseases (severe combined immune deficiencies, malignant Correspondence: Dr. Franco Locatelli, Oncoematologia Pediatrica, Università di Pavia, IRCCS Policlinico San Matteo, p.le Golgi, 2, 27100 Pavia, Italy. E-mail: f.locatelli@smatteo.pv.it osteopetrosis, hemophagocytic lymphohistiocytosis, etc.), which lead to an unstable hematologic or clinical balance. It has been recently and formally proved that UCBT recipients are exposed to a lower incidence and a lower severity of graft-versus-host disease (GVHD). 11,12 In particular, one study compared children given UCBT with others receiving bone marrow transplantation from a compatible relative and unequivocally showed that use of the former source of hematopoietic cells led to a statistically significant reduction in the incidence and severity of both acute and chronic GVHD. 11 The reduced incidence of chronic GVHD is of particular interest considering the detrimental impact played by this complication on a growing organism. The biological reasons for the reduction of GVHD after UCBT are still not precisely defined. One of the first hypothesis formulated to explain the reduced incidence and severity of GVHD in UCBT recipients was that these patients receive a significantly lower number of T-cells infused per kg of recipient body weight as compared to subjects given BMT (approximately 1 log less than a standard allogeneic marrow transplant). However, the study published by the New York Cord Blood Bank 8 documented that younger children given UCBT were exposed to a lower risk of GVHD than older patients. This finding strongly argues against the speculation that the reduced rate of GVHD is mainly due to the low number of T-cell infused, since younger patients received the highest T-cell doses. The combination of several immunologic properties and peculiarities of cord blood lymphocytes are likely responsible for the reduction of GVHD observed in UCBT recipients. 13 In fact, cord blood lymphocytes are naive (as proved by the higher number of cells expressing the RA isoform of the CD45 molecule), produce lower amounts of pro-inflammatory cytokines such as interferon (IFN)-γ and tumor necrosis factor (TNF)-α, are characterized by a lower frequency of interleukin (IL)-2, IFN-γ and TNF-α producing cells and display absent or markedly haematologica vol. 85(supplement to n. 11):November 2000
27 reduced responsiveness to allogeneic stimuli in a secondary mixed lymphocyte reaction (MLR). 14-17 Alloantigen-specific T-cells with suppressor phenotype have been suggested to exist among cord blood lymphocytes and they might play a role in the reduction of the risk of GVHD associated with UCBT. 18 Recently, attention has also been paid to the study of cord blood antigen-presenting cells (APC). These fundamental cells of the immune response have been documented to display unique peculiarities when they derive from cord blood. In fact, cord blood APC produce less interleukin-12 and interleukin-15 than APC of adult peripheral blood 19,20 and, as recently demonstrated, 21 they have characteristics of immaturity, resembling those observed in the socalled type 2 dendritic cells, which are believed to promote tolerance physiologically. Taken together, all these factors can be reasonably supposed to make less efficient both the afferent and efferent phases of the physiopathologic mechanisms of GVHD. Although UCBT offers a significant advantage over BMT with respect to GVHD occurrence, it is associated with more problems related to hematopoietic reconstitution. In fact, analyses of the patients subjected so far to UCBT have shown that, in comparison with patients given BMT, there is a higher risk of failed engraftment of the donor hematopoiesis, a modest delay in the kinetics of neutrophil recovery, and a more conspicuous delay in platelet reconstitution. 5-12 The engraftment probability and the kinetics of hematologic reconstitution are directly correlated to the number of infused placental cells. Furthermore, the experiences of the EUROCORD group and of the New York Cord Blood Bank both unequivocally document that the infused cell load has an important role in the successful outcome of the transplant, since significantly better results have been achieved in subjects who received at least 2-3x10 7 nucleated cells per kg of body weight. 6-10 The better results of transplanted patients receiving a higher number of cells are to be ascribed essentially to a reduction in transplant-related mortality. Since the average content of cord blood nucleated cells per unit before cryopreservation is between 0.8 and 1.5x10 9 , it is not surprising that UCBT is usually employed in children with a body weight lower than 35-40 Kg. In view of the delayed hematopoietic recovery, patients given UCBT should be carefully monitored, in order to detect any onset of bacterial and fungal infectious complications promptly. Likewise, it is considered advisable to perform UCBT in Centers with a solid experience in the treatment of profoundly immunocompromised patients and to administer prophylactic antibiotic and antimycotic agents. For the time being, there is no conclusive evidence that treatment with hematopoietic growth factors active on the granulocytic series (granulocyte colony-stimulating factor or granulocyte-macrophage colonystimulating factor) can significantly reduce the time required for engraftment. The reported low incidence of GVHD after UCBT has been hypothesized to be a major drawback in leukemia patients. In fact, since the role of allogeneic lymphocytes in the control and/or eradication of malignancy is well established, the absence or reduction of the component of graftversus-leukemia (GVL) activity associated with GVHD could represent a theoretical concern in leukemia subjects given UCBT. However, available data do not support the hypothesis that patients given UCBT enjoy a lower GVL effect. 9-12 One previously published study specifically focused on the role of UCBT in children with acute leukemia. 9 Irrespective of whether the cord blood was from a relative or an unrelated donor, the most important factor influencing survival in that cohort was disease state at the time of transplantation. In fact, among all 102 children, those belonging to the good risk group (i.e. children transplanted in 1 st or 2 nd complete remission) had a significantly better post-transplant outcome than poor-risk patients, 2-year Kaplan- Meier estimates of event-free survival for these groups being 49% and 8%, respectively (p=0.0002). This was a consequence of both an increased one-year transplant-related mortality and a higher 2-year relapse rate in the poor risk group as compared to in the good risk patients. In particular, the 2-year probability of leukemia recurrence in children belonging to the poorand good-risk groups was 77±14% and 31±9%, respectively (p= 0.01). The impact on relapse rate of disease state at time of transplantation was observed both in patients transplanted from a relative and, even though less evident, in recipients of unrelated UCBT. The increased probability of leukemia recurrence observed in patients given UCBT later in the course of the disease is not surprising given that disease status has been reported to be the most important factor influencing the risk of relapse, irrespective of the source of progenitors (bone marrow, peripheral blood or cord blood) and the type of donor (HLA-compatible relative, partiallymatched family donor or unrelated volunteer) employed. 22-25 Even though a formal, wellmatched comparison between the relapse rate of UCBT patients and that observed after marrow transplantation from related or unrelated donors was not performed, the outcome of good-risk children appears to be comparable to haematologica vol. 85(supplement to n. 11):November 2000
Page 1 and 2: Haematologica established in 1920 e
Page 3 and 4: haematologica Journal of Hematology
Page 5 and 6: 3 Table 1. Indications for allogene
Page 7 and 8: 5 ease-free survival for childhood
Page 9 and 10: 7 Allogeneic bone marrow transplant
Page 11 and 12: haematologica 2000; 85(supplement t
Page 13 and 14: 11 achieved. However the relapse ra
Page 15 and 16: 13 ease. This observation is confir
Page 17 and 18: 15 plant failure. The role of DLI i
Page 19 and 20: 17 non-myeloablative regimen. Blood
Page 21 and 22: apheretic products obtained after m
Page 23 and 24: 21 Kinetics of activation of CFC in
Page 25 and 26: 23 according to the flow cytometric
Page 27: 25 mal cell activators and inhibito
Page 31 and 32: 29 15 from activated cord versus ad
Page 33 and 34: 31 reported on the initial experien
Page 35 and 36: 33 Table 5. Timing and causes of tr
Page 37 and 38: 35 of children with storage disorde
Page 41 and 42: 39 parents wishes (the patient was
Page 45 and 46: 43 washing the cell suspension and
Page 47 and 48: 45 tive selection is usually around
Page 51 and 52: 49 chemotherapy blocks has been adm
Page 53 and 54: 51 Recently some clinical studies h
Page 55 and 56: 53 lymphoblastic leukaemia in Italy
Page 57 and 58: 55 Table 1. Summary of clinical dat
Page 59 and 60: 57 HLA-restricted cytomegalovirus (
Page 61 and 62: 59 that short-term artificial nutri
Page 63 and 64: 61 chain triglycerides in total par
Page 65 and 66: 63 1 2 3 4 5 Figure 1. Answers to t
Page 67 and 68: 65 References 1. Clarke DE, Raffin
Page 69 and 70: 67 therapy including colony-stimula
Page 71 and 72: 69 platin-thiotepa-etoposide is 34%
Page 75 and 76: 73 Multiple sclerosis MS is charact
Page 77 and 78: 75 Special Issues Conditioning The
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79 treatment of poor risk systemic
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haematologica 2000; 85(supplement t
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85 ly in terms of steroid-sparing a
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haematologica 2000; 85(supplement t
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91 patients, 10 with a systemic for
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