Year: 2012
Type: article
Abstract: Allogeneic Hematopoietic Cell Transplantation in Sickle Cells Disease: When and HowJohn F. TisdaleThe first successful hematopoietic stem cell transplantation (HSCT) in a patient with sickle cell disease (SCD) was reported in 1984 in a pediatric patient with coexisting acute myelogenous leukemia [1Johnson F.L. Look A.T. Gockerman J. et al.Bone-marrow transplantation in a patient with sickle-cell anemia.N Engl J Med. 1984; 311: 780-783Crossref PubMed Scopus (229) Google Scholar] and established the curative potential of this approach. Myeloablative conditioning with busulfan and cyclophosphamide followed by human leukocyte antigen (HLA)-matched marrow infusion was later successfully used in Europe [2Vermylen C. Cornu G. Ferster A. et al.Bone marrow transplantation in sickle cell disease: the Belgian experience.Bone Marrow Transplant. 1993; 12: 116-117PubMed Google Scholar, 3Bernaudin F. Souillet G. Vannier J.P. et al.Bone marrow transplantation (BMT) in 14 children with severe sickle cell disease (SCD): the French experience. GEGMO.Bone Marrow Transplant. 1993; 12: 118-121PubMed Google Scholar] and the United States [4Walters M.C. Patience M. Leisenring W. et al.Bone marrow transplantation for sickle cell disease.N Engl J Med. 1996; 335: 369-376Crossref PubMed Scopus (492) Google Scholar] as primary treatment for severe SCD in children without an underlying malignancy. Antithymocyte globulin was subsequently added to decrease the risk of graft rejection in this frequently alloimmunized population [4Walters M.C. Patience M. Leisenring W. et al.Bone marrow transplantation for sickle cell disease.N Engl J Med. 1996; 335: 369-376Crossref PubMed Scopus (492) Google Scholar]. Although indications for transplant have remained controversial in the pediatric setting, in 1 series patients were divided into 2 groups to reflect their access to care: those in Europe with access to care in whom severity criteria were used and those in Africa where access to such care is limited. In the second group the only indication was SCD, and disease severity criteria were not used. Although overall results were favorable, the best results were seen in the second group, suggesting that transplantation before complications are observed produces better outcomes [5Vermylen C. Cornu G. Ferster A. et al.Haematopoietic stem cell transplantation for sickle cell anaemia: the first 50 patients transplanted in Belgium.Bone Marrow Transplant. 1998; 22: 1-6Crossref PubMed Scopus (234) Google Scholar]. The most recent results reported in 2007 demonstrate that with the addition of antithymocyte globulin, rejection rates decreased from 22.6% to 3% and event-free survival rates rose to 95.3% among those undergoing transplantation after January 2000. These results establish HLA-matched transplants using myeloablative conditioning as the standard of care for eligible pediatric patients with SCD. Now, hundreds of affected pediatric subjects have undergone fully myeloablative allogeneic HSCT with favorable results.Although these results in children are encouraging, procedural toxicities that increase with advancing age have limited this approach to pediatric patients. The ability to achieve engraftment of allogeneic HSCs without myleoablative conditioning prompted many to consider this strategy in nonmalignant disorders as increased safety was assumed, potentially allowing application to older patients and patients with comorbidities. In many such studies, prompt myeloid engraftment was observed in all yet appeared to result from a donor T cell–mediated alloimmune response that was associated with significant rates of graft-versus-host disease (GVHD) driving both morbidity and mortality [6Childs R. Clave E. Contentin N. et al.Engraftment kinetics after nonmyeloablative allogeneic peripheral blood stem cell transplantation: full donor T-cell chimerism precedes alloimmune responses.Blood. 1999; 94: 3234-3241PubMed Google Scholar]. Furthermore, early studies attempting nonmyeloablative transplantation in SCD proved unsuccessful [7Iannone R. Casella J.F. Fuchs E.J. et al.Results of minimally toxic nonmyeloablative transplantation in patients with sickle cell anemia and beta-thalassemia.Biol Blood Marrow Transplant. 2003; 9: 519-528Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar]. Others began to explore reduced-intensity conditioning, which often contained agents that were ablative at near ablative doses, with improved success [8Krishnamurti L. Kharbanda S. Biernacki M.A. et al.Stable long-term donor engraftment following reduced-intensity hematopoietic cell transplantation for sickle cell disease.Biol Blood Marrow Transplant. 2008; 14: 1270-1278Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar]. Based on rapamycin's ability to promote T cell tolerance even when T cells are stimulated in the presence of costimulation [9Powell J.D. Lerner C.G. Schwartz R.H. Inhibition of cell cycle progression by rapamycin induces T cell clonal anergy even in the presence of costimulation.J Immunol. 1999; 162: 2775-2784PubMed Google Scholar] both in vitro and in vivo [10Powell J.D. Fitzhugh C. Kang E.M. et al.Low-dose radiation plus rapamycin promotes long-term bone marrow chimerism.Transplantation. 2005; 80: 1541-1545Crossref PubMed Scopus (31) Google Scholar], a clinical trial testing this approach was initiated in severely affected adults. The primary endpoint of the study was the proportion of patients with stable engraftment, with the incidence of GVHD as a secondary endpoint. HLA-identical relatives underwent granulocyte colony-stimulating factor mobilization, and these unmanipulated HSCs were infused after conditioning with alemtuzumab 1 mg/kg total, given over 5 days; a single dose of 300 cGy total body irradiation; and oral sirolimus (rapamycin) initiated on day –1. Stable mixed chimerism and disease reversion was observed in 9 of the first 10 patients treated [11Hsieh M.M. Kang E.M. Fitzhugh C.D. et al.Allogeneic hematopoietic stem-cell transplantation for sickle cell disease.N Engl J Med. 2009; 361: 2309-2317Crossref PubMed Scopus (317) Google Scholar]. Additionally, no GVHD was observed among engrafted patients. Expansion of the cohort to now 25 patients has resulted in similar rates of engraftment, with 22 of 25 patients disease-free again in the absence of GVHD. These data support mixed chimerism as a suitable goal for HSC transplantation in SCD.The success of this regimen provides indirect evidence for graft-specific tolerance, opening the possibility of expanding to alternative donor sources. Indeed, the main limitation has been a lack of HLA-matched sibling donors in most patients with SCD. To determine availability of alternative donor sources, 10 patients who met all study criteria on full screening for sibling-matched HSCT but who did not have a suitable donor were selected for alternative donor searching in the National Marrow Donor Program and Bone Marrow Donors Worldwide. Whereas 7 of 10 had a potential 6/6 matched unrelated donor, only 1 of 7 had a greater than 1% probability of having a 6/6 HLA match according to Haplogic. When cord blood units were searched, 9 of 10 had at least one 4/6 cord blood match identified (≥1.5 × 107 total nucleated cells/kg body weight and ABO matched). When higher degrees of matching (5/6) and higher cell doses were queried (2.5 × 107 total nucleated cells/kg body weight and ABO matched), only 2 patients had a suitable cord product (Hsieh, M. 2012; personal communication).Thus, nonmyeloablative haploidentical HSCT strategies are currently being explored because they appear to be the only current reliably obtainable stem cell source. Although extension of the low-dose total body irradiation–Campath–rapamycin approach may be feasible in the haploidentical setting, additional methods aimed at reducing the risk of both rejection and GVHD will likely be required. Cyclophosphamide given from 2 to 3 days after bone marrow transplantation has been shown to facilitate engraftment and prevent the development of GVHD by targeting activated lymphocytes. Recently, 14 individuals with SCD who received nonmyeloablative haploidentical bone marrow transplantation using postgraft cyclophosphamide were reported, with engraftment in about half of the subjects. Although higher rates of engraftment are desirable, these results are encouraging because they were achieved in the absence of significant GVHD and no mortality was seen [12Bolanos-Meade J. Fuchs E.J. Luznik L. et al.HLA-haploidentical bone marrow transplantation with posttransplant cyclophosphamide expands the donor pool for patients with sickle cell disease.Blood. 2012; 120: 4285-4291Crossref PubMed Scopus (329) Google Scholar]. Additionally, a haploidentical protocol using total body irradiation–Campath–rapamycin has also recently opened to accrual at the National Institutes of Health. The study is designed as a dose escalation study testing postgraft cyclophosphamide and accrual is ongoing.In summary, HSCT for patients with SCD is highly effective, reversing the phenotype even when low levels of donor engraftment are achieved with newer, less toxic regimens. Results in children with myeloablative conditioning in the current era suggest that this therapy is underutilized. Future well-designed studies testing nonmyeloablative conditioning regimens and alternative donor sources are poised to expand the application of the approach and lead the field in immune tolerance. Continued efforts to develop allogeneic transplantation for SCD, with the goal of maximizing engraftment rates while minimizing morbidity and mortality, are indeed justified.Choice of Alternative Donors for Aplastic AnemiaMary EapenTreatments for aplastic anemia include immune suppressive therapy (IST) with antithymocyte globulin (ATG), which lyses lymphocytes; cyclosporine, which blocks T lymphocyte function; and hematopoietic stem cell transplantation (HSCT), which replaces all hematopoietic progenitor cells, including lymphopoietic cells [1Young N.S. Bacigalupo A. Marsh J.C. Aplastic anemia: pathophysiology and treatment.Biol Blood Marrow Transplant. 2010; 16: S119-S125Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar]. There is general agreement that, when a human leukocyte antigen (HLA)-matched sibling is available, HSCT is first-line treatment for most patients with severe aplastic anemia (SAA). Conversely, IST is used as first-line therapy for patients who do not have an HLA-matched sibling and must seek an alternative donor [2Deeg H.J. O'Donnell M. Tolar J. et al.Optimization of conditioning for marrow transplantation from unrelated donors for patients with aplastic anemia after failure of immunosuppressive therapy.Blood. 2006; 108: 1485-1491Crossref PubMed Scopus (144) Google Scholar]. Whether alternative donor HSCT should be performed after failing one or more than one course of IST is uncertain and depends, in part, on patient factors predicting the likelihood of further response to IST and the likelihood of good outcome with HSCT, as well as timely availability of a suitable donor.Unrelated Adult Donor TransplantationUnrelated donor transplantation is an effective therapy for SAA but is limited by the availability of a suitably matched unrelated donor and is associated with higher risks of graft failure, graft-versus-host disease, and mortality than HLA-matched sibling transplantation. Selecting an appropriately matched donor for HSCT is an important component of success. Several groups have attempted to compare outcomes of transplantation for aplastic anemia using 8/8 HLA-matched children and with aplastic anemia undergoing transplantation and with unrelated donor bone marrow mortality risks were after HLA-matched transplants M. J. et of unrelated donor stem cell transplantation for children with severe aplastic J 2008; PubMed Scopus Google Scholar]. of overall survival were after 8/8 HLA-matched transplants with after HLA-matched transplants M. J. et of unrelated donor stem cell transplantation for children with severe aplastic J 2008; PubMed Scopus Google Scholar]. In survival after 8/8 HLA-matched unrelated donor bone marrow transplantation was higher at M. J. et of stem cell on outcomes after unrelated donor transplantation in severe aplastic Scopus Google Scholar]. In that survival rates were after peripheral blood stem cell transplantation. These support bone marrow as the graft when unrelated donor transplantation. in transplantation strategies including of donors have resulted in in survival after unrelated donor transplantation before before and now the absence of a suitably matched unrelated donor, cord blood has been used as an alternative from and the Blood suggest survival of about In addition to HLA and the less than cell dose in is likely that in the for survival is because these are often for patients who have of To are no of outcomes after a second course of IST and unrelated donor donor transplants have higher rates of graft failure, and graft-versus-host disease than HLA-matched sibling even when the donor and are 8/8 HLA donor performed in the and doses of total body to prevent graft regimens are associated with severe acute and secondary to early and secondary recent transplant conditioning regimens have used doses of in with cyclophosphamide and and H.J. G. G. et after marrow transplantation for aplastic anemia and anemia: a and of results in 1996; Google Scholar] identified cGy of as a single dose with cyclophosphamide and as the regimen in a radiation dose graft failure in of patients and survival was 3 or and decreased with of the was an important of the probability of overall survival in patients was with in older patients the dose of had no on graft at the dose of cyclophosphamide mixed recent from an clinical trial in the United States mortality in the cyclophosphamide 9 or mg/kg regimen and graft failure when cyclophosphamide was from the regimen J. H.J. S. et conditioning for marrow transplantation from unrelated donors in severe aplastic anemia: early results of a cyclophosphamide dose study at cyclophosphamide dose Blood Marrow Transplant. 2012; Full Text Full Text PDF PubMed Scopus Google Scholar]. to the cyclophosphamide mg/kg and 50 mg/kg regimen and the trial is to accrual early in of more HLA-matched unrelated donors and the of transplant conditioning regimens have had a significant on survival after transplantation for Bone marrow is the graft source. The of transplantation in patients without an HLA-matched donor further Cell Transplantation for is a disease to be by that the and and as well as in and In most the of the disease is by with or without in an of by clinical is by by T and to the component more the less and more often and to this the clinical is by including and and a more A. A. 2008; Full Text Full Text PDF PubMed Scopus Google is both clinical and of have been to the clinical according to the most is the from to 10 of the is as an increase of the after 3 to has the most important in and for a of the of is on that in include a of associated with acute and a of of or is by decreased for include for the treatment of acute and to the of decrease their and the progression of no has been shown to long-term a of patients an clinical at the associated with a response to is this group of patients those failing and clinical for which treatment are hematopoietic stem cell transplantation (HSCT) has been with over the in the treatment of severe that the of standard The is both from and from the of of transplants for indications and a HSCT for has been used G. R. stem-cell transplantation in 2008; Full Text Full Text PDF PubMed Scopus Google Scholar, Hematopoietic for the treatment of Marrow Transplant. 2010; PubMed Scopus Google Scholar] and patients have been treated who are in the of the for Blood and Marrow Transplantation or the for Blood and Marrow HSCT results in a of the immune A. et a and after stem cell transplantation in Med. 2005; PubMed Scopus Google Scholar] and in a of as by R. A. et HSCT for severe in a on disease and of 2005; PubMed Scopus Google Scholar]. patients were in or to and no data are currently from clinical response was reported in most of the studies, the outcome being favorable in patients transplanted in the an at the series and about the outcome in of support the of HSCT in patients with In a was reported more frequently in patients over patients M. et stem cell transplantation with an conditioning regimen in the 2012; PubMed Scopus Google blood stem cells are well in with the of granulocyte colony-stimulating factor and without results in a incidence of disease and must be by the of conditioning including busulfan or total body were not shown to result in a more of the disease S. et hematopoietic cell transplantation for a PubMed Scopus Google Scholar]. regimens and antithymocyte a low but a higher incidence of et stem cell transplantation in a 2009; Full Text Full Text PDF PubMed Scopus Google Scholar]. plus antithymocyte globulin is the most regimen reported to the a of and J. R. M. et al.Haematopoietic (HSCT) in severe of the for Blood and Marrow Transplantation Marrow Transplant. 2012; PubMed Scopus Google Scholar]. mortality from from to to from to to a better patient and the of conditioning for HSCT in have been recently by the J. R. M. et al.Haematopoietic (HSCT) in severe of the for Blood and Marrow Transplantation Marrow Transplant. 2012; PubMed Scopus Google Scholar] in of the clinical outcomes reported in the The patient for HSCT is one who is in the and both and with an patients should only be when is of in the or by of in in the the and reported in and studies that an to survival at 3 from HSCT is in to in on patients that of transplanted in the were stable or improved at a of after HSCT R. C. et stem cell transplantation for of the for Blood and Marrow Transplantation 2006; 12: PubMed Scopus Google Scholar]. is a disease and of long-term outcome is to evidence of of data from patients with a and is currently trial is also in R. et trial of stem cell transplantation for a 2012; PubMed Scopus Google Scholar]. F. The first successful hematopoietic stem cell transplantation (HSCT) in a patient with sickle cell disease (SCD) was reported in 1984 in a pediatric patient with coexisting acute myelogenous leukemia [1Johnson F.L. Look A.T. Gockerman J. et al.Bone-marrow transplantation in a patient with sickle-cell anemia.N Engl J Med. 1984; 311: 780-783Crossref PubMed Scopus (229) Google Scholar] and established the curative potential of this approach. Myeloablative conditioning with busulfan and cyclophosphamide followed by human leukocyte antigen (HLA)-matched marrow infusion was later successfully used in Europe [2Vermylen C. Cornu G. Ferster A. et al.Bone marrow transplantation in sickle cell disease: the Belgian experience.Bone Marrow Transplant. 1993; 12: 116-117PubMed Google Scholar, 3Bernaudin F. Souillet G. Vannier J.P. et al.Bone marrow transplantation (BMT) in 14 children with severe sickle cell disease (SCD): the French experience. GEGMO.Bone Marrow Transplant. 1993; 12: 118-121PubMed Google Scholar] and the United States [4Walters M.C. Patience M. Leisenring W. et al.Bone marrow transplantation for sickle cell disease.N Engl J Med. 1996; 335: 369-376Crossref PubMed Scopus (492) Google Scholar] as primary treatment for severe SCD in children without an underlying malignancy. Antithymocyte globulin was subsequently added to decrease the risk of graft rejection in this frequently alloimmunized population [4Walters M.C. Patience M. Leisenring W. et al.Bone marrow transplantation for sickle cell disease.N Engl J Med. 1996; 335: 369-376Crossref PubMed Scopus (492) Google Scholar]. Although indications for transplant have remained controversial in the pediatric setting, in 1 series patients were divided into 2 groups to reflect their access to care: those in Europe with access to care in whom severity criteria were used and those in Africa where access to such care is limited. In the second group the only indication was SCD, and disease severity criteria were not used. Although overall results were favorable, the best results were seen in the second group, suggesting that transplantation before complications are observed produces better outcomes [5Vermylen C. Cornu G. Ferster A. et al.Haematopoietic stem cell transplantation for sickle cell anaemia: the first 50 patients transplanted in Belgium.Bone Marrow Transplant. 1998; 22: 1-6Crossref PubMed Scopus (234) Google Scholar]. The most recent results reported in 2007 demonstrate that with the addition of antithymocyte globulin, rejection rates decreased from 22.6% to 3% and event-free survival rates rose to 95.3% among those undergoing transplantation after January 2000. These results establish HLA-matched transplants using myeloablative conditioning as the standard of care for eligible pediatric patients with SCD. Now, hundreds of affected pediatric subjects have undergone fully myeloablative allogeneic HSCT with favorable Although these results in children are encouraging, procedural toxicities that increase with advancing age have limited this approach to pediatric patients. The ability to achieve engraftment of allogeneic HSCs without myleoablative conditioning prompted many to consider this strategy in nonmalignant disorders as increased safety was assumed, potentially allowing application to older patients and patients with comorbidities. In many such studies, prompt myeloid engraftment was observed in all yet appeared to result from a donor T cell–mediated alloimmune response that was associated with significant rates of graft-versus-host disease (GVHD) driving both morbidity and mortality [6Childs R. Clave E. Contentin N. et al.Engraftment kinetics after nonmyeloablative allogeneic peripheral blood stem cell transplantation: full donor T-cell chimerism precedes alloimmune responses.Blood. 1999; 94: 3234-3241PubMed Google Scholar]. Furthermore, early studies attempting nonmyeloablative transplantation in SCD proved unsuccessful [7Iannone R. Casella J.F. Fuchs E.J. et al.Results of minimally toxic nonmyeloablative transplantation in patients with sickle cell anemia and beta-thalassemia.Biol Blood Marrow Transplant. 2003; 9: 519-528Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar]. Others began to explore reduced-intensity conditioning, which often contained agents that were ablative at near ablative doses, with improved success [8Krishnamurti L. Kharbanda S. Biernacki M.A. et al.Stable long-term donor engraftment following reduced-intensity hematopoietic cell transplantation for sickle cell disease.Biol Blood Marrow Transplant. 2008; 14: 1270-1278Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar]. Based on rapamycin's ability to promote T cell tolerance even when T cells are stimulated in the presence of costimulation [9Powell J.D. Lerner C.G. Schwartz R.H. Inhibition of cell cycle progression by rapamycin induces T cell clonal anergy even in the presence of costimulation.J Immunol. 1999; 162: 2775-2784PubMed Google Scholar] both in vitro and in vivo [10Powell J.D. Fitzhugh C. Kang E.M. et al.Low-dose radiation plus rapamycin promotes long-term bone marrow chimerism.Transplantation. 2005; 80: 1541-1545Crossref PubMed Scopus (31) Google Scholar], a clinical trial testing this approach was initiated in severely affected adults. The primary endpoint of the study was the proportion of patients with stable engraftment, with the incidence of GVHD as a secondary endpoint. HLA-identical relatives underwent granulocyte colony-stimulating factor mobilization, and these unmanipulated HSCs were infused after conditioning with alemtuzumab 1 mg/kg total, given over 5 days; a single dose of 300 cGy total body irradiation; and oral sirolimus (rapamycin) initiated on day –1. Stable mixed chimerism and disease reversion was observed in 9 of the first 10 patients treated [11Hsieh M.M. Kang E.M. Fitzhugh C.D. et al.Allogeneic hematopoietic stem-cell transplantation for sickle cell disease.N Engl J Med. 2009; 361: 2309-2317Crossref PubMed Scopus (317) Google Scholar]. Additionally, no GVHD was observed among engrafted patients. Expansion of the cohort to now 25 patients has resulted in similar rates of engraftment, with 22 of 25 patients disease-free again in the absence of GVHD. These data support mixed chimerism as a suitable goal for HSC transplantation in SCD. The success of this regimen provides indirect evidence for graft-specific tolerance, opening the possibility of expanding to alternative donor sources. Indeed, the main limitation has been a lack of HLA-matched sibling donors in most patients with SCD. To determine availability of alternative donor sources, 10 patients who met all study criteria on full screening for sibling-matched HSCT but who did not have a suitable donor were selected for alternative donor searching in the National Marrow Donor Program and Bone Marrow Donors Worldwide. Whereas 7 of 10 had a potential 6/6 matched unrelated donor, only 1 of 7 had a greater than 1% probability of having a 6/6 HLA match according to Haplogic. When cord blood units were searched, 9 of 10 had at least one 4/6 cord blood match identified (≥1.5 × 107 total nucleated cells/kg body weight and ABO matched). When higher degrees of matching (5/6) and higher cell doses were queried (2.5 × 107 total nucleated cells/kg body weight and ABO matched), only 2 patients had a suitable cord product (Hsieh, M. 2012; personal nonmyeloablative haploidentical HSCT strategies are currently being explored because they appear to be the only current reliably obtainable stem cell source. Although extension of the low-dose total body irradiation–Campath–rapamycin approach may be feasible in the haploidentical setting, additional methods aimed at reducing the risk of both rejection and GVHD will likely be required. Cyclophosphamide given from 2 to 3 days after bone marrow transplantation has been shown to facilitate engraftment and prevent the development of GVHD by targeting activated lymphocytes. Recently, 14 individuals with SCD who received nonmyeloablative haploidentical bone marrow transplantation using postgraft cyclophosphamide were reported, with engraftment in about half of the subjects. Although higher rates of engraftment are desirable, these results are encouraging because they were achieved in the absence of significant GVHD and no mortality was seen [12Bolanos-Meade J. Fuchs E.J. Luznik L. et al.HLA-haploidentical bone marrow transplantation with posttransplant cyclophosphamide expands the donor pool for patients with sickle cell disease.Blood. 2012; 120: 4285-4291Crossref PubMed Scopus (329) Google Scholar]. Additionally, a haploidentical protocol using total body irradiation–Campath–rapamycin has also recently opened to accrual at the National Institutes of Health. The study is designed as a dose escalation study testing postgraft cyclophosphamide and accrual is In summary, HSCT for patients with SCD is highly effective, reversing the phenotype even when low levels of donor engraftment are achieved with newer, less toxic regimens. Results in children with myeloablative conditioning in the current era suggest that this therapy is underutilized. Future well-designed studies testing nonmyeloablative conditioning regimens and alternative donor sources are poised to expand the application of the approach and lead the field in immune tolerance. Continued efforts to develop allogeneic transplantation for SCD, with the goal of maximizing engraftment rates while minimizing morbidity and mortality, are indeed for aplastic anemia include immune suppressive therapy (IST) with antithymocyte globulin (ATG), which lyses lymphocytes; cyclosporine, which blocks T lymphocyte function; and hematopoietic stem cell transplantation (HSCT), which replaces all hematopoietic progenitor cells, including lymphopoietic cells [1Young N.S. Bacigalupo A. Marsh J.C. Aplastic anemia: pathophysiology and treatment.Biol Blood Marrow Transplant. 2010; 16: S119-S125Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar]. There is general agreement that, when a human leukocyte antigen (HLA)-matched sibling is available, HSCT is first-line treatment for most patients with severe aplastic anemia (SAA). Conversely, IST is used as first-line therapy for patients who do not have an HLA-matched sibling and must seek an alternative donor [2Deeg H.J. O'Donnell M. Tolar J. et al.Optimization of conditioning for marrow transplantation from unrelated donors for patients with aplastic anemia after failure of immunosuppressive therapy.Blood. 2006; 108: 1485-1491Crossref PubMed Scopus (144) Google Scholar]. Whether alternative donor HSCT should be performed after failing one or more than one course of IST is uncertain and depends, in part, on patient factors predicting the likelihood of further response to IST and the likelihood of good outcome with HSCT, as well as timely availability of a suitable donor transplantation is an effective therapy for SAA but is limited by the availability of a suitably matched unrelated donor and is associated with higher risks of graft failure, graft-versus-host disease, and mortality than HLA-matched sibling transplantation. Selecting an appropriately matched donor for HSCT is an important component of success. Several groups have attempted to compare outcomes of transplantation for aplastic anemia using 8/8 HLA-matched children and with aplastic anemia undergoing transplantation and with unrelated donor bone marrow mortality risks were after HLA-matched transplants M. J. et of unrelated donor stem cell transplantation for children with severe aplastic J 2008; PubMed Scopus Google Scholar]. of overall survival were after 8/8 HLA-matched transplants with after HLA-matched transplants M. J. et of unrelated donor stem cell transplantation for children with severe aplastic J 2008; PubMed Scopus Google Scholar]. In survival after 8/8 HLA-matched unrelated donor bone marrow transplantation was higher at M. J. et of stem cell on outcomes after unrelated donor transplantation in severe aplastic Scopus Google Scholar]. In that survival rates were after peripheral blood stem cell transplantation. These support bone marrow as the graft when unrelated donor transplantation. in transplantation strategies including of donors have resulted in in survival after unrelated donor transplantation before before and now In the absence of a suitably matched unrelated donor, cord blood has been used as an alternative from and the Blood suggest survival of about In addition to HLA and the less than cell dose in is likely that in the for survival is because these are often for patients who have of To are no of outcomes after a second course of IST and unrelated donor Alternative donor transplants have higher rates of graft failure, and graft-versus-host disease than HLA-matched sibling even when the donor and are 8/8 HLA donor performed in the and doses of total body to prevent graft regimens are associated with severe acute and secondary to early and secondary recent transplant conditioning regimens have used doses of in with cyclophosphamide and and H.J. G. G. et after marrow transplantation for aplastic anemia and anemia: a and of results in 1996; Google Scholar] identified cGy of as a single dose with cyclophosphamide and as the regimen in a radiation dose graft failure in of patients and survival was 3 or and decreased with of the was an important of the probability of overall survival in patients was with in older patients the dose of had no on graft at the dose of cyclophosphamide mixed recent from an clinical trial in the United States mortality in the cyclophosphamide 9 or mg/kg regimen and graft failure when cyclophosphamide was from the regimen J. H.J. S. et conditioning for marrow transplantation from unrelated donors in severe aplastic anemia: early results of a cyclophosphamide dose study at cyclophosphamide dose Blood Marrow Transplant. 2012; Full Text Full Text PDF PubMed Scopus Google Scholar]. to the cyclophosphamide mg/kg and 50 mg/kg regimen and the trial is to accrual early in The of more HLA-matched unrelated donors and the of transplant conditioning regimens have had a significant on survival after transplantation for Bone marrow is the graft source. The of transplantation in patients without an HLA-matched donor further
Authors: John F. Tisdale, Mary Eapen, Riccardo Saccardi
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,650
OpenAlex ID: W1983095347