Family Donor Transplantation Research Articles

Stem Cell Transplantation for Congenital Dyserythropoietic Anemia. a Retrospective Study on Behalf of Severe Aplastic Anemia Working Party of the European Blood and Marrow Transplantation Group (EBMT)

INTRODUCTIONCongenital Dyserythropoietic Anemias (CDA) are a group of heterogeneous bone marrow disorders characterized by anemia, ineffective erythropoiesis and specific cytomorphological features involving bone marrow late erythroblasts. Patients may also show some dysmorphisms involving fingers and nails. In the last few years genetic mutation explaining most cases of CDA have been identified.The management of the disease is generally limited to blood transfusion and iron chelation. Some report have shown the efficacy of stem cell transplantation (SCT) as the only curative option for this disease, however data from literature is scarce and limited to a very small number of casesIn this retrospective study we describe the outcome of Stem Cell Transplantation in patients with CDA reported in the EBMT data base.PATIENTS AND METHODSThe study was conducted on behalf of Severe Aplastic Anemia Working Party (SAAWP) of the EBMT and was based on data of patients affected with CDA who underwent SCT and registered in the EBMT Data Base. Clinical information of the disease and details on transplant procedures and follow-up were collected by a specific form distributed to Centres participating in the study.RESULTSBetween 1996-2016, 39 patients (22 males-17 females) whose median age was 5.1 yo (range 0.9-38.2) underwent SCT from matched sibling donor (20, 51%), unrelated donor (17, 44%) or from other relatives (2, 5%) using bone marrow (30, 77%), peripheral blood (7, 18%) or cord blood (2, 5%) as cell source. All patients but one received a myeloblative regimen. Patients' characteristics and transplants outcome details are shown in Table 1. Median days to neutrophils and platelets engraftment were 21 and 34, respectively. Secondary graft failure occurred in 8 patients (20%). Median follow-up was 44 months (range 13-71). Overall survival at 36 months was 70%. Patients who were transplanted with iron overload and who were transplanted from unrelated donor had a significantly inferior outcome (36 month OS: 51% vs 92%, p =0.05 and 45% vs 90%, p 0.007, respectively).CONCLUSIONTo the best of our knowledge, this is the largest reported cohort of patients transplanted for CDA showing that family donor transplants have a better outcome and that iron overload negatively affects the procedure as reported in other red cell disorders. [Display omitted] DisclosuresPeffault De Latour:Amgen: Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding.

An Antithymocyte Globulin-Free Conditioning Regimen Using Fludarabine and Cyclophosphamide Is Associated with Good Outcomes in Patients Undergoing Matched Related Family Donor Transplantation for Aplastic Anemia

Allogeneic hematopoietic stem cell transplantation (HSCT) using fludarabine (Flu)-based conditioning regimens are being increasingly being used in patients with aplastic anemia (AA). We describe an antithymocyte globulin (ATG)-free conditioning regimen consisting of Flu and cyclophosphamide (Cy) in patients undergoing matched related donor (MRD) HSCT for AA. Between 2004 and 2019, 212 patients underwent MRD HSCT using Flu (30 mg/m2/day for 6 days) and Cy (60 mg/kg/day for 2 days) for conditioning. The graft source was peripheral blood stem cells in all patients. Graft-versus-host disease (GVHD) prophylaxis consisted mainly of cyclosporine and methotrexate, although 41 patients received post-transplantation Cy as part of a study. Engraftment occurred in 91% of patients at a median of 16 days, whereas 4 patients (1.8%) experienced primary graft failure and 15 (7.1%) died before achieving engraftment. Toxicity was minimal. The incidence of grade II-IV acute GVHD (aGVHD) was 27.9%, and that of grade III-IV aGVHD was 11.3%. Chronic GVHD occurred in 41.6%. 80% were free of immunosuppression at 60 months and long-term complications were seen in 8.4%. At a median of 46 months, 158 patients were alive and well, with a 5-year overall survival (OS) of 75.3 ± 3.0%. The 5-year OS was 80.6 ± 4.1% for patients age <20 years (n=93), 74.5 ± 4.6% for those age 20 to 40 years (n=91), and 59.7 ± 9.5% for those age >40 years (n=28) (P=.11). Patients classified as low risk had better OS compared with those at high risk (93.2 ± 2.9% versus 65.7 ± 4.1%; P=.000). Factors affecting OS on multivariate analysis included aGVHD (P=.02) and graft failure (P=.000). This large series using Flu/Cy for conditioning before MRD HSCT confirms good outcomes in patients with AA, with excellent outcomes in low-risk patients. Suitable modifications are needed to improve outcomes in high-risk patients.

Haploidentical Stem Cell Transplantation with Post-Transplant Cyclophosphamide for Primary Immune Deficiency Disorders in Children: Challenges and Outcome from a Tertiary Care Center in South India.

Haploidentical stem cell transplantation (haplo SCT) has emerged as an acceptable alternative to matched family donor transplantation for children diagnosed to have primary immune deficiency disorders (PIDs). We present data over 4 years on the challenges and efficacy of unmanipulated T cell replete haplo SCTs with post-transplant cyclophosphamide (PTCy) in children diagnosed to have PIDs. We performed a retrospective study in the pediatric blood and marrow transplantation unit where all children less than 18 years of age diagnosed to have PIDs and who underwent haplo SCT with PTCy from January 2014 to February 2018 were included in the study. Of the 16 transplants included in the study, 5 children were diagnosed to have Wiskott-Aldrich syndrome, 3 with congenital hemophagocytic lymphohistiocytosis, 2 each with Griscelli syndrome and Mendelian susceptibility to mycobacterial diseases, and one each with Chediak-Higashi syndrome, ORAI 1 mutation immune deficiency, severe combined immune deficiency, and Hyper IgM syndrome. The source of stem cells was PBSC in 62.5% and bone marrow in 32.5%. Engraftment by day 16–21 post hematopoietic stem cell transplantation was achieved in 75% transplants with 91% of these remaining in sustained complete chimerism. Acute skin and gut graft versus host disease of grade 2–3 were noted in 50% transplants and cytomegalovirus (CMV) reactivation in 43.7% transplants. One child with congenital HLH succumbed to refractory CMV, adenovirus, and BK virus infection. Cytokine release syndrome (CRS) was noted in 75% transplants with 2 children succumbing to the illness. Tocilizumab was successfully used early in one child. Overall mortality was found to be 37.5% with overall survival of 62.5% with a median follow-up of 23.3 months. In resource limited settings, PTCy has the potential to provide a cost-effective advantage in terms of accessibility of this curative procedure among children with PIDs.

Long Term Maintenance of Hickman Catheter in Methicillin Resistant Staphylococcus Colonized Patients Undergoing Haploidentical HSCT: Results of a Prospective Study

Topic Significance & Study Purpose/Background/Rationale Long term maintenance of Hickman catheter [HC] following allogeneic transplantation is a nursing challenge particularly in those colonized with Methicillin Resistant Staphylococcus Aureus [MRSA] or Coagulase Negative Staphylococcus [MRCoNS]. We prospectively analyzed the feasibility of long-term maintenance of HC after haploidentical family donor transplantation in 67 patients colonized with MRSA or MRCoNS employing Chlorhexidine impregnated patch [CIP,BIOPATCH 44150]. Methods, Intervention, & Analysis Patients undergoing haploidentical transplantation were screened for MRSA/MRCoNS with weekly nasal & skin swabs before transplantation & weekly thereafter for four weeks. Colonized patients were initiated on eradication protocol with Mupirocin ointment & Chlorhexidine bath. The patients were nursed in a class 1000 room with 1:1 nursing. HC dressing was carried out every 5 th day as inpatient & weekly thereafter with CIP and transparent dressing. Planned removal of HC was carried out at 180 days. HC which were retained beyond this period were taken care of by the caregivers who was intensively trained for the same. We analysed the incidence of catheter related bloodstream infections (CRBSI) or Hickman Catheter associated soft tissue Infections [HCASTI] following transplantation until the removal of HC. Findings & Interpretation 67 patients [males: 43, females: 24; malignant ds: 50, non-malignant ds: 17] who were colonized with MRSA [N=42] & MRCoNS [N=25] underwent PTCy based Haploidentical transplantation. The median age of the cohort was 32 years (range 2-65); 26 of those were Discussion & Implications Our study shows that with meticulous nursing coupled with intensive education of the patients & caregivers, long term maintenance of HC is possible without CRBSI or HCASTI. Employment of rigorous eradication program and application of Chlorhexidine based approach in HC dressing helped in minimizing the adverse impact of MRSA colonization on transplantation outcome with long term use of HC.

Outcomes Following Allogeneic Stem Cell Transplantation Using Non-sibling Family Donors.

For patients requiring allogeneic stem cell transplant, in the absence of a HLA-matched sibling, an extended donor search within the family may yield a suitable donor especially in societies with a high prevalence of consanguinity. We describe outcomes in transplants with non-sibling family donors, and compare outcomes with controls having a sibling donor transplant. Retrospective analysis of all matched related (non-sibling) donor transplants between 1995 and 2015. For comparison, appropriate age, sex and disease-matched patients were chosen from the sibling transplants (MSD) performed during the same time period (± 2years). Comparison between the fully matched non-sibling donor cohort and age, sex and disease-matched sibling donor transplants showed a significant increase in complications in the family donor group (viral infections, acute GVHD and rejection). Event-free survival and overall survival were significantly lower in the non-sibling donor cohort, and HLA disparity (1-2 antigen) further worsened the adverse impact. Though there was a significantly lower event-free and overall survival at 3years in the family donor cohort, this did not retain significance in the multivariate analysis. This data on allogeneic transplants using family donors showed higher complication rates and poorer outcomes. However in situations where financial constraints prevent access to matched unrelated donor sources, extended family searches may be fruitful in yielding a donor, and modifications in conditioning regimens and improvement in supportive care may help in improving the outcomes in family donor transplants.

Haploidentical Family Donor Transplantation: At the Crossroads of a Changing Paradigm.

The obvious advantage of haploidentical hematopoietic stem cell transplantation (HSCT) is that almost every patient who does not have HLA-identical donor or who urgently needs transplantation has at least one family member with whom to share one haplotype and who is promptly available as a donor. Over the past decade, haploidentical HSCT has spread to centers worldwide and several hundred patients have been treated even though significant variations on two main approaches have emerged over the past decade. Some centers have preferred an approach based on T cell depletion of G-CSF-mobilised peripheral blood progenitor cells (PBPCs); others have focused on manipulating the conditioning regimens and posttransplant immune suppression after the infusion of unmanipulated grafts.

In vivo T‐cell depletion using alemtuzumab in family and unrelated donor transplantation for pediatric non‐malignant disease achieves engraftment with low incidence of graft vs. host disease

In vivo T-cell depletion, using alemtuzumab therapy prior to SCT, can reduce the incidence of GVHD. This treatment has a potential to delay immune reconstitution resulting in increased morbidity due to viral illnesses. We retrospectively analyzed data on all pediatric patients with non-malignant disorders who received alemtuzumab-based conditioning regimens in our center over the last 10 yr (n = 91). Our data show an OS of 91.2%. The incidence of acute (grade 2-4) GVHD was 18.7% and that of chronic GVHD 5.5%. Viremia due to adenovirus, EBV and CMV was seen in 19.8%, 64.8% and 39.6% patients, respectively, with only two deaths attributed to viral infection (adenovirus). Chimerism level at three month was predictive of graft outcome. Nine patients, who had graft failure after first SCT, were salvaged with a second SCT using RIC and same donor (if available). Based on these results, we conclude that the use of in vivo T-cell depletion is safe, achieves good chimerism and does not lead to increased morbidity and mortality due to viral infections. It is associated with a reduced incidence of chronic GVHD.

HLA disparity is not crucial for the survival rate and severity of chronic health conditions in adult recipients following family donor hematopoietic stem cell transplantation.

The shortage of HLA-identical siblings or unrelated donors has restricted the application of hematopoietic stem cell transplantation (HSCT). Few studies have systematically assessed survival and chronic health conditions (CHCs) in the same cohort of patients after HLA-mismatched/haploidentical (mismatched) family donor transplantation. In the present study, we retrospectively analyzed the survival of 127 adult patients receiving either HLA-matched (71 cases) or HLA-mismatched (56 cases) family donor transplantation. Of 127 patients, 81 patients survived at least 2 years after HSCT and were still alive until the present investigation. We evaluated the CHCs in 76 survivors (41 matched and 35 mismatched). CHC-related information was scored according to the Bone Marrow Transplant Survivor Study questionnaire. There was no significant difference in overall survival or disease-free survival between HLA-matched and -mismatched transplant recipients. The CHCs were less severe in HLA-mismatched recipients than in matched cohorts. Multivariate analysis identified that age over 40 years at transplantation and presence of chronic graft-versus-host disease were independent risk factors for CHCs, while anti-thymocyte globulin-containing conditioning regimens might be protective. However, HLA disparity was not crucial for either the survival rate or CHCs. In conclusion, HLA-mismatched family donor transplantation can achieve comparable therapeutic effects to HLA-identical sibling transplantation.

Outcome of aplastic anemia in adolescence: a survey of the Severe Aplastic Anemia Working Party of the European Group for Blood and Marrow Transplantation.

We analyzed the outcome of 537 adolescents (age 12-18 years) with idiopathic aplastic anemia included in the database of the Severe Aplastic Anemia Working Party of the European Group for Blood and Marrow Transplantation comparing: i) matched family donor hematopoietic stem cell transplantation performed as first-line treatment with ii) front-line immunosuppressive therapy not followed by subsequent transplant given for failure and with iii) hematopoietic stem cell transplantation performed after failed front-line immunosuppressive therapy. Overall survival was 86% in the matched family donor hematopoietic stem cell transplantation group, 90% in patients given front-line immunosuppressive alone (those who did not fail this treatment and who did not receive subsequent rescue with hematopoietic stem cell transplantation) and 78% in subjects who underwent hematopoietic stem cell transplantation post failed front-line immunosuppressive therapy (P=0.14). Event-free survival in the same groups was respectively 83%, 64% and 71% (P=0.04). Cumulative incidence of rejection was 8% in matched family donor hematopoietic stem cell transplantation and 9% in transplants post failed front-line immunosuppression (P=0.62). Cumulative incidence of acute graft-versus-host disease was 12% in matched family donor transplants and 18% in transplants post failed immunosuppression (P=0.18). Chronic graft-versus-host disease was higher in matched family donor hematopoietic stem cell transplantation (8%) than in transplants post failed immunosuppressive therapy (20%) (P=0.0009). Cumulative incidence of post-therapy malignancies was 0.7% in matched family donor transplantations, 7% in transplantations post failed immunosuppression and 21% after front-line immunosuppression (P=0.0017). In the whole cohort, under multivariate analysis, the diagnosis to treatment interval of two months or under positively affected overall survival whereas up-front immunosuppression alone (with no subsequent rescue transplants) negatively affected event-free survival. In transplanted patients an interval from diagnosis to treatment of 2 months or under, bone marrow as source of cells and first-line matched family donor transplants provided a significant advantage in overall and event-free survival. Aplastic anemia in adolescents has a very good outcome. If a matched family donor is available, hematopoietic stem cell transplantation using bone marrow cells is the first choice treatment. If such a donor is not available, immunosuppressive treatment may still be an acceptable second choice, also because, in case of failure, hematopoietic stem cell transplantation is a very good rescue option.

Unmanipulated Haploidentical Transplants Compared with Other Alternative Donors and Matched Sibling Grafts

We studied 459 consecutive patients with hematologic malignancies, median age 44 years (range, 15 to 71 years), who underwent transplantation with grafts from identical sibling donors (SIB; n = 176), matched unrelated donors (MUD; n = 43), mismatched unrelated donors (mmUD; n = 43), unrelated cord blood (UCB; n = 105) or HLA-haploidentical family donors (HAPLO; n = 92). Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and methotrexate in the SIB recipients; antithymocyte globulin for the MUD, mmUD, and UCB recipients; and post-transplantation cyclophosphamide, cyclosporine, and mycophenolate in the HAPLO recipients. Conditioning regimens were mostly myeloablative (69%). Advanced disease phase was more frequent, but not significantly so, in the HAPLO and mmUD groups (P = .08). Acute GVHD grade II-IV was significantly less frequent in the HAPLO, UCB, and MUD groups (14% to 21%) compared with the SIB (31%) and mmUD (42%) groups (P < .001), and there was a trend toward less moderate-severe chronic GVHD in the HAPLO and UCB groups (P = .053). The proportion of patients off cyclosporine at 1 year ranged from 55% for the SIB group to 81% for the HAPLO group (P < .001). Transplantation-related mortality at 2 years was lower in the HAPLO and SIB groups (18% to 24%) compared with the MUD, mmUD, and UCB groups (33% to 35%; P = .10). Relapse rate was comparable in the 5 groups (P = .80). The 4-year actuarial survival was 45% in the SIB group, 43% in the MUD group, 40% in the mmUD group, 34% in the UCB group, and 52% in the HAPLO group (P = .10). In multivariate analysis, advanced disease was a negative predictor of survival (hazard ratio [HR], 2.4; P < .0001), together with a diagnosis of acute leukemia (HR, 1.8; P = .0001); HAPLO grafts were comparable to SIB (P = .80), whereas UCB had inferior survival (P = .03). In conclusion, unmanipulated haploidentical family donor transplants are an additional option for patients lacking a matched sibling donor.

Host natural killer immunity is a key indicator of permissiveness for donor cell engraftment in patients with severe combined immunodeficiency

BackgroundSevere combined immunodeficiency (SCID) can be cured by using allogeneic hematopoietic stem cell transplantation, and the absence of host immunity often obviates the need for preconditioning. Depending on the underlying genetic defect and when blocks in differentiation occur during lymphocyte ontogeny, infants with SCID have absent or greatly reduced numbers of functional T cells. Natural killer (NK) cell populations are usually absent in the SCID-X1 and Janus kinase 3 forms of SCID and greatly reduced in adenosine deaminase deficiency SCID but often present in other forms of the disorder.ObjectiveTo determine if SCID phenotypes indicate host permissiveness to donor cell engraftment.MethodsA retrospective data analysis considered whether host NK cells influenced donor T-cell engraftment, immune reconstitution, and long-term outcomes in children who had undergone nonconditioned allogeneic stem cell transplantation between 1990 and 2011 in the United Kingdom. Detailed analysis of T- and B-cell immune reconstitution and donor chimerism was compared between the NK+ (n = 24) and NK− (n = 53) forms of SCID.ResultsOverall, 77 children underwent transplantation, with survival of 90% in matched sibling donor/matched family donor transplants compared with 60% when alternative donors were used. Infants with NK−SCID were more likely to survive than NK+ recipients (87% vs 62%, P < .01) and had high-level donor T-cell chimerism with superior long-term recovery of CD4 T-cell immunity. Notably, 33% of children with NK+SCID required additional transplantation procedures compared with only 8% of children with NK−SCID (P < .005).ConclusionsNK−SCID disorders are highly permissive for donor T-cell engraftment without preconditioning, whereas the presence of NK cells is a strong indicator that preparative conditioning is required for engraftment of T-cell precursors capable of supporting robust T-cell reconstitution.

A critical review of which children with acute myeloid leukaemia need stem cell procedures.

The last decades have seen parallel improvements in chemotherapy-based and haematopoietic stem cell transplantation (HSCT) regimens for acute myeloid leukaemia (AML) in children. There has been no consensus on indication for HSCT. Reserving HSCT for high-risk and relapsed patients spare many patients from the long-term toxicity of this treatment. The results of matched unrelated donor HSCT equal family donor transplantation and the presence of a matched sibling should no longer be a transplant indication. Minimal residual disease measured by flow cytometry may identify poor responders benefitting from HSCT in first complete remission (CR1) and those with a favourable response to induction therapy who do not need HSCT even with adverse cytogenetic aberrations. FLT3-internal tandem duplication without NPM1 mutation has a very high relapse rate despite favourable response and HSCT is indicated in CR1 in these cases. Finding the optimal indications for HSCT is a delicate balance between risk of relapse and late effects.

Trasplante alogénico de precursores hematopoyéticos de sangre de cordón umbilical de donante no emparentado: primera experiencia, en tres casos, con donantes del banco público chileno de células de cordón

Public cord blood banks are a source of hematopoietic stem cells for patients with hematological diseases who lack a family donor and need allogeneic transplantation. In June 2007 we started a cord blood bank with units donated in three maternity wards in Santiago, Chile. We report the first three transplants done with cord blood units form this bank. Cord blood units were obtained by intrauterine collection at delivery. They were depleted of plasma and red cells and frozen in liquid nitrogen. Tests for total nucleated cells, CD34 cell content, viral serology, bacterial cultures and HLA A, B and DRB1 were done. Six hundred cord blood units were stored by March 2012. Three patients received allogeneic transplant with cord blood from our bank, two with high risk lymphoblastic leukemia and one with severe congenital anemia. They received conditioning regimens according to their disease and usual supportive care for unrelated donor transplantation until full hematopoietic and immune reconstitution was achieved. The three patients had early engraftment of neutrophils and platelets. The child corrected his anemia and the leukemia patients remain in complete remission. The post-transplant course was complicated with Epstein Barr virus, cytomegalovirus and BK virus infection. Two patients are fully functional 24 and 33 months after transplant, the third is still receiving immunosuppression.

Increased availability of family donors for hematopoietic stem cell transplantation in a population with increased incidence of consanguinity

The study was planned to determine the frequency of parental and non-sibling family donor transplants in our center and to investigate the rate of familial donor availability at two HLA-typing laboratories in Turkey. Among 203 patients who underwent hematopoietic stem cell transplantation (HSCT), 151 (74.4%) received stem cells from siblings, 48 (23.6%) from non-sibling family donors, two (1.0%) from unrelated cord blood, and two (1.0%) autologous transplantation. Of these 48 patients received stem cells from non-sibling family donors; donors were mothers for 26 (12.8%), fathers for 20 (9.9%), and aunts for two (1.0%). The rate of transplants from parental donors was 22.6% in this patient population with increased frequency of inherited diseases (58.1%). Among these 203 patients, there was consanguinity between parents in 60.6% of the patients. Of 833 subjects applying as donor candidates to HLA-typing laboratories, 527 (63.3%) had HLA 6/6 identical family donors. Among 527 full-matched donors, 479 (90.9%) were sibling, 21 (4.0%) were fathers, and 17 (3.2%) were mothers. The remaining 10 (1.9%) were other relatives. The results have shown that the unfavorable factor of consanguinity marriage may increase the availability of family donors for HSCT in particularly developing countries where large donor registries are lacking.

A Fludarabine Based Conditioning Regimen Associated with A Good Survival Following HLA Identical Sibling/Family Donor Transplants in Patients with Aplastic Anemia.

Abstract 1194Poster Board I-216Between January 2001 and June 2009, 120 patients with aplastic anemia underwent HLA identical sibling or family donor transplants using a combination of Fludarabine 150-180 mg/m2 over 5 days and Cyclophosphamide 120 mg/kg over 2 days as the conditioning regimen. Antithymocyte globulin (ATG) 10 mg/kg x 4 days in addition was used in 34 patients. Graft versus host disease (GVHD) prophylaxis consisted of Cyclosporine with low dose Methotrexate. Graft source included peripheral blood stem cells (PBSC) in 108 and G-CSF stimulated bone marrow in 12. Seventy patients (58.3%) were considered as high risk (presence of fever/infection at time of HSCT or >20 transfusions prior to HSCT or failed previous immunosuppressive therapy).There were 79 males and 41 females with a median age of 22 years (range: 2 - 51) including 36 children (age <15 years). PBSC was used in 108 while BM was the graft source in 12. The median cell dose infused was 7.1 × 108 MNC/Kg for PBSC (range: 1.9 – 19.6) and 4.9 × 108 TNC/Kg for bone marrow (range: 2.1 to 9.9). One hundred and thirteen patients (94.1%) engrafted while 2 (1.6%) had primary graft failure and 5 expired within the first 2 weeks due to infection. The median time to neutrophil engraftment (ANC > 0.5 × 109/L) was 12 days (range: 7-19) while platelet engraftment (Platelet count > 20 × 109/L) occurred at a median of 13 days (range: 0 -30). Acute GVHD occurred in 38 patients (33.3%) with grade III-IV GVHD in 13.1%. Acute GVHD was not significantly lower in patients where ATG was used in conditioning (21.8% with ATG vs 38.2% without ATG; p = 0.129). Nine patients (7.5%) had veno-occlusive disease of the liver while 11 (9.1%) had hemorrhagic cystitis; all responded well to supportive therapy. Bacterial infections were documented in 28% of transplant recipients while fungal infections (both probable and definite) occurred in 23%. CMV reactivation was seen in <5%. Chronic GVHD occurred in 32.6% of evaluable transplant recipients and was limited in a majority of patients. At a median follow up of 30 months (range: 1 – 105), 88 patients (73.3%) are alive and well. Causes of death included sepsis in 19, acute GVHD in 7, chronic GVHD in 4, primary graft failure in 1 and road traffic accident in 1 patient. The overall survival was similar among children (75%) and adults (72.6%). The overall survival was significantly lower in the high risk group (60%) compared to the low risk group (92%; p = 0.0001). Conclusion:A combination of fludarabine and cyclophosphamide as conditioning for aplastic anemia is associated with good engraftment, a very low incidence of primary or secondary graft failure and good overall survival. Toxicity is low but acute and chronic GVHD remain significant problems. Sepsis continues to remain the major cause of death in these patients. Disclosures:No relevant conflicts of interest to declare.

Allogeneic Hematopoietic Stem-Cell Transplantation for Leukocyte Adhesion Deficiency

Leukocyte adhesion deficiency is a rare primary immune disorder caused by defects of the CD18 beta-integrin molecule on immune cells. The condition usually presents in early infancy and is characterized by deep tissue infections, leukocytosis with impaired formation of pus, and delayed wound healing. Allogeneic hematopoietic stem-cell transplantation offers the possibility of curative therapy, and with patient numbers at any individual center being limited, we surveyed the transplant experience at 14 centers worldwide. The course of 36 children with a confirmed diagnosis of leukocyte adhesion deficiency who underwent hematopoietic stem-cell transplantation between 1993 and 2007 was retrospectively analyzed. Data were collected by the registries of the European Society for Immunodeficiencies/European Group for Blood and Marrow Transplantation, and the Center for International Blood and Marrow Transplant Research. At a median follow-up of 62 months (extending to 14 years), the overall survival rate was 75%. Myeloablative conditioning regimens were used in 28 patients, and reduced-intensity conditioning in 8 patients, with no deaths in this subgroup. Survival rates after matched family donor and unrelated donor transplants were similar, with 11 of 14 matched family donor and 12 of 14 unrelated donor recipients alive; mortality was greatest after haploidentical transplants, after which 4 of 8 children did not survive. Twenty-seven transplant recipients were alive, with full donor engraftment in 17 cases, mixed multilineage chimerism in 7 patients, and mononuclear cell-restricted chimerism in an additional 3 cases. Hematopoietic stem-cell transplantation offers long-term benefit in leukocyte adhesion deficiency and should be considered as an early therapeutic option if a suitable HLA-matched stem-cell donation is available. Reduced-intensity conditioning was particularly safe, and mixed-donor chimerism seems sufficient to prevent significant symptoms, although careful long-term monitoring will be required for these patients.

Alternative Allogeneic Donor Sources for Transplantation for Childhood Diseases: Unrelated Cord Blood and Haploidentical Family Donors

Allogeneic stem cell transplantation has been demonstrated to be curative in a wide variety of pediatric malignant and nonmalignant diseases, and can be traced back over 50 years ago to the original report of Thomas et al. HLA matched sibling donors have been the gold standard for pediatric recipients requiring allogeneic donors for both nonmalignant and malignant conditions. However, only 25% of potential pediatric recipients possesses an HLA-matched sibling donor, and the frequency is even less in those with genetic nonmalignant conditions because of genetically affected other siblings within the family. Therefore, 75% to 90% of potential pediatric recipients require alternative allogeneic donor cells for treatment of their underlying conditions. Potential alternative allogeneic donor sources include unrelated cord blood donors, unrelated adult donors, and haploidentical family donors. In this article we review the experience of both unrelated cord blood donor and haploidentical family donor transplants in selected pediatric malignant and nonmalignant conditions.

Outcome of Bone Marrow Transplantation for Myelofibrosis.

Myelofibrosis is a myeloproliferative disorder characterized by splenomegaly, bone marrow fibrosis and immature white and red blood cells. Allogeneic transplantation is the only curative therapy. In this study, we analyzed the outcomes of 320 patients receiving allogeneic hematopoietic stem cell transplants for myelofibrosis between 1989 and 2002, using the databases of the Center for International Bone Marrow Transplant Research (CIBMTR), a research affiliation of the International Bone Marrow Transplant Registry (IBMTR) and the National Marrow Donor Program (NMDP). This is the largest report of transplantation for myelofibrosis. Patients received a variety of conditioning and graft versus host disease prophylaxis regimens. Most patients received ablative conditioning with either TBI (n=117) or Busulfan (n=150) and cyclophosphamide. Bone marrow was the graft source in 208 patients. 170 transplants were from an HLA-identical sibling donor, 117 from an unrelated donor (MUD), and 33 from an alternative related donor. Median ages at transplant were 45 (<1–73), 47 (1–69) and 40 (<1–65) years, respectively. Median follow up times for survivors were 41 (3–136), 48 (4–124) and 32 (7–118) months, respectively. Both early and long-term survival rates were higher after HLA-identical sibling transplantation. 100-day mortality was 22% after sibling transplants, 42% after MUD transplants, and 27% after alternative family donor transplants. Corresponding 5 year overall survival rates were 39%, 31% and 31%. In multivariate analysis of 215 adult recipients of myeloablative transplants, having an HLA-identical sibling donor, Karnofsky performance score greater than or equal to 90%, younger age, more recent date of transplantation, and absence of blasts in peripheral blood prior to transplantation correlated with better survival. Among 18 patients with all of these favorable factors, the five-year probability of survival was 81%. In conclusion, 1) allogeneic transplantation cures approximately 1/3 of patients with myelofibrosis; 2) young patients with HLA-matched sibling donors have superior survival; 3) results have improved over the last decade. Future research directions will focus on the use of nonmyeloablative conditioning regimens for myelofibrosis.

The Role of Race on Survival after Alternative Donor Hematopoietic Progenitor Cell Transplant for Pediatric Acute Leukemia: Provocative Single Center Data.

Allogeneic blood or bone marrow transplant (BMT) can be a curative treatment for many children and adolescents with acute leukemia. With advances in unrelated donor transplant, others and we have shown that unrelated donor BMT can have similar survival to matched sibling BMT. There are several reports describing outcomes after matched related donor transplantation among various ethnic groups. Thus far, there are no published studies comparing outcomes among ethnic groups after alternative donor transplantation. Anecdotally, however, there have been concerns regarding outcomes among racial and ethnic groups, especially African-Americans. In order to address this question, we utilized our institutional database to analyze survival among children and adolescents receiving an alternative donor BMT at Children's Hospital of Wisconsin from 1988-present. We compared survival in Caucasians and African-Americans undergoing unrelated donor and mismatched related donor transplantation (including haploidentical donors). One hundred and twenty four Caucasians underwent matched and mismatched unrelated donor transplantation compared to 11 African Americans. The 2-year probabilities of overall survival were significantly better for Caucasians at 53% (95% CI 44–62) than for African Americans, 18% (95% CI 2–45), p=0.01. Fifty-four Caucasians and 9 African Americans received mismatched family donor transplantation. Corresponding probabilities of overall 2-year survival were 38% (95% CI 25–51) and 30% (95% CI 5–64), respectively. Interestingly, our data show no statistically significant difference in survival after mismatched related donor transplantation between the Caucasian and African-American cohorts. Our data should be interpreted cautiously as the number of African Americans transplanted at our institution is few. Additionally, our analysis is limited by our inability to adjust for disease status at transplantation, HLA disparity and other known risk factors that may impact survival. Nevertheless these observations from a single institution cannot be ignored and warrant further analysis in a larger cohort such that outcomes after transplantation may be adjusted appropriately for relevant risk factors. We believe that a national database/registry study will have the numbers necessary to answer the questions that need to be asked regarding outcomes with alternative donor transplantation in the African-American population. We also believe that as cell processing and supportive care technologies improve mismatched family member transplantation outcomes, these advances could have a significant impact in improving leukemia-free survival for African-American children and adolescents.

Long-term outcome of a Phase II study of BM transplants, partially depleted ex-vivo of CD5-positive and CD8-positive T-lymphocytes in unrelated and related donor 1 antigen mismatched recipients

Mismatched family donor and unrelated donor BM transplants are associated with a high risk of acute GvHD. White T-cell depletion is the best method to reduce risk of acute GvHD, there was a reluctance to use T-cell depletion in the mismatched setting because of increased risk of rejection and relapse. Partial T-cell depletion, by the panning of CDS and CD8 positive T cells may reduce complications related to GvHD without compromising outcomes. In a long-term follow-up of a Phase II study of partial T-cell depletion by panning for BM transplant, 32 recipients received transplants from a single-Ag (HLA A, B, or DR) mismatched family donor; or an HLA serologically-matched unrelated donor. Patients were studied for engraftment, GHD, relapse and survival. 30 (94%) of the patients marrow engrafted. The cumulative risk of Grade 2-4 acute GvHD was 62 - 9%; of Grade 3-4 GvHD, 11 - 6%. The 4-year cumulative risk of relapse was 18 - 8% and actuarial survival was 44 - 9%. Partial T-cell depletion had a low rate of severe acute GvHD without compromising engrafment or relapse risk.