Well-matched Unrelated Donor Research Articles

IL‐10 promoter polymorphisms influence susceptibility to aGvHD and are associated with proportions of CD4+FoxP3+ lymphocytes in blood after hematopoietic stem cell transplantation

Four hundred and ninety-five patients (390 and 105 grafted from unrelated and sibling (SIB) donors, respectively) and their donors were analyzed for the impact of interleukin-10 (IL-10) promoter genotype [rs18000896 (-1082 G/A), rs18000871 (-819 C/T) and rs18000872 (-592 C/A)] on the outcome of hematopoietic stem cell transplantation (HSCT). Patients having ACC haplotype were at a lower risk of acute graft versus host disease (aGvHD, grade > I) if transplanted from human leukocyte antigen (HLA) well-matched (10/10) unrelated donors (20/135 vs 39/117, P < 0.001, Pcorr = 0.002), which was not seen if patients were transplanted from either sibling (SIB) or poorly matched (<10/10) unrelated donors (MUD). In addition, GCC haplotype positive recipients of unrelated donor transplants tended to be more susceptible to aGvHD (68/199 vs 39/169, P = 0.019, Pcorr = 0.057). Multivariate logistic regression analysis in the MUD transplanted group showed that donor-recipient human leukocyte antigen (HLA) mismatch [odds ratio (OR) = 3.937, P = 0.001] and a lack of ACC haplotype in recipients (OR = 0.417, P = 0.013) played a significant role as independent risk factors of aGvHD grade > I. ACC carriers had higher proportions of FoxP3+ lymphocytes gated in CD4+ lymphocytes as compared with patients with other IL-10 haplotypes. It was seen at the time of hematological recovery (mean ± SEM: 3.80 ± 0.91% vs 2.06 ± 0.98%, P = 0.012) and 2 weeks later (5.32 ± 0.87% vs 2.50 ± 0.83%, P = 0.013); -592 C/A polymorphism was separately analyzed and it was found that AA homozygotes tended to have a higher incidence of aGvHD (8/15 vs 116/456, P = 0.034) and low proportions of FoxP3 CD4+ lymphocytes in blood (0.43 ± 0.22% vs 4.32 ± 0.71%, P = 0.051) measured 2 weeks after hematological recovery. Functional IL-10 polymorphism associated features influenced the risk of aGvHD with a positive effect of ACC on the pool of Treg in blood.

Equality Of Access To Transplant For Ethnic Minority Patients Through Use Of Cord Blood and Haploidentical Transplants

It is well accepted that patients of ethnic minorities who lack a sibling donor are poorly represented on the international unrelated donor panels. As recently as 2000, only 30% of such patients were able to find an unrelated donor suitable for transplantation. Historically these patients would have either not been transplanted, or would receive transplants from unrelated donors with two or more HLA mismatches. Continued expansion of the international donor inventory, and the advent of cord blood and haploidentical transplantation has improved the prospects for transplantation for such patients and, through the expertise of search staff within donor registries and histocompatibility laboratories, transplant centres are increasingly able to identify early on those patients who are unlikely to find a well-matched unrelated adult donor. Surprisingly, however, few contemporary data have been published to show the impact of these search strategies and alternative stem cell sources on provision of transplant to those of non-white Northern European origin.We consecutively enrolled and prospectively followed up (from search request to last contact or death) 332 patients referred by four UK transplant centres to the Anthony Nolan Graft Identification and Advisory Service (GIAS) for identification of an unrelated adult donor or cord blood unit. Of these, 248 (74.7%) were of white Northern European (WNE) descent, and 84 (25.3%) non-WNE. The underlying disease did not differ significantly between ethnicities. The median number of UK donors listed on the search report was 8 (range 0 to 3395) and 0 (0 to 42) respectively, and on BMDW 127 (0 to 38245) and 5.5 (0 to 380) respectively. 69.3% of WNE and 20.5% of non-WNE patients found a 10/10 HLA-matched donor at confirmatory typing (CT) (p<0.001); 96.3% of WNE and 61.4% of non-WNE found at least a 9/10 HLA-matched donor (p<0.001). Non-WNE patients had more cord blood transplants (21.3% vs 3.8%, p<0.001) and more haploidentical transplants (10.6% vs 1.3%, p<0.001). There was no significant difference in the number of patients reaching transplant (WNE 63.3%, non-WNE 56.0%, p=0.185) when considering all of the graft sources. Patients of non-WNE background had a significantly slower time from first CT request to identification of an unrelated donor for transplant (median 27 days vs 33.5 days, p= 0.02), and from search request to transplant with any graft source (median 110 days vs 132 days, p=0.03). However, when the cumulative incidence of transplantation with death as a competing risk was considered, there was no difference between ethnic groups (log rank p=0.185, see figure). The median time from search request to transplant by graft source was 120.5 days for adult unrelated donors (n=179), 143 days for cord blood (n=16) and 91 days for haploidentical donors (n=6) (p=0.626). [Display omitted] These data show that the chance of receiving a transplant for patients of a non-WNE descent has improved considerably compared to historical literature. The majority of non-WNE patients were able to find a 9 or 10/10 matched donor, and many of those who could not were afforded the option of a cord blood or haploidentical donor transplant within a similar timescale. Whilst times to transplant do remain slightly longer for non-WNE patients, mainly due to a more protracted CT stage, they now stand an equal chance of reaching transplant. However, whether survival following transplant is similar between ethnic groups remains to be seen. Disclosures:No relevant conflicts of interest to declare.

Alternative Donor Hematopoietic Transplantation For Patients Older Than 50 Years With AML In First Complete Remission: Unrelated Donor and Umbilical Cord Blood Transplantation Outcomes

Post-remission allogeneic transplantation is increasingly used for treatment of the high-risk acute myeloid leukemia (AML) affecting older adults. We analyzed 740 adults over age 50 with AML in first complete remission (CR1) to compare the effectiveness of volunteer unrelated donor (URD) and umbilical cord blood (UCB) graft sources in providing a successful transplant. For prospective cases reported (2005-2010) to the Center for International Blood and Marrow Transplant Research and Eurocord, we evaluated 8/8 HLA allele matched (at HLA-A, -B, -C, -DRB1) n=441; 7/8 matched URD n=94 and UCB n=205 for the outcomes of engraftment, treatment related (non-relapse) mortality (TRM), relapse, leukemia free survival (LFS) and overall survival (OS) using the cumulative incidence and Kaplan-Meier estimators and multivariate Cox regression modeling. Patient age (median 58, range 50-75), gender and CMV serostatus were similar across the treatment groups. However, UCB recipients were less likely to achieve CR within 8 weeks, more likely to report Intermediate and unfavorable risk cytogenetics, more likely to receive reduced-intensity conditioning compared to myeloablative conditioning regimens, and receive cyclosporin rather than tacrolimus-based GVHD prophylaxis.After a median follow-up of 50, 61 and 37 months in 8/8 URD, 7/8 URD and UCB grafts, neutrophil and platelet recovery was slower in UCB compared to URD recipients; the day-42 incidence of neutrophil recovery in UCB recipients was 85% compared to 98% and 92% in 8/8 and 7/8 URD recipients. While there were no significant differences in rates of grade II to IV acute GVHD (35%, 36% and 44% in UCB, 8/8 URD and 7/8 URD recipients respectively), the 3-year incidence of chronic GVHD was significantly lower in UCB recipients (28% compared to 53% and 59% in 8/8 and 7/8 URD recipients. Compared to 8/8 URD transplants, multivariate analysis confirmed higher TRM after transplantation of UCB grafts, but only in the first 3 months (HR 2.83, p<0.0001) with similar risks thereafter (HR 1.00, p=0.99). Compared to 8/8 URD transplants, TRM was higher after 7/8 URD transplants (HR 1.73, p=0.005). There were no significant differences in relapse risks between the three groups; compared to 8/8 URD transplants, relapse risks after UCB and 7/8 URD transplants were HR 1.15, p=0.36 and HR 0.86, p=0.47, respectively. These hazards yielded higher adjusted 3-year LFS after 8/8 URD (39% [95% CI 34%-43%]) compared to 7/8 URD (34% [95% CI 24%-43%]) and UCB transplants (28% [95% CI 22%-35%]), p=0.015) and adjusted 3-year OS of 43% (95% CI 38%-48%), 37% (95% CI 27%-46%) and 30% (95% CI 23%-37%), respectively (p=0.003). Relapse risks were greater in patients with intermediate or unfavorable risk cytogenetics, independent of graft type and leukemia-free and overall survival were also worse in patients with unfavorable risk cytogenetics and in patients over age 60. For the older population with AML, allotransplantation in CR1 can provide extended leukemia-free survival for 30%-43% of patients using any of these graft sources. While 8/8 URD transplants are preferred for patients who can promptly obtain a well-matched URD, for ethnic or racial minorities, UCB grafts provide a meaningful chance of extended LFS, even though nearly all UCB grafts are HLA mismatched.Additionally, the rapid availability of UCB provides effective therapy for older patients with expected short initial remissions: settings where ongoing consolidation therapy has not been effective in limiting risks of relapse. Later TRM and relapse rates were similar, lower risks of chronic GVHD and the need for long-term immunosuppression and its morbidities may be of particular value for these older patients. These encouraging results suggest that allotransplantation need not be withheld from older patients and for clinically suitable AML patients, can produce extended and even curative long-term survival. Disclosures: GluckmanCord use: Honoraria; gamida: Honoraria.

Survival Improvements Following Myeloablative Allogeneic Hematopoietic Cell Transplantation For Acute Lymphoblastic Leukemia In Adolescents and Young Adults Have Been Comparable To Younger Children: A Study From The Cibmtr

Adolescents and young adults (AYAs) with cancer have not experienced survival improvements over time to the same extent as younger and older patients. Studies in acute lymphoblastic leukemia (ALL) have identified differences in chemotherapy treatment approaches, adherence and possibly outcomes for AYAs treated in pediatric vs. adult settings. To determine if these same issues are operative in ALL patients treated with hematopoietic cell transplantation (HCT), we compared outcomes among 2730 patients including 1008 children (<15 years), 1244 AYAs (15-40 years) and 478 older adults (> 40 years) receiving myeloablative allogeneic HCT for ALL at US centers over three time periods (1990-1995, 1996-2001, and 2002-2007). All patients were in first or second complete remission at HCT; Ph+ patients were included; umbilical cord blood transplant recipients were excluded. The proportions of patients receiving peripheral blood transplants and receiving HCT using well-matched unrelated donors increased over time in all three age groups. From 1996-2001 to 2002-2007, transplant volume increased by 7% in children, 50% in AYAs, and 180% in older adults. Our analysis demonstrated that 5-year overall survival varied inversely with age group, but survival for AYAs over time improved at rates comparable to survival in children (Figure). Multivariate analyses adjusting for important patient and disease characteristics confirmed that older age was associated with poorer survival (hazard ratio 2.2 for older adults and 1.7 for AYA vs. children, P<0.001); however, no significant interactions were observed between age and time period confirming that changes in survival rates over time were similar between the groups even after statistical adjustment for other factors. Similar findings were observed for transplant-related mortality (TRM) and relapse. Transplantation techniques and outcomes were also explored for a subset of 131 AYAs (ages 15-25) transplanted at 46 pediatric or 92 adult centers. Although limited by small numbers, univariate analyses did not show differences in probabilities of overall survival, TRM, or relapse by center type. Patients transplanted at pediatric centers had a longer time from diagnosis to transplant than patients transplanted at adult centers (p=0.024), and were more likely to receive bone marrow vs. peripheral blood stem cell graft (p<0.001). Conditioning regimens (p=0.04) and GVHD prophylaxis (p<0.01) also differed. Taken together, these findings suggest that, in contrast to what has been observed for other cancers over time, survival following myeloablative allogeneic HCT for AYA's has improved at a rate comparable to other age groups. There appear to be differences in transplant timing and techniques for AYAs depending on whether treatment occurs in a pediatric or adult center but transplant outcomes did not significantly differ, in contrast to survival differences reported in the non-transplant setting. In summary, AYAs are experiencing improvements comparable with younger children, and appear to have similar outcomes whether transplanted at pediatric or adult centers. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

The role of hematopoietic cell transplantation in adult ALL: Clinical equipoise persists

Adults with acute lymphoblastic leukemia (ALL) in first complete remission (CR1) may be treated either with ongoing systemic chemotherapy or with allogeneic hematopoietic cell transplantation (alloHCT). Despite the presence of phase III trials to support clinical decision-making, we hypothesized that physicians who treat adult ALL would demonstrate wide practice variation. Canadian hematologists who treat ALL were surveyed electronically. Overall, 69 of 173 physicians responded (40%). There was high agreement with offering alloHCT for ALL with high-risk cytogenetics or induction failure after a single chemotherapy cycle. However, only a minority of respondents felt that age >35 years was an indication for alloHCT in CR1. Almost all respondents (96%) felt that a well-matched unrelated donor was an acceptable alternative to a sibling donor. There was uncertainty about the role of cord blood (53% agree) and the utility of reduced intensity conditioning HCT (41% agree). In contrast to the results of the MRC/ECOG study, respondents considered alloHCT to be particularly helpful in high-risk patients. Consensus was lacking on the use of cord blood, RIC alloHCT, and the application of MRD. Equipoise exists on the role of alloHCT in CR1 in ALL, suggesting that further trials in this area are required.

Reduced-Intensity Hematopoietic Cell Transplantation for Patients with Primary Myelofibrosis: A Cohort Analysis from the Center for International Blood and Marrow Transplant Research

We evaluated outcomes and associated prognostic factors in 233 patients undergoing allogeneic hematopoietic cell transplantation (HCT) for primary myelofibrosis (MF) using reduced-intensity conditioning (RIC). The median age at RIC HCT was 55 yr. Donors were a matched sibling donor (MSD) in 34% of RIC HCTs, an HLA well-matched unrelated donor (URD) in 45%, and a partially matched/mismatched URD in 21%. Risk stratification according to the Dynamic International Prognostic Scoring System (DIPSS) was 12% low, 49% intermediate-1, 37% intermediate-2, and 1% high. The probability of survival at 5 yr was 47% (95% confidence interval [CI], 40% to 53%). In a multivariate analysis, donor type was the sole independent factor associated with survival. Adjusted probabilities of survival at 5-yr were 56% (95% CI, 44% to 67%) for MSD, 48% (95% CI, 37% to 58%) for well-matched URD, and 34% (95% CI, 21% to 47%) for partially matched/mismatched URD (P = .002). The relative risk (RR) for NRM was 3.92 (P = .006) for well-matched URD and 9.37 (P < .0001) for partially matched/mismatched URD. Trends toward increased NRM (RR, 1.7; P = .07) and inferior survival (RR, 1.37; P = .10) were observed in DIPSS intermediate-2/high-risk patients compared with DIPSS low/intermediate-1 risk patients. Our data indicate that RIC HCT is a potentially curative option for patients with MF, and that donor type is the most important factor influencing survival in these patients.

Hematopoietic Stem Cell Transplantation for Sickle Cell Disease: More Options and Many Unanswered Questions

Sickle cell disease (SCD) is an inherited hemoglobinopathy leading to polymerization of hemoglobin S in the deoxygenated state. The resulting vaso-occlusion with ischemia and reperfusion injury accounts for most of the morbidity and shortened life-expectancy. Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only established curative therapy for SCD. Initial trials included only the most severely affected patients, using a myeloablative conditioning and HLA-identical sibling donors, resulting in event-free survival (likely cure) of >85% [1]. While successful HSCT can halt the progression of SCD existing organ damage may not be reversible. Therefore it seems reasonable to extend this procedure to the less severely affected patients at a younger age. Based on registry data, HSCT is much underutilized for SCD and that is due to several unresolved issues. Less than 15% of patients with SCD have a matched, related donor and those identified have often been reluctant to participate. For the majority of SCD patients an alternative donor is required. While there are more than 10 million adult volunteers in various registries around the world, finding a well-matched unrelated donor has been difficult for patients of African-American ancestry due to their unique HLA-phenotypes. Umbilical cord blood cells (UCB) from siblings have been used successfully as a source of stem cell for HSCT. Unrelated cord blood transplants have been increasingly used for other HSCT indications and may represent an attractive option for SCD patients, due to the better tolerance of HLA-disparity. A recent report from three international registries showed the feasibility of this approach. Despite the use of myeloablative conditioning, engraftment failure remained a challenge, especially when a high cell dose was not available [2]. Haploidentical related donors are theoretically a much more readily available stem cell source. The difficulties encountered with this approach included the technical complexity of T-lymphocyte depletion, risk of rejection and delayed immunologic recovery. Intensive chemo-radiotherapy has therefore been required. Recently a novel approach with the use of post-transplantation high dose cyclophosphamide showed engraftment without excessive graft-versus-host disease [3]. If the success is confirmed more SCD patients may be considered for HSCT.

Allogeneic hematopoietic stem cell transplantations in acute lymphoblastic leukemia in children and adolescents

Background. ALL is the most common indication for allogeneic hematopoietic stem cell transplantation (allo- HSCT) in children. Objective. The analysis of results of therapy in children and adolescents treated for ALL with allo-HSCT. Patients and methods. A total number of 41 patients undergoing allo-HSCT due to ALL between 2003 and 2012. In 17 patients HSCT was performed from related donor and in 24 from unrelated donor. A source of hematopoietic stem cells was peripheral blood in 21 patients, bone marrow in 18 patients and cord blood in 2 patients. Results. At present, 27 (65.8%) patients stay alive. Among 14 deaths, 8 were regarded as transplant-related mortality, and 6 as a relapse of disease. Transplant-related mortality was 8/41 (19.5%), including 7 (17%) in early posttransplant period (before day +100). Probability of survival for all patients was: pDFS=0.652±0.091 (mean disease-freesurvival was 3.8 years, 95%CI=2.7-4.8), pOS=0.630±0.080 (mean survival 3.9 years, 95%CI=3.0-4.8). The only factor predicting overall survival was time of pre-transplant relapse: for very early relapses pOS=0.333±0.157, for early relapses pOS=0.666±0.272 and for late relapses pOS=0.833±0.152 (p=0.010). Conclusions. Allo-HSCT from well-matched unrelated donors or genoidentical sibling donors is an effective treatment with acceptable toxicity in pediatric ALL. Precise HLA typing and matching resulted in a low incidence of acute and extensive chronic GVHD which is an important achievement for the quality of life in children and adolescents. The results from this study demonstrate the feasibility of a harmonized HSCT approach in pediatric ALL.

Comparison of Allogeneic Stem Cell Transplantation from Familial-Mismatched/Haploidentical Donors and from Unrelated Donors in Adults with High-Risk Acute Myelogenous Leukemia

To weigh the pros and cons of familial-mismatched/haploidentical transplantation (FMT) in patients with high-risk acute myelogenous leukemia, we assessed outcomes of 23 patients who underwent FMT, using reduced-intensity conditioning with total body irradiation 800 cGy/busulfan/fludarabine/antithymocyte globulin without ex vivo T cell depletion, compared to 33 patients who underwent well-matched unrelated donor transplantation (WM-UDT) and 13 who underwent partially matched unrelated donor transplantation (PM-UDT) during the same period. The FMT patients had not only a similar pattern of engraftment and immune reconstitution as the WM-UDT and PM-UDT patients but also comparable incidences and severity of acute and chronic graft-versus-host disease. The FMT patients did not experience any form of engraftment failure. However, the cumulative incidence of cytomegalovirus DNAemia was significantly higher in the FMT group compared with the other groups (P = .036). After a median follow-up of 28 months, overall survival, disease-free survival, relapse, and nonrelapse mortality were 83%, 74%, 20%, and 7%, respectively, for WM-UDT; 51%, 51%, 31%, and 18% for PM-UDT; and 66%, 64%, 26%, and 10% for FMT. This demonstrates a trend for favorable survival outcomes of WM-UDT over FMT and of FMT over PM-UDT. However, we found no significant statistical differences in survival according to donor type. These data need to be interpreted cautiously because of limited power calculations due to the small number of each donor group. This pilot study suggests the feasibility of FMT using our novel regimen with careful evaluation of CMV DNAemia compared with WM-UDT and PM-UDT. Further trials with larger numbers of patients, comparing FMT directly with transplantation with other donor types, are needed.

Subsequent Malignant Neoplasms after Hematopoietic Cell Transplantation

Subsequent malignant neoplasms (SMNs) developing after hematopoietic cell transplantation (HCT) are a well-described complication (1–6). The magnitude of risk of SMNs after HCT ranges from 4-fold to 11-fold that of the general population. The estimated actuarial incidence is reported to be 3.5% at 10 years, increasing to 12.8% at 15 years among recipients of allogeneic HCT. The differing clinicopathologic characteristics of SMNs preclude assessment of risk factors in aggregate. It has become conventional practice to classify SMNs into three distinct groups (7): (i) myelodysplasia (t-MDS)/acute myeloid leukemia (t-AML); (ii) lymphoma, including lymphoproliferative disorders; and (iii) solid tumors. While t-MDS/AML and lymphoma develop relatively early in the post-transplantation period, secondary solid tumors have a longer latency. The magnitude of risk and associated risk factors for the development of SMNs are summarized in Table 1, and detailed in the sections below. Table 1 Magnitude of Risk and Populations at Increased Risk of Subsequent Malignant Neoplasms after Hematopoietic cell Transplantation Magnitude of Risk of Subsequent Malignant Neoplasm Therapy-related myelodysplasia/ acute myeloid leukemia The cumulative probability of developing t-MDS/t-AML ranges from 1.1% to 24.3% at 20 to 43 months after autologous HCT. In patients treated with alkylating agents, t-MDS/t-AML usually appears 4 to 7 years after exposure. The majority of patients present with multilineage dysplasia and peripheral cytopenias. There is a high prevalence of abnormalities involving chromosomes 5 (−5/del[5q]) and 7 (−7/del[7q]). AML secondary to topoisomerase II inhibitors presents as overt leukemia. The latency ranges from 6 months to 5 years, and is associated with balanced translocations involving chromosome bands 11q23 or 21q22. The common and nonspecific nature of cytopenias after autologous HCT has necessitated the creation of criteria for diagnosing t-MDS/t-AML after HCT. These include (i) significant marrow dysplasia in at least two cell lines, (ii) peripheral cytopenias without alternative explanations, and (iii) blasts in the marrow defined by French-American-British classification (8). Because many patients may not have an increase in blasts, presence of a clonal cytogenetic abnormality in addition to morphologic criteria of dysplasia may aid in making this diagnosis. An increased risk of t-MDS/t-AML is associated with older age at HCT (1), pretransplantation therapy with alkylating agents, topoisomerase II inhibitors, and radiation therapy (3), use of peripheral blood hematopoietic cells, stem cell mobilization with etoposide, difficult stem cell harvests, conditioning with TBI, number of CD34+ cells infused, and a history of multiple transplants (1, 3, 9–11). The diagnosis of t-MDS/t-AML after autologous HCT confers a poor prognosis, with a median survival of 6 months in patients treated with conventional chemotherapy. In fact, t-MDS/t-AML is a major cause of nonrelapse mortality in patients undergoing autologous HCT (3, 12). Allogeneic HCT has been attempted with actuarial survival ranging from 0% to 24% at 3 years (13). Among t-MDS/t-AML patients with balanced aberrations, 11q23 translocations are an independent adverse risk factor (14). Treatment-related mortality (TRM) and relapse were reported to be 41% and 27% at 1 year and 48% and 31% at 5 years, respectively in large cohort of patients undergoing allogeneic HCT (15). Disease-free (DFS) and overall survival (OS) were 32% and 37% at 1 year and 21% and 22% at 5 years, respectively. Age older than 35 years; poor-risk cytogenetics; t-AML not in remission or advanced t-MDS; and donor other than an HLA-identical sibling or a partially or well-matched unrelated donor had adverse impacts on DFS and OS. Because the poor outcomes of allogeneic transplant for t-MDS/t-AML are related in part to the high risk of TRM, it is important to evaluate the role of reduced intensity conditioning approaches in this setting. Preliminary reports suggest that allogeneic HCT using reduced-intensity conditioning is feasible and may result in improved outcomes.

T Cell–Depleted Partial Matched Unrelated Donor Transplant for Advanced Myeloid Malignancy: KIR Ligand Mismatch and Outcome

To evaluate the applicability of high-dose conditioning, CD34 selection, and enhanced natural killer (NK) cellalloreactivity reported as promising after haploidentical transplantation, we tested the same strategy for patients with advanced/high-risk myeloid leukemia lacking either related or well-matched unrelated donors (URD). In a prospective multicenter clinical trial using pretransplantation conditioning of thiotepa (5 mg/kg/day × 2), fludarabine (40 mg/mg/M(2)/day × 5), and total body radiation (800 cGy) plus thymoglobulin (2.5 mg/kg/day × 2), as well as a CD34 selected filgrastim stimulated peripheral blood graft from a partial matched URD, we treated 24 patients. The patients (median age 40 [range: 22-61]) were mismatched at 1-3 of 10 HLA loci with their donors; all were mismatched at HLA-C. Thirty-seven percent were ethnic or racial minorities. Twenty-one of 24 engrafted promptly with 1 primary graft failure and 2 early deaths. The cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) (34%, 95% confidence interval [CI], 14-54%), chronic GVHD (20%, 95% CI, 2%-38%), and relapse (26%, 95% CI, 8%-84%) were unaffected by KIR ligand donor:recipient mismatch (n = 5) versus KIR ligand match (n = 19). Only 3 (12%) had grade III-IV GVHD. Nonrelapse occurred in 17% (95% CI, 30%-31%) by 100 days and in 35% (95% CI, 15%-55%) by 1 year. Two-year survival and leukemia-free survival were each 40% (95% CI, 21%-59%) and was similar in KIR ligand matched or mismatched patients. Infections, mostly in the first 2 months, were frequent, and were the cause of death in 5patients (35% of deaths). T cell recovery and NK cell proliferation and functional maturation were not altered by KIR ligand match or mismatch status. For these high-risk patients, this high intensity regimen and T depleted approach yielded satisfactory outcomes, but logistical difficulties in arranging URD grafts for patients with high-risk, unstable leukemia limited accrual. Improvements in peritransplantation disease control and additional measures to augment the allogeneic graft-versus-leukemia effect are still required.

The Comparison of Allogeneic Stem Cell Transplantation From Family-Mismatched/Haploidentical Donors with Unrelated Donors in Adults with High-Risk Acute Myeloid Leukemia,

Abstract 4164Since August 2008, we have been continuously doing allogeneic stem cell transplantation (SCT) from family-mismatched/haploidentical donors (FMT) in high-risk acute myeloid leukemia (AML) lacking of HLA-identical siblings, well-matched unrelated donors (WM-UD), and partially-matched unrelated donors (PM-UD), and a pilot study about the encouraging outcomes of FMT using unmanipulated donor cells and less aggressive conditioning regimen without T-cell depletion were reported at last ASH (2010;116:Abstract 3533). We herein investigated the clinical outcomes of FMT in high-risk AML compared to SCT from WM-UD and PM-UD in order to weigh up the pros and cons of FMT.Between August 2008 to December 2010, 69 adult patients with high-risk AML underwent allogeneic SCT from WM-UD (n=33), PM-UD (n=13), and FMT (n=23). Conditioning regimen of FMT consisted of total body irradiation (800 cGy), fludarabine (150 mg/m2/day), busulfex (6.4 mg/kg/day), and ATG (thymoglobulin, Genzyme, 5.0 mg/kg). Unmanipulated granulocyte colony stimulating factor-mobilized peripheral blood stem cells (PBSCs) were used for FMT. Patients (n=46) transplanted from WM-UD and PM-UD received myeloablative (n=23, 70%) or reduced-intensity conditioning (n=14, 30%), and bone marrow (n=11, 23%) or PBSCs (n=36, 77%). Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and short course of methotrexate, which was identical for the three donor groups.The type of AML was de novo (n=59, 86%) and secondary (n=10, 14%). The majority of patients (n=66, 95%) had intermediate (n=52, 75%) or unfavorable (n=14, 20%) cytogenetic and molecular features based on criteria of 2011 NCCN guidelines. Three patients with favorable cytogenetics were second complete remission (n=2) or had persistent disease (n=1) at transplantation. All but one patients (99%) and 49 donors (71%) were cytomegalovirus (CMV)-seropositive. Offspring (n=12), mothers (n=7), and siblings (n=4) were donors for FMT. There was no significant difference in patients and transplant characteristics, such as age and pre-transplant disease status, among the three donor groups.All patients were successfully engrafted. The median time to neutrophil (>0.5^109/L) and platelet (>20^109/L) recovery were 12 days (range, 10–21) and 13 days (range, 8–60) for WM-UR, 12 days (range, 9–22) and 13 days (range, 9–25) for PM-UR, and 11 days (range, 10–17) and 12 days (range, 8–40) for FMT, respectively. There was no significant difference in the neutrophil (P=0.370) and platelet (P=0.487) recovery times between groups. With 24 months (range, 6–34) of median follow-up for surviving patients, overall survival (OS), disease-free survival (DFS), relapse, and non-relapse mortality were 82.7%, 82.9%, 9.4%, and 7.6% for WM-UD, 61.5%, 61.5%, 30.8%, and 7.7% for PM-UD, and 68.9%, 70.0%, 17.9%, and 12.1% for FMT. Multivariate analyses revealed that PM-UD had significantly inferior OS (HR 3.68, 95% CI 1.04–13.1) and DFS (HR 3.1, 95% CI 0.90–10.73), and higher relapse rate (HR 6.09, 95% CI 1.28–29.01) than WM-UD, whereas no significant difference in FMT [OS (HR 2.08, 95% CI 0.59–7.30), DFS (HR 1.95, 95% CI 0.60–6.40), and relapse (HR 1.19, 95% CI 0.55–2.57)]. The occurrence of acute GVHD (aGVHD) with grade II-IV (WM-UD vs. PM-UD vs. FMT; 48.5% vs. 38.5% vs. 52.2%; P = 0.65) and chronic GVHD (cGVHD; WM-UD vs. PM-UD vs. FMT; 51.9% vs. 38.5% vs. 47.8%; P = 0.25) were not significantly different in three donor groups. CMV reactivation was more common in FMT (91.3%, P=0.047) than WM-UD (66.7%) and PM-UD (61.5%), but the occurrence of CMV disease was not different (WM-UD vs. PM-UD vs. FMT; 6.1% vs. 7.7% vs. 17.4%; P=0.390). Causes of death were the recurrence of leukemia (n=3) and refractory cGVHD (n=1) for WM-UD, the recurrence of leukemia (n=4) and aGVHD combined with CMV enteritis (n=1) for PM-UD, and the recurrence of leukemia (n=4) and aGVHD combined with CMV enteritis (n=1), and CMV enteritis combined with veno-occlusive disease (n=1) for FMT.We demonstrate that survival outcomes of FMT using a Korean-adapted protocol are comparable to SCT from WM-UD in contrast to PM-UD showing inferior outcomes than WM-UD. Our data suggest that FMT may be a better option than PM-UD for high-risk AML in the absence of WM-UD as well as HLA-identical sibling donors if complemented by more efficient CMV prophylactic measures, which needs to be validated with more large scale prospective trials in the future. Disclosures:No relevant conflicts of interest to declare.

Unrelated cord blood transplantation for thalassaemia: a single-institution experience of 35 patients

Our study was designed to prospectively determine whether or not unrelated cord blood transplantation (CBT) can produce outcomes comparable to related donor transplantation for children with β-thalassaemia. In 35 patients, 40 transplants were performed between October 2003 and September 2009. HLA matching at enrolment was 6/6 (n=8), 5/6 (n=16), 4/6 (n=27), or 3/6 (n=1) by low-resolution HLA-A, -B, and high-resolution DRB1. These patients received non-manipulated grafts without ex vivo expansion or T-cell depletion. The median number of nucleated and CD34+ cells infused was 7.8 × 10(7)/kg (range, 2.8-14.7 × 10(7)/kg) and 4.0 × 10(5)/kg (range, 1.7-19.9 × 10(5)/kg), respectively. The 5-year OS and thalassaemia-free survival after the first transplant were 88.3 and 73.9%, respectively. The cumulative incidence of TRM at 2 years was 11.7%. Fourteen patients developed chronic skin GVHD. Thirty patients were alive and transfusion-independent with a Lansky performance score ≥80% achieved between 6 and 76 months post transplant (median, 36 months). These data compare acceptably with the survival rates of related-donor BMT for thalassaemia and suggest that patients without an available HLA-compatible sibling but who have well-matched unrelated donors should also be considered for CBT.

High-Risk Pediatric Acute Lymphoblastic Leukemia: To Transplant or Not to Transplant?

Because survival with both chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT) approaches to high-risk pediatric acute lymphoblastic leukemia (ALL) generally improves through the years, regular comparisons of outcomes with either approach for a given indication are needed to decide when HSCT is indicated. Improvements in risk classification are allowing clinicians to identify patients at high risk for relapse early in their course of therapy. Whether patients defined as high risk by new methods will benefit from HSCT requires careful testing. Standardization and improvement of transplant approaches has led to equivalent survival outcomes with matched sibling and well-matched unrelated donors; however, survival using mismatched and haploidentical donors is generally worse. Trials comparing chemotherapy and HSCT must obtain sufficient data about therapy and stratify the analysis to assess the outcomes of best-chemotherapy with best-HSCT approaches.

Graft-Versus-Tumor Effect In Patients with Graft-Versus-Host Disease Defined by NIH Consensus Criteria

AbstractAbstract 2343 Background.The National Institutes of Health consensus criteria (NCC) for chronic graft-versus-host disease (GVHD) are based on clinical manifestations rather than onset time after transplantation. Previous studies about the feasibility of the new criteria have been performed in patients who survived beyond 100 days after transplantation and had GVHD presenting after day 100. In order to investigate and compare the clinical impact of acute and chronic GVHD by NCC on survival, a cohort including patients with GVHD presenting ‘before’ as well as ‘after’ day 100 is needed. Additionally, a proper statistical tool should be applied to clarify the effect of GVHD on survival outcomes, because the occurrence of GVHD is a well known time-dependent event. In this context, we examined a cohort including all patients who underwent allogeneic stem cell transplantation (SCT) in order to investigate clinical impact of acute or chronic GVHD by NCC on survival outcomes. Methods.We retrospectively investigated 771 patients who underwent allogeneic SCT between January 2002 to December 2008. To study a homogenous cohort, patients received 2 allogeneic SCT and/or donor-lymphocyte-infusion was excluded. We used time-dependent analyses to reveal the effect of GVHD on survival outcomes. In particular, to approach the effects of GVHD as a time-dependent covariate on competing risks [relapse or transplant-related mortality (TRM)], we analyzed cause-specific hazards by Cox proportional hazards regression model (Cartese G, Andersen PK. Biometrical Journal 2009;51:138–158). Results.The median age was 36 years (range, 15–68). Patients had various hematologic malignancies (AML/ALL/CML/MDS/MM, 361/226/86/67/31, respectively) and were transplanted from matched sibling (n=485), well-matched unrelated donors (n=154), partially-matched unrelated donors (n=101), and mismatched unrelated donors (n=31). Conditioning regimens consisted of myeloablative (n=536) and reduced-intensity regimens (n=235). GVHD prophylaxis consisted of cyclosporine and short-course methotrexate for related SCT and tacrolimus and short-course methotrexate for unrelated SCT. Among 771 patients, 540 patients were diagnosed with GVHD after transplantation. According to onset time of GVHD, in 348 patients GVHD developed within 100 days after SCT, whereas in 156 patients GVHD occurred more than 100 days after SCT. Using the NCC, we classified patients as three categories regardless of onset time: (1) acute GVHD (n=215), if patients had only acute features (no chronic features) during the course of GVHD, (2) acute GVHD with following chronic GVHD (n=118), if patients had any chronic features after the occurrence of acute GVHD, and (3) chronic GVHD (n=207), if patients had any chronic features at the onset of GVHD. Multivariate analyses using cause-specific hazards revealed that acute GVHD was significantly associated with lower relapse incidence [HR (95% CI) 0.65 (0.44–0.94), P=0.023]. However, it did not influence disease-free survival (DFS, P=0.602) and overall survival (OS, P=0.294) due to higher TRM in patients with acute GVHD [HR (95% CI) 1.74 (1.15–2.61), P=0.008]. Acute GVHD with following chronic GVHD was also associated with lower relapse incidence [HR (95% CI) 0.31 (0.15–0.66), P=0.002] and higher TRM [HR (95% CI) 2.89 (1.65–5.04), P<0.001], which did not influence DFS (P=0.567) and OS (P=0.820). On the other hand, the occurrence of chronic GVHD significantly reduced relapse rates [HR (95% CI) 0.46 (0.29–0.75), P=0.002] without increasing TRM (P=0.177). Indeed, this effect was translated into improved DFS [HR (95% CI) 0.67 (0.48–0.95), P=0.023]. Conclusions.Our data show that both acute and chronic GVHD by NCC reduced the risk of relapse, demonstrating the presence of graft-versus-tumor (GVT) effect by the occurrence of GVHD and no difference according to the clinical features (acute or chronic) by NCC. However, survival benefit was only observed in chronic GVHD by NCC compared to acute GVHD with/without following chronic GVHD by NCC due to higher TRM. This study represents the first one demonstrating the GVT effect of GVHD defined by NCC in a cohort including GVHD presenting ‘before’ as well as ‘after’ day 100 using appropriate time-dependent analyses by cause-specific hazards by Cox proportional hazards regression model. Disclosures:No relevant conflicts of interest to declare.

Long-Term Outcomes of TBI-Based Myeloablative SCT In 292 Consecutive Adults with Ph-Negative ALL: Similar Outcomes for Transplantation Using Related Donor, Well-Matched Unrelated Donor, or Partially Matched Unrelated Donor Sources

AbstractAbstract 2355 Background:The graft-versus-leukemia effect in adult acute lymphoblastic leukemia (ALL) has now been definitely confirmed from the ‘matched related donor (RD) versus no donor’ comparisons. However, no definite conclusions can be extracted from these data as to whether or not there is a survival advantage to RD-stem cell transplantation (SCT) over other therapeutic modalities for both high-risk and standard-risk patients with Philadelphia (Ph)-negative ALL. In addition, ‘RD versus no donor’ approach is becoming outmoded, as in many studies those previously in a ‘no donor’ category are now undergoing unrelated donor (URD)-SCT. Aims:We report long-term outcomes of total body irradiation-based myeloablative SCT in 292 consecutive adults with Ph-negative ALL who received transplants at our center between 1995 and 2008 (median follow-up of survivors, 85 months). This study focused on following questions: (1) How different are the outcomes of SCT according to the donor sources? (2) Which factors are important to determination of transplantation outcome? (3) Which URD should be chosen? (4) Is there a role of autologous (AUTO)-SCT plus maintenance chemotherapy? Methods:Median age was 25 years (range, 15–63 years). Overall, 237 (81.2%) of 292 patients had one or more high-risk features, including adverse cytogenetics [t(4;11), t(8;14), complex (>=5 abnormalities), Ho-Tr], older age (>=35 years), high leukocyte counts (>=30×109/L for B-ALL, >=100×109/L for T-ALL), or delayed first complete remission (CR1; >28 days). Two hundred and forty-one patients (82.5%) were transplanted in CR1; 22 (7.6%) in CR2; and 29 (9.9%) in advanced status. URD sources were classified as well-matched (WM), partially matched (PM), and mismatched (MM) based on a new proposed guideline from the NMDP-CIBMTR. Donor sources were RD (n=132), WM-URD (n=30), PM-URD (n=19), MM-URD (n=19), and AUTO (n=92). All patients and donors provided written informed consent, and the treatment protocol was approved by the institutional review board of The Catholic University of Korea. Results:Cumulative incidence of relapse at 5 years was 48.5% for AUTO versus 32.6% for RD, 19.4% for WM-URD, 32.3% for PM-URD, and 51.0% for MM-URD (RR, 2.70; 95% CI, 1.65 to 4.42; p<0.001). In multivariate analyses, other factors associated with higher relapse risk included transplantation in CR2 or later (p<0.001), T-lineage ALL (p=0.020), and adverse cytogenetics (p=0.038). Cumulative incidence of non-relapse mortality (NRM) at 5 years was 40.5% for MM-URD versus 19.6% for SD, 20.3% for WM-URD, 15.8% for PM-URD, and 9.8% for AUTO (RR, 3.09; 95% CI, 1.32 to 7.25; p=0.010). Patients older than 35 years had higher NRM (p=0.007). As a result, disease-free survival (DFS) at 5 years was inferior using AUTO (46.1%; RR, 1.69; 95% CI, 1.14 to 2.51; p=0.010) or MM-URD (26.3%; RR, 2.03; 95% CI, 1.05 to 3.95; p=0.036), compared to RD sources, while DFS from all other donor sources was approximately equivalent (53.5% for RD, 63.3% for WM-URD, and 57.0% for PM-URD). Transplantation in CR2 or later (p<0.001), older age (p=0.020), and adverse cytogenetics (p=0.041) were associated with poorer DFS. In a pairwise comparison of outcomes between RD-SCT and AUTO-SCT for patients in CR1, the inferiority of AUTO-SCT was observed, particularly in high-risk patients. Conversely, in standard-risk patients, AUTO-SCT yielded comparable outcomes to RD-SCT. Summary/Conclusions:Our long-term data suggest that outcomes are similar for transplantation using SD, WM-URD, or PM-URD sources, and these may be considered the best donor sources for adults with Ph-negative ALL, especially for those with high-risk features. Disclosures:No relevant conflicts of interest to declare.

Permissive HLA-DPB1 Mismatching Compared to a Non-Permissive Mismatching Significantly Improves Overall Survival Following Allogeneic Transplantation In Patients with Both 10/10 and 9/10 Matched Unrelated Donors

AbstractAbstract 227It is well established that the use of a donor matched for 9–10/10 alleles at HLA-A,-B,-C,-DRB1,-DQB1 significantly improves overall survival (OS) after unrelated donor (UD) haematopoietic stem cell transplantation (HSCT). Whilst the matching status for HLA-DPB1 alleles has been shown to influence transplant complications (relapse and graft-versus-host disease (GVHD), its impact on survival has not been well defined. The current unmet need in clinical practice is an approach to stratify selection criteria when a clinician is confronted with the choice between several 10/10 or 9/10 matched unrelated donors.There is now considerable interest in exploring different types of matching criteria to define permissive HLA-DPB1 mismatches which may be associated with an improved outcome. We have previously shown that HLA-DPB1 permissiveness can be functionally defined by the characterization of shared T cell epitopes (TCE) recognized by alloreactive T cells. In this model, allelic HLA mismatches are classified as permissive if they do not involve TCE disparities, and as non-permissive if they do. Using this concept, we developed two overlapping algorithms of permissivity for allelic HLA-DPB1 mismatches, on the basis of 3 (TCE3) or 4 (TCE4) groups of DPB1 alleles encoding immunogenic TCE. Data from relatively small prospective studies has shown a worse outcome to be associated with non-permissive DPB1 TCE disparities.Here, we present outcomes in 9123 UD-HSCT pairs, collected through the International Histocompatibility Working Group (IHWG). The cohort was comprised of 5809 10/10 matched transplant pairs and 3314 9/10 matched pairs. Within the 10/10 and 9/10 matched pairs three groups of patients were identified: 1. Zero DPB1 mismatches (i.e. allele matched), 2. Permissive DPB1 mismatch, 3. Non-permissive DPB1 mismatch. The model was adjusted for disease severity, source of stem cells, conditioning regimen, use of T-cell depletion, patient/donor gender and patient age.In line with DPB1 allele frequencies in worldwide populations, the number of transplants scored as permissive was higher for TCE3 (4398/7270 [60.4%]) than for TCE4 (2577/7270 [35.4%]). Using the DPB1 permissive mismatch transplants as the reference group (either 10/10 or 9/10 matched), we showed that DPB1 allelic matches resulted in similar survivals to DPB1 permissive mismatches, both in the 10/10 (HR 0.96, p=0.498 for TCE3 and HR 0.99, p=0.85 for TCE4) and the 9/10 setting (HR 0.97, p=0.70 for TCE3 and HR 0.99, p=0.96 for TCE4).In contrast, survival was significantly worse in the presence of a non-permissive TCE3 or TCE4 mismatch, both in the 10/10 (HR 1.15, p=0.0005 for TCE3 and HR 1.13, p=0.0035 for TCE4) and in the 9/10 matched setting (HR 1.13, p=0.0140 for TCE3 and HR 1.11, p=0.0448 for TCE4). The survival detriment appeared to be due to a significantly increased non-relapse mortality (TCE3: 10/10 HR 1.27, p<0.001 and 9/10 HR 1.21, p=0.0001; TCE4: 10/10 HR 1.24, p<0.001 and 9/10 HR 1.13, p=0.0514), as well as an increase in grades II-IV acute GVHD (TCE3: 10/10 HR 1.17, p<0.001 and 9/10 HR 1.29, p<0.001; TCE4: 10/10 HR 1.12, p=0.0035 and 9/10 HR 1.19, p<0.0001). There was no significant difference in disease relapse between permissive and non-permissive mismatched pairs. Finally, using the 10/10 DPB1 permissive mismatched group as a reference, we found survival to be similar for 10/10 DPB1 non-permissive (HR 1.15) and 9/10 DPB1 permissive (HR 1.20) or DPB1 allele matched (HR 1.17) transplants.In conclusion, our results suggest that extending donor selection to include HLA-DPB1 both allelic and functional TCE matching may result in better prediction of survival for patients. These findings provide an attractive new algorithm to stratify donor choice when several well-matched UD are identified. Disclosures:No relevant conflicts of interest to declare.

The outcome of full-intensity and reduced-intensity conditioning matched sibling or unrelated donor transplantation in adults with Philadelphia chromosome–negative acute lymphoblastic leukemia in first and second complete remission

AbstractWe examined the efficacy of reduced-intensity conditioning (RIC) and compared outcomes of 93 patients older than 16 years after RIC with 1428 patients receiving full-intensity conditioning for allografts using sibling and unrelated donors for Philadelphia-negative acute lymphoblastic leukemia (ALL) in first or second complete remission. RIC conditioning included busulfan 9 mg/kg or less (27), melphalan 150 mg/m2 or less (23), low-dose total body irradiation (TBI; 36), and others (7). The RIC group was older (median 45 vs 28 years, P < .001) and more received peripheral blood grafts (73% vs 43%, P < .001) but had similar other prognostic factors. The RIC versus full-intensity conditioning groups had slightly, but not significantly, less acute grade II-IV graft-versus-host disease (39% vs 46%) and chronic graft-versus-host disease (34% vs 42%), yet similar transplantation-related mortality. RIC led to slightly more relapse (35% vs 26%, P = .08) yet similar age-adjusted survival (38% vs 43%, P = .39). Multivariate analysis showed that conditioning intensity did not affect transplantation-related mortality (P = .92) or relapse risk (P = .14). Multivariate analysis demonstrated significantly improved overall survival with: Karnofsky performance status more than 80, first complete remission, lower white blood count, well-matched unrelated or sibling donors, transplantation since 2001, age younger than 30 years, and conditioning with TBI, but no independent impact of conditioning intensity. RIC merits further investigation in prospective trials of adult ALL.

Allogeneic transplantation for therapy-related myelodysplastic syndrome and acute myeloid leukemia

AbstractTherapy-related myelodysplastic syndromes (t-MDSs) and acute myeloid leukemia (t-AML) have a poor prognosis with conventional therapy. Encouraging results are reported after allogeneic transplantation. We analyzed outcomes in 868 persons with t-AML (n = 545) or t-MDS (n = 323) receiving allogeneic transplants from 1990 to 2004. A myeloablative regimen was used for conditioning in 77%. Treatment-related mortality (TRM) and relapse were 41% (95% confidence interval [CI], 38-44) and 27% (24-30) at 1 year and 48% (44-51) and 31% (28-34) at 5 years, respectively. Disease-free (DFS) and overall survival (OS) were 32% (95% CI, 29-36) and 37% (34-41) at 1 year and 21% (18-24) and 22% (19-26) at 5 years, respectively. In multivariate analysis, 4 risk factors had adverse impacts on DFS and OS: (1) age older than 35 years; (2) poor-risk cytogenetics; (3) t-AML not in remission or advanced t-MDS; and (4) donor other than an HLA-identical sibling or a partially or well-matched unrelated donor. Five-year survival for subjects with none, 1, 2, 3, or 4 of these risk factors was 50% (95% CI, 38-61), 26% (20-31), 21% (16-26), 10% (5-15), and 4% (0-16), respectively (P < .001). These data permit a more precise prediction of outcome and identify subjects most likely to benefit from allogeneic transplantation.

Transplant Outcomes in Acute Leukemia (II)

Currently, it is possible to find a hematopoietic stem cell (HSC) donor for virtually all patients with acute leukemia who have an indication to receive an allogeneic hematopoietic stem cell transplant (HSCT) and lack a human leukocyte antigen (HLA)-identical sibling or a well-matched HLA unrelated donor (URD). According to the ethnicity of the patients and the donor registry, approximately 25% to 60% of patients will not find an 8/8 HLA-matched unrelated donor. Other alternative donors, such as HLA-mismatched related donor or unrelated donor umbilical cord blood (UCB), have emerged to solve the lack of a sibling or well-matched URD. In the haploidentical HSCT setting, new techniques of T-cell depletion, new approaches using combinations of immunosuppressive drugs or different conditioning regimens, and developments on immunotherapy have focused attention on this option. Therefore, any physician has to carefully evaluate, for each patient in need of an allograft, all of the possible alternatives in order to choose the best HSC donor, taking into account type of disease to be transplanted, urgency of transplantation, donor characteristics, and center experience. This review evaluates the current status of haploidentical HSCT in acute leukemia, its advantages and remaining limitations compared to other stem cell sources, and how these data may be used in the development of donor selection algorithms.