HLA Allele-matched Unrelated Donor Research Articles

An Optimized Search Prognosis Tool to Predict 8/8 HLA Allele-Matched Unrelated Donor Procurement

For patients in need of allogeneic transplantation who lack an HLA-identical sibling, an 8/8 HLA allele-matched unrelated donor (URD) is a standard alternative. However, delays in URD procurement can adversely impact patient care. Recipient genotype and search assessment (MSKv1.0)-based tools can predict search prognosis for many, but both tools have lower performance in non-European ancestry patients. Using the MSKv1.0 tool, we analyzed searches from 1530 potential allograft recipients (including 863 who underwent transplantation) with the aim of creating an optimized MSKv2.0 search prognosis tool that can classify a URD search as either Good or Poor with a high level of accuracy while also limiting an ambiguous Fair search prognosis regardless of patient ancestry. By MSKv2.0, the 8/8 URD search prognosis distribution was 57% Good, 21% Fair, and 22% Poor in Europeans and 15% Good, 21% Fair, and 63% Poor in non-Europeans. Importantly, compared to MSKv1.0, the likelihood of Fair categorization was reduced to <25% with comparable Fair rates (P=.847) in both European and non-European groups. Moreover, all patients with an MSKv2.0 Good prognosis had an 8/8 URD identified, and almost all of those who underwent transplantation had an 8/8 URD (Europeans, 99%; non-Europeans, 98%; P=.504). The MSKv2.0 tool also was highly accurate at classifying Poor searches, with <10% identifying an 8/8 URD, and almost all patients who underwent transplantation (Europeans, 95%; non-Europeans, 96%) receiving an alternative donor. Using preliminary search results, MSKv2.0 accurately classifies patients by likelihood of 8/8 URD procurement, greatly facilitating triage to 8/8 URD (Good prognosis) or alternative donor (Poor prognosis) transplantations.

Relapse Is the Most Common Treatment Failure Post HSCT in Children with ALL below 4 Years of Age Given a Chemo-Based Conditioning Regimen. Results from the Prospective Multinational Forum-Trial

Background: Relapse and non-relapse mortality (NRM) are the major causes of treatment failure in infants and young children with high-risk ALL undergoing HSCT. Conditioning regimens for this high-risk population usually omit total body irradiation (TBI) to avoid acute and long-term side effects that are more pronounced in this age group. The optimal chemotherapeutic approach aiming improved event-free survival (EFS) and low NRM is not yet defined. Methods: The prospective FORUM trial used two myeloablative chemo-conditioning regimens for children <4 years (yrs) of age: fludarabine (FLU), thiotepa (THIO) and either intravenous busulfan (BU) or treosulfan (TREO) as described previously (Peters et al., JCO 2021). This report includes 194/202 patients (pts) (107 male, 87 female) from 26 countries enrolled in FORUM who received HSCT (5 pts received TBI-based conditioning and 3 pts with unknown conditioning were excluded). Median age at HSCT was 2.2 yrs (6 months - 4 yrs; 38 pts 0-1yrs (20%), 53 pts 1-2yrs (27%), 53 pts 2-3yrs (27%), 50 pts 3-4yrs (26%)). Stem cell source was bone marrow in 132 (68%) pts, peripheral blood stem cells in 37 (19%), and cord blood in 24 (13%). Donors were HLA-matched siblings (MSD) in 39 (20%) pts and 9 or 10/10 HLA allele-matched unrelated donors (MUD) in 155 (80%) pts.Clonal genetic abnormalities reported at diagnosis included 9 pts with BCR-ABL, 13 pts with TEL-AML, and 53 pts with KMT2A r-rearrangements; all pts underwent HSCT in complete morphological remission (CR) (142 pts CR1; 50 pts CR2, 2 pts CR3). FLU/THIO/BU and FLU/THIO/TREO were used in 101, and 93 HSCTs, respectively. Graft-versus-host-disease (GvHD)-prophylaxis was Cyclosporin-A-based in 90%; recipients of MUD-grafts also received ATG and 3 doses of methotrexate. At data cut-off, median follow-up (FU) was 3 yrs (range, 3 months - 7.2 yrs). Results: 3-yrs OS was 0.69±0.04, 3-yrs EFS was 0.52±0.04; 3-yrs Cumulative incidence of relapse (CIR) was 0.44+0.04, and 3-yrs NRM was 0.05 ± 0.02. OS and EFS did not differ between pts < 2 and 2-4 yrs of age at HSCT (Table 1). Pts transplanted in CR 1 had significantly better EFS (0.58±0.04) as compared to >CR1pts (0.36±0.07, p=0.01); due to a higher CIR. OS was worse for the 53 pts with KMT2A-rearrangements (3-yrs OS 0.56±0.08 vs. 0.73±0.04, p=0.040). EFS for pts < 1 yr of age at diagnosis was significantly inferior as compared to older pts (3-yrs EFS 0.40±0.05 vs. 0.63±0.05, p=0.002). OS/EFS were not significantly different when donor type, stem cell source, and immunophenotype were compared (Table 1). At 3-yrs, OS was 0.63±0.05 and 0.76±0.05 and EFS was 0.52±0.05 and 0.51±0.06 (p=0.794) for the FLU/THIO/BU and FLU/THIO/TREO-group, respectively (p=0.075) with no significant difference in CIR and TRM. However, pts who relapsed post-HSCT had a better 3-yr post-relapse OS after FLU/THIO/TREO compared to FLU/THIO/BU (0.38±0.11; 0.16±0.07. p = 0.012) respectively. Most relapses occurred prior to 1 yr after HSCT. Acute GVHD occurred in 32 pts (20 pts experienced grade III/IV) with no significant difference between the two conditioning regimen). The 3-yr incidence of chronic GVHD (cGVHD) was comparable between the BU- and -TREO-group (p = 0.943). cGVHD/relapse-free survival at 3 yrs for FLU/THIO/BU was 0.44±0.05 and for FLU/THIO/TREO 0.41±0.06 (p=0.943). In multivariate analysis, remission > CR1 and the presence of KMT2A, negatively influence OS while EFS was worse for patients who underwent HSCT > CR1 or had ALL-diagnosis below 1 yr of age. Donor type, stem cell source, age between 1 and 4 yrs at HSCT, conditioning regimen, and PCR-MRD positivity pre-HSCT did not significantly influence outcome. 1-yr TRM was low for both conditioning regimens (0.06±0.02 for FLU/THIO/BU and 0.03±0.02 after FLU/THIO/TREO (n.s.) Conclusion: Within the FORUM-trial, infants and young children receiving HSCT after conditioning with either BU- or TREO containing regimens have a lower OS and EFS as compared to children above the age of 4 yrs due to a higher CIR. Because of decreased NRM, these results represent an improvement as compared to previously reported series; however, KMT2A-rearrangement continues to be an obstacle to successful HSCT. Pre- and post-transplant immunotherapeutic strategies aimed at reducing relapse-incidence without increasing chemotherapy-associated complications are needed. Figure 1: 3-yrs OS according to Conditioning Flu: fludarabine, Thio: thiotepa, Treo: treosulfan, Bu: busulfan Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Racial Disparities in Access to Alternative Donor Allografts Persist in the Era of “Donors for All”

Racial Disparities in Access to Alternative Donor Allografts Persist in the Era of “Donors for All”

HLA-A alleles influencing NK cell function impact AML relapse following allogeneic hematopoietic cell transplantation

AbstractHLA-B allotypes exhibiting the Bw4 epitope trigger variable inhibitory signaling of KIR3DL1 receptor types, where strong inhibitory HLA-B and KIR3DL1 allele combinations are associated with increased risk for relapse of acute myelogenous leukemia (AML) following allogeneic hematopoietic cell transplantation (HCT). Several HLA-A allotypes also exhibit the Bw4 epitope. Studies with natural killer (NK) cell clones have demonstrated NK inhibition via KIR3DL1 by HLA-A Bw4+ allotypes, but did not delineate strengths of inhibition or hierarchies of NK education. Using primary NK cells from healthy donors, we demonstrate that HLA-A*23, HLA-A*24, and HLA-A*32 proteins are expressed at different densities and exhibit different capacities to educate and inhibit KIR3DL1-expressing NK cells in vitro. Among the HLA-A Bw4+ allotypes, HLA-A*24 and HLA-A*32 demonstrate the strongest inhibitory capacity. To determine if HLA-A allotypes with strong inhibitory capacity have similar negative impact in allogeneic HCT as HLA-B Bw4+ allotypes, we performed a retrospective analysis of 1729 patients with AML who received an allogeneic HCT from a 9/10 or 10/10 HLA allele-matched unrelated donor. Examination of the donor-recipient pairs whose Bw4 epitope was exclusively contributed from HLA-A*24 and A*32 allotypes revealed that patients with HLA-A*24 who received an allograft from a KIR3DL1+ donor experienced a higher risk of disease relapse (hazard ratio, 1.65; 95% confidence interval, 1.17-2.32; P = .004) when compared with patients without a Bw4 epitope. These findings indicate that despite weak affinity interactions with KIR3DL1, common HLA-A allotypes with the Bw4 epitope can interact with KIR3DL1+ donor NK cells with clinically meaningful impact and provide additional insight to donor NK alloreactivity in HLA-matched HCT.

Differences in Graft-versus-Host Disease Characteristics between Haploidentical Transplantation Using Post-Transplantation Cyclophosphamide and Matched Unrelated Donor Transplantation Using Calcineurin Inhibitors.

We assessed differences in presentation and response to therapy in 394 consecutive patients who developed acute or chronic graft-versus-host disease (GVHD) after receiving their first allogeneic transplantation (HSCT) from a 10/10 HLA allele-matched unrelated donor (MUD; n=179) using calcineurin inhibitors or a T cell-replete haploidentical donor (haplo; n=215) and post-transplantation cyclophosphamide at our center between 2005 and 2017. The median duration of follow-up for survivors was 52.5 months. The cumulative incidences for grade II-IV and grade III-IV acute GVHD at day 180 post HCT were similar, at 39% and 14%, respectively, for haplo-HSCT compared with 50% and 16% for MUD HSCT (P not significant). Haplo-HSCT recipients had a lower cumulative incidence of moderate to severe chronic GVHD, at 22% (severe, 19%), compared with 31% (severe, 29%) for MUD HSCT recipients (P=.026). The time to onset of moderate to severe chronic GVHD was faster for haplo-HSCT recipients (213 days versus 280 days; P=.011). Among patients with grade II-IV acute GVHD, there was no significant between-group difference in organ involvement, with skin the most affected (75% for haplo-HSCT versus 70% for MUD HSCT), followed by the gastrointestinal tract (71% versus 69%) and liver (14% versus 17% MUD). For chronic GVHD, haplo-HSCT recipients had less involvement of the eyes (46% versus 75% for MUD; P < .001) and of the joints/fascia (12% versus 36%; P=.001). Also for cGVHD patients, haplo-HSCT recipients and MUD HSCT recipients had similar all-cause mortality (22% versus 18%; P=.89), but the former were more likely to be off immunosuppression at 2 years post-HCT (63% versus 43%; P=.03) compared with MUD.

Choice of conditioning regimens for bone marrow transplantation in severe aplastic anemia

AbstractAllogeneic bone marrow transplantation (BMT) is curative therapy for the treatment of patients with severe aplastic anemia (SAA). However, several conditioning regimens can be used for BMT. We evaluated transplant conditioning regimens for BMT in SAA after HLA-matched sibling and unrelated donor BMT. For recipients of HLA-matched sibling donor transplantation (n = 955), fludarabine (Flu)/cyclophosphamide (Cy)/antithymocyte globulin (ATG) or Cy/ATG led to the best survival. The 5-year probabilities of survival with Flu/Cy/ATG, Cy/ATG, Cy ± Flu, and busulfan/Cy were 91%, 91%, 80%, and 84%, respectively (P = .001). For recipients of 8/8 and 7/8 HLA allele-matched unrelated donor transplantation (n = 409), there were no differences in survival between regimens. The 5-year probabilities of survival with Cy/ATG/total body irradiation 200 cGy, Flu/Cy/ATG/total body irradiation 200 cGy, Flu/Cy/ATG, and Cy/ATG were 77%, 80%, 75%, and 72%, respectively (P = .61). Rabbit-derived ATG compared with equine-derived ATG was associated with a lower risk of grade II to IV acute graft-versus-host disease (GVHD) (hazard ratio [HR], 0.39; P < .001) but not chronic GVHD. Independent of conditioning regimen, survival was lower in patients aged >30 years after HLA-matched sibling (HR, 2.74; P < .001) or unrelated donor (HR, 1.98; P = .001) transplantation. These data support Flu/Cy/ATG and Cy/ATG as optimal regimens for HLA-matched sibling BMT. Although survival after an unrelated donor BMT did not differ between regimens, use of rabbit-derived ATG may be preferred because of lower risks of acute GVHD.

Outcomes of Unrelated Bone Marrow Transplantation in Patients with Thalassemia

Introduction. Bone marrow transplantation from an HLA-matched related or unrelated donor remains the only curative treatment for patients with thalassemia. Although one third of patients with thalassemia can find a matched unrelated donor (MUD) few patients were treated by MUD transplantation. Early experience with the use of MUD transplant in class 3 patients with thalassemia resulted in high rates of graft rejection and transplant-related mortality with thalassemia-free (TFS) survival of 53% (La Nasa G et al. Blood 2002). Significant improvements in MUD transplantation in recent years have prompted us to consider it also for high risk patients with thalassemia.Methods. All patient-donor pairs were typed at high resolution for HLA-A, -B, -C, -DRB1, -DQA1, -DQB1, and DPB1. Fourteen consecutive patients with a median age of 5 years (range, 2-17.2) received unrelated bone marrow transplantation for thalassemia. Four patients were in class 1, 2 were in class 2 and 8 were in class 3 of risk. All patients were treated with the conditioning regimen consisting of weight-based IV Bu, thiotepa (10 mg/kg/d), CY (200 mg/kg) and thymoglobulin (10 mg/kg) preceded by preconditioning with hydroxyurea (30 mg/kg/d), azathioprine (3 mg/kg/d) from D −45, and fludarabine (30 mg/m2/d) from D −16 through D −12. Patients received CSA, methylprednisolone and a short course of MTX as GVHD prophylaxis.Results. Between May 2009 and December 2017 un unrelated donor search was performed for 47 patients at our Institute. Forty one patients were Caucasian and 6 patients black African origin. Among Caucasians 16/41 (39%) found a 10/10 and 5/41 (12%) a 9/10 HLA allele-matched unrelated donor, while 1 of 6 black African patients (16.6%) found a 10/10 HLA-matched donor. Among 22 patients with a suitable donor (10/10 or 9/10 HLA allele-matched) 14 received transplantation, 2 patients withdrew consent, 1 patient's donor refused donation, and the remaining 5 patients are awaiting transplant.Twelve patients received 10/10 and 2 patients 9/10 HLA allele-matched grafts. Eight patients had permissive DPB1 mismatches while 2 patients had non-permissive mismatches in the HvG direction and 4 patients in the GvH direction. Median TNC/kg and CD34+/kg infused were 7.2x108 (range, 3.95-12.5) and 7.75x106 (range, 3.47-16.4), respectively. Sustained engraftment occurred in all patients. The median time to neutrophil and platelet recovery was 20 days (range, 15-27) and 19 days (range, 15-28), respectively. All but one patient showed 100% donor chimerism. The patient with stable mixed chimerism (48% donor DNA) has remained transfusion independent for over 3 years with hemoglobin levels >13.5-14 g/dL. Grade 2 and 3-4 acute GVHD occurred in 3 (21%) and 2 (14%) patients, respectively. Two patients developed mild (skin) or severe (skin, gut and liver) chronic GVHD. There was no association between non permissive DPB1 mismatches in the GvH direction and GVHD. All but one patient are alive and are off immunosuppressive therapy. One patient died due to chronic GVHD-related complications. The median follow-up among surviving patients was 2.8 years (range, 0.8-8.6). The 5-year OS and TFS probabilities were 90% (95% CI 47 to 99%) (Figure 1). Patients showed suboptimal CD4+ recovery within the first year: absolute (mean±SEM) cells/ul of CD4+ at 6 months was 223±48. At 12 and 24 months recovery of CD4+, CD8+, CD19+ and CD56+ were 597±122, 1077±228, 331±75, 229±64 and 812±284, 1067±405, 218±82, 112±22, respectively.One patient developed mild to moderate hepatic sinusoidal obstruction syndrome which resolved with supportive care. CMV reactivation occurred in 9 patients and none developed CMV disease. One patient developed adenovirus gastroenteritis. EBV reactivation occurred in 4 patients; one developed posttransplant lymphoproliferative disorder that was successfully treated with Rituximab. Bacterial infections were common: 5 (38%) patients developed gram negative or gram positive sepsis and 4 (29%) patients pneumonia. Probable invasive fungal infections occurred in 2 (14%) patients.Conclusions. This study showed that unrelated donor BMT can successfully cure a proportion of patients with thalassemia. Remarkably, despite 57% of patients were in class 3 of risk the 5-year OS and TFS rates were 90%. We conclude that class 3 patients with thalassemia who have a suitably matched unrelated donor should not be denied the option of transplantation. DisclosuresNo relevant conflicts of interest to declare.

Significance of HLA 1-locus mismatch and ATG administration in unrelated hematopoietic stem cell transplantation

HLA 1-locus-mismatched unrelated donors (1MMUD) are used in allogeneic hematopoietic stem cell transplantation (allo-HCT) for patients who lack an HLA-matched donor. Here we retrospectively reviewed 3,313 patients with acute leukemia or myelodysplastic syndrome who underwent bone marrow transplantation from an HLA allele-matched unrelated donor (MUD) or 1MMUD in 2009-2014. We compared the outcomes of MUD (n＝2,089) and 1MMUD with antithymocyte globulin [ATG; 1MM-ATG (＋) ; n＝109] with those of 1MMUD without ATG [1MM-ATG (-) ; n＝1,115]. In the 1MM-ATG (＋) group, the median total dose of ATG (thymoglobulin) was 2.5 (range, 1.0-11.0) mg/kg. The rates of grade III-IV acute GvHD, non-relapse mortality (NRM), and overall mortality were significantly lower in the MUD group than in the 1MM-ATG (-) group [hazard ratio (HR) 0.77; P＝0.016; HR, 0.74, P<0.001; and HR, 0.87, P＝0.020, respectively]. Similarly, the rates of grade III-IV acute GvHD, NRM, and overall mortality were significantly lower in the 1MM-ATG (＋) group than in the 1MM-ATG (-) group (HR, 0.42, P＝0.035; HR, 0.35, P<0.001; and HR, 0.71, P＝0.042, respectively). Even in the recent cohort, the outcome of allo-HCT from 1MM-ATG (-) was inferior to that of allo-HCT from MUD. Nevertheless, the negative impact of 1MMUD disappeared with the use of low-dose ATG without exacerbating the risk of relapse.

The impact of alternative donor types on viral infections in pediatric hematopoietic stem cell transplantation.

Viral infections remain one of the most important complications following allogeneic HSCT. Few reports compare virus infection between different donor types in pediatric patients. We retrospectively analyzed viral infections and the outcome of one hundred and seventy‐one pediatric patients (median 7.38 years) who underwent allogeneic HSCT from matched related donor (MRD, n = 71), 10 of 10 HLA allele‐matched unrelated donors (MUD1; n = 29), 9 of 10 HLA allele‐matched unrelated donors (MUD2; n = 40), and haploidentical donors (n = 31). PCR screening for BK virus, adenovirus, Epstein‐Barr virus, parvovirus B19, human herpesvirus 6, and CMV were performed routinely weekly. Infections between 0‐30, 31‐100, and 101 days‐2 years were identified separately. BK virus and CMV reactivations were significantly low in MRD transplant patients (P = .046 and P < .0001, respectively), but incidences of all virus infections between MUD1, MUD2, and haplo‐HSCT were found statistically not different. The OS was found to be affected by having one or multiple virus infection (P = .04 and P = .0008). Despite antiviral prophylaxis and treatments, post‐transplant viral infections are associated with reduced overall survival. Haplo‐HSCT is comparable with MUD transplantation in the setting of viral infections. A larger study group and prospective studies are needed to confirm this observation.

Contribution of Revised International Prognostic Scoring System Cytogenetics to Predict Outcome After Allogeneic Stem Cell Transplantation for Myelodysplastic Syndromes: A Study From the French Society of Bone Marrow Transplantation and Cellular Therapy.

The prognosis of myelodysplastic syndromes (MDS) after allogeneic stem cell transplantation is critically determined by cytogenetic abnormalities, as previously defined by International Prognostic Scoring System (IPSS) cytogenetics. It has been shown that a new cytogenetic classification, included in the IPSS-R (cytogenetic-IPSS-R [C-IPSS-R]), can better predict the outcome of untreated MDS patients. In this study, we assessed the impact of the IPSS-R cytogenetic score (C-IPSS-R) on the outcome of 367 MDS patients transplanted from HLA-identical siblings or HLA allele-matched unrelated donors. According to the C-IPSS-R, 178 patients (48%) fell in the good risk, 102 (28%) in the intermediate risk, 77 (21%) in the poor risk, and 10 (3%) in the very poor risk group. In multivariate analysis, after a median follow-up of 4 years, the poor and very poor-risk categories correlated with shorter overall survival (OS) (4-year OS, 32%; hazard ratio [HR], 1.59; P = 0.009 and OS, 10%; HR, 3.18; P = 0.002, respectively) and higher cumulative incidence of relapse (CIR) (CIR, 52%; HR, 1.82; P = 0.004 and CIR, 60%; HR, 2.44; P = 0.060, respectively). Overall, the C-IPSS-R changed the IPSS cytogenetic risk only in 8% of cases but identified a new risk group, the very poor C-IPSS-R category, with dismal outcome after allogeneic stem cell transplantation (10% 4-year OS, 60% 4-year CIR). Posttransplantation maintenance therapy should be investigated in prospective trials for patients with high-risk C-IPSS-R karyotypes.

Contribution of IPSS-R Cytogenetics to Predict Outcome after Allogeneic Stem Cell Transplantation for Myelodysplastic Syndromes: A Study from the French Society of Bone Marrow Transplantation and Cell Therapy (SFGM-TC)

The prognosis of myelodysplastic syndromes (MDS) after allogeneic stem cell transplantation (allo-SCT) is critically determined by cytogenetic abnormalities. In this study, we assessed the impact of the IPSS-R cytogenetic score (C-IPSS-R) on the outcome of 367 patients with MDS transplanted from HLA-identical siblings or HLA allele-matched unrelated donors. According to the C-IPSS-R 178 patients (48%) fell in the good risk, 102 (28%) in the intermediate risk, 77 (21%) in the poor risk and 10 (3%) in the very poor risk group. In multivariate analysis, the poor and very poor-risk categories correlated with shorter overall survival (HR = 1.59, P = 0.009 and HR = 3.18, P = 0.002, respectively) and higher relapse rates (HR = 1.82, P = 0.004 and HR = 2.44, P = 0.060, respectively), after a median follow-up of 4 years. Overall, the C-IPSS-R changed the IPSS cytogenetic risk only in 8% of cases but identified a new risk group with dismal prognosis. These findings urge the investigation of new post-transplant therapeutic approaches for patients with very poor C-IPSS-R karyotypes, including maintenance therapy. DisclosuresNo relevant conflicts of interest to declare.

Busulfan, Fludarabine, and Alemtuzumab As a Reduced Toxicity Regimen for Children with Malignant and Nonmalignant Diseases Improves Engraftment and Graft-versus-Host Disease without Delaying Immune Reconstitution

For children receiving allogeneic hematopoietic stem cell transplants (HSCTs), the toxicity of the conditioning regimen and graft failure remain challenges. We previously reported that targeted i.v. busulfan, fludarabine, and rabbit anti-thymocyte globulin (rATG) decreased toxicity but had a graft failure rate of 21%. To improve the engraftment rate, we replaced ATG with alemtuzumab, a monoclonal Ab targeting CD52. Thirty-five children with malignant and nonmalignant diseases were enrolled in this phase II prospective study. Twelve children had HLA-matched related donors (MRDs), 16 had 10 of 10, and 7 had 9 of 10 HLA allele-matched unrelated donors (MUDs). Thirty-one of 34 evaluable patients (91%) achieved a durable engraftment. All 3 patients who rejected had a nonmalignant disease and received a MUD transplantation (2 mismatched at 1 antigen). Three patients died of a transplantation-related complication (9% ± 5.2%). Seven patients had disease relapse or progression, 2 of whom died. At a median follow-up of 35 months (range, 15-85 months), the event-free survival (EFS) was 61% ± 9.0% and the overall survival (OS) was 78% ± 7.5%. The median time to neutrophil recovery, B cell, and T cell reconstitution were 16 days, 3 months, and 6 months, respectively. At 1 year, the median donor chimerism in whole blood, CD3, CD14/15, and CD19 subsets were 97%, 87%, 100%, and 99%, respectively. Six patients (17% ± 6.6%) developed acute graft-versus-host disease (aGVHD), only 2 of which were >grade II. Two patients (8% ± 5.4%) progressed to chronic GVHD (cGVHD). These results suggest that replacement of rATG with alemtuzumab may improve engraftment as well as decrease cGVHD rates without resulting in delays in immune reconstitution.

Long-term outcomes of HLA-matched sibling compared with mismatched related and unrelated donor hematopoietic stem cell transplantation for chronic phase chronic myelogenous leukemia: a single institution experience in China

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative therapy for chronic myelogenous leukemia (CML). In this study, the long-term outcomes of HLA-matched sibling donor (MSD) with mismatched related donor (MRD) and unrelated donor (URD) transplantation for CML in the first chronic phase (CML-CP1) using different graft vs. host disease (GVHD) prophylaxis regimens according to donor source and the degree of HLA matching were compared. The data of 91 patients with CML-CP1 were analyzed with respect to GVHD, overall survival (OS), and transplant-related mortality (TRM). The incidence of grade II-IV acute GVHD was 25.5% in the MSD and 40.5% in the MRD/URD group (P = 0.133). The 1-year cumulative incidence of chronic GVHD was not different between the MSD and the MRD/URD groups, while extensive chronic GVHD was different between the two groups (31.9% vs. 10.8%, P = 0.023). The 5-year cumulative relapse rate was not different between the MSD and the MRD/URD groups, while TRM was different between the two groups (6.6% vs. 26.3%, P = 0.010). The 5-year cumulative OS was 90.9%, 71.5%, and 85.4% in the MSD, the MRD/URD, and the HLA allele-matched URD transplantation, respectively (MSD vs. MRD/URD, P = 0.013; MSD vs. HLA allele-matched URD, P = 0.437). In conclusion, survival in HLA allele-matched URD is equivalent to MSD, but in MRD and mismatched URD is inferior to MSD in patients with CML-CP1 undergoing allo-HSCT using different GVHD prophylaxis regimens according to donor source and degree of HLA matching. Patients undergoing MRD/URD transplantation have an equal quality of life as patients undergoing MSD transplantation.

The probability of identifying a 10/10 HLA allele-matched unrelated donor is highly predictable

Identification of an unrelated HLA allele-matched hematopoietic stem cell (HSC) donor is a costly and time-consuming procedure. To improve search logistics, we have limited the search period to 6 months and have introduced a probability estimate of the chances of identifying a 10/10 HLA allele-matched donor. Probabilities were classified as high (>95%), intermediate (50%) and low (<5% chance) based on allele and haplotype frequencies. By analyzing 350 consecutive searches between 2002 and 2005 (1719 donors tested), the probability estimates turned out to be correct for 96% (high), 88% (low) and 56% (intermediate) patients. For searches with a high probability of success, at least one of the 10 most frequent haplotypes in Caucasoids was found in 69% of the patients, but in only 11% of the patients with a low-probability estimate (P<0.00001). Survival probability at 3 years was significantly higher for HSCT patients classified with a high-probability estimate when compared to patients in the intermediate/low-probability groups (74 vs 51 and 54% respectively, P=0.01). The same difference in survival probabilities was observed when only 10/10 matched unrelated HSCT patients were analyzed. In the intermediate-/low-probability groups, patients with alternative (haploidentical, autologous) or mismatched unrelated donors had similar survival estimates. Probability prediction is therefore feasible in the search process for unrelated donors and can guide the therapeutic strategy.

Comparable Survival and Transplant-Related Mortality Following Allogeneic Hematopoietic Cell Transplantation from HLA Allele-Matched Unrelated and HLA-Identical Sibling Donors.

Comprehensive analyses of unrelated donor (URD) and recipient HLA-matching for allogeneic hematopoietic cell transplantation (AHCT) have demonstrated better outcomes when allele typing is performed using high-resolution nucleotide sequence-based techniques. To evaluate survival following myeloablative AHCT using allele-level HLA-matched URD as compared with HLA-identical sibling donors, we analyzed outcomes for 430 patients treated at our center between March 1991 and April 2005. Sequence-based allele typing was retrospectively performed for HLA-A, B, C, DR and DQ when not done at time of AHCT for URD (n = 124; 29%) and non-sibling related donors (n = 19; 4%). Donors were HLA-identical siblings (n = 276; 64%), HLA allele-matched URD (n = 52; 12%), single HLA-locus mismatched donors (n = 52; 12%), or > 1 locus mismatched donors (n = 50; 12%). The median age at transplant was 23.4 years (range: 0.2 – 61). The most common diagnoses were AML (n = 107; 25%), CML (n = 90; 21%), ALL (n = 86; 20%) and MDS (n = 50; 12%). Total body irradiation-based preparative regimens were used for 283 patients (66%). Bone marrow (BM) was the graft for 388 patients (90%) and GCSF-mobilized peripheral blood stem cells (PBSC) for the remaining 42 (10%). Graft-versus-host disease (GVHD) prophylaxes were cyclosporine and methotrexate (n = 327; 76%), long methotrexate (n = 42; 10%), T-cell depletion (n = 19; 4%), or other regimens (n = 42; 10%). With a median follow-up of 4.8 years (range: 0.2 – 12.1), the 5-year estimate of overall survival (OS) for the entire group was 48.2% (95% CI: 45.7 – 50.7) and transplant-related mortality (TRM) was 31.4% (95% CI: 28.8 – 34). As shown in the Table, OS and TRM were indistinguishable between AHCT performed with HLA-identical siblings compared with HLA allele-matched URD. There was also no difference in grade III – IV acute GVHD (P = .46) between these two groups whereas there was a trend towards more extensive chronic GVHD (HR 1.8; 95% CI: 0.9 – 3.6; P = 0.12) for the URD recipients. Using a multivariate analysis to adjust for advanced disease, age (> vs ≤ 30 years), graft (BM vs PBSC) and female-to-male gender mismatch, there remained no difference in OS between HLA-identical siblings and HLA allele-matched URD (P = 0.67). These results demonstrate that key outcomes (OS, TRM, and severe acute GVHD) are equivalent in recipients of grafts from either allele-level 10/10 HLA-matched URD or HLA-identical siblings.Overall SurvivalTRMNumberHazard Ratio95% CIP valueHazard Ratio95% CIP valueHLA-ID Sibling2761--1--HLA-ID URD521.10.7 – 1.70.670.80.4 – 1.60.581 Locus MM521.30.9 – 2.00.191.40.8 – 2.40.25> 1 Locus MM502.01.4 – 2.9< 0.0012.61.7 – 4.1< 0.001