HLA-identical Unrelated Donor Research Articles

Casting Hope, Defying Odds: Unveiling the Impact of Haplo-Identical Stem Cell Transplant in Myeloid Malignancies - a Tertiary Cancer Care Center Experience

Background & Significance: Only 30% to 40% of patients in need of a curative stem cell transplant (SCT) could find a suitable matched sibling donor. For Indian patients, the likelihood of locating a 10/10 HLA identical unrelated donor within limited donor registries is approximately 14%. However, this probability has the potential to rise to 60% if registries with over 1,000,000 registered donors are available. 1,2 Consequently, there is an increasing inclination in India to perform haploidentical transplantations utilizing the post-transplantation cyclophosphamide (PTCY) platform developed by the Johns Hopkins group. 3 The outcomes of haploidentical stem cell transplantation (haplo-SCT) for the treatment of AML were enhanced in the 1990s with the introduction of a T-cell depletion (TCD) strategy followed by a myeloablative conditioning regimen. 4,5 In the last two decades, significant progress in haplo-SCT for hematological malignancies, especially AML, includes donor selection algorithms, improved grafts, GVHD prophylaxis, and enhanced immunologic recovery, benefiting patients. 6 Here, we present our experience of haplo-identical stem cell transplants in myeloid malignancies at our centre. Study design & Methods: We conducted a retrospective study at our site. Patients with myeloid malignancy who underwent haplo-identical stem cell transplant between Jan 2018 - Jan 2023 were included in the study and the follow-up was done till July 2023. Haplo-identical transplants done for diagnosis other than myeloid malignancy were excluded. The objectives of the study were to assess the non-relapse mortality [NRM] rate at day +100, relapse rate, graft-versus-host disease - free relapse-free survival [GRFS] and overall survival [OS] of the study cohort. GRFS was defined as a combined outcome including mortality from any cause, recurrence of malignancy, acute GVHD of grade 3 to 4, or chronic GVHD necessitating systemic immune suppression therapy. 7 Descriptive statistics (including median, mean, and range) were used to describe the central tendency and dispersion of variables. The probability of overall survival [OS] and graft versus host disease relapse free survival [GRFS] was estimated by the method of Kaplan and Meier. Probabilities of relapse or progression of malignancy, RRM, and day-100 NRM were summarized using cumulative incidence estimates All statistical analysis were done using statistical package for social science software (SPSS 21, IBM SPSS Statistics). Results: We have analysed 29 patients with various myeloid malignancies who have underwent haploidentical SCT from Jan 2018 to Jan 2023. There were 28 AML and 1 MDS patients. The median age was 35 (range, 16 - 59) and there were 22 males and 7 females. Conditioning intensity was myeloablative in 19 (65.5%), reduced intensity conditioning (RIC) in 8 (27.6%) and NMA in 2 (6.9%) patients. There were 10 (34.5%) patients in complete remission 1(CR1) and 19 (65.5%) in CR2. Hematopoietic Cell Transplantation-specific Comorbidity Index [HCT-CI] score was as low 11 (37.9%), intermediate 8 (27.6%) and high 10 (34.5%) patients respectively. Median time to neutrophil engraftment was 16 days (range, 12 - 25) and platelet engraftment was 17 days (range, 11 - 32). Median CD34 stem cell dose was 6.25 x 10*6/kg (range, 3.1 - 8.09) x 10*6/kg. Grade II-IV acute GVHD over first +100 days post SCT was observed in 6 (20.7) patients, and grade III-IV acute GVHD and chronic GVHD at follow up of one year was 3 (10.3) respectively. CMV reactivation by +100days was seen in 18 (62.06%) patients. Relapse was seen in 10 (34.5%) patients, out of which 2 patients are alive and 8 expired due to progressive disease. At median follow up of 13 months, OS is 60.3% (CI: 39.7% - 75.9%) and GRFS is at a median follow-up of 6 month was 51.2% (CI: 35.6% - 71%). Fig:1 NRM was 10.3% and 17.24% at +100 days and at last follow-up respectively. Fig:2 Conclusion: In conclusion, our study demonstrates favorable outcomes in terms of NRM (non-relapse mortality) with a low rate of 10.3% at 100 days after haploidentical SCT. The results also show promising overall survival (OS) and GVHD-free, relapse-free survival (GRFS) rates, supporting the potential of haploidentical transplants as an effective treatment option for myeloid malignancies. Further long-term follow-up and research are needed to validate and optimize these findings.

P1326: FACTORS ASSOCIATED WITH THE OUTCOME OF ALLO-HSCT FOR ADVERSE-CYTOGENETIC RISK ACUTE MYELOID LEUKEMIA

Background: Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) remains the unique intention-curative consolidation strategy in patients with Acute Myeloid Leukemia (AML) with unfavorable cytogenetic risk. It is a high-cost procedure with significant transplant-related mortality (TRM), therefore, the correct selection of candidates for allo-HSCT resembles as a crucial issue. Aims: To describe the outcome of this procedure and to identify those patients who could obtain a better benefit. The primary endpoint was Overall Survival (OS) and secondary endpoints were relapse-free survival (RFS), cumulative incidence of Graft-versus-host disease (GVHD), cumulative incidence of relapse and (TRM). Methods: We conducted an observational retrospective study in patients with adverse-risk cytogenetically defined AML (Upon the European LeukemiaNet 2017 criteria and the results of the Next Generation Sequencing) who underwent a first allo-HSCT in two tertiary referral centers between 2010 and 2020. Results: We analyzed 82 patients with a median age at the moment of transplant of 55 (R 22-73) years. The median time from diagnosis to transplant was 5 (IR 4-7) months. Forty-two (51,2%) were women. Twenty-six patients (31,7%) had an identical HLA sibling donor and 37 (45,1%) had an unrelated HLA identical donor. A myeloablative conditioning was performed in 60 (51%) patients and in 48 (59,8%) the source of HSC was bone marrow. The majority (81,7%) had a first complete remission (CR1) at the moment of transplant and 13,4% had a partial response or a refractory disease (PR/RD). The 41,5% patients had a low comorbidity index score (HCT-CI<3). With a median follow up of 36 months, the OS at 1 and 3 years was 67% (95% CI 64-66%) and 48% (95% CI 45-51%) respectively. The RFS at 1 and 3 years was 62% (95% CI 61-63%) and 45% (95% CI 43-47%), the cumulative incidence of relapse at 1 and 3 years was 18% (95% CI 11-28%) and 29% (95% CI 19-40%) and the TRM at 1 and 3 years was 21% (95% CI 13-30 %) and 28% (95% CI 19-39%) respectively. The cumulative incidence of acute GVHD grade III-IV at day +100 was 17% (95% CI 9-26%). The cumulative incidence of moderate-severe chronic GVHD at 1 and 3 years was 21% (95% CI 13-30 %) and 31% (95% CI 21-42%) respectively. There were no differences in OS regarding age (p=0,2), sex (p=0,9), HCT-CI score (p=0,7), type of donor (p=0,4), acute GVHD (p=0,5), HSCT source (p=0,06), conditioning (p=0,04) and subtype of ELN2017 (p=0,9). A worse OS was observed in patients with PR/RD (HR 1,5 95% CI 1,2-1,9) (p<0,01) compared to those in first complete remission. The OS at two years was 28% (95% CI 26-30) and 59% (95% CI 58-60) respectively (Figure 1). Sixty-six patients were analyzed for OS depending on the development of cGVHD. The OS at 2 years of the patients who did not develop cGVHD (n= 32) was 58% (95% CI 56-60) of those with a mild cGVHD (n=10) was 85% (95% CI 83-87) of those with a moderate cGVHD (n=15) was 79% (95% CI 77-81) and of those who develop a severe cGVHD (n=9) was 64% (95% CI 61-67). Therefore, a worse OS was observed in patients who did not develop cGVHD or had a severe grade compared to those who had a mild or moderate cGVHD HR 5 (95% CI 1,8-15) (p<0,01). Image:Summary/Conclusion: In our series, Allo-HSCT in adverse-cytogenetic risk AML are associated with better OS when it is performed in first complete remission and its benefit is unclear performed in partial response or in a refractory disease, where other strategies should be considered. The development of mild or moderate cGVHD was associated with a better overall survival.

Myeloproliferative neoplasms – a global view

Myeloproliferative neoplasms – a global view

Relapse risk factors during allogeneic stem cell transplantation in children, adolescents and young adults with acute lymphoblastic leukemia

More than 20–25 % of patients with acute leukemia underwent transplantation of HSC from HLA-identical sibling or unrelated donor had relapse.Therefore, the purpose of this study was to evaluate the influence of different factors on the risk of post-transplantation relapse in children and teenagers with acute lymphoblastic leukemia (ALL).The gender, the age of a donor at the time of transplantation; the gender, the age of a recipient at the time of transplantation; the type, the number of relapses of previous HSCTs; the type of conditioning; the type of transplantation; the source of stem cells; transplant parameters; the acute (aGVHD) and chronic (cGVHD) graft-versus-host disease or its absence; the KIRalloreactivity of donor NK cells were estimated as risk factors for the disease relapse in our study.We established that the recipient’s age of less than 4 years at the time of transplantation (p = 0.0042); the time of relapse (very early and early) (p = 0.0047); the absence of aGVHD (p = 0.0183) or cGVHD (p = 0.0384) have been the important factors for the disease relapse of patients with ALL after allogeneic HSC transplantation.

First experience of allogeneic haematopoietic stem cell transplantation in patients with mantle cell lymphoma with a mutation in the &lt;i&gt;TP53&lt;/i&gt; gene

Introduction. Mutations in the TP53 gene in patients with mantle cell lymphoma (MCL TP53+) are associated with a low response to intensive chemotherapy (CT) and adverse outcomes. Allogeneic haematopoietic stem cells transplantation (allo-HSCT) is a curative approach in MCL-TP53+ patients.Aim. Efficacy and safety assessment of allo-HSCT in MCL-TP53+ patients.Main findings. During 2016–2020, allo-HSCT in MCL TP53+ was performed in three patients. Two of them were grafted from HLA-identical unrelated donors, and one — from a haploidentical donor. Pre-transplant conditioning was “fludarabine + treosulfan + melphalan” in one case, and “fludarabine + busulfan” — in the other two. In three patients, leukocyte and platelet counts were recovered at days +18 and +20, +17 and +21, +19 and +16 after allo-HSCT, respectively. Acute graft-versushost disease (aGVHD) was observed in all patients (grade I — in 2 patients, grade IV — in 1 patient). One patient developed chronic GVHD (cGVHD) of moderate grade. All three patients exhibited complete remission and 100% donor chimerism in allo-HSCT follow-up of 6, 15 and 40 months, respectively.

Влияние аллореактивности естественных киллерных клеток на эффективность аллогенной трансплантации гемопоэтических стволовых клеток с деплецией α/β TCR/CD19+ лимфоцитов у педиатрических пациентов с острыми лейкозами

Natural killer (NK) cells constitute the first lymphocyte population to recover after an allogeneic hematopoietic stem cell transplantation (HSCT). It is believed that NK cell alloreactivity is regulated by the difference between activating and inhibitory signals from activating and inhibitory killer cell immunoglobulin-like receptors (KIRs). Human Leukocyte Antigen (HLA) molecules serve as ligands for KIR receptors. NK cell alloreactivity is determined by a KIR-HLA mismatch between donor and patient as well as the presence of specific activating KIR genes. Numerous recent studies show that several factors influence the effectiveness of the graft-versus-leukemia reaction. In particular, these factors include donor’s KIR genotype and the transplant protocol. The aim of the study is to evaluate the influence of KIR genotype of both HLA-haploidentical related donors and HLA-identical unrelated donors on the relapse risk and survival of acute leukemia patients after allogeneic HSCT. The study includes 142 patients (the median age 11) with acute myeloid leukemia (n = 70) and acute lymphoid leukemia (ALL) (n = 72) received first HLA-identical unrelated (n = 64) and HLA-haploidentical (n = 78) with α/βTCR-depleted allogeneic HSCT. All patients were in complete hematologic remission at the moment of HSCT. Peripheral blood mononuclear cells were collected after the administration of granulocyte colony-stimulating factor and used as the source of hematopoietic stem cells. Results of the study are consistent with the conception that potential NK alloreactivity depends on the transplant protocol – conditioning regimen, transplant processing and post-transplant graft-versus-host-disease prophylaxis. The key finding of this study is that more number of activating KIR genes in donor’s KIR genotype is associated with better overall survival of ALL patients (0,67 (95% CI: 0,53–0,81) vs 0,31 (95% CI: 0,07–0,55); р = 0,016). A similar effect was observed for the event-free survival. We failed to find a beneficial effect of NK alloreactivity based on the «ligand-ligand» model in the HLA-haploidentical related HSCT. NK alloreactivity for the same patient group, based on receptor-ligand» model also showed no significant beneficial effect, however there was a tendency for better overall survival for patients transplanted from potentially NK alloreactive donors (0,76 (95% CI: 0,63–0,88) vs 0,56 (95% CI: 0,32–0,81); р = 0,486). In summary, it is recommended to consider donor’s KIR genotype as additional criteria for donor selection prior to allogeneic HSCT for all patients.

OR8 Killer cell immunoglobulin-like receptor genotype BX1 and centromeric gene-content motifs influences survival after 3-models of allogeneic hematopoietic stem cell transplantation

Aim To investigate the role of donor killer cell immunoglobulin-like receptor (KIR) in allogeneic hematopoietic stem cell transplantation (allo-HSCT) and to develop a donor selection strategy for Chinese population. Methods In this 5-year retrospective study, we performed KIR genotyping on a total of 626 donor and recipient pairs by PCR-SSP. All patients underwent HSCT, comprising 219 HLA-identical sibling HSCT, 210 HLA-identical unrelated donor (URD) HSCT, and 197 HLA haplo-identical HSCT, for treatment of myeloid and lymphoid leukemia. Results Donor KIR genotypes and KIR gene motifs influenced transplantation outcomes for AML/MDS but not ALL/NHL patients in 3 models of transplants. In sibling HSCT for AML/MDS patients (n = 128), KIR mismatch between patient and donor had a better overall survival (OS; 87.3% versus 69.3%; P = 0.027) and reduced grade III to IV acute graft-versus-host disease (aGVHD; 4.6% versus 13.6%; P = 0.029). However, the effect was not observed in URD (n = 122) and haplo-identical HSCT (n = 108) for AML/MDS patients. Multivariate analysis indicated that centromeric B motifs contributed to improved survival in all models of transplants: (1) In sibling HSCT, donors’ haplotype cB-tA/tB were associated with improved OS compared with cA-tB (96.6% versus 71.2%; P = 0.021) or cA-tA (96.6% versus 72.1%; P = 0.017); (2) In URD-HSCT, donors with Cen -B were associated with a significantly improved OS (HR = 0.256; 95% CI, 0.084 to 0.774; P = 0.016) and RFS (HR = 0.252; 95% CI, 0.084 to 0.758; P = 0.014); (3) In haplo-identical HSCT, the same effect of Cen -B was observed on OS (HR, 0.335; 95% CI, 0.164 to 0.667; P = 0.002), RFS (HR, 0.331; 95% CI, 0.167 to 0.657; P = 0.002), and NRM (HR, 0.286; 95% CI, 0.120 to 0.683; P = 0.005). Regarding the KIR genotypes, compared with other donor KIR B/x genotypes: (1) In sibling HSCT, genotype Bx1 was a risk factor for lower OS (HR, 8.667; 95% CI, 2.321 to 32.37; P = 0.001) and RFS (HR, 9.207; 95% CI, 2.631 to 32.22; P = 0.001); (2) The same negative effect of Bx1 was also found in URD-HSCT (OS: P = 0.047; RFS: P = 0.041) and haplo-identical HSCT (OS: P = 0.002; RFS: P = 0.002). Conclusions Avoiding the selection of Bx1 donors is strongly advisable for AML/MDS patients undergoing both related and unrelated HSCT whereas the presence of the Cen -B motifs was rather recommended in donor selection.

Primary Analysis of the Effect of Hematopoietic Stem Cell Transplantation in the Treatment of 98 Cases of T Cell Lymphoma

Objective To investigate the effect of hematopoietic stem cell transplantation in the treatment of T cell lymphoma.Methods The clinical data of 98 patients with T cell lymphoma (T-NHL) treated by hematopoietic stem cell transplantation from June 2001 to December 2015 in our center were retrospectively analyzed.Results (1) 98 T-NHL patients, 62 males and 36 females, aged 7-64 years (median age 27 years). Disease subtypes: 30 cases of T-cell lymphoblastic lymphoma, 24 cases of NK / T cell lymphoma, 22 cases of peripheral T-cell lymphoma (PTCL, NOS), 19 cases of variable large cell lymphoma (ALCL), and 3 cases of subcutaneous panniculitic T cell lymphoma. Transplantation type: 55 cases of autologous transplantation, 43 cases of allogeneic transplantation. The follow-up was ended in April 2016, the duration of following-up ranged from 2 to 178 months (median follow-up time was 20 months). (2) 55/98 patients with autologous hematopoietic stem cell transplantation (auto-HSCT), 31 males and 24 females, aged 7-64 years (median age 27 years). Disease subtypes: 19 cases of anaplastic large cell lymphoma (ALCL) , 15 cases of NK / T cell lymphoma, 13 cases of peripheral T-cell lymphoma (PTCL, NOS), 5 cases of T cell lymphoblastic lymphoma, and 3 cases of subcutaneous panniculitic T cell lymphoma. The 3 year overall survival (OS) and disease-free survival (EFS) were 79.6% and 58.4%, respectively. (3) 43/98 patients with allogeneic hematopoietic stem cell transplantation (allo-HSCT), 31 males and 12 females, aged 8-52 years (median age 27 years). Disease subtypes: 25 cases of T lymphoblastic lymphoma, 9 cases of NK / T cell lymphoma, and 9 cases of peripheral T cell lymphoma (PTCL, NOS). Transplant subtypes: 23 cases of haploidentical transplantation, 12 cases of HLA-identical sibling donor transplantation, 6 cases of HLA-identical unrelated donor transplantation, and 2 cases of umbilical cord blood transplantation. The 3 year EFS and OS of allo-HSCT were 58.3% and 56.7%, respectively. (4) 38/55 patients with CR1 status before auto-SCT, 3 year OS and EFS were 82.8% and 60.7% respectively. 17/55 patients with non-CR1 status before auto-HSCT, 3 year OS and EFS were 57.2% and 47.8%. Compared with non-CR1 group, the OS and PFS of CR1 group were better, but failed to show significant statistical difference (p>0.05), which may be related to the less number of cases and sub types of the two groups do not match the correlation. (5) 31/98 cases were young and high-risk patients (age < 60 years, IPI score ≥3).16/31 cases treated with allo-HSCT, the 3 year OS and EFS were 73.1% and 70.5%. 15/31 cases treated with auto-HSCT, the 3 year OS and EFS were 48.4% and 27.8%. The OS and EFS of the two groups were significantly different (P=0.001).Conclusion Hematopoietic stem cell transplantation can improve the efficacy of T cell lymphoma. Auto-HSCT in first complete remission (CR1) enables T-NHL patients with greater benefit. Allo-HSCT can cure some T-NHL patients, which can be considered for the treatment of young and high-risk T-NHL patients. DisclosuresNo relevant conflicts of interest to declare.

Using EasyMatch® to anticipate the identification of an HLA identical unrelated donor: A validated efficient time and cost saving method

In the absence of an HLA matched familial donor, a search for an unrelated donor or cord blood unit is initiated through worldwide registries. Although a first look-up on available HLA information of donors in the “book” at BMDW (Bone Marrow Donor Worldwide) can provide a good estimation of the number of compatible donors, the variety of resolution typing levels requires confirmatory typing (CT) which are expensive and time consuming. In order to help recipient centers in their work. The French donor registry (France Greffe de Moelle/Agence de la Biomedecine) has recently developed a software program called “EasyMatch®” that uses haplotype frequencies to compute the likelihood of phenotypic match in donors according to various typing resolution levels.The goal of our study is to report a single monocentric user-experience with EasyMatch®, demonstrating that its routine use reduced the cost and the delay of the donor search in our center, allowing the definition of a new strategy to search compatible unrelated donors.The strategy was first established on a retrospective cohort of 217 recipients (185 adults and 32 children=before score) and then validated on a prospective cohort of 171 recipients (160 adults and 11 children=after score).For all patients, we calculated the delay between the registration day and the donor identification day, and the number of CT requested to the donor centre. Considering both groups, we could observe a significant decrease of the number of CT from 8 to 2 (p<0,001), and a significant decrease of the median delay to identify a suitable donor from 43 to 31days (p<0.0001).EasyMatch® estimates the number of potentially identical donors, but doesn’t foresee availability of the donors. It provides us an easy tracking of mismatches, an estimation of the number of potential donors, the selection of population following ethnic origin of patients and a high prediction when probability is high or low. It affords a new approach of donor search in our daily work and improves the efficiency in the great challenge of the compatible donor identification.

Impact of Early Post-Transplant Complications on Survival of Patients with Myelodysplastic Syndrome Undergoing Allo-SCT Following Reduced Intensity Conditioning: An SFGM-TC Study

BackgroundWith the ever-rising number of patients undergoing allogeneic stem cell transplantation (allo-SCT), the number of those requiring admission to the intensive care unit (ICU) has also increased over the last two decades. Indeed, allo-SCT is associated with potentially life-threatening complications such as conditioning-regimen toxicity, graft-versus-host disease (GVHD) and relapse.Several studies suggest that ICU admission may fail to provide benefits with a mortality rate attaining 95% in a subset of allo-SCT patients. Therefore, ICU triage policies have been set in order to identify patients who have the best chances of recovering from life-threatening complications. Not only were those policies based on studies that were restricted to patients admitted to ICU, but they also included very heterogeneous cohorts of patients in terms of underlying disease, patients characteristics and transplantations modalities. In addition, interpretation of the data is confounded by the inclusion of both autologous and allogeneic SCT patients and the absence of a clear distinction between acute, chronic and refractory GVHD.With the purpose of identifying factors that affect overall survival (OS), we conducted a retrospective multicenter study on a homogenous cohort. The aim of this study was to establish a new prognostic score usable in screening patients requiring ICU and bases on early post-transplant complications.Patients and methodsTransplantation modalities were made as homogeneous as possible using the following inclusion/exclusion criteria: (i) Patients with myelodysplastic syndrome aged more than 18 years referred for first allo-SCT following RIC with at least one year of follow-up (ii) source of stem cell was marrow or blood from either a sibling or an HLA-identical unrelated donor at allelic level (so called 10/10).Patients who received allo-SCT from an HLA-mismatched donor, cord blood or T-cell-depleted graft were excluded as well as patients with CMML. Consequently, 275 consecutive patients with MDS who underwent allo-SCT between January 1999 and December 2009 in 24 French and Belgian centers were identified.Patient and donor characteristics, transplantation modalities and complications occurred within 100 days after transplant were considered for univariate analysis. Multivariate Cox proportional hazards regression was used to investigate prognostic factors by backward stepwise analysis of the factors considered significant in univariate analysis. A prognostic score for 3-year OS was designed using the variables from the multivariate model and according to the rounded HRs values. Risk categories derived from this score were compared using log-rank test.ResultsIn multivariate analysis, 3-year OS was influenced by grade III/IV acute GVHD [HR=2.8; CI95=1.8-4.3; p<0.001], relapse before d+100 after transplant [HR=3; CI95=1.9-4.7; p<0.001), and the lack of platelet recovery (defined as the first occurrence of a stable platelet count ≥ 20G/L before d+100, persisting for more than 7 days without transfusion) [HR=6.6; CI95=4.1-10.6; p<0.001]. Therefore, a prognostic score was based on grade III/IV acute GVHD (1 point), relapse before d+100 (1point), lack of platelet recovery (2 points). Thus, this score discriminated three risk groups: good (score=0; n=191, 3-year OS=63%), intermediate (score=1; n=50; 3-year OS=20%) and poor (score≥2; n=34; 3-year OS=3%) p<0.001.ConclusionOur new score based on early post-transplant complications appears to be simple and helpful in screening RIC allo-SCT patients who require ICU. This prognostic score should be validated in larger cohorts. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Outcomes of allogeneic hematopoietic stem cell transplantation for 18 patients with paroxysmal nocturnal haemoglobinuria

目的评价异基因造血干细胞移植（allo-HSCT）治疗阵发性睡眠性血红蛋白尿症（PNH）的疗效。方法回顾性分析2007年12月至2015年2月间接受allo-HSCT治疗的18例PNH患者临床资料，其中原发PNH 4例，再生障碍性贫血-PNH综合征（AA-PNH）14例。9例为单倍体相同供者移植（其中1例为双份脐血植入失败后行挽救性单倍体相同供者移植），7例为HLA相合同胞供者移植，2例为HLA相合无关供者移植。13例患者接受改良白消安/环磷酰胺方案为主的清髓性预处理，5例接受非清髓性预处理（氟达拉滨+抗胸腺细胞球蛋白+环磷酰胺或白消安方案）。移植物抗宿主病（GVHD）预防：同胞供者移植为环孢素联合短程甲氨蝶呤，单倍体相同供者及无关供者移植为环孢素或他克莫司、霉酚酸酯联合短程甲氨蝶呤。结果所有患者均获造血重建（其中1例患者脐血植入失败后行单倍体相同供者移植）。中性粒细胞绝对计数≥0.5×109/L的中位时间为移植后11（10~26）d，PLT恢复至≥20×109/L的中位时间为移植后15（11~120）d。3例（17.6%）患者发生急性GVHD（aGVHD），其中Ⅱ度2例，Ⅳ度1例。2例（12.5%）发生局限型慢性GVHD（cGVHD）。中位随访14.6（2.0～86.7）个月，18例患者中死亡3例（17.6%），死因分别为重度aGVHD、肺部重症感染、肺部感染合并移植相关血栓性微血管病。预期5年无病生存率为（80.5±10.2）%。无复发病例。结论allo-HSCT治疗PNH疗效确切，预后良好，在抗补体C5单抗尚未广泛应用的情况下，可作为有价值的治疗手段。

Hematopoietic stem cell transplantation for Morquio A syndrome.

Morquio A syndrome features systemic skeletal dysplasia. To date, there has been no curative therapy for this skeletal dysplasia. No systemic report on a long-term effect of hematopoietic stem cell transplantation (HSCT) for Morquio A has been described. We conducted HSCT for 4 cases with Morquio A (age at HSCT: 4-15years, mean 10.5years) and followed them at least 10years (range 11-28years; mean 19years). Current age ranged between 25 and 36years of age (mean 29.5years). All cases had a successful full engraftment of allogeneic bone marrow transplantation without serious GVHD. Transplanted bone marrow derived from HLA-identical siblings (three cases) or HLA-identical unrelated donor. The levels of the enzyme activity in the recipient's lymphocytes reached the levels of donors' enzyme activities within two years after HSCT. For the successive over 10years post-BMT, GALNS activity in lymphocytes was maintained at the same level as the donors. Except one case who had osteotomy in both legs one year later post BMT, other three cases had no orthopedic surgical intervention. All cases remained ambulatory, and three of them could walk over 400m. Activity of daily living (ADL) in patients with HSCT was better than untreated patients. The patient who underwent HSCT at four years of age showed the best ADL score. In conclusion, the long-term study of HSCT has demonstrated therapeutic effect in amelioration of progression of the disease in respiratory function, ADL, and biochemical findings, suggesting that HSCT is a therapeutic option for patients with Morquio A.

Allogeneic Hematopoietic Stem Cell Transplantation in Mantle Cell Lymphoma: A Retrospective Analysis of 7 Patients

Mantle cell lymphoma (MCL) is a B cell non-Hodgkin's lymphoma characterized by a poor prognosis. Many different therapeutic approaches including intensive chemotherapy as well as new targeted therapies are established. However, overall survival remains unsatisfying. As the sole curative option, allogeneic hematopoietic stem cell transplantation (HSCT) has been described, but only a limited number of patients qualify for this procedure. We have retrospectively analyzed 7 patients with stage IV MCL undergoing allogeneic HSCT at our institution. A myeloablative regimen was used in 1 patient, while the other 6 patients received reduced-intensity conditioning. Four patients had an HLA-identical sibling, and the remaining 3 patients had an HLA-identical unrelated donor. One patient developed acute graft-versus-host disease (skin, grade III; intestine, grade II). Two patients died from transplant-related causes, 3 patients died due to progressive disease and the remaining 2 patients are still in complete remission 147 and 8 months after transplantation. Allogeneic HSCT offers a therapeutic treatment option for selected patients in a relapsed/refractory setting. The incorporation of novel agents has improved the outcome of patients with MCL. Thus, the role and optimal time point of allogeneic HSCT should be reevaluated in randomized trials.

Haplo-Cord Transplantation Vs Unrelated Donor Stem Cell Transplantation in Patients with AML/MDS Older Than 50

Haplo-cord Transplantation Vs Unrelated Donor Stem Cell Transplantation In Patients with AML/MDS older than 50Between 2007 and 2013, 109 patients with AML/MDS who were 50 years and older and had no HLA- matched related donor underwent allogeneic hematopoietic stem cell transplant. 64 had an HLA identical unrelated donor and received fludarabine/melphalan/alemtuzumab conditioning and post transplant tacrolimus for graft vs host disease (GVHD) prophylaxis. 45 underwent haplo-cord (HC) SCT with fludarabine/melphalan/ thymoglobulin; post-transplant tacrolimus and MMF. We compared patient characteristics and transplant outcomes between both groups. (Table 1) Age distribution and ASBMT risk category were similar. There were more patient’s with AML in the HC group. (P=0.01) Time to neutrophil recovery, treatment related mortality (TRM), relapse rate, progression free survival (PFS) and overall survival (OS) were nearly identical between the two groups. Time to platelet recovery was on average 5 days longer after HC (p=0.05) The incidences of acute and chronic GVHD were very low in both groups, in part due to the use of in-vivo T cell depletion.HC transplant with reduced intensity conditioning is a curative treatment for older patients with AML/MDS who lack HLA identical unrelated donors. Despite inclusion of many patients with high risk features, nearly two thirds were estimated to be alive one year after transplant and very few had chronic GVHD. Haplo-cord grafts are more readily available, a potential advantage over MUD grafts in situations where transplant is needed urgently. TableMatched Unrelated DonorHaplo CordPN6445Age (range)62 (50-73)62 (50-74)AML/MDS45/2041/5 0.01ASBMTLow/Int /High21/6/3015/10/200.7KPS9090Time to ANC >50010110.1Time to Plt >2018230.05PFS@ 1 Y (95% CI)46 (34-58)41 (26-56)0.6OS@ 1 Y (95% CI)57 (44-70)64 (49-79)0.8Cum Inc TRM @100 d (95% CI)9 (2-16)9 (0-18)0.2Cum Inc TRM @ 1 Y(95% CI)25 (14-36)29 (15-44)0.2Cum Inc Relapse @ 1Y (95% CI)30 (18-42)26 (12-40)0.5Cum Inc AGVHD @ 100 D (95% CI)25 (14-36)29 (13-43)0.7Cum Inc CGVHD @ 1 Y (95% CI)6 (0-12)7 (0-15)0.9 Disclosuresvan Besien:Miltenyi: Research Funding. Mark:Millennium: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Onyx: Research Funding, Speakers Bureau; Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Artz:Miltenyi: Research Funding.

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.

Allogeneic hematopoietic stem cell transplant for hematological malignancies from mismatched 9/10 human leukocyte antigen unrelated donors: comparison with transplants from 10/10 unrelated donors and human leukocyte antigen identical siblings

We studied the outcome of 213 patients who received allo-HSCT for hematological malignancies, 121 (57%) from HLA identical siblings, 63 (29%) from 10/10 HLA identical unrelated donors and 29 (14%) from 9/10 HLA mismatched unrelated donors. Engraftment was lower in the 9/10 HLA group (90%) than in the 10/10 HLA group (95%) than in the sibling group (99%); 3 months CI of aGVHD ≥ 2 was 32% (23–41), 20% (15–26) and 27% (23–32) respectively; the one year CI of extensive cGVHD was 21% (13–30), 9% (5–13) and 17% (14–21) respectively. The median OS was 10 months (5–21), 18 months (11-NR) and 60 months (31-NR) respectively with 2-years probability of 19% (8–44), 43% (31–59) and 63% (54–74) respectively. TRM was significantly higher in the 9/10 HLA group with 1 year CI of 45% (35–55), compared to 33% (27–39) in the unrelated 10/10 HLA group and 12% (9–15) in the identical siblings group (p < 0.001).

Celiac Disease Transmitted By Unrelated Cord Blood Stem Cell Transplantation (CBST)

Celiac disease is due to intolerance to certain cereal proteins leading to immune-mediated small bowel villous atrophy and malabsorption. Specifically, the gliadin component of wheat, and the prolamin component of rye and barley are implicated in causing disease. BMT and CBST have been known to transmit immune associated diseases such as diabetes mellitus immune thrombocytopenic purpura from an affected donor to transplant recipient. We observed the occurrence of Celiac disease in a patient a year following cord blood stem cell transplantation (CBST) for acute myelogenous leukemia (AML- FAB M2) in complete second remission (CR-2). The patient had no history of celiac disease prior to CBST nor any family member. The cord donor was HLA-identical unrelated male donor with HLA types: A3, B7 (w6), DR (B1), DR (B5). The family history of the donor was unavailable for celiac disease. The CBST was complicated by grade 2 skin Graft versus Host Disease (GVHD), which responded to steroid therapy. A year post transplantation she developed persistent mucous diarrhea with tinge of blood associated with abdominal cramps. Investigations for infectious causes such as CMV enteritis were negative and colonsocopy did not reveal any evidence of GVHD. Gastrointestinal symptoms persisted and did not respond to steroid and prograf therapy. Subsequent duodenal and jejunal biopsy revealed subtotal villous atrophy with cryptic hyperplasia suggestive of celiac disease. Antigliadin IgA and IgG, reticulin IgA and Endomysial IgA andibodies were elevated. A diagnosis of post-CBST coeliac disease was made. She responded well to gluten-free diet and became symptom-free. A literature review identifies only from donor to recipient one previous example of transmission of celiac disease following HSCT. This case could be the second case of celiac disease following transplantation and the first one post CBST. An association of celiac disease with some HLA types, including DQA1.0501, and DQB1.0201, in conjunction with the haplotypes A30, B18, DR3, DRw52, and DQ2 was recently noted. The donor of this case exhibit HLA DQ A1.0501 and DQ B1.0201 alleles. The findings suggest transfer of celiac disease by cord stem cells and confirm the immune nature of the disease. In addition the propensity to develop T-cell non-Hodgkin lymphoma and transmission of celiac disease by CBST support T cell concept in celiac disease. Autoimmune enteropathy should be considered in patient with persistent diarrhea post hemopoietic stem cell transplant.

Long-term follow-up after allogeneic stem cell transplantation in patients with myelodysplastic syndromes or secondary acute myeloid leukemia: a single center experience

We performed a single center analysis of 60 adult patients (33 males and 27 females) with myelodysplastic syndromes (MDS) or secondary acute myeloid leukemia (AML) who underwent allogeneic hematopoietic stem cell transplantation (HCT) at our institution. Allogeneic stem cell in patients were transplanted between 1988 and 2010, 28 had an human leukocyte antigen (HLA)-identical sibling donor, 23 had an HLA-identical unrelated donor, and 9 had an 1 allele mismatched donor. The median age at time of HCT was 44 (range: 18-68) years. Conditioning therapy was myeloablative in 36 patients and consisted of a reduced-intensity conditioning (RIC) regimen in 24 patients. Graft-versus-host disease (GvHD) prophylaxis was performed with a combination of methotrexate and cyclosporine A in 36 patients, and cyclosporine A plus mycophenolate mofetil in 24 patients. The 10-year probability of overall survival was 46 %. In a multivariate analysis, we identified pretransplantation serum ferritin as the only independent adverse prognostic variable predicting survival in our patients.

Reduced Relapse Risk In Patients With AML After Hhcmv-Replication Post Transplantation-First Results Of a Prospective Registration Trial

AbstractAbstract 5503 IntroductionEarly detection of inapparent replicative human cytomegalovirus (HCMV) infection together with its preemptive antiviral treatment has led to a marked reduction of life-threatening HCMV disease after allogeneic hematopoietic stem cell transplants (alloSCT). A new aspect of HCMV reactivation and pretransplant HCMV serostatus has recently emerged by an earlier retrospectively performed report from us showing that the occurrence of a HCMV-reactivation after transplant reduces the risk for relapse in patients with AML and NHL. This idea was supported by a study by Scheper and co-worker (Leukemia, 2013) reporting recently, that gamma-delta T cells elicited by HCMV reactivation after alloSCT cross-recognize HCMV and leukemia. Here we evaluate the potential impact of early HCMV replication in a prospectively performed observational study about the occurrence of a HCMV- reactivation after T cell repleted alloSCT on the risk for leukemic relapse in patients with AML (Registration Trial DRKS00004300). Patients and MethodBetween January 2012 and March 2013 we enrolled in this trial 83 patients with AML who were consecutively transplanted at the University Hospital of Essen. 48 of 83 patients received a myeloablative (TBI based conditioning n=27, chemotherapy based conditioning n=23) and 35 patients a RIC regimen. Patients were transplanted in 1.CR (n=40), 2.CR (n=23) or more progressive disease stages (n=20) from HLA-identical sibling donor (n=17) or HLA-identical unrelated donor (URD) (n=42) or mismatched unrelated donor (n=24). The median age of patients was 53 years (range 18-72) and that of the donors 38 years (range 12-61). GVHD prophylaxis was performed with MTX and CSA, or CSA and MMF with or without ATG (n=64) (30-60mg total dose). The incidence of acute GVHD grade 2-4 was statistically not different in both groups (78% versus 85%). ResultsHCMV status of recipient (R) or donors (D) were in 29% R-/D-, 8% R-/ D+; 34% D+/R- and 29% R+/D+. Patients with a documented HCMV-reactivation (HCMV-R) had an estimated relapse incidence (CIR) at 1-year after transplant of only 8% compared to 43% in patients without a HCMV-R (p=0.03). Patients in more progressive disease phase of AML (N=43) benefit more from a HCMV-R in regard of CIR than patients in 1.CR of AML (0% versus 55% estimate for relapse at 1-year after transplant for patients with HCMV-R compared to patients without HCMV –R, p=0.028). One-year overall survival was statistically not different in both groups. Non relapse mortality was greater in patients with HCMV reactivation 37.8% versus 12.5%, p=0.1)ConclusionThe first result of this prospective study confirms an independent advantageous effect of early HCMV replication on the leukemic relapse risk in patients with AML after transplant, which was more pronounced in patients in progressive disease phase of AML than patients in 1.CR of AML. Disclosures:Off Label Use: The off-label use of HCG will be presented here for the first tiem for treatment of chronic GVHD and will clearly marked as off-label use.

Do different conditioning regimens really make a difference?

Over the past 15 years, the use of reduced-intensity/nonmyeloablative conditioning regimens before allogeneic hematopoietic stem cell transplantation has been increasing. Despite major disparities in the level of myeloablation, intensity of immunosuppression (including great diversity of in vivo T-cell depletion), and postgraft immunomodulation, the different approaches have contributed jointly to a modification of the stage of allogeneic stem cell transplantation: transplantation-related procedure mortality has been decreased dramatically, allowing allogeneic immunotherapy to be used in previously excluded populations, including elderly patients, young but clinically unsuitable patients, patients with lymphoid malignancies or solid tumors, and patients without an HLA-identical related or unrelated donor. Together, these diverse regimens have provided one of the biggest breakthroughs since the birth of allogeneic BM transplantation. However, consensus on how to reach the optimal goal of minimal transplantation-related mortality with maximum graft-versus-tumor effect is far from being reached, and further studies are needed to define optimal conditioning and immunomodulatory regimens that can be integrated to reach this goal. These developments, which will most likely vary according to different clinical situations, have to be compared continuously with advances achieved in traditional allogeneic transplantation and nontransplantation treatments. However, the lack of prospective comparative trials is and will continue to make this task challenging.