Unrelated Hematopoietic Stem Cell Research Articles

A survey on preoperative autologous blood donation policy in bone marrow stem cell donors in Italy.

The high safety of homologous blood components, together with the introduction of the Patient Blood Management strategy, has led to the progressive abandonment of preoperative autologous blood donation (PAD) in surgery. Furthermore, recent scientific publications provide evidence about the non-usefulness of PAD in the collection of hematopoietic stem cells (HSC) from bone marrow (BM), also in consideration of harvest procedure safety. Nevertheless, no conclusive studies have been published yet. Blood Establishments (BE) and Bone Marrow Collection Centers (BMCC) participated in a specific qualitative survey proposed by Italian National Blood and Transplant centers with the support of the relevant Italian Scientific Societies. The survey aimed at evaluating the policy adopted for PAD in related and unrelated adult HSC donors in Italy during the period 2018-2020. Forty-one BE corresponding to 37 BMCC filled in the questionnaire. Of 830 BM donors, 661 (80%) underwent 1063 PAD (mean 1.6 PAD/donor). The remaining 169 donors (20%) underwent BM harvest without PAD. No serious adverse events were reported for either donor group. In the case of ineligibility of donors for the PAD program, due to low hemoglobin values, 7/10 centers shifted donors to peripheral blood stem cell collection and three centers chose a different donor. Remarkably, only 51% of the PAD units requested were eventually transfused during the BM harvest process. Finally, the iron support policy among centers was heterogeneous. The results of this survey show that PAD is heterogeneously applied in Italian BMCC, as in other countries. However, all BMCC except two are willing to adopt a Patient Blood Management strategy as an alternative approach to adult related and unrelated BM donor harvests.

Retrospective Lineage Tracing of Pediatric Acute Myeloid Leukemia Using Single-Cell Whole Genome Sequencing

Background Acute myeloid leukemia (AML) accounts for 15-20% of all pediatric acute leukemias and is a very heterogeneous disease, both genetically and phenotypically. Although survival has increased gradually during the last decades, relapse-rates remain around 20-30%, and children who relapse have a relatively poor outcome. Still, the exact cause of pediatric AML (pAML) remains unclear. Previously, we found an increased clonal mutation burden in leukemic blasts of a subset of pAML cases, including the ones characterized by RUNX1-RUNX1T1 translocations. Here, we study the mutation accumulation and clonal evolution of pAML to elucidate the timing of driver accumulation and mutational processes underlying leukemogenesis in children. Methods All pAML bone marrow samples were acquired via the biobank of the Princess Máxima Center for pediatric oncology after ethical approval was obtained. We used primary template-directed amplification (PTA) to accurately analyze the complete genomes of single cells at nucleotide resolution. For PTA-mediated whole genome sequencing (WGS), we sorted single leukemic blasts, hematopoietic stem cells (HSCs), multipotent progenitor cells (MPPs) and several differentiated cell types. Subsequently, WGS data was used to study mutation accumulation and to perform phylogenetic lineage tracing of different cell types of the same patient. Results Thus far, we have analyzed the single-cell WGS data of 18 cells from two AML samples characterized by NUP98-NSD1 and RUNX1-RUNX1T1 fusions. We identified multiple cells that immunophenotypically resembled HSCs, MPPs and more mature cell types from different lineages, that shared the fusion gene with the AML blasts (Figure 1). Moreover, a subset of these cells shared one or more additional driver mutations with the immunophenotypically defined bulk leukemic blasts. Subsequent mutation analysis showed that cells with the oncogenic fusion had an increased somatic mutation burden compared to cells without the fusion. Accordingly, we studied mutational signatures to identify the processes underlying this mutation burden. Interestingly, besides the expected mutational signatures, we found that the increased mutation burden was mainly characterized by SBS18, a signature that is associated with damage induced by oxidative stress. This process was active throughout the leukemic lineage, whereas unrelated HSCs and MPPs of the same patients did not display this signature. This finding indicates that the process was specific for the leukemic lineage and therefore likely cell intrinsic. Next, we used driver and passenger mutations to construct phylogenetic lineage trees and found that the accumulation of drivers occurred stepwise. We show that the oncogenic fusion was the first driving event in different patients, followed by accumulation of additional driver mutations. For example, in one patient, based on the clock-like mutation burdens in the separate branches, we could estimate that the first drivers were already present when the patient was between 7.5 to 9 years old (Figure 1, branch A), while this patient was diagnosed at 15.2 years. We have previously identified similar patterns in multiple MLL-rearranged therapy-related AML (t-AML) patients. Both in the t-AML and pAML cases, some leukemic blasts did not have any additional genetic drivers compared to the phenotypical stem and progenitor cells. Conclusions We used single-cell WGS to identify pre-leukemic cells in bone marrow samples of pAML patients, which shared both the oncogenic rearrangement and additional driver mutations with the AML blasts. These pre-leukemic cells showed an increased mutation load, caused by distinct mutational processes. In addition, these cells were immunophenotypically and functionally stem-cell like, contributing to hematopoiesis. Our analyses show that, despite their aberrations, these cells still have differentiation potential. Interestingly, the first driver aberrations of pAML originated years before diagnosis. These data suggest that genetic driving aberrations may not be the only underlying mechanism of AML development in children. Noncoding drivers, epigenetic changes or environmental influences may play an important role in the final steps towards leukemogenesis. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Hematopoietic Stem-Cell Transplant Registry in Poland: 2020 Summaries

In the pandemic year 2020, 634 allogeneic hematopoietic stem-cell (HSC) transplants were performed in Poland, including fully matched and haploidentical family donors (n=248) as well as unrelated donors transplantation (n=386). In 48 recipients (7.6%) for allogeneic transplantation, hematopoietic bone marrow cells were transplanted, and in 586 recipients (92.4%), peripheral blood hematopoietic cells. The effect of the pandemic was noticeable but not disastrous-the number of HSC transplants from unrelated donors was lower by 9% compared to 2019 and the use of haploidentical donors slightly increased compared to 2019. Out of all 386 unrelated HSC transplants, the material for 143 transplants (37%) came from international donors, whereas for 243 transplants (63%) material collected from domestic donors was used. Along with the increase in the number of potential bone marrow donors in the national resources, the share of transplants from Polish donors in the total number of transplants increased noticeably from 2006 to 2020. The total number of allogeneic transplants performed in 18 Polish transplant centers between 2006 and 2020 is 7426. Total transplant rates (cumulative number of all allogeneic HSC transplants performed from 2006 to 2020 per 1 million inhabitants) differs between regions and for regions with nonzero number of transplants varies from 520 in Mazowieckie Voivodship to 14 in Lodzkie Voivodship.

Impact of COVID-19 Pandemic on Global Unrelated Stem Cell Donations in 2020 - Report from World Marrow Donor Association

Introduction: World Marrow Donor Association (WMDA) promotes global collaboration for the benefit of stem cell donors and transplant patients. WMDA activities include recording the number of unrelated hematopoietic stem cell (HSC) donations globally.Because the COVID-19 pandemic also has an impact on the treatment of patients with other diseases, we hypothesise that it also impacted the practice of unrelated hematopoietic stem cell transplantation (HSCT).We used the 2020 WMDA data to examine the trends in unrelated HSC donations during the COVID-19 pandemic globally, per continent and per country/region.Methods: Donor registries (DRs) and cord blood banks (CBBs) from 61 countries participated in the 2020 survey, compared to 59 countries in the 2019. Slight differences in participation between the data sets of 2019 and 2020 do not explain the trends we observe in HSC donations. Country/region-specific COVID-19 data on cases and deaths were obtained from the data repository operated by the Johns Hopkins University Center for Systems Science and Engineering(https://github.com/CSSEGISandData/COVID-19, accessed July 12, 2021); and population data were retrieved from the Worldometer website(https://www.worldometers.info/, accessed July 12, 2021).Results: HSC donations from unrelated donors (peripheral blood stem cells (PBSC) and bone marrow (BM)) decreased from 20,330 in 2019 to 19,623 in 2020 (-3.5%), compared to an average annual growth rate of 3.9% from 2015 to 2019 (figure 1). The 3.5% decrease is composed of a 29.0% decrease for BM and a 2.6% increase for PBSC, resulting in a drop in the BM share of unrelated HSC donations from 19.3% in 2019 to 14.2% in 2020. The number of cord blood unit (CBU) shipments globally decreased with 3.5% from 2,851 to 2,750. The percentage of national use of HSC products (PBSC and BM) increased from 51.2% to 53.5%.When considering the continent on which the patient is transplanted (table 1), the change rate of use of HSC donated products in 2020 vs. 2019 ranged from -28.0% in South America to +18.2% in Africa. In absolute numbers, the largest decrease of HSC donations occurred for patients in Asia (n=-485) followed by Europe (n=-205), and the largest increase occurred in North America (n=+88) followed by Oceania (n=+25). The share of HSC donations requiring intercontinental transport decreased from 24.6% in 2019 to 21.9% in 2020.In terms of the country/region of transplant (table 2), the largest percentage decrease occurred in Colombia (-90,5%) followed by Russia (-55,5%). In absolute numbers, the largest decrease occurred in Turkey (-147), with Japan following (-128, although Japan saw an increase of CBU use of +106). The highest growth rate was observed in Iran (+28,7%), followed by South Africa (+28,2%). In absolute figures, the greatest increase occurred in Italy (+67). The two countries receiving the largest HSC donation numbers showed no major changes versus the previous year: USA: +0.6% (although a decrease for CBU of -21,0% was observed) and Germany: -2.4%.We did not find any significant correlation between the numbers of COVID-19 cases or COVID-19-related deaths per 1 million inhabitants with the HSC donation numbers (Spearman's r=0.05 for cases and =0.08 for deaths).Discussion: The decline in the number of unrelated HSC donations in 2020 suggests an impact of the COVID-19 pandemic on HSC donation and unrelated HSCT.The significant decrease in BM collections and intercontinental/cross-border shipments can be explained by logistically complex processes, as well the increased risk to the donor of being exposed to an operative procedure. CBU as a stem cell source potentially circumvents these logistical complications. However, on a global scale our data does not show increased use of CBU suggesting that decisions to use CBU as a stem cell source did not change in the pandemic .We were unable to demonstrate a correlation between country/region-specific severity of the pandemic and HSC donation numbers. We suspect this is due to the data quality of reported number of COVID-19 cases and COVID-19-related deaths. Also, we did not gather monthly data and therefore could not specify pandemic waves.In conclusion, we would like to point out the fact that global exchanges of HSC products continued and only decreased slightly is an extraordinary achievement of DRs, CBBs and their donors and is a testament to the importance of international collaborations in the WMDA. [Display omitted] DisclosuresDevine: Orca Bio: Consultancy, Research Funding; Johnsonand Johnson: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Magenta Therapeutics: Current Employment, Research Funding; Tmunity: Current Employment, Research Funding; Vor Bio: Research Funding; Kiadis: Consultancy, Research Funding; Be the Match: Current Employment. Shaw: Orca bio: Consultancy; mallinkrodt: Other: payments. Forman: Mustang Bio: Consultancy, Current holder of individual stocks in a privately-held company; Lixte Biotechnology: Consultancy, Current holder of individual stocks in a privately-held company; Allogene: Consultancy.

Stable pulmonary function after haploidentical stem cell transplantation with post-transplant cyclophosphamide: a single center experience

Prior studies have reported pulmonary function tests (PFT) before and after related and unrelated allogeneic hematopoietic stem cell transplantation (HSCT). However, limited data exist on the evaluation of lung function after haploidentical stem cell transplantation (HAPLO) with post-transplant cyclophosphamide (PTCY). We retrospectively reported the evaluation of PFTs at screening before HAPLO in 80 patients at 100 days and 1 year of follow-up. The proportion of surviving patients with available PFTs at 100 days and 1 year were 86% and 68%, respectively. During the follow-up period, four patients met the criteria for bronchiolitis obliterans syndrome and two for interstitial lung disease. Overall survival was 73% (95% CI 62–82%) at 2 years. We observed a significant reduction in diffusing capacity of the lungs for carbon monoxide (DLCO) corrected for the most recent hemoglobin concentration (DLCOc) at 100 days after HAPLO. However, an overall substantial stable pulmonary function was observed at 1 year.

Physical and Psychosocial Donation Experiences Of Older Adult Related HSC Donors (>60 yrs.) Compared To Those Of Younger Adult Donors

During the past two decades, there have been multiple investigations of unrelated hematopoietic stem cell (HSC) donor safety and health-related quality of life (HRQoL). During this same time period, there have been few investigations of related donor safety and HRQoL – particularly older related donors. Co-morbid conditions may be particularly likely to affect the risk of donation to related donors >60 years of age. As older related siblings are increasingly asked to donate, it is critical to understand HRQoL in this group. Findings presented here are the first from a 5-year investigation of related donor safety and HRQoL (RDSafe). The goal was to compare HRQoL among older adult related donors to that of younger related and unrelated adult donors.Participants included older adult related HSC donors (ages >60 yrs; n=106) and adult related (n=55) and unrelated (n=46) HSC donors ages 18-60 who donated PBSCs at domestic U.S. centers between 3/2010 and 4/2013. Findings presented here are based on structured telephone interviews completed pre-donation and 4 weeks post-donation. Interviews focused on socio-demographics, physical and mental health status, and donation-related perceptions using well-validated instruments. Odds-ratios for dichotomous variables and t-tests for continuous variables were used to examine pre- and post-donation differences (older donors versus the two younger donor groups). DemographicsAs expected, given known demographic differences between the groups, older related donors were less likely to be employed, and more likely be white, married, and to have children. Pre-donation psychosocial and donation-related: Pre-donation, older related donors reported higher importance of religion/spirituality (t=2.60; p<0.01) than did younger unrelated donors and better general emotional health (SF-12v2) than did both younger groups (unrelated t=2.26; p<0.03; related t=2.05; p=0.04). They did not differ from either of the two younger groups on other psychosocial variables (e.g., depression, anxiety). Older donors were less ambivalent about (t=-2.47; p<0.05) and more satisfied with the decision to donate (t=2.51; p<0.05) than were younger unrelated donors. They did not differ on these variables from younger related donors. Older donors were less likely to have consulted family/friends about the donation (OR=0.35; 0.13-0.98) than younger unrelated donors but more likely to have consulted professionals than either of the younger groups (younger unrelated OR=2.70; 1.30-5.56; younger related OR=1.96; 1.01-3.85). Older donors were less likely to have been discouraged by others from donating (OR=0.45; 0.21-0.95) and more likely to have been encouraged (OR=2.50; 1.12-5.56) than younger unrelated donors – they did not differ from younger related donors on these variables. Although older donors reported poorer general pre-donation physical status (SF-12v2) than did both younger groups (unrelated t=-3.67; p<0.001; related t=-3.25; p=0.001), they did not differ from either younger group on any of 14 donation-related medical/work/family concerns about donation. Donation experience/effects: Although older donors continued to report somewhat poorer post-donation general health status than did younger unrelated donors (t=-2.25; p=0.03), they were less likely to report that the donation was painful (unrelated t=-1.90; p=0.06; related t=-2.28; p=0.02) and less likely to have taken pain medication than younger unrelated donors during the donation process (OR=0.36; 0.17-0.76). They were also less likely to report that they would feel responsible if the donation was not successful than were either younger group (unrelated t=-2.12; p<0.05; related t=-2.44; p=0.02). There were no differences between older and younger donors in the proportion that felt back to normal by the post-donation interview or any of 12 other donation-related side effects.These findings are very reassuring, as older donors are increasingly being asked to donate for their siblings. Despite having somewhat poorer overall general health that is likely age-related, the fact that older donors experience similar – and in some domains better – donation-related HRQoL compared to younger donors is a critical finding. Further data from this study detailing specific medical toxicities experienced by these older related donors will help better understand how to counsel these donors pre-collection. Disclosures:No relevant conflicts of interest to declare.

The Impact of Foundation of the National Turkish Donor Registry, Turkok on Donor Matching Kinetics

Purpose: Turkish Stem Cell Coordination Center (TURKOK) was established by the Turkish Ministry of Health in April 2015 in order to facilitate unrelated hematopoietic stem cell (HSC) transplantation in Turkey. The donor recruitment task has been linked to the Turkish Crescent's (National Blood Product Provider) nationwide distributed branches. As of July 2017, more than 300.000 volunteer donors are registered into the database. As of July 2017 they have facilitated more than 300 HSCTs. Transplant Registry Istanbul (TRIS) and Transplant Registry Ankara (TRAN) are two University affiliated donor search - co-ordination centers, which are officially responsible for the search, matching and organization of the delivery for unrelated donor HSC in Turkey. The foundation of TURKOK should have theoretically decreased our time spent to find a suitable matched donor. The aim of this study is to compare the time frames between admission, confirmation, work-up, and infusion of HSC between TURKOK and other WMDA or NMDP facilitated International Volunteer Donor Registries.Subjects & Methods: In 2015 1000 allogeneic HSCTs were peformed in Turkey and only 18% were from MUDs. This is a single center analysis of a dedicated active HSCT center, which is performing >70 allogeneic HSCTs per year and utilizing alternative donor sources >50%. Patient charts were reviewed retrospectively and 51 patients who admitted to our center within 2015-2017 for various high risk hematological malignancies (mostşy acute leukemia, in which allogeneic HSCT was indicated, were identified for this study. Patients were divided into two groups: (1) Patients who had received HSC from matched unrelated donors (MUD-T) (10/10-9/10) facilitated by TURKOK (N=36) ; (2) 15 patients who had received HSC from International Registries facilitated by TRIS or TRAN (MUD-I) . The duration between application and finding a suitable match (tAM), duration between matching and confirmation (tMC) and time from application to HSC transplantation (tATX) were calculated for each of these two groups. The time duration between admission and donor identification and admission to HSCT were not distributed normally. The mean values were compared between two groups by Mann-Whitney U test. p < 0.05 was considered statistically significant.Results: In 51 HSC recipients the overall median durations for tAM, tMC and tATX were 71 (range, 1-172), 33 (range, 1-181) and 97 (range, 13-172), respectively. In MUD-I overall median durations for tAM, tMC and tATX were 90 (range, 1-170), 40.5 (range, 1-181) and 98 (range, 13-172), whereas in MUD-T the timelines for tAM, tMC and tATX were 37 (range, 4-172), 17 (range, 6-151) and 96 (range, 73-128), respectively. The p values for comparative analysis betwen MUD-I and MUD-T for tAM, tMC and tATX were p=0.005, p=0.007 and p>0.05, respectively.Conclusion: In this relative limited size of HSC recipients from MUDs we observed accelerated kinetics for tAM and tMC, which means having a National Registry have a positive impact on finding an available match and confirmation process. On the other hand this improvement did not translate into rapid HSCT. The tATX between MUD-I and MUD-T are not significant. TURKOK has to establish and improve the organization of confirmed donor for collection of HSCs. The decreased timeline from application to confirmation is encouraging, but the time spent from confirmation to work/up and collection are still high. As TURKOK is a recently established donor bank, there is room for improvement. DisclosuresNo relevant conflicts of interest to declare.

First case report of a NUP98-PMX1 rearrangement in de novo acute myeloid leukemia and literature review

BackgroundThe nucleoporin 98 (NUP98)-paired related homeobox 1 (PMX1) fusion gene, which results from t(1;11)(q23;p15), is rare in patients with acute myeloid leukemia (AML). Currently, only two cases of chronic myeloid leukemia in the accelerated phase or blast crisis and three cases of therapy-related AML have been reported. Here, we first report a patient with de novo AML carrying the NUP98-PMX1 fusion gene.Case presentationA 49-year-old man diagnosed with AML presented the karyotype 46,XY,t(1;11)(q23;p15)[20] in bone marrow (BM) cells. Fluorescence in situ hybridization analysis using dual-color break-apart probes showed the typical signal pattern. Reverse transcription-polymerase chain reaction (RT-PCR) analysis suggested the presence of the NUP98-PMX1 fusion transcript. The patient received idarubicin and cytarabine as induction chemotherapy. After 3 weeks, the BM aspirate showed complete remission, and the RT-PCR result for the NUP98-PMX1 fusion gene was negative. Subsequently, the patient received three cycles of high-dose Ara-c as consolidation chemotherapy, after which he underwent partially matched (human leukocyte antigen–DP locus mismatch) unrelated allogeneic hematopoietic stem cell transplantation (HSCT). The follow-up period ended on September 30, 2020 (6 months after HSCT), and the patient exhibited no recurrence or transplantation-related complications.ConclusionThis is the first report of a patient with de novo AML carrying the NUP98-PMX1 fusion gene. The reported case may contribute to a more comprehensive profile of the NUP98-PMX1 rearrangement, but mechanistic studies are warranted to fully understand the role of this fusion gene in leukemia pathogenesis.

Optimization of the criteria for cord blood unit selection for transplantation in recipients of the different age groups: current view and prospects in Ukraine

Umbilical cord blood has been widely used to treat both malignant and non-malignant hematological diseases for over 30 years. During this time, more than 40,000 successful hematopoietic stem cell (HSC) transplantations of umbilical cord blood have been performed. However, today in Ukraine there is no public umbilical cord blood bank established for unrelated HSC transplantation to patients with oncohematological disorders (both children and adults). In this regard, the HSC units must be purchased abroad or the patients are sent to foreign clinics for high-cost treatment. The organization of a public umbilical cord blood bank in Ukraine would help in a short time to meet the needs of patients with oncohematological disorders for donor HSCs for unrelated transplantation and save significant funds for the treatment of patients abroad. According to the experience of the world's leading oncohematological centers, when it is impossible to find either a related or haploidentical donor or in all available registries – a unrelated transplant, the search continues in the registers of public cord blood banks and an umbilical cord blood unit that matches the criteria is usually found. The optimal choice of umbilical cord blood unit is crucial to maximize the likelihood of successful transplant engraftment and recipient survival after the transplantation, so the criteria for cord blood unit selection for unrelated transplantation are a bit broader than those used when matching donor-recipient pairs. The review presents the main criteria for cord blood unit selection according to the assessment of its quality, cell dose, HLA matching for unrelated transplantation to recipients of different age groups in accordance with international guidelines developed by the National Marrow Donor Program (NMDP), USA Center for International Blood and Brain Transplantation Research (CIBMTR), in collaboration with the NMDP Council Advisory Group, as well as in accordance with the American Society for Transplantation and Cellular Therapy (ASTCT) and the Seventh Edition of the NetCord-FACT International Standards for Cord Blood Collection, Banking, and Release for Administration.

Health-Related Quality-of-Life Comparison of Adult Related and Unrelated HSC Donors: An RDSafe Study.

Multiple investigations have documented the health-related quality-of-life (HRQoL) and donation-related experiences of unrelated donors (URDs), but similar investigations of the related donor (RD) experience have been less common. The central goal of this study was to longitudinally examine and compare HRQoL of RD and URD hematopoietic stem cell (HSC) donors from predonation through 1 year postdonation. This prospective investigation included adult HSC donors ages 18 to 60 years who donated bone marrow or peripheral blood stem cells at one of 48 geographically diverse US transplant/donor centers and completed HRQoL interviews at predonation and 4 weeks and 1 year postdonation. At predonation, related donors were less ambivalent about donation (t=-3.30; P=.001), more satisfied with their decision to donate (t=2.65; P=.009), and more likely to define themselves as donors (t=2.94; P=.004) than were URDs. However, related donors were more concerned about the use of needles (odds ratio [OR]=2.19; P=.012), about who would pay for the procedure (OR=2.80; P=.011), and the possibility that they would feel responsible if the transplant failed (t=2.31; P=.022). Shortly postdonation, related donors were more likely to report donation-related pain (t=2.50; P=.013) and lightheadedness (OR=3.63; P=.028). At 1 year postdonation, related donors were less likely to be fully recovered from donation (OR=0.10; P=.010) and more likely to report a longer recovery period following donation (t=2.57; P=.011), although this latter finding was primarily due to the percentage of related versus unrelated donors not fully recovered at 1 year postdonation (10% versus 1%). Taken together, these findings suggest that current related donor management practices may be sufficient in preparing related donors for the psychological aspects of donation but that there may be more to do in terms of calibrating the description of donation-related experiences and recovery time to the related donor group (i.e., descriptions of donation experiences based on unrelated donation may not provide best estimates of experience for this group).

Ulusal Gönüllü Kök Hücre Verici Bankası (TÜRKÖK) Kurulması Akraba Dışı Hematopoietik Kök Hücre Nakli Etkinliğimizi Nasıl Etkiledi? Geriye Dönük Tek Merkez Değerlendirmesi

Ulusal Gönüllü Kök Hücre Verici Bankası (TÜRKÖK) Kurulması Akraba Dışı Hematopoietik Kök Hücre Nakli Etkinliğimizi Nasıl Etkiledi? Geriye Dönük Tek Merkez Değerlendirmesi

Outcomes of myeloablative, T cell deplete unrelated donor hematopoietic stem cell transplantation at a single center.

e19525 Background: Myeloablative conditioning (MAC) and unrelated donor (UD) hematopoietic cell transplantation (HCT) are associated with increased non-relapse mortality (NRM) compared with matched related donor (MRD) HCT [18%, 21%, and 32% for MRD, Matched UD (MUD), and mismatched MUD (MMUD), respectively, p &lt; 0.001] (Saber et al, 2012). Our center uses alemtuzumab as means of T cell depletion to mitigate NRM risk in UD HCT. Here, we report outcomes utilizing this strategy. Methods: We retrospectively analyzed adult patients (pts) who received alemtuzumab-based T cell deplete MAC UD HCT from August 2012 to December 2017. Outcomes were estimated via Kaplan Meier and cumulative incidence methods. Results: Sixty-eight pts underwent T cell deplete MAC UD HCT for AML/MDS (n = 32), ALL (n = 18), lymphoma (n = 5), and other diseases (n = 13). Thirty-nine (57.4%) underwent a MUD HCT, while 29 (42.4%) underwent a MMUD (≤ 9/10 match) HCT. Median follow up was 35.5 months (m) (range 1.5 – 71.1). Median age was 46 years (range 21 - 68), 58.8% were male. Nineteen AML pts (67.9% of all AML) were considered high risk defined as secondary AML (n = 3), CR2 or more (n = 9), primary induction failure (n = 6) or having gross residual disease at time of HCT (n = 1). At 24 m, overall survival (OS) for the entire cohort was 65.3% (95%CI (CI) 53.5%- 77.2%), GVHD relapse-free survival (GRFS) was 54.8% (CI 42.8%- 66.9%), NRM was 10.4% (CI 4.5%- 19.2%), and relapse incidence (RI) was 27.3% (CI 17.1%- 38.5%). None of the 68 pts had graft failure or rejection. In the AML/MDS cohort, at 24 m OS was 52.3% (CI 33.9%- 70.7%), GRFS was 41.4% (CI 23.9%- 59%), NRM was 9.7% (CI 2.4%- 23.2%), and RI was 39.1% (CI 21.8%- 56.2%). Non-AML/MDS pts at 24 m had OS, GRFS, NRM and RI of 76.8% (CI 62.6%- 90.9%), 66.7% (CI 51.3%- 82.08%), 11.1% (CI 3.4%- 23.9%), and 16.7% (CI 6.6%- 30.6%), respectively. The table summarizes our outcomes. Conclusions: We show that alemtuzumab-based MAC conditioning for UD HCT has the benefit of being well tolerated with low NRM and high GRFS, while having comparable RI and OS compared to published outcomes of T cell replete MAC UD HCT (Saber et al, 2012). However, the retrospective nature without a comparator is a major limitation which necessitates a future prospective study to validate these findings. [Table: see text]

P006 To test or not to test: The importance of HLA antibody testing and HLA-DP typing in unrelated donor hematopoietic stem cell transplantation (HSCT)

P006 To test or not to test: The importance of HLA antibody testing and HLA-DP typing in unrelated donor hematopoietic stem cell transplantation (HSCT)

Abstract LB-052: Detection of rare, deleterious clonal mutations during unrelated allogeneic hematopoietic stem cell transplants using an error correction pipeline for NGS

Abstract While next-generation sequencing (NGS) has transformed our ability to characterize the genome, it is limited in detection of rare mutations due to a high error rate of ~0.5-2.0%. We have developed an error correction pipeline and previously demonstrated that our process is capable of detecting variants as rare as 1:10,000 or 0.0001 VAF. Using our error correction pipeline, we have recently identified leukemia-related hematopoietic clones in a cohort of young healthy bone marrow donors (median age 26). In the context of allogeneic hematopoietic stem cell transplantation (HSCT), we sought to determine whether these detected leukemia-related clones of donor origin selectively engraft and correlate with transplant-related morbidities in recipients post-HSCT. Genomic profiles of pre-transplant donor samples were compared to the genomic profiles of corresponding recipient samples post-HSCT. Results show that two-thirds of the healthy donor samples harbor deleterious hematopoietic clones and that these specific clones are significantly more likely to engraft compared to benign clones. We also found that 75% of recipients who had at least one persistently engrafted, deleterious mutation developed chronic GvHD versus 50% of those without persistently engrafted clones with deleterious mutations. In comparing the results from our error correction pipeline and conventional short tandem repeat (STR) testing for donor-patient chimerism, we showed that our method provides a highly sensitive approach to both screening for donors without deleterious clones and monitoring residual disease in recipients following hematopoietic stem cell transplants (HSCT). Furthermore, the clinical implications of these results warrant a large-scale study using our error correction pipeline to detect rare variants in HSCT. Citation Format: Wing Hing Wong, Andrew Young, Todd Druley. Detection of rare, deleterious clonal mutations during unrelated allogeneic hematopoietic stem cell transplants using an error correction pipeline for NGS [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-052.

Motives for joining an unrelated HSC donor registry: description, categorization, and association with donor availability.

A challenge for registries of unrelated hematopoietic stem cell (HSC) donors is to recruit and retain sufficient donors for patients needing transplants. Many registered HSC donors opt-out when called as a potential match for a patient. Anecdotal evidence suggests that motives for joining a registry may be linked to the donation decision. The primary goals of this investigation were to describe the range of motives for joining a registry and to examine donor availability by motive type. A diverse sample of 357 potential HSC donors from the Anthony Nolan registry in the UK was asked about their motives for joining and their decision to continue or opt-out after matching a patient was recorded. Motives for joining (N = 557) were first coded and categorized into 17 specific motive types and then arranged along a spectrum from internal to external. Internal values-based motives were most prevalent and availability was highest among potential donors expressing these motives (92%) and lowest among those expressing external motives (pressure, incentives; 0%). Although further research is needed to confirm these findings, they suggest that registries should assess donors' motives for joining at recruitment in order to conduct follow-up to ensure commitment among those potential members expressing external motives.

485 - Unrelated Hematopoietic Stem Cell (HSC) Transplant Outcomes. Results From the Argentine Registry

485 - Unrelated Hematopoietic Stem Cell (HSC) Transplant Outcomes. Results From the Argentine Registry

Effectiveness of Search for an Unrelated Donor of Hematopoietic Stem Cells using Russian Date Base "Bone Marrow Donor Search": Experience of Raisa Gorbacheva Memorial Institute for Children Oncology, Hematology and Transplantation

Background &amp; Aims. The key condition for allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the presence of HLA-compatible related or unrelated donor. If related donor is not found, further search is carried out in the Bone Marrow Donor Worldwide (BMDW) international data base, which is not effective enough (about 80-85 %), because of genotype specificity of Russian Federation residents. The recruitment procedure using BMDW takes a lot of time and is expensive. Therefore, there are good reasons to develop an alternative Russian data base, Bone Marrow Donor Search (BMDS), which includes data from Russian bone marrow donor registries and has a good potential. The aim is to evaluate the effectiveness of hematopoietic stem cell (HSC) donor search and transplant quality using the BMDS search system. Methods. 34 allo-HSCT recipients with malignancies and hematological diseases were enrolled in the study in RM Gorbacheva Scientific Research Institute of Pediatric Hematology and Transplantation from November, 2012, to March, 2016. A HLA-compatible donor was found for each patient in the BMDS (www.bmds.info), which includes data from 13 Russian registries of HSC donors. Results. 34 allo-HSCTs were performed from unrelated donors recruited using Russian registries: 1 in 2012; 3 in 2013; 5 in 2014; 21 in 2015; and 4 in the 1&lt;sup&gt;st&lt;/sup&gt; quarter of 2016. The greatest effectiveness of the BMDS search was in 2015 (14 %, n = 17). In 30 cases (88.2 %) a complete 10/10 compatibility for 5 HLA-gene loci was observed; in 4 cases (11.8 %) there was an incomplete compatibility (9/10). AB0 compatibility was only in 7 cases (20.6 %). In 15 cases (44.1 %) bone marrow was used for transplant harvesting; in 19 cases (55.9 %) peripheral blood stem cells were harvested by means of cytapheresis. The CD34+ count in the transplant was 1.2-12.0 х 10&lt;sup&gt;6&lt;/sup&gt; CD34+ cell/kg (median: 5.0 * 10&lt;sup&gt;6&lt;/sup&gt; CD34+ cell/kg). Engraftment was observed in 79.4 % of cases (п = 27), graft failure in 17.7 % of cases (n = 6), and early posttransplant mortality in 2.9 % of cases (n = 1). Conclusion. There was an increasing efficiency of search for a HLA-compatible unrelated HSC donor using a Russian BMDS search system for Russian residents with a graft quality similar to the one found in the international BMDW database.

Predictors of General Discomfort, Limitations in Activities of Daily Living, and Intention of a Second Donation in Unrelated Hematopoietic Stem Cell Donation

We performed a retrospective study to predict the risk factors related to general discomfort, limitations in activities of daily living (ADLs), and intention of a second donation in hematopoietic stem cell (HSC) donation. The subjects of this study were 1,868 consecutive unrelated volunteer donors who donated HSCs through the Korea Marrow Donor Program between November 2007 and April 2014. Bone marrow (BM) collections were performed without administration of granulocyte-colony stimulating factor (G-CSF) and peripheral blood stem cell (PBSC) collections were performed after mobilization with G-CSF administered subcutaneously for 4 or 5 consecutive days at a daily dose of around 10 mcg/kg of body weight. General discomfort and limitations in ADLs were assessed by numerical measurement (scores of 0 to 10), and donor’s intention of a second donation by yes or no reply. The post-donation questionnaires were completed within 48 hours after HSC collection, and at 1 week, 4 weeks, and 4 months thereafter. Pre-donation and post-donation predictors of general discomfort and limitations in ADLs were identified using univariate and multivariate linear regression considering donor demographic and clinical characteristics (age, sex, collection method, collection period) and the intention of a second donation on day 1. Pre-donation and post-donation predictors of the intention of a second donation were identified using univariate and multivariate logistic regression considering donor demographic and clinical characteristics (age, sex, collection method, collection period). Men represented 76.77% of donors. The median age at donation was 28 years (range, 19-51), and about 93.00% of donors were younger than 40 years of age. Among HSC collection, 61.88% were completed in a day. PBSC and BM collections accounted for 94.49% and 5.51% of HSC collections, respectively. Predictors of general discomfort included female sex (P< 0.0001), BM collection (P< 0.0001) or PBSC collection through a central line (P= 0.0349), 2-day collection (P= 0.0150), and negative or undetermined intention of a second donation on day 1 (P< 0.0001). Predictors of limitations in ADLs included age group of 30-39 years (P= 0.0046), female sex (P< 0.0001), BM collection (P< 0.0001) or PBSC collection through a central line (P< 0.0001), and negative or undetermined intention of a second donation on day 1 (P< 0.0001). The only predictor of positive intention of a second donation was male sex (P= 0.0007). Age, sex, collection method and period, and intention of a second donation should be considered risk factors when unrelated HSC donation is performed. As a collection method, PBSC collection through a peripheral line is recommended to alleviate physical stress and to improve ADLs. Female donors are more sensitive to HSC collection than male donors, and male sex of the donor is predictive of positive intention of a second donation. DisclosuresNo relevant conflicts of interest to declare.

Predictors of general discomfort, limitations in activities of daily living and intention of a second donation in unrelated hematopoietic stem cell donation.

We performed a retrospective study of 1868 consecutive unrelated donors to predict the risk factors related to general discomfort, limitations in activities of daily living (ADLs) and intention of a second donation in hematopoietic stem cell (HSC) donation. General discomfort and limitations in ADLs were assessed by numerical measurement (scores of 0-10) and donor's intention of a second donation by yes or no reply. The post-donation questionnaires were completed within 48 h after HSC collection and at 1 week, 4 weeks, and 4 months thereafter. Predictors of general discomfort included female sex (P<0.0001), bone marrow (BM) collection (P<0.0001) or PBSC collection through a central line (CL; P=0.0349), 2-day collection (P=0.0150) and negative or undetermined intention of a second donation on day 1 (P<0.0001). Predictors of limitations in ADLs included age group of 30-39 years (P=0.0046), female sex (P<0.0001), BM collection (P<0.0001) or PBSC collection through a CL (P<0.0001) and negative or undetermined intention of a second donation on day 1 (P<0.0001). The only predictor of positive intention of a second donation was male sex (P=0.0007). Age, sex and collection method and period should be considered risk factors when unrelated HSC donation is performed.

OR52 HLA typing from a deceased donor who received hematopoietic stem cell transplant

Here we present a case of challenging typing for a deceased donor who is also hematopoietic stem cell (HSC) transplant recipient. A local deceased donor (DD) was typed with SSP method from peripheral blood sample as A2; B44, 62; Cw9,16; DR4,7; DQ2,7; DQA1∗02, 03; DPB1∗04:02, 11:01; DPA1∗01, 02. After typing was reported, it was immediately found out DD received HSC transplant from an unrelated donor in 2001 at another center. DD has full engraftment on death so HLA typing based on peripheral blood sample is likely the typing for her HSC donor. Typing for DD before HSC was found to be: A2; B44, 62; CW5, 9; DR4,7; DQ7,9, while her HSC donor is A2; B44, 62; Cw9,16; DR4,7; DQ2,7. DQA1∗ and DP typing were not performed in 2001 and no stored DNA can be found. There are two mismatched antigen on HLA-CW and -DQ. This confirmed that initial typing results for DD in fact were typing for her HSC donor, not typing for the kidneys. One kidney was exported to a patient with anti-HLA DP antibodies at another center. The receiving center asked to determine HLA-DP phenotype for DD. Without other source of somatic DNA, a piece of blood vessel from harvested kidney was used to extra DNA for DPB1∗ SSP typing. The blood vessel was contaminated with blood from her HSC donor. It was found that there are four DPB1 antigens: DPB1∗04:02, 11:01, and DPB1∗01:01, 04:01. HSC donor typing is the typing got from blood sample of DD: DPB1∗04:02, 11:01. So DPB1∗01:01, 0401 were deduced as the presumptive typing for this deceased donor. Fortunately there is no anti-HLA-DP DSA for the designated recipient. In summary, a deceased donor was mistakenly typed based on improper source of specimen. Recipients of HSC transplant rarely become deceased organ donors. However, many patients received HLA-DP mismatched unrelated HSC transplant because usually HLA-DP was not matched. Anti-HLA-DP antibodies are found in lots of patients waiting for kidney transplant. This case highlights the importance of communication with deceased donor team, and proper sample collection to achieve accurate deceased donor typing and excellent virtual cross match.